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Supportive Treatments: Hold the Mind Strong During Cancer
Demet Sag, PhD
Psychiatric treatments
Cancer is described under a general terminology of uncontrolled cell proliferation and changes that results in out of control development. Thus, correcting the cell division and immune control are the two focus areas. Yet, on the other side of the coin like any given terminal diseases there is another big factor that needs to be resolved that is mental health. This is usually not well discussed among many. After all fighting with a disease is a game of strength. I think that is one of the reason we say congrats to many cancer survivors since they won not only with their treatment but also with their psychological strength. However, it is like a balloon after the disease the battle is still on.
Here are the few articles discussing mainly advanced cancer patient’s psychiatric conditions, their clinical treatments, and training of the healthcare givers including oncologists, nurses, social workers, and other ancillary staff.
Last fifty years there is an improvement to cure mental illnesses yet there are many unresolved issues like passing blood brain barrier or specificity etc. Many of these drugs also used for the adjuvant treatment of cancer-related symptoms. Some of these are pain, hot flashes, pruritus, nausea and vomiting, fatigue, and cognitive impairment. However, the condition of cancer patient requires making psychopharmacology to improve quality life of cancer patients.
There new drugs with less side-effects and safer pharmacological profiles, has been a major advance in clinical psycho-oncology.
Since at least 25-30% of patients with cancer and an even higher percentage of patients in an advanced phase of illness meet the criteria for a psychiatric diagnosis, including depression, anxiety, stress-related syndromes, adjustment disorders, sleep disorders and delirium.
About 50% of patients with advanced cancer meet criteria for a psychiatric disorder, the most common being adjustment disorders (11%-35%) and major depression (5%-26%).
At least 30-40% of patients with cancer and even a higher percentage of patients in an advanced phase of illness.
In addition, age is a big issue since the outcomes and treatments changes based on expectations and challenges in their life. It is now possible to diagnose early and treat more means tolerance level to aggressive treatments also increases. In older patients aging and cancer and in younger patient’s career and relationships broken. This is not just a longevity but improving the quality of life of a patient after cancer’s transition from likely death to survival. Therefore, it is equally important to give their life back fully so there is an increased awareness on psychosocial issues and quality of life.
For example, there is a Psycho-oncology group in National Cancer Center. They are now conducting several clinical studies such as biological studies (neuro-imaging studies), studies to establish novel treatment strategy (n-3 poly unsaturated fatty acid), and multi-faceted intervention study (screening and individually tailored psychotherapy and pharmacotherapy). Hope to see more studies combining not only treat the physiological symptoms but psychological factors.
Table 1. Prevalence of Psychiatric Disorders in Advanced Cancer
Mehta RD1, Roth AJ2. Psychiatric considerations in the oncology setting. CA Cancer J Clin. 2015 Jul-Aug;65(4):300-14. doi: 10.3322/caac.21285. Epub 2015 May 26.
Grassi L1, Caruso R, Hammelef K, Nanni MG, Riba M. Efficacy and safety of pharmacotherapy in cancer-related psychiatric disorders across the trajectory of cancer care: a review. Int Rev Psychiatry. 2014 Feb;26(1):44-62. doi: 10.3109/09540261.2013.842542.
Holland JC,Morrow GR,Schmale A, et al. A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. J Clin Oncol. 1991; 9: 1004–1011.
Pitman RK,Lanes DM,Williston SK, et al. Psychophysiologic assessment of posttraumatic stress disorder in breast cancer patients.Psychosomatics. 2001; 42: 133–140. Web of Science® Times Cited: 21
The Relation between Coagulation and Cancer affects Supportive Treatments
Demet Sag, PhD
Coagulation and Cancer
There are several supportive therapies for cancer patients. One of the most important one is controlling the blood intake. This is sometimes observe keeping the blood cell count at certain levels, or providing safe blood/blood products to avoid any contaminations or infections,
The relation between cancer and coagulation was known for a long time but it was becoming clear recently. Having coagulapathies also reduce the survival of patients since they can’t response to given treatments. Thus, it is necessary to give supportive therapies to control the coagulation. Problems in coagulation may develop from inherited (genetics), or acquired due to given therapies that cause varying abnormalities towards bleeding or thrombose at many levels. The thrombotic events are important since they are the second leading cause of death in cancer patients (after cancer itself). The presence of these coagulopathies determines the survival rate, length of survival either short-term or long-term, as well as relapses.
Cancer and Coagulation from start to finish:
Thrombotic risk factors in cancer patients
Patient related
Cancer related
Treatment related
.
Patient Related:
Older age
Bed rest
Obesity
Previous thrombosis
Prothrombotic mutations
High leukocyte and platelet counts
Comorbidities
Cancer related:
a. Site of cancer:
brain,
pancreas,
kidney,
stomach,
lung,
bladder,
gynecologic,
hematologic malignancies
b. Stage of cancer:
advanced stage and
initial period after diagnosis
Treatments:
Hospitalization
Surgery
Chemo- and
hormonal therapy
Anti-angiogenic therapy
Erythropoiesis stimulating agents
Blood transfusions
CVC, central venous catheters
Radiations
Thromboembolic events can be venous or arterial.
Venous events include
deep vein thrombosis (DVT),
pulmonary embolism (PE)
together categorized as venous thromboembolism (VTE).
Arterial events, include
stroke, myocardial infarction and
arterial embolism.
Increase in the rate of venous thromboembolism (VTE) over time. Results are presented as annual rates of deep venous thrombosis (DVT), pulmonary embolism (PE) without deep venous thrombosis, and both between 1995 and 2003. Significant trends for increasing rates were observed for all 3 diagnoses (P < .0001). The rate of increase was found to be greater in the subgroup of patients who received chemotherapy. Error bars represent 95% confidence intervals.
There is an increase in both venous and arterial eventsrecently with “unacceptably high” event rates documented in the most contemporary studies:
There are significant consequences to the occurrence of thromboembolism in this setting:
requirement for long-term anticoagulation,
a 12% annual risk of bleeding complications,
an up to 21% annual risk of recurrent VTEand
potential impact on chemotherapy delivery and patient quality of life.
Therapeutic interventions enhance the risk of VTE in cancer.
Cancer patients undergoing surgery have a two-fold increased risk of postoperative VTE as compared to non-cancer patients, and this elevation in risk can persist for a period up to 7 weeks
Hospitalization also substantially increases the risk of developing VTE in cancer patients (OR 2.34, 95% CI 1.63 – 3.36)
The use of systemic chemotherapy is associated with a 2-to 6-fold increased risk of VTE compared to the general population.
Anti-angiogenic agents, particularly thalidomide and lenalidomide, have been associated with high rates of VTE when given in combination with dexamethasone or chemotherapy.
Bevacizumab-containing regimens have been associated with increased risk for an arterial thromboembolic event (hazard ratio [HR] 2.0, 95% CI 1.05- 3.75) but the data for risk of VTE are conflicting
Sunitinib and sorafenib, agents targeting the angiogenesis pathway, have also similarly been associated with elevated risk for arterial (but not venous) events [RR 3.03 (95% CI, 1.25 to 7.37)]
Anticoagulants and Cancer Coagulopathies
There are many studies on coagulation and use of anti-coagulants yet the same patient may also thrombose at any given time so the coagulant therapies should be under close surveillance. The study (PMID:111278600) by Palereti et all in 2000 to many compared this issue.
fig1_10.1002_cncr.23062
Palereti et al. showed that:
“The outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy.
Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer.
Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p <0.01; RR 6.2 (95% CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance”.
They concluded that “patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy.”
Cancer and Coagulation in more detail at Molecular Level:
Cancer is a complex disease from its initiation to its treatment. In the body the response to drugs generates side effects for being foreign (immune responses and inflammation), toxic, or disturbing the hemostasis of the coagulation system. In addition, activation of oncogenic pathways cab also be activated that may not only effect the development of the cancer but also may induce oncogenes to activate dormant cancer cells. In the coagulation system the balance is important to keep anti-coagulant state, with oversimplification, such as having certain number of tissue factor (TF) that is a receptor determines the anticoagulant state. However, certain pro-oncogenic genes like RAS, EGFR, HER2, MET, SHH and loss of tumor suppressors (PTEN, TP53) change the gene regulation so they alter the expression, activity and vesicular release of coagulation effectors, as exemplified by tissue factor (TF). As a result, there is a bridge between the coagulation-related genes (coagulome) and specific cancer coagulapathies, such as in glioblastoma multiforme (GBM), medulloblastoma (MB), etc. Therefore, these coagulome can be a great target not only to inhibit angiogenesis and tumor growth but also prevent any coagulopathies, use in single genomics/circulating cancer cells as well as grading the level of cancer specifically.
Tumor-hemostatic system interactions. Tumor cells activate the hemostatic system in multiple ways. Tumor cells may release procoagulant tissue factor, cancer procoagulant and microparticles (MP) that can directly activate the coagulation cascade. Tumor cells may also activate the host’s hemostatic cells (endothelial cells and platelets), by either release of soluble factors or by direct adhesive contact, thus further enhancing clotting activation.
Microparticle (MP) production and activities in cancer. Tumor cells actively release MP but also promote MP formation by platelets. Tissue factor (TF) and phosphatidylserine (PS) expression on the surfaces of both platelet- and tumor-derived MP are involved in blood clotting activation and thrombus formation. On the other hand, the elevated content of proangiogenic factors in platelet-derived MP (VEGF, vascular endothelial growth factor, FGF, fibroblast growth factor, PDGF, platelet-derived growth factor), render these elements also important mediators of the neangiogenesis process. Finally, intracellular transfer of MP may occur between cancer cells, leading to a horizontal propagation of oncogenes and amplification of their angiogenic phenotype.
Immune Response and Cancer with Coagulopathies:
I. Goufman et al also suggested that plasma level of IgG autoantibodies to plasminogen changes during cancer coagulopathies.
Their data based on ELISA measurements of their patients:
with benign prostatic hyperplasia (n=25),
prostatic cancer (n=17),
lung cancer (n=15), and
healthy volunteers (n=44).
High levels of IgG to plasminogen were found
in 2 (12%) of 17 healthy women, in 1 (3.6%) of 27 specimens in a healthy man,
in 17 (68%) of 25 specimens in prostatic cancer,
in 10 (59%) of 17 specimens in lung cancer,
in 5 (30%) of 15 specimens in benign prostatic hyperplasia.
Comparison of plasma levels of anti-plasminogen IgG by affinity chromatography showed 3-fold higher levels in patients with prostatic cancer vs. healthy men.
Structure and function of platelet receptors initiating blood clotting.
There is a missed or overlooked concept about coagulation and cancer. In their article they mainly focused on the structure and function of key platelet receptors taking role in the thorombus formation and coagulation.
At the clinical level, recent studies reveal the link between coagulation and other pathophysiological processes, including platelet activation, inflammation, cancer, the immune response, and/or infectious diseases. These links are likely to underpin the coagulopathy associated with risk factors for venous thromboembolic (VTE) and deep vein thrombosis (DVT). At the molecular level, the interactions between platelet-specific receptors and coagulation factors could help explain coagulopathy associated with aberrant platelet function, as well as revealing new approaches targeting platelet receptors in diagnosis or treatment of VTE or DVT. Glycoprotein (GP)Ibα, the major ligand-binding subunit of the platelet GPIb-IX-V complex, that binds the adhesive ligand, von Willebrand factor (VWF), is co-associated with the platelet-specific collagen receptor, GPVI. The GPIb-IX-V/GPVI adheso-signaling complex not only initiates platelet activation and aggregation (thrombus formation) in response to vascular injury or disease but GPIbα also regulates coagulation through a specific interaction with thrombin and other coagulation factors.
Clinical Data and Some Samples of Biomarkers:
Development of biomarkers and management of cancer coagulapathies are underway since there are times this coagulapathies may be as deadly as the cancer itself.
*Pancreatic cancer patients are assigned a score of 2 based on site of cancer and therefore there were no patients in the low-risk category
**included 4-weekly screening ultrasonography
***enrolled only high-risk patients
Table 4
ASCO and NCCN Recommendations for Treatment of VTE in Cancer
ASCO
NCCN
Initial treatment
LMWH is the preferred approach for the initial 5-10 days
LMWH, UFH or factor Xa antagonists according to patient’s characteristics and clinical situation
Long term treatment
LMWH for at least 6 months is preferred.
LMWH is preferred
VKA are acceptable when LMWH is not available.
Indefinite anticoagulation in patients with active cancer or persistent risk factors
Indefinite anticoagulation in patients with active cancer.
Thrombolytic therapy in initial treatment
Restricted to patients with life- or limb-threatening thrombotic events
Restricted to massive or submassive PE with moderate or severe right ventricular enlargement or dysfunction
Inferior vena cava filters
Restricted to patients with contraindications to anticoagulation or recurrent VTE despite adequate long-term LMWH
Restricted to patients with contraindications to or failure of anticoagulation, cardiac or pulmonary dysfunction severe enough to make any new PE life-threatening or multiple PE with chronic pulmonary hypertension
Treatment of catheter-related thrombosis
NA
LMWH or VKA for as long as catheter is in place or for 1 to 3 months after catheter removal
Phenotype similarity clustering of cases according to HPO terms. Heat map showing pairwise phenotypic similarity among affected members of pedigrees, cases with classical syndromes and cases with variants in ACTN1. The groups are ordered through complete-linkage hierarchical clustering within each class and P values of phenotypic similarity are shown in a scatterplot superimposed over a histogram showing the distribution of P values.
Phenotype clusters 18 and 29. Illustrative subgraphs of the HPO showing terms for the phenotype clusters 18 (15 cases) and 29 (16 cases). Arrows indicate direct (solid) or indirect (dashed) is a relations between terms in the ontology. DMPV: decreased mean platelet volume; PA: phenotypic abnormality; Plt-agg: platelet aggregation abnormality.
Westbury et al.Genome Medicine 2015 7:36 doi:10.1186/s13073-015-0151-5
Rare variants identified inMYH9and validated by Sanger sequencing
Case
Transcript variant ENST00000216181
Protein variant ENSP00000216181
HGMD variant
Classification
PLT, ×109/L
MPV, fL and/or presence of macrothrombocytes
OtherMYH9-RD characteristics
B200760
22:36744995 G/A
S96L
Yes
PV
180
Macrothrombocytes
None
B200771
22:36705438 C/A
D578Y
No
VUS
184
10.1
None
B200423
22:36696237 G/A
A971V
No
VUS
262
10.2
None
B200024
22:36691696 A/G
S1114P
Yes
VUS
164
NA
None
B200245
VUS
53
11.1, Macrothrombocytes
None
B200243
22:36691115 G/A
R1165C
Yes
PV
22
Macrothrombocytes
None
B200594
PV
46
Macrothrombocytes
None
B200595a
PV
61
Macrothrombocytes
None
B200614
22:36688151 C/T
D1409N
No
VUS
319
9.8
None
B200752
VUS
149
10.1, Macrothrombocytes
None
B200855
VUS
95
16.8, Macrothrombocytes
None
B200208
22:36688106 C/T
D1424N
Yes
PV
99
13.6
None
B200010
22:36685249 G/C
S1480W
No
VUS
244
NA
None
B200244
22:36678800 G/A
R1933X
Yes
PV
26
Macrothrombocytes
Döhle inclusions
Other MYH9-RD characteristics sought were the presence of Döhle inclusions, cataract, deafness or renal pathology.
aFather of B200594.
Westbury et al.
Westbury et al.Genome Medicine 2015 7:36 doi:10.1186/s13073-015-0151-5
Pathogenic and likely pathogenic variants identified in genes associated with autosomal recessive and X-linked recessive bleeding and platelet disorders
Case
Position
Gene
Ref
Alt
Genotype
HGMD
Effecta
Haematological HPO terms
Other HPO terms
Classification:
Variant
Phenotype
B200286
3:148881737
HPS3
G
C
C|C
Yes
Abnormal splicing
Bleeding with minor or no trauma, subcutaneous haemorrhage, menorrhagia, postpartum haemorrhage, impaired ADP-induced platelet aggregation, impaired epinephrine-induced platelet aggregation, epistaxis, prolonged bleeding after surgery, prolonged bleeding after dental extraction, increased mean platelet volume.
Impaired epinephrine-induced platelet aggregation, bleeding with minor or no trauma, subcutaneous haemorrhage, epistaxis, menorrhagia, prolonged bleeding after surgery, abnormal dense granules.
Reduced factor IX activity, impaired ADP-induced platelet aggregation, bleeding with minor or no trauma, spontaneous haematomas, abnormal number of dense granules.
PV
Partially explained
B200452
X:154124407
F8
C
G
G
Yes
S2125T
Reduced factor VIII activity, persistent bleeding after trauma, prolonged bleeding after surgery, prolonged bleeding after dental extraction, bleeding requiring red cell transfusion, impaired collagen-induced platelet aggregation, bleeding with minor or no trauma, joint haemorrhage, abnormal platelet shape, abnormal number of dense granules.
PV
Partially explained
B200772
X:154176011
F8
A
G
G
No
F692S
Reduced factor VIII activity, bruising susceptibility, impaired ADP-induced platelet aggregation, impaired collagen-induced platelet aggregation, impaired thromboxane A2 agonist-induced platelet aggregation, impaired ristocetin-induced platelet aggregation, impaired arachidonic acid-induced platelet aggregation, impaired thrombin-induced platelet aggregation, abnormal platelet granules, bleeding with minor or no trauma.
LPV
Possibly partially explained
Alt: alternative; Ref: reference.
aEffect considered relative to the Consensus Coding Sequence (CCDS) for each gene.
Westbury et al.
Westbury et al.Genome Medicine 2015 7:36 doi:10.1186/s13073-015-0151-5
Table 2
TFPI and TF tumor mRNA expression across clinicopathological breast cancer subtypes
mRNA expression (tumor)
Protein levels (plasma)
Characteristic
Groups
Total TFPI (α + β)
P
TFPIα
P
TFPIβ
P
TF
P
Total TFPI
P
Free TFPI
P
TF
P
T-status
T1
−0.146
0.054
−0.135
0.257
−0.084
0.201
−0.023
0.652
72.01
0.013
10.82
0.997
4.14
0.125
T2-T3
0.085
0.018
0.060
0.054
65.02
10.82
4.66
Grade
G1-G2
−0.022
0.850
−0.005
0.424
−0.033
0.743
0.271
0.003
71.04
0.082
10.66
0.682
4.63
0.557
G3
−0.045
−0.113
0.004
−0.229
66.12
10.97
4.14
N-status
Negative
−0.109
0.091
−0.136
0.127
−0.082
0.104
0.005
0.881
69.93
0.183
10.77
0.869
4.95
0.282
Positive
0.104
0.078
0.110
0.032
66.00
10.90
4.14
ER status
Positive
−0.067
0.317
−0.082
0.557
−0.056
0.183
0.001
0.784
69.42
0.240
10.91
0.671
4.42
0.409
PR status
Negative
0.076
0.011
0.123
0.057
65.44
10.52
5.28
Positive
−0.131
0.021
−0.145
0.075
−0.112
0.014
0.085
0.244
69.81
0.195
11.19
0.175
4.32
0.246
HER2-status
Negative
0.161
0.108
0.182
−0.127
65.92
10.08
5.04
Negative
−0.072
0.054
−0.101
0.073
−0.041
0.154
0.004
0.731
68.45
0.893
10.68
0.287
4.47
0.428
Positive
0.313
0.301
0.228
0.103
69.09
12.05
4.78
HR status
Yes
0.076
0.326
0.007
0.587
0.114
0.221
0.016
0.991
64.78
0.161
10.41
0.568
5.26
0.470
No
−0.066
−0.080
−0.052
0.014
69.57
10.94
4.47
Triple-negative status
Yes
−0.051
0.886
−0.110
0.718
0.041
0.635
−0.158
0.326
63.21
0.072
10.06
0.345
5.23
0.969
No
−0.029
−0.048
−0.027
0.055
69.73
10.99
4.57
Median values for TFPI and TF mRNA expression in tumors and protein levels in plasma according to clinically defined groups. Corresponding P-values (unadjusted) are shown. Significant P-values in bold. TFPI, tissue factor pathway inhibitor; TF, tissue factor; HER2, human epidermal growth factor receptor 2.Abbreviations: T, tumor; G, grade; N, node; ER, estrogen receptor; PR, progesterone receptor; HR, hormone receptor.
Table 3
Significant association betweenTFPIsingle nucleotide polymorphisms (SNPs) and clinicopathological characteristics and molecular subtypes
Characteristic
SNP
Risk allele
Odds ratio
95% CI
P
False discovery rate
T status
T1
Reference
Reference
Reference
Reference
T2 to T3
rs10153820
A
3.14
1.44, 6.86
0.004
0.056
TN status (ER-/PR-/HER2-negative)
No
Reference
Reference
Reference
Reference
Yes
rs8176541a
G
2.62
1.11, 5.35
0.026
0.092
rs3213739a
G
2.58
1.34, 4.99
0.005
0.033
rs8176479a
C
3.10
1.24, 7.72
0.015
0.071
rs2192824a
T
2.44
1.39, 4.93
0.002
0.033
N status
Positive
Reference
Reference
Reference
Reference
Negative
rs10179730
G
3.34
1.42, 7.89
0.006
0.083
Basal tumor subtype
Non-basal
Reference
Reference
Reference
Reference
Basal
rs3213739a
G
2.23
1.15, 4.34
0.018
0.107
rs8176479a
C
2.79
1.12, 6.96
0.028
0.107
rs2192824a
T
2.41
1.24, 4.65
0.009
0.107
rs10187622a
C
5.20
1.17, 23.20
0.031
0.107
Luminal B tumor subtype
Non-luminal B
Reference
Reference
Reference
Reference
Luminal B
rs16829086a
T
2.09
1.03, 4.25
0.041
0.191
rs10179730a
G
3.53
1.47, 8.46
0.005
0.066
rs10187622a
T
2.73
1.24, 6.03
0.013
0.091
Normal-like tumor subtype
Non-normal-like
Reference
Reference
Reference
Reference
Normal-like
rs5940
T
22.17
4.43, 110.8
0.0002
0.003
aSNPs representing a haplotype effect. SNPs are listed by ascending chromosome positions. TFPI, tissue factor pathway inhibitor; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor 2.
Table 4
Significant correlations betweenTFPIsingle nucleotide polymorphisms (SNPs) andTFPImRNA expression in breast tumors
Probe
SNP
Region
Allelesa
Minor allele frequency
Beta
r
P
False discovery rate
TFPIα
rs2192824b
Intronic
C:T
0.490
−0.209
−0.180
0.029
0.200
TFPIα
rs7594359b
Intronic
C:T
0.483
−0.219
−0.184
0.025
0.200
TFPIβ
rs3213739b
Intronic
G:T
0.417
0.187
0.213
0.010
0.032
TFPIβ
rs8176479b
Intronic
C:A
0.238
0.184
0.192
0.021
0.049
TFPIβ
rs2192824b
Intronic
C:T
0.490
−0.267
−0.273
0.001
0.011
TFPIβ
rs12613071b
Intronic
T:C
0.158
0.284
0.208
0.011
0.032
TFPIβ
rs2192825b
Intronic
T:C
0.466
−0.251
−0.249
0.002
0.012
TFPIβ
rs7594359b
Intronic
C:T
0.483
−0.248
−0.247
0.002
0.012
TFPIα + β
rs2192824b
Intronic
C:T
0.490
−0.168
−0.161
0.050
0.187
TFPIα + β
rs12613071b
Intronic
T:C
0.158
0.238
0.164
0.048
0.187
TFPIα + β
rs7594359b
Intronic
C:T
0.483
−0.190
−0.178
0.030
0.187
aMajor:minor. bSNPs representing a haplotype effect. mRNA expression was assayed by the Agilent Human V2 Gene Expression 8x60k array, and probes for tissue factor pathway inhibitor (TFPI)α, TFPIβ and total TFPI (TFPIα + β) mRNA were analyzed. Alleles for the positive DNA strand (UCSC annotated) are shown, and SNPs are listed by ascending chromosome positions.
“Eight TFPI SNPs were found to be correlated to total TFPI protein levels in patient plasma (Table 5). The A-T-A-C-T-A-C-G haplotype composed of these eight SNPs (rs8176541-rs3213739-rs8176479-rs2192824-rs2192825-rs16829088-rs7594359-rs10153820) represented a common haplotype (frequency 0.19) with quite strong correlation to total TFPI protein; r = 0.481 (B = 14.62, P = 6.35 × 10−10). No correlation between TFPI SNPs and free TFPI protein, or between TF SNPs and TF protein in plasma was observed (P >0.05, data not shown). Adjusting for age had no effect on the correlation (data not shown).”
Table 5
Significant correlations betweenTFPIsingle nucleotide polymorphisms (SNPs) and total TFPI protein levels in plasma
Protein
SNP
Region
Allelesa
Minor allele frequency
Beta
r
P
False discovery rate
Total TFPI
rs8176541b
Intronic
G:A
0.283
15.64
0.571
7.69 × 10−14
1.08 × 10−12
Total TFPI
rs3213739b
Intronic
G:T
0.417
11.35
0.488
5.38 × 10−10
3.77 × 10−9
Total TFPI
rs8176479b
Intronic
C:A
0.238
12.22
0.480
1.20 × 10−9
5.62 × 10−9
Total TFPI
rs2192824b
Intronic
C:T
0.490
−9.88
−0.404
3.81 × 10−7
1.07 × 106
Total TFPI
rs2192825b
Intronic
T:C
0.466
−7.55
−0.301
2.40 × 10−4
5.30 × 10−4
Total TFPI
rs16829088b
Intronic
G:A
0.250
11.23
0.424
1.00 × 10−7
3.51 × 10−7
Total TFPI
rs7594359b
Intronic
C:T
0.483
−6.90
−0.275
6.90 × 10−4
0.001
Total TFPI
rs10153820b
Near 5UTR
G:A
0.125
−7.79
−0.215
0.009
0.016
aMajor:minor. bSNPs representing a haplotype effect for total tissue factor pathway inhibitor (TFPI). Alleles for the positive DNA strand (UCSC annotated) are shown.
In sum, combination of molecular physiology and genomics will improve the conditions of the patients not only to diagnose early or to monitor the disease but also to streamline the current drugs to be more efficient and therapeutic.
I. Goufman, V. N. Yakovlev, N. B. Tikhonova, R. B. Aisina, K. N. Yarygin, L. I. Mukhametova, K. B. Gershkovich, D. A. Gulin,Autoantibodies to Plasminogen and Their Role in Tumor Diseases, Bulletin of Experimental Biology and Medicine, 2015, 158,4, 493
Sarah K Westbury, Ernest Turro, Daniel Greene, Claire Lentaigne, Anne M Kelly, Tadbir K Bariana, Ilenia Simeoni, Xavier Pillois, Antony Attwood, Steve Austin, Sjoert BG Jansen, Tamam Bakchoul, Abi Crisp-Hihn, Wendy N Erber, Rémi Favier,Nicola Foad, Michael Gattens, Jennifer D Jolley, Ri Liesner, Stuart Meacham, Carolyn M Millar, Alan T Nurden, Kathelijne Peerlinck, David J Perry, Pawan Poudel, Sol Schulman, Harald Schulze, Jonathan C Stephens, Bruce Furie, Peter N Robinson, Chris van Geet, Augusto Rendon, Keith Gomez, Michael A Laffan, Michele P Lambert, Paquita Nurden, Willem H Ouwehand, Sylvia Richardson, Andrew D Mumford, Kathleen Freson, Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders, Genome Medicine, 2015, 7,1
In the name of Translation from a food born pathogen to a friendly vaccine: Listeria monocytogenes
Curator: Demet Sag, PhD, CRA, GCP
Is it a far fetch? Friend or Foe?
Listeria monocytogenes is a Gram-positive, facultative intracellular pathogen bacterium. It is used as a prototypes for an experimental model to understand the fundamental processes of adaptive immunity and virulence. 10 species of L. monocytogenes is identified in both humans and animals, L. ivanovii mainly infects ungulates (eg. sheep and cattle), while other species (L. innocua, L. seeligeri, L. welshimeri, L. grayi, L. marthii, L. rocourtiae, L. fleischmannii and L. weihenstephanensis) are essentially saprophytes. Within the species of L. monocytogenes, several serovars (e.g., 4b, 1/2a, 1/2b and 1/2c) are highly pathogenic and account for a majority of clinical isolations.
Gram-negative bacteria has inner and outer membranes and they are most studied; yet mechanics of protein secretion across the single cell membrane of Gram-positive is not. The protein secretion in gram positive bacteria is complex not only it requires translocation of polypeptides across the bacterial membrane into the highly charged environment of the membrane-cell wall interface but also folding specifically. As a result, protein folding mechanism and stability investigated for the role of PrsA2 and PrsA-like so that optimizing the virulence and protein secretion become possible.
Pathogen: Listeriosis
Listeria monocytogenes is a food-borne pathogen determined in 1980s causing an opportunistic disease called listeriosis which is widespread in nature being part of the faecal flora of many mammals. In addition to contaminated food resources (1-10%), may occur sporadically or in outbreaks. It can be difficult to control and may cause severe clinical outcomes, especially in pregnant women, children and the elderly. The mechanism of pathogenity based on simply altering the actin cytoskeleton structure. Infection causes a spectrum of illness, ranging from febrile gastroenteritis to invasive disease, including bacteraemia, sepsis, and meningoencephalitis.
This organisms copes well with bile acids and acidic environment such as glutamate decarboxylase and arginine deiminase systems to survive in competitive microbiome of GI.
This information may benefit developing effective vaccines, designing pharmabiotics; even including probiotics, prebiotics, or phages.
Nutrition:
Altering dietary habit assumed to control a disease. The effects of various fatty acids on bacterial clearance and disease outcome through suppression or activation of immune responses can’t be simplified down to one or two kinds of fatty acids in foodborne pathogens. Commonly they have a specialized carbohydrate metabolism so they can utilize fatty acids of host and the host may use the end products for an energy resource. The compared food-borne pathogens include Salmonella sp., Campylobacter sp.,Shiga toxin-producing Escherichia coli, Shigella sp., Listeria monocytogenes, and Staphylococcus aureus.
Genetics:
This bacterium has a complex transcriptional machinery to adept, invade several types of cells, and survive. It happens through RNA-based regulation in bacteria in cell biology at the chromatin level during bacterial infection. This includes clathrin, atypical mitochondrial fragmentation, and several hundred non-coding RNAs (ncRNAs) in the Listeria genome. Patho-epigenetics becoming an attractive field. Improved bioinformatics may help to classify these changes under specific regulatory mechanisms and networks to determine their function and use.
The Toxin, Vaccine and Immunotheraphy
The virulence of Listeria monocytogenes mainly depends on a listeriolysin O (LLO) which is a thiol-activated, cholesterol-dependent, pore-forming toxin, and highly immunogenic. In addition, biochemically, LLO, a toxin that belongs to the family of cholesterol-dependent cytolysins (CDCs), exhibits potent cell type-non-specific toxicity and is a source of dominant CD4(+) and CD8(+) T cell epitopes. Hence, it is the major target for innate and adaptive immune responses in different animal models and humans.
As a result, during infection bacteria escape from phagocytosis, allow bacteria to infest the cells and multiply. Thus, due to it’s naturally immunomodulation role this mechanisms is under investigation so that it can be used for cancer immunotherapies for developing immune tolerance. Since it has effective cytotoxicity. Thus, co-administration of this toxin or using as an adjuvant with vaccine vectors are also under research. LLO has diverse biological activities such as cytotoxicity, apoptosis induction, endoplasmic reticulum stress response, modulation of gene expression,
Since FDA approved Sipuleucel-T (Provenge, Dendreon, Seattle, WA), which consists of antigen-loaded dendritic cells (DCs), there is a boom in immunotherapy applications. Yet, there is a shortcoming of this application because of its limited scope in immune response. However, Listeria monocytogenes (Lm) naturally targets DCs in vivo and stimulates both innate and adaptive cellular immunity. Lm-based vaccines engineered to express cancer antigens have demonstrated striking efficacy applications.
Meningitis
On the other hand, there is a caution to be taken in clinics since L. monocytogenes most often presents as acute bacterial meningitis, particularly in weaken immune system of patients such as elderly, already sick patients as secondary infection/opportunistic, and those with already immune fragile state. L. monocytogenes CNS the infections may present as acute bacterial meningitis, meningoencephalitis, or acute encephalitis.
References and Further readings:
PMCID: PMC3574585 PMID: 22595054
Le DT(1), Dubenksy TW Jr, Brockstedt DG. “Clinical development of Listeria monocytogenes-based immunotherapies”. 20. Semin Oncol. 2012 Jun;39(3):311-22. doi: 10.1053/j.seminoncol.2012.02.008.
PMCID: PMC3987759 PMID: 24826075
Liu D(1).“Molecular approaches to the identification of pathogenic and nonpathogenic Listeriae”. 16. Microbiol Insights. 2013 Jul 22;6:59-69. doi: 10.4137/MBI.S10880. eCollection 2013.
PMCID: PMC4385656 PMID: 25874208
Hernández-Flores KG(1), Vivanco-Cid H(2). Biological effects of listeriolysin O: implications for vaccination. Biomed Res Int. 2015;2015:360741. doi: 10.1155/2015/360741. Epub 2015 Mar 22.
PMCID: PMC4369580 PMID: 25241232
Maertens de Noordhout C(1), Devleesschauwer B(2), Angulo FJ(3), Verbeke G(4), Haagsma J(5), Kirk M(6), Havelaar A(7), Speybroeck N(8). “The global burden of listeriosis: a systematic review and meta-analysis”. 2. Lancet Infect Dis. 2014 Nov;14(11):1073-82. doi: 10.1016/S1473-3099(14)70870-9. Epub 2014 Sep 15.
PMID: 24911203
Cossart P(1), Lebreton A(2). “A trip in the “New Microbiology” with the bacterial pathogen Listeria Monocytogenes”. 3. FEBS Lett. 2014 Aug 1;588(15):2437-45. doi: 10.1016/j.febslet.2014.05.051. Epub 2014 Jun 6.
PMCID: PMC4005144 PMID: 24822197
Hernandez-Milian A(1), Payeras-Cifre A(1). “What is new in listeriosis?”. Biomed Res Int. 2014;2014:358051. doi: 10.1155/2014/358051. Epub 2014 Apr 14.
PMCID: PMC4179725 PMID: 25325017
Schultze T(1), Izar B(2), Qing X(1), Mannala GK(1), Hain T(1). “Current status of antisense RNA-mediated gene regulation in Listeria monocytogenes”. 5. Front Cell Infect Microbiol. 2014 Sep 30;4:135. doi: 10.3389/fcimb.2014.00135.
eCollection 2014.
PMCID: PMC3924034 PMID: 24592357
Guariglia-Oropeza V(1), Orsi RH(1), Yu H(2), Boor KJ(1), Wiedmann M(1), Guldimann C(1). “Regulatory network features in Listeria monocytogenes-changing the way we talk”. 6. Front Cell Infect Microbiol. 2014 Feb 14;4:14. doi: 10.3389/fcimb.2014.00014.
eCollection 2014.
PMCID: PMC3920067 PMID: 24575393
D’Orazio SE(1). ”Animal models for oral transmission of Listeria monocytogenes”. 7. Front Cell Infect Microbiol. 2014 Feb 11;4:15. doi: 10.3389/fcimb.2014.00015. eCollection 2014.
PMCID: PMC3921577 PMID: 24575392
Cahoon LA(1), Freitag NE(1). “Listeria monocytogenes virulence factor secretion: don’t leave the cell without a Chaperone”. 8. Front Cell Infect Microbiol. 2014 Feb 12;4:13. doi: 10.3389/fcimb.2014.00013.eCollection 2014.
PMCID: PMC3913888 PMID: 24551601
Gahan CG(1), Hill C(2).“Listeria monocytogenes: survival and adaptation in the gastrointestinal tract”. 9. Front Cell Infect Microbiol. 2014 Feb 5;4:9. doi: 10.3389/fcimb.2014.00009. eCollection 2014.
“Trial Watch: DNA vaccines for cancer therapy”. 10. Oncoimmunology. 2014 Jan 1;3(1):e28185. Epub 2014 Apr 1.
PMID: 24018504
Carrillo-Esper R(1), Carrillo-Cordova LD, Espinoza de los Monteros-Estrada I, Rosales-Gutiérrez AO, Uribe M, Méndez-Sánchez N. “Rhombencephalitis by Listeria monocytogenes in a cirrhotic patient: a case report and literature review”. 11. Ann Hepatol. 2013 Sep-Oct;12(5):830-3.
PMCID: PMC3708349 PMID: 23698167
Harrison LM(1), Balan KV, Babu US. “Dietary fatty acids and immune response to food-borne bacterial infections”. 12. Nutrients. 2013 May 22;5(5):1801-22. doi: 10.3390/nu5051801.
PMCID: PMC3899140 PMID: 23399758
Sun R(1), Liu Y. “Listeriolysin O as a strong immunogenic molecule for the development of new anti-tumor vaccines”. 13. Hum Vaccin Immunother. 2013 May;9(5):1058-68. doi: 10.4161/hv.23871. Epub 2013 Feb 11.
PMCID: PMC3638699 PMID: 23653659
Sherrid AM(1), Kollmann TR. “Age-dependent differences in systemic and cell-autonomous immunity to L. Monocytogenes”. 14. Clin Dev Immunol. 2013;2013:917198. doi: 10.1155/2013/917198. Epub 2013 Apr 7.
PMCID: PMC3543101 PMID: 23125201
Pizarro-Cerdá J(1), Kühbacher A, Cossart P.” Entry of Listeria monocytogenes in mammalian epithelial cells: an updated view”. Cold Spring Harb Perspect Med. 2012 Nov 1;2(11). pii: a010009. doi: 10.1101/cshperspect.a010009.
Renal (Kidney) Cancer: Connections in Metabolism at Krebs cycle and Histone Modulation
Curator: Demet Sag, PhD, CRA, GCP
Through Histone Modulation
Renal cell carcinoma accounts for only 3% of total human malignancies but it is still the most common type of urological cancer with a high prevalence in elderly men (>60 years of age).
Most kidney cancers are renal cell carcinomas (RCC). RCC lacks early warning signs and 70 % of patients with RCC develop metastases. Among them, 50 % of patients having skeletal metastases developed a dismal survival of less than 10 % at 5 years.
There are three main histopathological entities:
Clear cell RCC (ccRCC), dominant in histology (65%)
Papillary (15-20%) and
Chromophobe RCC (5%).
There are very rare forms of RCC shown in collecting duct, mucinous tubular, spindle cell, renal medullary, and MiTF-TFE translocation carcinomas.
Different subtypes of clear cell RCC can be defined by HIF patterns as well as by transcriptomic expression as defined by ccA and ccB subtypes. Papillary RCC also demonstrates distinct histological subtypes. A recently described variant denoted as clear cell papillary RCC is VHL wildtype (VHL WT), while other clear cell tumors are characterized by VHL mutation, loss, or inactivation (VHL MT).
KEY POINTS
Renal cell cancer is a disease in which malignant (cancer) cells form in tubules of the kidney.
Smoking and misuse of certain pain medicines can affect the risk of renal cell cancer.
Signs of renal cell cancer include
Blood in your urine, which may appear pink, red or cola colored
A lump in the abdomen.
Back pain just below the ribs that doesn’t go away
Weight loss
Fatigue
Intermittent fever
Factors that can increase the risk of kidney cancer include:
Older age.
High blood pressure (hypertension).
Treatment for kidney failure.(long-term dialysis to treat chronic kidney failure)
Certain inherited syndromes.
von Hippel-Lindau disease
Tests that examine the abdomen and kidneys are used to detect (find) and diagnose renal cell cancer.
Tumour of a diameter of 7 cm (approx. 23⁄4 inches) or smaller, and limited to the kidney. No lymph node involvement or metastases to distant organs.
Stage II
Tumour larger than 7.0 cm but still limited to the kidney. No lymph node involvement or metastases to distant organs.
Stage III
any of the following
Tumor of any size with involvement of a nearby lymph node but no metastases to distant organs. Tumour of this stage may be with or without spread to fatty tissue around the kidney, with or without spread into the large veins leading from the kidney to the heart.
Tumour with spread to fatty tissue around the kidney and/or spread into the large veins leading from the kidney to the heart, but without spread to any lymph nodes or other organs.
Stage IV
any of the following
Tumour that has spread directly through the fatty tissue and the fascia ligament-like tissue that surrounds the kidney.
Involvement of more than one lymph node near the kidney
Involvement of any lymph node not near the kidney
Distant metastases, such as in the lungs, bone, or brain.
Grade Level
Nuclear Characteristics
Grade I
Nuclei appear round and uniform, 10 μm; nucleoli are inconspicuous or absent.
Grade II
Nuclei have an irregular appearance with signs of lobe formation, 15 μm; nucleoli are evident.
Grade III
Nuclei appear very irregular, 20 μm; nucleoli are large and prominent.
Grade IV
Nuclei appear bizarre and multilobated, 20 μm or more; nucleoli are prominent
GENETICS:
90% or more of kidney cancers are believed to be of epithelial cell origin, and are referred to as renal cell carcinoma (RCC), which are further subdivided based on histology into clear-cell RCC (75%), papillary RCC (15%),
chromophobe tumor (5%), and oncocytoma (5%).
Nephrectomy continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). Research is still underway to developed targeted agents against the vascular endothelial growth factor (VEGF) molecule and related pathways as well as inhibitors of the mammalian target of rapamycin (mTOR),
clear cell RCC (ccRCC) doesn’t respond well to radiation chemotherapy due to high radiation resistancy. The hallmark genetic features of solid tumors such as KRAS or TP53 mutations are also absent. However, there is a well-designed association presented between ccRCC and mutations in the VHL gene
Hereditary RCC, accounts for around 4% of cases, has been a relatively dominant area of RCC genetics.
Causative genes have been identified in several familial cancer syndromes that predispose to RCC including
VHLmutations in von Hippel-Lindau disease that predispose to ccRCC and VHL is somatically mutated in up to 80% of ccRCC
METmutations in familial papillary renal cancer,
dominantly activating kinase domainMET mutation reported in 4–10% of sporadic papillary RCC[2].
FH (fumarate hydratase) mutations in hereditary leiomyomatosis and renal cell cancer that predispose to papillary RCC
FLCN(folliculin) mutations in Birt-Hogg-Dubé syndrome that predispose to primarily chromophobe RCC.
In addition, there are germline mutations:
in theTSC1/2 genes predispose to tuberous sclerosis complex where approximately 3% of cases develop ccRCC,
in the SDHB(succinate dehydrogenase type B) in patients with paraganglioma syndrome shows elevated risk to develop multiple types of RCC.
GWAS in almost 6000 RCC cases demonstrated that loci on 2p21 and 11q13.3 play a role in RCC. Although EPAS1 gene encoding a transcription factor operative in hypoxia-regulated responses in 2p21 , 11q13.3 has no known coding genes.
There has been, however, comparatively less progress in the elaboration of the somatic genetics of sporadic RCC.
Absent mutations in sporadic RCC:
somaticFH mutations
somatic mutations ofTSC12 and SDHB
Present mutations in sporadic ccRCC (chromophobe RCC) are
TSC1mutations occur in 5% of ccRCCs and
somatic mutations inFLCN rare
may predict for extraordinary sensitivity to mTORC1 inhibitors clinically.
The COSMIC database reports somatic point mutations in TP53 in 10% of cases, KRAS/HRAS/NRAS combined ≤1%, CDKN2A 10%, PTEN 3%, RB1 3%, STK11/LKB1 ≤1%, PIK3Ca ≤1%, EGFR1% and BRAF ≤1% in all histological samples. Further information can be found at (http://www.sanger.ac.uk/ genetics/CGP/cosmic/) for the RCC somatic genetics.
HIF- and hypoxia-mediated epigenetic regulation work together due to histone modification because HIF activate several chromatin demethylases, including JMJD1A (KDM3A), JMJD2B (KDM4B), JMJD2C (KDM4C) and JARID1B (KDM5B), all of which are directly targeted by HIF.
A number of histone modifying genes are mutated in renal cell carcinoma. These include the H3K36 trimethylase SETD2, the H3K27 demethylase UTX/KDM6A, the H3K4 demethylase JARID1C/KDM5C and the SWI/SNF complex compenent PBRM1, shown in this cartoon to represent their relative activities on Histone H3.
Hyper-methylation is observed on RASSF1 highly (50% f RCC) yet less on VHL and CDKN2A, yet there is a methylation and silencing observed on TIMP3 and secreted frizzled-related protein 2.
RCC is ONE OF THE “CILIOPATHIES” among Polycystic Kidney Disease (PKD), Tuberous Sclerosis Complex (TSC) and VHL Syndrome. The main display of cysts is dysfunctional primary cilia.
VHL proteostasis involves the chaperone mediated translocation of nascent VHL peptide from the ribosome to the TRiC/CCT chaperonin, where folding occurs in an ATP dependent process. The VBC complex is formed while VHL is bound to TRiC, and the mature complex is then released. Three different classes of mutation exist: Class A mutations prevent binding of VHL to TRiC, and abrogate folding into a mature complex. Class B mutations prevent association of Elongins C and B to VHL. Class C mutations inhibit interaction between VHL and HIF1 a.
Model for the control of the fate of nephron progenitor cells. Eya1 lies genetically upstream of Six2. Six2 labels the nephron progenitor cells, which can either maintain a progenitor state and self-renew or differentiate via the Wnt4-mediated MET. Wnt4 expression is under the direct control of Wt1. β-Catenin is involved in both progenitor cell fates through activation of different transcriptional programs. Active nuclear phosphorylated Yap/Taz shifts the progenitor balance toward the self-renewal fate. Eya1 and Six2 interact directly with Mycn, leading to dephosphorylation of Mycn pT58, stabilization of the protein, increased proliferation, and potentially a shift of the nephron progenitor toward self-renewal. Genes activated in Wilms’ tumors are depicted in green, and inactivated genes are in blue. Deregulation of Yap/Taz in Wilms’ tumors results in phosphorylated Yap not being retained in the cytoplasm as it should, but it translocates to the nucleus and thus shifts the progenitor cell balance toward self-renewal. This model is likely a simplification, as it presumes that all Wilms’ tumors, regardless of causative mutation, are caused by the same mechanism.
Epigenetic aberrations associated with Wilms’ tumor
Chinese Case Study:PMCID:PMC4471788
They u8ndertook this study based on association of low circulating adiponectin concentrations with a higher risk of several cancers, including renal cell carcinoma. Thus they demonstrated that by case–control study that ADIPOQ rs182052 is significantly associated with ccRCC risk.
They investigated the frequency of three single nucleotide polymorphisms (SNPs), rs182052G>A, rs266729C>G, rs3774262G>A, in the adiponectin gene (ADIPOQ). 1004 registered patients with clear cell renal cell carcinoma (ccRCC) compared with 1108 healthy subjects (n = 1108).
The first table presents the characteristics of 1004 patients with clear cell renal cell carcinoma and 1108 cancer-free controls from a Chinese Han population. The Second and third table shows the SNP results.
Table 1: The characteristics of the examined population.
aThe protein–protein interaction for the identified 8 proteins in STRING (10 necessary proteins/genes were added into the network so as to find the potential strong connection among them. The red dottedlines circled three main pathways. b The ingenuity pathway analysis (IPA) for all these 18 genes showing that oxidative phosphorylation, mitochondria dysfunction and granzyme A are the significantly activated pathways (fold change over 1.5, P < 0.05). c The possible mechanism related mitochondria functions: unspecific condition like inflammation, carcinogens, radiation (ionizing or ultraviolet), intermittent hypoxia, viral infections which is carcinogenesis in our study that damages a cell’s oxidative phosphorylation. Any of these conditions can damage the structure and function of mitochondria thus activating a respiratory chain changes (Complex I, II, III, IV) and also cytochrome c release. When the mitochondrial dysfunction persists, it produces genome instability (mtDNA mutation), and further lead to malignant transformation (metastasis) via increased ROS and apoptotic resistance. (Color figure online)
RENAL CELL CARCINOMA AND METABOLISM goes hand to hand in genes encoding enzymes of the Krebs cycle suppress tumor formation in kidney cells. This includes Succinate dehydrogenase (SDH), Fumarate hydratase (FH). As a result of accumulation of succinate or fumarate causes the inhibition of a family of 2-oxoglutarate-dependent dioxygeneases.
The FH and SDH genes function as two-hit tumor suppressor genes.
SDH has a complex of 4 different polypeptides (SDHA-D) function in electron transfer, catalyzes the conversion of succinate to fumarate. Furthermore, heterozygous germline mutations in SDHsubunits predispose to pheochromocytoma/paraganglioma. FH function to convert fumarate to malate. When its mutations presented as heterozygous germline, it predisposes hereditary leiomyomatosis and renal cell cancer (HLRCC). Among them about 20–50% of HLRCC families are typically papillary-type 2 (pRCC-2) and overwhelmingly aggressive.RCC is increasingly being recognized as a metabolic disease, and key lesions in nutrient sensing and processing have been detected.
Regulation of Prolyl Hydroxylases by Tricarboxylic Acid (TCA) Cycle Intermediates. Prolyl hydroxylases use TCA cycle intermediates to help catalyze the oxygen, iron and ascorbate dependent- addition of a hydroxyl side chain to a Pro402 and Pro564 of HIF alpha subunits, leading to VHL binding and degradation. Defects in either fumarate hydratase or succinate dehydrogenase will drive up levels of fumarate and succinate, which competitively bind prolyl hydroxylases, and prevent HIF prolyl hydroxylation. This results in higher intracellular HIF levels.
HIF regulation and mTOR pathway connections. Hypoxia blocks HIF expression in a TSC1/2 and REDD dependent pathway [155]. HIF1α appears to be both TORC1 and TORC2 dependent, whereas HIF2α is only TORC2 dependent [275]. Signaling via TORC2 appears to upregulate HIF2α in an AKT dependent manner [69].
TREATMENT:
Based on the types of renal cancers the treatment method may vary but the general scheme is:
Drugs Approved for Kidney (Renal Cell) Cancer
Food and Drug Administration (FDA) approved drugs for kidney (renal cell) cancer. Some of the drug names link to NCI’s Cancer Drug Information summaries.
Immune regulation of renal tumor cells. A: When an antigen presenting cell (APC) engages a T-cell via a cognate T-cell receptor (TCR) and CD28, T-cell cell activation occurs. B: Early and late T-cell inhibitory signals are mediated via CTLA-4 and PD-1 receptors, and this occurs via engagement of the APC via B7 and PD-L1, respectively. C: Inhibitory antibodies against CTLA-4 and PD-1 can overcome T-cell downregulation and once again allow cytokine production.
Phase III Trials of Targeted Therapy in Metastatic Renal Cell Carcinoma
RCC renal cell carcinoma, RR response rate, OS overall survival, PFS progression free survival, VEGFvascular endothelial growth factor, IFNa interferon alpha, mTOR mammalian target of rapamycin. AVORENAVastin fOr RENal cell cancer, CALBG Cancer and Leukemia Group B. TARGET Treatment Approaches in Renal Cancer Global Evaluation Trial. AXIS Axitinib in Second Line. ARCC Advanced Renal-Cell Carcinoma. RECORD-1 REnal Cell cancer treatment withOral RAD001 given Daily.
aIncluding serum lactate dehydrogenase level of more than 1.5 times the upper limit of the normal range, a hemoglobin level below the lower limit of the normal range; a corrected serum calcium level of more than 10 mg per deciliter (2.5 mmol per liter), a time from initial diagnosis of renal-cell carcinoma to randomization of less than 1 year, a Karnofsky performance score of 60 or 70, or metastases in multiple organs.
A summary is provided for RCCAA that have been defined at the molecular level. RCCAA are characterized with regard to their antigen category, their prevalence of (over)expression among total RCC specimens evaluated, whether RCCAA expression is modulated by hypoxia or tumor DNA methylation status, and which HLA class I and class II alleles have been reported to serve as presenting molecules for T cell recognition of peptides derived from a given RCCAA.
Abbreviations: CT = Cancer-Testis Antigens; ML = Multi-lineage Antigens; NR = Not Reported; OF = Oncofetal Antigen; aORF = altered open reading frame; ORF = open reading frame; RCC = Renal cell carcinoma; WT = Wild-Type;
Agents that are currently or soon-to-be in clinical trials are summarized with regard to their anticipated impact(s) on Type-1 anti-tumor T cell (Te) activation, function, survival and recruitment into the TME. Additional anticipated effects of drugs on suppressor cells (Treg and MDSC) are also summarized. Key: ↑, agent is expected to increase parameter; ↓, agent is expected to inhibit parameter; +/−, minimal increase or decrease is expected in parameter as a consequence of treatment with agent; ?, unknown effect of agent on parameter.
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Monoclonal Antibody treatment means a biological therapy where monoclonal antibodies is used to initiate development of specific antibodies (protein molecules produced by the B cells as a primary immune defense), so that they can fight against antigens (substances that are capable of inducing a specific immune response) specifically to kill extracellular/ cell surface target. Thus, the application of this types of therapies are not limited to cancer but also rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, and some infectious diseases such as Ebola.
To eliminate or reduce the effects of chemotherapeutic agents. Thus chemotherapeutics agents attached to monoclonal antibodies.
Diagnostic process:
Monoclonal antibodies again used as a vehicle to locate the tumorigenic cancer cells in the body. There can be several methods but one of them is carrying radioactive substances to cancer cells so that they can be labelled in vivo. However, there are less invasive ways to do as well. As a result, there are new combination of methods such as:
nuclear imaging,
surgical mapping, and
direct therapy in multiple settings either alone, or in conjunction with chemotherapeutic agents, adjuvant.
How do monoclonal antibody drugs work?
Naked monoclonal antibodies:
Make the cancer cell more visible to the immune system.
Action is to boost immune system.
Example: Alemtuzumab (Campath®), chronic lymphocytic leukemia (CLL) by binding to the CD52 antigen on lymphocytes.
Block immune checkpoint inhibitor proteins
Treatments that target PD-1 or PD-L1.
PD-1 is a checkpoint protein on T cells, called “off switch” of T cells since PD-1 prevents from attacking other cells in the body. Yet, when it is overexpressed on the cancer cells, tumors escape from immune system, because when PD-1 binds to PD-L1, T cells thinks these cells are body’s own normal cells.
a, Tumour cells express both cancer-driving mutations and ‘passenger’ mutations that cause the expression of neoantigens — ‘new’ molecular structures that, when presented by MHC proteins on the cell surface, are recognized by T cells of the immune system as being foreign, leading to an immune response against the tumour. However, interactions between the receptor PD-1 and its ligand PD-L1, which are expressed on tumour cells, T cells and other immune cells such as macrophages, activate signalling pathways that inhibit T-cell activity and thus inhibit the antitumour immune response. b, Antibodies that block the PD-1 pathway by binding to PD-1 or PD-L1 can reactivate T-cell activity and proliferation, leading to enhanced antitumour immunity.
Examples are:
Pembrolizumab (Keytruda®)
Nivolumab (Opdivo®)
There is a possibility of developing an autoimmune reaction. The most common side effects include fatigue, cough, nausea, skin rash, and itching. Rarely more serious problems in the lungs, intestines, liver, kidneys, hormone-making glands, or other organs may occur.
Treatments that target CTLA-4
Another protein is CTLA-4 to control T cells, “off switch”.
Example: Ipilimumab (Yervoy®) is a monoclonal antibody that attaches to CTLA-4 and stops it from working. This can boost the body’s immune response against cancer cells.
Block antigens on cancer cells (or other nearby cells).
Example: Trastuzumab, when HER2 is activated, binds to these proteins and stops antigens from becoming active in breast and stomach cancer cells.
Example: Rituxan specifically attaches to CD20 that is found only on B cells so when these labelled B cells can be visible to immune system. There are certain types of lymphomas predisposed due to malfunctioning B cells.
Block growth signals. Prevent signal amplification for cell growth.
The cells like to amplify their message in danger or during certain metabolisms so they secrete or produce a type of chemicals called growth factors. These factors then attaches to specific receptors on the surface of normal cells and cancer cells. Thus, signaling the cells to grow faster than the normal cells. The action is preventing the signals to be received by monoclonal.
Example:
Cetuximab (Erbitux), targets epidermal growth factor. Thus its function utilized to cure colon cancer, head and neck cancers.
Stop new blood vessels from forming.
Tumors needs to grow so in the body they need blood vessel formation to feed the cell growth (angiogenesis)
Example; Bevacizumab (Avastin) targets vascular endothelial growth factor (VEGF) and blocks the angiogenesis.
Conjugated monoclonal antibodies (tagged, labeled, or loaded antibodies).
Deliver chemotherapy to cancer cells.
They are monoclonal antibodies (mAbs) joined to a chemotherapy drug or to a radioactive particle to locate cancer cells directly through targeting specific antigen after circulating in the bloodstream. They are used as a homing device.
Chemo-labeled antibodies: Also called as antibody-drug conjugates (ADCs) and provide powerful chemotherapy (or other) drugs attached to them.
Brentuximab vedotin (Adcetris®), an antibody that targets the CD30 antigen on lymphocytes, attached to MMAE (a chemo drug) against Hodgkin lymphoma and anaplastic large cell lymphoma.
Ado-trastuzumab emtansine (Kadcyla®, also called TDM-1), an antibody that targets the HER2 protein, attached to DM1 (a chemo drug) against cells overexpressing HER2 in breast cancer
Toxin attached protein: Denileukin diftitox (Ontak®) is not an antibody but it is a protein, cytokine known as interleukin-2 (IL-2) and attached to diphtheria toxin that recognizes CD25 antigen to treat lymphoma of the skin (cutaneous T-cell lymphoma).
Radiolabeled antibodies:Deliver radiation to cancer cells.
The other method, less preferred, is radiation-linked monoclonal antibodies. This time low radiation in long term used to target the cancer cells but it is suggested that this method has elevated outcome to kill the cancer cells than conventional high-dose external beam radiation.
Example; Ibritumomab (Zevalin), is an approved treatment. The targeted disease is for non-Hodgkin’s lymphoma.
Treatment with this type of antibody also referred as radioimmunotherapy (RIT).
Bispecific monoclonal antibodies
If the drug contains two parts of 2 different mAbs, meaning they can attach to 2 different proteins at the same time, they are called Bispecific monoclonal antibodies since they attack two proteins at the same time.
Example: Blinatumomab (Blincyto), can attach CD 19 which is found on some leukemia and lymphoma cells and CD3 on T cells. Thus, brings opponents, immune and malignant cancer cells, to defeat cancer.
THE OTHER SIDE OF THE COIN: SAFETY
Possible side effects of monoclonal antibodies
Delivery is intravenously and since Mabs are themselves are proteins sometimes presents side effects like an allergic reaction yet compared to chemotherapy drugs these effects are much less. .
Fever
Chills
Weakness
Headache
Nausea
Vomiting
Diarrhea
Low blood pressure
Rashes
Examples:
Bevacizumab (Avastin®), high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.
Cetuximab (Erbitux®), serious rashes in some people.
Model mAb production plant design and capabilities. A model large scale mAb production plant employs multiple bioreactors configured to supply a single purification train. A plant having six individual 15 kL bioreactors is potentially capable of supplying 10 tons of purified mAb per year using conventional technologies, or 4–5 products with 1 ton demands. This enormous capacity per plant would result in a marked decrease in drug substance production costs, and results in significant excess capacity throughout the biopharmaceutical industry.
Production:
Production capacity estimates for mammalian cell-derived mAbsa
Year
CMO
Product company
Total
Capacity at 2 g/L
Capacity at 5 g/L
2007
500 kL
1,800 kL
2,300 kL
70 tons/yr
170 tons/yr
2010
700 kL
2,700 kL
3,400 kL
100 tons/yr
255 tons/yr
2013
1,000 kL
3,000 kL
4,000 kL
120 tons/yr
300 tons/yr
aCapacity estimates from ref. Ransohoff TC, Ecker DM, Levine HL, Miller J. Cell culture manufacturing capacity: trends and outlook through 2013. PharmSource. 2008
Estimated demand for therapeutic mAbs and Fc-fusion products in 2009. The total demand for the top 15 mAbs and Fc-fusions in 2009 is estimated to be approximately 7 tons, with the four largest volume products requiring approximately one ton per year. More than half of the products were estimated to require less than 200 kg per year.
Distribution of average wholesale prices for mAb and Fc-fusions in 2008. The average U.S. wholesale prices per gram for 15 commercial mAbs and Fc-fusions are shown. The minimum is approximately $2,000 per gram, and the median is approximately $8,000 per gram. Note that a significant price erosion (50% of the minimum shown here) for a product with modest demand (100 kg/yr) could result in an unprofitable market, as revenues for the therapeutic product ($100 million/yr) may never provide a positive return on investment.
Sensitivity analysis of mAb drug substance COGs for the model plant (six 15kL bioreactors)
aThe new facility based on disposables is assumed to cost just one-quarter of model plant to build, and uses only the number of bioreactors (‘n’) needed to satisfy the demand.
bA 10-year straight line depreciation is used to estimate the depreciation costs.
cRaw material costs per gram are assumed to be slightly higher for the disposable facility.
dLabor costs for the new facility are assumed to be just 40% of the model plant (100 vs 250 staff, respectively).
eA constant cost per batch is assumed for the CMO, all-inclusive of production, testing and release.
Abbreviations: Structure: Ch, chimeric; Hm, humanized; Hu, human; Mu, murine. Regulatory Path: A, accelerated approval; F, fast-track; P, priority review; O, orphan indication. 1-, first-line therapy; a, conditional approval; b, rituximab refractory; c, refractory to chemotherapy; d, single-agent; e, estimate; m, metastatic; n/a, information not available; p, prophylaxis. Sources: 20 Compounds that defined biotech, Signals online magazine at www.signalsmag.com; ReCap database; Biopharmaceutical Products in the U.S. and European markets 6th edition, Ronald A. Rader, ed; Pharma Sales and BioPharmInsights databases; Reichert JM, Ph. D.; personal communications. Development times and sales estimates for some Second Tier mAbs are based on limited information.
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Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011 Dec 21;480(7378):480-9. doi: 10.1038/nature10673. Review. PubMed PMID: 22193102; PubMed Central PMCID: PMC3967235.
Elert E. Calling cells to arms. Nature. 2013 Dec 19;504(7480):S2-3. doi: 10.1038/504S2a. PubMed PMID: 24352361.
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011 Dec 21;480(7378):480-9. doi: 10.1038/nature10673. Review. PubMed PMID: 22193102; PubMed Central PMCID: PMC3967235.
Dolgin E. FDA narrows drug label usage. Nature. 2009 Aug 27;460(7259):1069. doi: 10.1038/4601069a. PubMed PMID: 19713906.
Ellis LM, Reardon DA. Cancer: The nuances of therapy. Nature. 2009 Mar 19;458(7236):290-2. doi: 10.1038/458290a. PubMed PMID: 19295595.
Sredni B, Caspi RR, Klein A, Kalechman Y, Danziger Y, Ben Ya’akov M, Tamari T, Shalit F, Albeck M. A new immunomodulating compound (AS-101) with potential therapeutic application. A new immunomodulating compound (AS-101) with potential therapeutic application. Nature. 1987 Nov 12-18;330(6144):173-6. PubMed PMID: 3118216.
Modified from Carter P (November 2001). “Improving the efficacy of antibody-based cancer therapies”. Nat. Rev. Cancer 1 (2): 118–29. doi:10.1038/35101072.PMID11905803.
(John, Martin et al. 2005, Robert, Ann et al. 2006, Albert, Edvardas et al. 2012, Claro, Karen et al. 2012, Gideon, Nancy et al. 2013, Michael, Ke et al. 2013, Thomas, Albert et al. 2013, Hyon-Zu, Barry et al. 2014, Larkins, Scepura et al. 2015, Sandra, Ibilola et al. 2015, Sean, Gideon et al. 2015)Hudson PJ, Souriau C (January 2003). “Engineered antibodies”. Nat. Med. 9 (1): 129–34. doi:10.1038/nm0103-129. PMID12514726.
Krauss WC, Park JW, Kirpotin DB, Hong K, Benz CC (2000). “Emerging antibody-based HER2 (ErbB-2/neu) therapeutics”. Breast Dis 11: 113–124. PMID15687597.
Joyce1, Johanna A.; Fearon, Douglas T. (April 3, 2015). “T cell exclusion, immune privilege, and the tumor microenvironment”. Science 348 (6230 74-80).doi:10.1126/science.aaa6204.
Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 241. ISBN0-443-07145-4.
Hooks MA, Wade CS, Millikan WJ (1991). “Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation”. Pharmacotherapy 11(1): 26–37. PMID1902291.
(John, Martin et al. 2005, Robert, Ann et al. 2006, Albert, Edvardas et al. 2012, Claro, Karen et al. 2012, Gideon, Nancy et al. 2013, Michael, Ke et al. 2013, Thomas, Albert et al. 2013, Hyon-Zu, Barry et al. 2014, Larkins, Scepura et al. 2015, Sandra, Ibilola et al. 2015, Sean, Gideon et al. 2015)
Albert, D., K. Edvardas, G. Joseph, C. Wei, S. Haleh, L. L. Hong, D. R. Mark, B. Satjit, W. Jian, G. Christine, B. Julie, B. B. Laurie, R. Atiqur, S. Rajeshwari, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis.” Clinical Cancer Research: 3212-3217.
Claro, R. A. d., M. Karen, K. Virginia, B. Julie, K. Aakanksha, H. Bahru, O. Yanli, S. Haleh, L. Kyung, K. Kallappa, R. Mark, S. Marjorie, B. Francisco, C. Kathleen, C. Xiao Hong, B. Janice, A. Lara, K. Robert, K. Edvardas, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma.” Clinical Cancer Research: 5845-5849.
Gideon, M. B., S. S. Nancy, C. Patricia, C. Somesh, T. Shenghui, S. Pengfei, L. Qi, R. Kimberly, M. P. Anne, T. Amy, E. K. Kathryn, G. Laurie, L. R. Barbara, C. W. Wendy, C. Bo, T. Colleen, H. Patricia, I. Amna, J. Robert and P. Richard (2013). “First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 4911-4916.
Hyon-Zu, L., W. M. Barry, E. K. Virginia, R. Stacey, D. Pedro, S. Haleh, G. Joseph, B. Julie, F. Jeffry, M. Nitin, K. Chia-Wen, N. Lei, S. Marjorie, T. Mate, C. K. Robert, K. Edvardas, J. Robert, T. F. Ann and P. Richard (2014). “U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3902-3907.
John, R. J., C. Martin, S. Rajeshwari, C. Yeh-Fong, M. W. Gene, D. John, G. Jogarao, B. Brian, B. Kimberly, L. John, H. Li Shan, C. Nallalerumal, Z. Paul and P. Richard (2005). “Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen.” Clinical Cancer Research 11(18).
Larkins, E., B. Scepura, G. M. Blumenthal, E. Bloomquist, S. Tang, M. Biable, P. Kluetz, P. Keegan and R. Pazdur (2015). “U.S. Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy.” The oncologist.
Michael, A., L. Ke, J. Xiaoping, H. Kun, W. Jian, Z. Hong, K. Dubravka, P. Todd, D. Zedong, R. Anne Marie, M. Sarah, K. Patricia and P. Richard (2013). “U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2289-2293.
Robert, C. K., T. F. Ann, S. Rajeshwari and P. Richard (2006). “United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2955-2960.
Sandra, J. C., F.-A. Ibilola, J. L. Steven, Z. Lillian, J. Runyan, L. Hongshan, Z. Liang, Z. Hong, Z. Hui, C. Huanyu, H. Kun, D. Michele, N. Rachel, K. Sarah, K. Sachia, H. Whitney, K. Patricia and P. Richard (2015). “FDA Approval Summary: Ramucirumab for Gastric Cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3372-3376.
Sean, K., M. B. Gideon, Z. Lijun, T. Shenghui, B. Margaret, F. Emily, H. Whitney, L. Ruby, S. Pengfei, P. Yuzhuo, L. Qi, Z. Ping, Z. Hong, L. Donghao, T. Zhe, H. Ali Al, B. Karen, K. Patricia, J. Robert and P. Richard (2015). “FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2436-2439.
Thomas, M. H., D. Albert, K. Edvardas, C. K. Robert, M. K. Kallappa, D. R. Mark, H. Bahru, B. Julie, D. B. Jeffrey, H. Jessica, R. P. Todd, J. Josephine, A. William, M. Houda, B. Janice, D. Angelica, S. Rajeshwari, T. F. Ann and P. Richard (2013). “U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma.” Clinical Cancer Research: 4559-4563.
Monoclonal Antibody Therapy: What is in the name or clear description?
Curator: Demet Sag, PhD, CRA, GCP
What is in the name?
Nomenclature is important part of the scientific community so we can stay on the same page in all kinds of communications for clarity. Therefore, a defined nomenclature scheme for assigning generic, or nonproprietary, names to monoclonal antibody drugs is used by the World Health Organization’s International Nonproprietary Names (INN) and the United States Adopted Names (USAN). In general, word stems are used to identify classes of drugs, in most cases placed at the end of the word.
Knowing what Antibody relies on understanding of immune response system so that one can modify the cells, choose correct biomarkers from the primary pathways (like Notch, WNT etc), know signaling from outside to inside (like GPCRs, MAPKs, nuclear transcription receptors), personalized gene make up (genomics) and key gene regulation mechanisms. Thus, immunomodulation can be done for immunotherapies. The admiration of these cells generate the new era called biosensors.
All monoclonal antibody names end with the stem -mab.
Unlike most other pharmaceuticals, monoclonal antibody nomenclature uses different preceding word parts (morphemes) depending on antibody structure and function. These are officially called sub-stemsand sometimes erroneously infixes.
This nomenclature is also used for fragments of monoclonal antibodies, such as antigen binding fragments and single-chain variable fragments.
The nomenclature has been updated. The main criteria is naming the origin, target, make up/type of antibody, ans of course suffix to show it is a monoclonal antibody.
Components
Substem for origin/source.
The substem preceding the -mab suffix denotes the animal from which the antibody is obtained.
The first monoclonal antibodies were produced
in mice (substem -o-), yielding the ending -omab; usually Mus musculus, the house mouse),
primates (-i-), yielding -imab;
usually Macaca irus, the Crab-eating Macaque.
Need and RD:
There was a dis-advantage of using non-human Abs since they induce immune responses that are generating side effects, such as provoking allergy reactions, due to fast clearance from the body lost effectiveness etc.
As a result, new types of monoclonal antibodies were engineered developed to avoid negative impacts.
Mainly placing human origin sequences:
Chimeric, the constant region is replaced with the human form so the substem used is -xi-., in which case it is called
Humanized, Part of the variable regions, typically everything but the complementarity determining regions, may also be substituted, so substem used is -zu-.
Partly chimeric and partly humanized antibodies use -xizu-.
*These three substems do not indicate the foreign species used for production.
Thus,
the human/mouse chimeric antibody ba-s-il-i-ximab ends in -ximab
the human/macaque antibody go-m-il-i-ximab ends in -ximab.
Pure human antibodies use -u-.
Rat/mouse hybrid antibodies:
They can be engineered with binding sites for two different antigens.
These drugs, termed trifunctional antibodies, have the substem -axo–.
Substem for target The substem precedingthe source of the antibody refers to the medicine’s target.
Examples of targets are:
tumors,
organ systems like the circulatory system, or
Infectious agents like bacteria or viruses.
However;
The term targetdoes not imply what sort of action the antibody exerts.
Therapeutic, prophylactic and diagnostic agents are not distinguished by this nomenclature.
In the naming scheme as originally developed, these substems mostly consist of a consonant, a vowel, then another consonant. For ease of pronunciation and to avoid awkwardness, the final consonant may be dropped if the following source substem begins with a consonant (such as -zu- or -xi-).
Examples of these include:
-ci(r)- for the circulatory system,
-li(m)-for the immune system (limstands for lymphocyte) and
-ne(r)-or -neu(r)- for the nervous system.
This results in endings like –li-mu-mab (immune system, human) or –ci-ximab (circulatory system, chimeric, consonant r dropped).
In 2009, new and shorter target substems were introduced.
They mostly consist of a consonant, plus a vowel which is omitted if the source substem begins with a consonant.
For example, human antibodies targeting the immune system receive names ending in -lumab instead of the old -limumab. Some endings like -ciximab remain unchanged.
Prefix
The prefix carries no special meaning and should be unique for each medicine.
Additional words
A second word may be added if there is another substance attached or linked. If the drug contains a radioisotope, the name of the isotope precedes the name of the antibody.
Examples
New convention
Olara-t-u-mab
is an antineoplastic. Its name is composed of olara- + -t- + -u- + -mab.
shows that the drug is a human monoclonal antibody acting against tumors.
Benra-li-zu-mab
a drug designed for the treatment of asthma,
benra-+ -li- + -zu- + -mab, marking it as a humanized antibody acting on the immune system.
Recently, the bispecific antibodies, a novel class of therapeutic antibodies, have yielded promising results in clinical trials. In April 2009, the bispecific antibody catumaxomab was approved in the European Union.
Elert E. Calling cells to arms. Nature. 2013 Dec 19;504(7480):S2-3. doi: 10.1038/504S2a. PubMed PMID: 24352361.
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011 Dec 21;480(7378):480-9. doi: 10.1038/nature10673. Review. PubMed PMID: 22193102; PubMed Central PMCID: PMC3967235.
Dolgin E. FDA narrows drug label usage. Nature. 2009 Aug 27;460(7259):1069. doi: 10.1038/4601069a. PubMed PMID: 19713906.
Ellis LM, Reardon DA. Cancer: The nuances of therapy. Nature. 2009 Mar 19;458(7236):290-2. doi: 10.1038/458290a. PubMed PMID: 19295595.
(John, Martin et al. 2005, Robert, Ann et al. 2006, Albert, Edvardas et al. 2012, Claro, Karen et al. 2012, Gideon, Nancy et al. 2013, Michael, Ke et al. 2013, Thomas, Albert et al. 2013, Hyon-Zu, Barry et al. 2014, Larkins, Scepura et al. 2015, Sandra, Ibilola et al. 2015, Sean, Gideon et al. 2015)
Albert, D., K. Edvardas, G. Joseph, C. Wei, S. Haleh, L. L. Hong, D. R. Mark, B. Satjit, W. Jian, G. Christine, B. Julie, B. B. Laurie, R. Atiqur, S. Rajeshwari, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis.” Clinical Cancer Research: 3212-3217.
Claro, R. A. d., M. Karen, K. Virginia, B. Julie, K. Aakanksha, H. Bahru, O. Yanli, S. Haleh, L. Kyung, K. Kallappa, R. Mark, S. Marjorie, B. Francisco, C. Kathleen, C. Xiao Hong, B. Janice, A. Lara, K. Robert, K. Edvardas, F. Ann and P. Richard (2012). “U.S. Food and Drug Administration Approval Summary: Brentuximab Vedotin for the Treatment of Relapsed Hodgkin Lymphoma or Relapsed Systemic Anaplastic Large-Cell Lymphoma.” Clinical Cancer Research: 5845-5849.
Gideon, M. B., S. S. Nancy, C. Patricia, C. Somesh, T. Shenghui, S. Pengfei, L. Qi, R. Kimberly, M. P. Anne, T. Amy, E. K. Kathryn, G. Laurie, L. R. Barbara, C. W. Wendy, C. Bo, T. Colleen, H. Patricia, I. Amna, J. Robert and P. Richard (2013). “First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 4911-4916.
Hyon-Zu, L., W. M. Barry, E. K. Virginia, R. Stacey, D. Pedro, S. Haleh, G. Joseph, B. Julie, F. Jeffry, M. Nitin, K. Chia-Wen, N. Lei, S. Marjorie, T. Mate, C. K. Robert, K. Edvardas, J. Robert, T. F. Ann and P. Richard (2014). “U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3902-3907.
John, R. J., C. Martin, S. Rajeshwari, C. Yeh-Fong, M. W. Gene, D. John, G. Jogarao, B. Brian, B. Kimberly, L. John, H. Li Shan, C. Nallalerumal, Z. Paul and P. Richard (2005). “Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen.” Clinical Cancer Research11(18).
Larkins, E., B. Scepura, G. M. Blumenthal, E. Bloomquist, S. Tang, M. Biable, P. Kluetz, P. Keegan and R. Pazdur (2015). “U.S. Food and Drug Administration Approval Summary: Ramucirumab for the Treatment of Metastatic Non-Small Cell Lung Cancer Following Disease Progression On or After Platinum-Based Chemotherapy.” The oncologist.
Michael, A., L. Ke, J. Xiaoping, H. Kun, W. Jian, Z. Hong, K. Dubravka, P. Todd, D. Zedong, R. Anne Marie, M. Sarah, K. Patricia and P. Richard (2013). “U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2289-2293.
Robert, C. K., T. F. Ann, S. Rajeshwari and P. Richard (2006). “United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2955-2960.
Sandra, J. C., F.-A. Ibilola, J. L. Steven, Z. Lillian, J. Runyan, L. Hongshan, Z. Liang, Z. Hong, Z. Hui, C. Huanyu, H. Kun, D. Michele, N. Rachel, K. Sarah, K. Sachia, H. Whitney, K. Patricia and P. Richard (2015). “FDA Approval Summary: Ramucirumab for Gastric Cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 3372-3376.
Sean, K., M. B. Gideon, Z. Lijun, T. Shenghui, B. Margaret, F. Emily, H. Whitney, L. Ruby, S. Pengfei, P. Yuzhuo, L. Qi, Z. Ping, Z. Hong, L. Donghao, T. Zhe, H. Ali Al, B. Karen, K. Patricia, J. Robert and P. Richard (2015). “FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.” Clinical cancer research : an official journal of the American Association for Cancer Research: 2436-2439.
Thomas, M. H., D. Albert, K. Edvardas, C. K. Robert, M. K. Kallappa, D. R. Mark, H. Bahru, B. Julie, D. B. Jeffrey, H. Jessica, R. P. Todd, J. Josephine, A. William, M. Houda, B. Janice, D. Angelica, S. Rajeshwari, T. F. Ann and P. Richard (2013). “U.S. Food and Drug Administration Approval: Carfilzomib for the Treatment of Multiple Myeloma.” Clinical Cancer Research: 4559-4563.
Modified from Carter P (November 2001). “Improving the efficacy of antibody-based cancer therapies”.Nat. Rev. Cancer1(2): 118–29.doi:10.1038/35101072.PMID11905803.
Rang, H. P. (2003).Pharmacology. Edinburgh: Churchill Livingstone. p. 241.ISBN0-443-07145-4.
Hooks MA, Wade CS, Millikan WJ (1991). “Muromonab CD-3: a review of its pharmacology, pharmacokinetics, and clinical use in transplantation”.Pharmacotherapy11(1): 26–37.PMID1902291.
Are we there yet? Life is a journey so the science.
Governor Brown announced Precision Medicine initiative for California on April 14, 2015. UC San Francisco is hosting the two-year initiative, through UC Health, which includes UC’s five medical centers, with $3 million in startup funds from the state. The public-private initiative aims to leverage these funds with contributions from other academic and industry partners.
With so many campuses spread throughout the state and so much scientific, clinical and computational expertise, the UC system has the potential to bring it all together, said Atul Butte, MD, PhD, who is leading the initiative.
At the beginning of 2015 President Obama signed this initiative and assigned people to work on this project.
Previously NCI Director Harold Varmus, MD said that “Precision medicine is really about re-engineering the diagnostic categories for cancer to be consistent with its genomic underpinnings, so we can make better choices about therapy,” and “In that sense, many of the things we’re proposing to do are already under way.”
The proposed initiative has two main components:
a near-term focus on cancers and
a longer-term aim to generate knowledge applicable to the whole range of health and disease.
Both components are now within our reach because of advances in basic research, including molecular biology, genomics, and bioinformatics. Furthermore, the initiative taps into converging trends of increased connectivity, through social media and mobile devices, and Americans’ growing desire to be active partners in medical research.
Since the human genome is sequenced it became clear that actually there are few genes than expected and shared among organisms to accomplish same or similar core biological functions. As a result, knowledge of the biological role of such shared proteins in one organism can be transferred to another organism.
It was necessary to generate a dynamic yet controlled standardized collection of information with ever changing and accumulating data. It was called Gene Ontology Consortium. Three independent ontologies can be reached at (http://www.geneontology.org) developed based on :
biological process,
molecular function and
cellular component.
We need a common language for annotation for a functional conservation. Genesis of the grand biological unification made it possible to complete the genomic sequences of not only human but also the main model organisms and more:
· the budding yeast, Saccharomyces cerevisiae, completed in 1996
· the nematode worm Caenorhabditis elegans, completed in 1998
· the fruitfly Drosophila melanogaster,
· the flowering plant Arabidopsis thaliana
· fission yeast Schizosaccharomyces pombe
· the mouse , Mus musculus
On the other hand, as we know there are allelic variations that underlie common diseases and complete genome sequencing for many individuals with and without disease is required. However, there are advantages and disadvantages as we can carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies but there are problems such as computing the data efficiently and sharing the information without tempering privacy. Therefore we should be mindful about few main conditions including:
models of the allelic architecture of commondiseases,
sample size,
map density and
sample-collection biases.
This will lead into the cost control and efficiency while identifying genuine disease-susceptibility loci. The genome-wide association studies (GWAS) have progressed from assaying fewer than 100,000 SNPs to more than one million, and sample sizes have increased dramatically as the search for variants that explain more of the disease/trait heritability has intensified.
In addition, we must translate this sequence information from genomics locus of the genes to function with related polymorphism of these genes so that possible patterns of the gene expression and disease traits can be matched. Then, we may develop precision technologies for:
Diagnostics
Targeted Drugs and Treatments
Biomarkers to modulate cells for correct functions
With the knowledge of:
gene expression variations
insight in the genetic contribution to clinical endpoints ofcomplex disease and
their biological risk factors,
share etiologic pathways
therefore, requires an understanding of both:
the structure and
the biology of the genome.
These studies demonstrated hundreds of associations of common genetic variants with over 80 diseases and traits collected under a controlled online resource. However, identifying published GWAS can be challenging as a simple PubMed search using the words “genome wide association studies” may be easily populated with un-relevant GWAS.
National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (http://www.genome.gov/gwastudies), an online, regularly updated database of SNP-trait associations extracted from published GWAS was developed.
Therefore, sequencing of a human genome is a quite undertake and requires tools to make it possible:
to explore the genetic component incomplex diseases and
to fully understand the genetic pathways contributing tocomplex disease
The rapid increase in the number of GWAS provides an unprecedented opportunity to examine the potential impact of common genetic variants on complex diseases by systematically cataloging and summarizing key characteristics of the observed associations and the trait/disease associated SNPs (TASs) underlying them.
With this in mind, many forms can be established:
to describe the features of this resource and the methods we have used to produce it,
to provide and examine key descriptive characteristics of reported TASs such as estimated risk allele frequencies and odds ratios,
to examine the underlying functionality of reported risk loci by mapping them to genomic annotation sets and assessing overrepresentation via Monte Carlo simulations and
to investigate the relationship between recent human evolution and human disease phenotypes.
This procedure has no clear path so there are several obstacles in the actual functional variant that is often unknown. This may be due to:
trait/disease associated SNPs (TASs),
a well known SNP+ strong linkage disequilibrium (LD) with the TAS,
an unknown common SNP tagged by a haplotype
rare single nucleotide variant tagged by a haplotype on which the TAS occurs, or
Copy Number variation (CNV), a linked copy number variant.
There can be other factors such as
Evolution,
Natural Selection
Environment
Pedigree
Epigenetics
Even though heritage is another big factor, the concept of heritability and its definition as an estimable, dimensionless population parameter as introduced by Sewall Wright and Ronald Fisher almost a century ago.
As a result, heritability gain interest since it allows us to compare of the relative importance of genes and environment to the variation of traits within and across populations. The heritability is an ongoing mechanism and remains as a key:
to selection in evolutionary biology and agriculture, and
to the prediction of disease risk in medicine.
Table 1.
Reported TASs associated with two or more distinct traits
Chromosomal region
Rs number(s)
Attributed genes
Associated traits reported in catalog
1p13.2
rs2476601, rs6679677
PTPN22
Crohn’s disease, type 1 diabetes, rheumatoid arthritis
* The well known association of JAZF1 with prostate cancer was reported with a p value of 2 × 10−6 (18), which did not meet the threshold of 5 × 10−8 for this analysis.
aCJD = Creutzfeldt-Jacob disease; DVT = deep venous thrombosis; HFE = hemochromatosis; T1DM = type I diabetes; T2DM = type II diabetes.
bThe associated allele is the SNP associated with disease, regardless of whether it is the derived or the ancestral allele. The frequencies for this allele are given.
cThe reference that claims this to be a reproducible association, as well as the reference from which the allele frequencies were taken. For allele frequencies obtained from a meta-analysis, only the reference claiming reproducible association is given.
dAllele frequency obtained from the literature involving a European population. Either the general population frequency or the frequency in control groups in an association study was used. To reduce bias, when a control frequency was used for Europeans, a control frequency was also used for Africans. The total number of chromosomes surveyed is given in parentheses after each frequency.
eAllele frequency obtained from the literature involving a West African population. The total number of chromosomes surveyed is given in parentheses after each frequency.
fδ = The difference in the allele frequency between Europeans and Africans.
aAD = Alzheimer disease; AIDS = acquired immunodeficiency syndrome; ARDS = acute respiratory distress syndrome; CAD = coronary artery disease; Hp = Helicobacter pylori; MI = myocardial infarction; MS = multiple sclerosis; RA = rheumatoid arthritis; RSV = respiratory syncytial virus; SCD = sickle cell disease.
bThe associated allele is the SNP associated with disease, regardless of whether it is the derived or the ancestral allele. The frequencies for this allele are given.
cThe reference that reported association with the listed disease/phenotype.
dFrequency obtained from the Seattle SNPs database for the European sample. The total number of chromosomes surveyed is given in parentheses after each frequency.
eFrequency obtained from the Seattle SNPs database for the African American sample. The total number of chromosomes surveyed is given in parentheses after each frequency.
fδ = The difference in the allele frequency between African Americans and Europeans.
gAssociated allele in database is A.
hAssociated allele in reference is A.
iThis SNP was not from the Seattle SNPs database; instead, allele frequencies from Begovich et al. (2004) were used.
They reported that “The SNPs associated with common disease that we investigated do not show much higher levels of differentiation than those of random SNPs. Thus, in these cases, ethnicity is a poor predictor of an individual’s genotype, which is also the pattern for random variants in the genome. This lends support to the hypothesis that many population differences in disease risk are environmental, rather than genetic, in origin. However, some exceptional SNPs associated with common disease are highly differentiated in frequency across populations, because of either a history of random drift or natural selection. The exceptional SNPs are located in AGT, DRD3, ALOX5AP, ICAM1, IL1B, IL4, IL6, IL8, and PON1. Of note, evidence of selection has been observed for AGT (Nakajima et al. 2004), IL4(Rockman et al. 2003), IL8 (Hull et al. 2001), and PON1 (Allebrandt et al. 2002). Yet, for the vast majority of the common-disease–associated polymorphisms we examined, ethnicity is likely to be a poor predictor of an individual’s genotype.”
In 2002The International HapMap Project was launched:
to provide a public resource
to accelerate medical genetic research.
Two Hapmap projects were completed. In phase I the objective was to genotype at least one common SNP every 5 kilobases (kb) across the euchromatic portion of the genome in 270 individuals from four geographically diverse population. In Phase II of the HapMap Project, a further 2.1 million SNPs were successfully genotyped on the same individuals.
The re-mapping of SNPs from Phase I of the project identified 21,177 SNPs that had an ambiguous position or some other feature indicative of low reliability; these are not included in the filtered Phase II data release. All genotype data are available from the HapMap Data Coordination Center (http://www.hapmap.org) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP).
In the Phase II HapMap we identified 32,996 recombination hotspots3,6,36 (an increase of over 50% from Phase I) of which 68% localized to a region of≤5 kb. The median map distance induced by a hotspot is 0.043 cM (or one crossover per 2,300 meioses) and the hottest identified, on chromosome 20, is 1.2 cM (one crossover per 80 meioses). Hotspots account for approximately 60% of recombination in the human genome and about 6% of sequence (Supplementary Fig. 6).
In addition to many previously identified regions in HapMap Phase I including LARGE, SYT1 andSULT1C2 (previously called SULT1C1), about 200 regions identified from the Phase II HapMap that include many established cases of selection, such as the genes HBB andLCT, the HLA region, and an inversion on chromosome 17. Finally, in the future, whole-genome sequencing will provide a natural convergence of technologies to type both SNP and structural variation. Nevertheless, until that point, and even after, the HapMap Project data will provide an invaluable resource for understanding the structure of human genetic variation and its link to phenotype.
FUNCTIONAL GENOMICS AND DATA FOR MEDICINE: BIOINFORMATICS/COMPUTER BIOLOGY
HMM libraries, such as PANTHER, Pfam, and SMART, are used primarily to recognize and annotate conserved motifs in protein sequences.
In the genomic era, one of the fundamental goals is to characterize the function of proteins on a large scale.
PANTHER, for relating protein sequence relationships to function relationships in a robust and accurate way under two main parts:
the PANTHER library (PANTHER/LIB)- collection of “books,” each representing a protein family as a multiple sequence alignment, a Hidden Markov Model (HMM), and a family tree.
the PANTHER index (PANTHER/X)- ontology for summarizing and navigating molecular functions and biological processes associated with the families and subfamilies.
PANTHER can be applied on three areas of active research:
to report the size and sequence diversity of the families and subfamilies, characterizing the relationship between sequence divergence and functional divergence across a wide range of protein families.
use the PANTHER/X ontology to give a high-level representation of gene function across the human and mouse genomes.
to rank missense single nucleotide polymorphisms (SNPs), on a database-wide scale, according to their likelihood of affecting protein function.
PRINTS is a compendium of protein motif ‘fingerprints’. A fingerprint is defined as a group of motifs excised from conserved regions of a sequence alignment, whose diagnostic power or potency is refined by iterative databasescanning (in this case the OWL composite sequence database).
The information contained within PRINTS is distinct from, but complementary to the consensus expressions stored in the widely-used PROSITE dictionary of patterns.
However, the position-specific amino acid probabilities in an HMM can also be used to annotate individual positions in a protein as being conserved (or conserving a property such as hydrophobicity) and therefore likely to be required for molecular function. For example, a mutation (or variant) at a conserved position is more likely to impact the function of that protein.
In addition, HMMs from different subfamilies of the same family can be compared with each other, to provide hypotheses about which residues may mediate the differences in function or specificity between the subfamilies.
Several computational algorithms and databases for comparing protein sequences developed and matured:
The profile has a different amino acid substitution vector at each position in the profile, based on the pattern of amino acids observed in a multiple alignment of related sequences.
Profile methods combine algorithms with databases: A group of related sequences is used to build a statistical representation of corresponding positions in the related proteins. The power of these methods therefore increases as new sequences are added to the database of known proteins.
Multiple sequence alignments (Dayhoff et al. 1974) and profiles have allowed a systematic study of related sequences. One of the key observations is that some positions are “conserved,” that is, the amino acid is invariant or restricted to a particular property (such as hydrophobicity), across an entire group of related sequences.
The dependence of profile and pattern-matching approaches (Jongeneel et al. 1989) on sequence databases led to the development of databases of profiles
SMART (Schultz et al. 1998;Letunic et al. 2002), which combine expert analysis with the well-developed HMM formalism for statistical modeling of protein families (mostly families of related protein domains).
Either knowing its family membership to predict its function, or subfamily within that family is enough (Hannenhalli and Russell 2000).
Phylogenetic trees (representing the evolutionary relationships between sequences) and
The PANTHER/LIB HMMs can be viewed as a statistical method for scoring the “functional likelihood” of different amino acid substitutions on a wide variety of proteins. Because it uses evolutionarily related sequences to estimate the probability of a given amino acid at a particular position in a protein, the method can be referred to as generating “position-specific evolutionary conservation” (PSEC) scores.
Schematic illustration of the process for building PANTHER families.
Family clustering.
Multiple sequence alignment (MSA), family HMM, and family tree building.
Family/subfamily definition and naming.
Subfamily HMM building.
Molecular function and biological process association.
Of these, steps 1, 2, and 4 are computational, and steps 3 and 5 are human-curated (with the extensive aid of software tools).
Altschul, S.F., Madden, T.L., Schäffer, A.A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D.J. 1997. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res. 25: 3389–3402.
Bateman, A., Birney, E., Cerruti, L., Durbin, R., Etwiller, L., Eddy, S.R., Griffiths-Jones, S., Howe, K.L., Marshall, M., and Sonnhammer, E.L. 2002. The Pfam protein families database. Nucleic Acids Res. 30: 276–280.
Green R, Krause J, Briggs A, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz M. et al. A Draft Sequence of the Neanderthal Genome. Science. 2010;328:710–722. doi: 10.1126/science.1188021.
Views of Content Presentations – Track One @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA, January 26 to January 28, 2015
8:30AM–12:00PM, January 28, 2015 – Morality, Ethics & Public Law in PM, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
2:00PM–5:00PM, January 27, 2015 – Personalizing Evidence in the Learning Healthcare System & Biomarker Discovery Technologies, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
9:15AM–2:00PM, January 27, 2015 – Regulatory & Reimbursement Frameworks for Molecular Testing, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
3:30PM –5:15PM, January 26, 2015 – NGS Applications: Impact of Genomics on Cancer Care @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
1:00PM – 1:15PM, January 26, 2015 – Clinical Methodologies of NGS – LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
10:30AM-12PM, January 26, 2015 – NGS Applications: Impact of Genomics on Cancer Care – LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
1:00PM 11/13/2014 – Panel Discussion Genomics in Prenatal and Childhood Disorders @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:30AM 11/13/2014 – Role of Genetics and Genomics in Pharmaceutical Development @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:00AM 11/13/2014 – Welcome from Gary Gottlieb, M.D., Partners HealthCare @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
4:00PM 11/12/2014 – Panel Discussion Novel Approaches to Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
1:15PM 11/12/2014 – Keynote Speaker – International Genetics Health and Disease @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:30AM 11/12/2014 – Personalized Medicine Coalition Award & Award Recipient Speech @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:00AM 11/12/2014 – Keynote Speaker – Past, Present and Future of Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:50AM 11/12/2014 – Keynote Speaker – CEO, American Medical Association @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:20AM 11/12/2014 – Special Guest Keynote Speaker – The Future of Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
10th Annual Personalized Medicine Conference at the Harvard Medical School, November 12-13, 2014, The Joseph B. Martin Conference Center at Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA
Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center
Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com
The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference,11/28-29, 2012, Harvard Medical School, Boston, MA
GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”
AGENDA – Personalized Diagnostics, February 16-18, 2015 | Moscone North Convention Center | San Francisco, CA Part of the 22nd Annual Molecular Medicine Tri-Conference
attn #3: Investors in HealthCare — Platforms in the Ecosystem of Regulatory & Reimbursement – Integrated Informational Platforms in Orthopedic Medical Devices, and Global Peer-Reviewed Scientific Curations: Bone Disease and Orthopedic Medicine –Draft
Multi-drug, Multi-arm, Biomarker-driven Clinical Trial for patients with Squamous Cell Carcinoma called the Lung Cancer Master Protocol, or Lung-MAP launched by NCI, Foundation Medicine, and Five Pharma Firms
Precision Medicine for Future of Genomics Medicine is The New Era
Demet Sag, PhD, CRA, GCP
Are we there yet? Life is a journey so the science.
Governor Brown announced Precision Medicine initiative for California on April 14, 2015. UC San Francisco is hosting the two-year initiative, through UC Health, which includes UC’s five medical centers, with $3 million in startup funds from the state. The public-private initiative aims to leverage these funds with contributions from other academic and industry partners.
With so many campuses spread throughout the state and so much scientific, clinical and computational expertise, the UC system has the potential to bring it all together, said Atul Butte, MD, PhD, who is leading the initiative.
At the beginning of 2015 President Obama signed this initiative and assigned people to work on this project.
Previously NCI Director Harold Varmus, MD said that “Precision medicine is really about re-engineering the diagnostic categories for cancer to be consistent with its genomic underpinnings, so we can make better choices about therapy,” and “In that sense, many of the things we’re proposing to do are already under way.”
The proposed initiative has two main components:
a near-term focus on cancers and
a longer-term aim to generate knowledge applicable to the whole range of health and disease.
Both components are now within our reach because of advances in basic research, including molecular biology, genomics, and bioinformatics. Furthermore, the initiative taps into converging trends of increased connectivity, through social media and mobile devices, and Americans’ growing desire to be active partners in medical research.
Since the human genome is sequenced it became clear that actually there are few genes than expected and shared among organisms to accomplish same or similar core biological functions. As a result, knowledge of the biological role of such shared proteins in one organism can be transferred to another organism.
I remember when I was screening the X-chromosome by using deletion/duplication mapping and using P elements and bar balancers as a tool to keep the genome stable to identify transregulating elements of ovo gene, female germline specific Drosophila melanogaster germline sex determination gene. At the time for my dissertation, I screened X-chromosome using 45 deficiency strains, I found that these trans-regulating regions were grouped into 12 loci based on overlapping cytology. Five regions were trans-regulating activators, and seven were trans-regulating repressors; extrapolating to the entire genome, this result predicted nearly 85 loci. This one gene may expressed three proteins at different time of development and activate/downregulate various regions to accommadate proper system development in addition to auto-regulate and gene dose responses. Drosophila has only four chromosomes but the cellular interactions and signaling mechanisms are still complicated yet as not complicated as human. I do appreciate the new applications and upcoming changes.
Now, the technology is much better and precision is the key to establish to use in clinics. However, we have new issues to overcome like computing such a big data, align properly, analyze effectively, compare and contrast the outcomes to identify the variations that may function in on population, or two etc. At the end of the day collaboration, standardization, and data sharing are few of the key factors.
It is necessary to generate a dynamic yet controlled standardized collection of information with ever changing and accumulating data so Gene Ontology Consortium is created. Three independent ontologies can be reached at (http://www.geneontology.org) developed based on :
biological process,
molecular function and
cellular component.
We need a common language for annotation for a functional conservation. Genesis of the grand biological unification made it possible to complete the genomic sequences of not only human but also the main model organisms and more. some examples include:
the budding yeast, Saccharomyces cerevisiae,
the nematode worm Caenorhabditis elegans
the fruitfly Drosophila melanogaster,
the flowering plant Arabidopsis thaliana
fission yeast Schizosaccharomyces pombe
the mouse , Mus musculus
On the other hand, as we know there are allelic variations that underlie common diseases and complete genome sequencing for many individuals with and without disease is required. However, there are advantages and disadvantages as we can carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies but there are problems such as computing the data efficiently and sharing the information without tempering privacy. Therefore we should be mindful about few main conditions including:
models of the allelic architecture of common diseases,
sample size,
map density and
sample-collection biases.
This will lead into the cost control and efficiency while identifying genuine disease-susceptibility loci. The genome-wide association studies (GWAS) have progressed from assaying fewer than 100,000 SNPs to more than one million, and sample sizes have increased dramatically as the search for variants that explain more of the disease/trait heritability has intensified.
In addition, we must translate this sequence information from genomics locus of the genes to function with related polymorphism of these genes so that possible patterns of the gene expression and disease traits can be matched. Then, we may develop precision technologies for:
Diagnostics
Targeted Drugs and Treatments
Biomarkers to modulate cells for correct functions
With the knowledge of:
gene expression variations
insight in the genetic contribution to clinical endpoints ofcomplex disease and
their biological risk factors,
share etiologic pathways
therefore, requires an understanding of both:
the structure and
the biology of the genome.
These studies demonstrated hundreds of associations of common genetic variants with over 80 diseases and traits collected under a controlled online resource. However, identifying published GWAS can be challenging as a simple PubMed search using the words “genome wide association studies” may be easily populated with unrelevant GWAS.
National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (http://www.genome.gov/gwastudies), an online, regularly updated database of SNP-trait associations extracted from published GWAS was developed.
Therefore, sequencing of a human genome is a quite undertake and requires tools to make it possible:
to explore the genetic component in complex diseases and
to fully understand the genetic pathways contributing to complex disease
The rapid increase in the number of GWAS provides an unprecedented opportunity to examine the potential impact of common genetic variants on complex diseases by systematically cataloging and summarizing key characteristics of the observed associations and the trait/disease associated SNPs (TASs) underlying them.
With this in mind, many forms can be established:
to describe the features of this resource and the methods we have used to produce it,
to provide and examine key descriptive characteristics of reported TASs such as estimated risk allele frequencies and odds ratios,
to examine the underlying functionality of reported risk loci by mapping them to genomic annotation sets and assessing overrepresentation via Monte Carlo simulations and
to investigate the relationship between recent human evolution and human disease phenotypes.
This procedure has no clear path so there are several obstacles in the actual functional variant that is often unknown. This may be due to:
trait/disease associated SNPs (TASs),
a well known SNP+ strong linkage disequilibrium (LD) with the TAS,
an unknown common SNP tagged by a haplotype
rare single nucleotide variant tagged by a haplotype on which the TAS occurs, or
Copy Number variation (CNV), a linked copy number variant.
There can be other factors such as
Evolution,
Natural Selection
Environment
Pedigree
Epigenetics
Even though heritage is another big factor, the concept of heritability and its definition as an estimable, dimensionless population parameter as introduced by Sewall Wright and Ronald Fisher almost a century ago.
As a result, heritability gain interest since it allows us to compare of the relative importance of genes and environment to the variation of traits within and across populations. The heritability is an ongoing mechanism and remains as a main factor:
to selection in evolutionary biology and agriculture, and
to the prediction of disease risk in medicine.
Reported TASs associated with two or more distinct traits
Chromosomal region
Rs number(s)
Attributed genes
Associated traits reported in catalog
1p13.2
rs2476601, rs6679677
PTPN22
Crohn’s disease, type 1 diabetes, rheumatoid arthritis
* The well known association of JAZF1 with prostate cancer was reported with a p value of 2 × 10−6, which did not meet the threshold of 5 × 10−8 for this analysis.
aCJD = Creutzfeldt-Jacob disease; DVT = deep venous thrombosis; HFE = hemochromatosis; T1DM = type I diabetes; T2DM = type II diabetes.
bThe associated allele is the SNP associated with disease, regardless of whether it is the derived or the ancestral allele. The frequencies for this allele are given.
cThe reference that claims this to be a reproducible association, as well as the reference from which the allele frequencies were taken. For allele frequencies obtained from a meta-analysis, only the reference claiming reproducible association is given.
dAllele frequency obtained from the literature involving a European population. Either the general population frequency or the frequency in control groups in an association study was used. To reduce bias, when a control frequency was used for Europeans, a control frequency was also used for Africans. The total number of chromosomes surveyed is given in parentheses after each frequency.
eAllele frequency obtained from the literature involving a West African population. The total number of chromosomes surveyed is given in parentheses after each frequency.
fδ = The difference in the allele frequency between Europeans and Africans.
aAD = Alzheimer disease; AIDS = acquired immunodeficiency syndrome; ARDS = acute respiratory distress syndrome; CAD = coronary artery disease; Hp = Helicobacter pylori; MI = myocardial infarction; MS = multiple sclerosis; RA = rheumatoid arthritis; RSV = respiratory syncytial virus; SCD = sickle cell disease.
bThe associated allele is the SNP associated with disease, regardless of whether it is the derived or the ancestral allele. The frequencies for this allele are given.
cThe reference that reported association with the listed disease/phenotype.
dFrequency obtained from the Seattle SNPs database for the European sample. The total number of chromosomes surveyed is given in parentheses after each frequency.
eFrequency obtained from the Seattle SNPs database for the African American sample. The total number of chromosomes surveyed is given in parentheses after each frequency.
fδ = The difference in the allele frequency between African Americans and Europeans.
gAssociated allele in database is A.
hAssociated allele in reference is A.
iThis SNP was not from the Seattle SNPs database; instead, allele frequencies from Begovich et al. (2004) were used.
They reported that “The SNPs associated with common disease that we investigated do not show much higher levels of differentiation than those of random SNPs. Thus, in these cases, ethnicity is a poor predictor of an individual’s genotype, which is also the pattern for random variants in the genome. This lends support to the hypothesis that many population differences in disease risk are environmental, rather than genetic, in origin. However, some exceptional SNPs associated with common disease are highly differentiated in frequency across populations, because of either a history of random drift or natural selection. The exceptional SNPs given are located in AGT, DRD3, ALOX5AP, ICAM1, IL1B, IL4, IL6, IL8, and PON1.
Of note, evidence of selection has been observed for AGT (Nakajima et al. 2004), IL4(Rockman et al. 2003), IL8 (Hull et al. 2001), and PON1 (Allebrandt et al. 2002). Yet, for the vast majority of the common-disease–associated polymorphisms we examined, ethnicity is likely to be a poor predictor of an individual’s genotype.”
In 2002 the International HapMap Project was launched:
to provide a public resource
to accelerate medical genetic research.
Two Hapmap projects were completed.
In phase I the objective was to genotype at least one common SNP every 5 kilobases (kb) across the euchromatic portion of the genome in 270 individuals from four geographically diverse population.
In Phase II of the HapMap Project, a further 2.1 million SNPs were successfully genotyped on the same individuals.
The re-mapping of SNPs from Phase I of the project identified 21,177 SNPs that had an ambiguous position or some other feature indicative of low reliability. These are not included in the filtered Phase II data release. All genotype data are available from the HapMap Data Coordination Center located at (http://www.hapmap.org) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP).
In the Phase II HapMap we identified 32,996 recombination hotspots (an increase of over 50% from Phase I) of which 68% localized to a region of≤5 kb. The median map distance induced by a hotspot is 0.043 cM (or one crossover per 2,300 meioses) and the hottest identified, on chromosome 20, is 1.2 cM (one crossover per 80 meioses). Hotspots account for approximately 60% of recombination in the human genome and about 6% of sequence.
In addition to many previously identified regions in HapMap Phase I including LARGE, SYT1 andSULT1C2 (previously called SULT1C1), about 200 regions identified from the Phase II HapMap that include many established cases of selection, such as the genes HBB andLCT, the HLA region, and an inversion on chromosome 17. Finally, in the future, whole-genome sequencing will provide a natural convergence of technologies to type both SNP and structural variation. Nevertheless, until that point, and even after, the HapMap Project data will provide an invaluable resource for understanding the structure of human genetic variation and its link to phenotype.
HMM libraries, such as PANTHER, Pfam, and SMART, are used primarily
to recognize and
to annotate conserved motifs in protein sequences.
In the genomic era, one of the fundamental goals is to characterize the function of proteins on a large scale.
PANTHER, for relating protein sequence relationships to function relationships in a robust and accurate way under two main parts:
the PANTHER library(PANTHER/LIB)- collection of “books,” each representing a protein family as a multiple sequence alignment, a Hidden Markov Model (HMM), and a family tree.
the PANTHER index (PANTHER/X)- ontology for summarizing and navigating molecular functions and biological processes associated with the families and subfamilies.
PANTHER can be applied on three areas of active research:
to report the size and sequence diversity of the families and subfamilies, characterizing the relationship between sequence divergence and functional divergence across a wide range of protein families.
use the PANTHER/X ontology to give a high-level representation of gene function across the human and mouse genomes.
to rank missense single nucleotide polymorphisms (SNPs), on a database-wide scale, according to their likelihood of affecting protein function.
PRINTS is ” a compendium of protein motif ‘fingerprints’. A fingerprint is defined as a group of motifs excised from conserved regions of a sequence alignment, whose diagnostic power or potency is refined by iterative databasescanning (in this case the OWL composite sequence database)”.
The information contained within PRINTS is distinct from, but complementary to the consensus expressions stored in the widely-used PROSITE dictionary of patterns.
However, the position-specific amino acid probabilities in an HMM can also be used to annotate individual positions in a protein as being conserved (or conserving a property such as hydrophobicity) and therefore likely to be required for molecular function. For example, a mutation (or variant) at a conserved position is more likely to impact the function of that protein.
In addition, HMMs from different subfamilies of the same family can be compared with each other, to provide hypotheses about which residues may mediate the differences in function or specificity between the subfamilies.
The profile has a different amino acid substitution vector at each position in the profile, based on the pattern of amino acids observed in a multiple alignment of related sequences.
Profile methods combine algorithms with databases:
A group of related sequences is used to build a statistical representation of corresponding positions in the related proteins. The power of these methods therefore increases as new sequences are added to the database of known proteins.
Multiple sequence alignments (Dayhoff et al. 1974) and profiles have allowed a systematic study of related sequences. One of the key observations is that some positions are “conserved,” that is, the amino acid is invariant or restricted to a particular property (such as hydrophobicity), across an entire group of related sequences.
The dependence of profile and pattern-matching approaches (Jongeneel et al. 1989) on sequence databases led to the development of databases of profiles
SMART (Schultz et al. 1998;Letunic et al. 2002), which combine expert analysis with the well-developed HMM formalism for statistical modeling of protein families (mostly families of related protein domains).
Either knowing its family membership to predict its function, or subfamily within that family is enough (Hannenhalli and Russell 2000).
Phylogenetic trees (representing the evolutionary relationships between sequences) and
The PANTHER/LIB HMMs can be viewed as a statistical method for scoring the “functional likelihood” of different amino acid substitutions on a wide variety of proteins. Because it uses evolutionarily related sequences to estimate the probability of a given amino acid at a particular position in a protein, the method can be referred to as generating “position-specific evolutionary conservation” (PSEC) scores.
The process for building PANTHER families include:
Family clustering.
Multiple sequence alignment (MSA), family HMM, and family tree building.
Family/subfamily definition and naming.
Subfamily HMM building.
Molecular function and biological process association.
Of these, steps 1, 2, and 4 are computational, and steps 3 and 5 are human-curated (with the extensive aid of software tools).
Conclusion:
Precision medicine effort is the beginning of a new journey to provide better health solutions.
Altschul, S.F., Madden, T.L., Schäffer, A.A., Zhang, J., Zhang, Z., Miller, W., and Lipman, D.J. 1997. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res. 25: 3389–3402.
Bateman, A., Birney, E., Cerruti, L., Durbin, R., Etwiller, L., Eddy, S.R., Griffiths-Jones, S., Howe, K.L., Marshall, M., and Sonnhammer, E.L. 2002. The Pfam protein families database. Nucleic Acids Res. 30: 276–280.
Green R, Krause J, Briggs A, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz M. et al. A Draft Sequence of the Neanderthal Genome. Science. 2010;328:710–722. doi: 10.1126/science.1188021.
Views of Content Presentations – Track One @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA, January 26 to January 28, 2015
8:30AM–12:00PM, January 28, 2015 – Morality, Ethics & Public Law in PM, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
2:00PM–5:00PM, January 27, 2015 – Personalizing Evidence in the Learning Healthcare System & Biomarker Discovery Technologies, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
9:15AM–2:00PM, January 27, 2015 – Regulatory & Reimbursement Frameworks for Molecular Testing, LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
3:30PM –5:15PM, January 26, 2015 – NGS Applications: Impact of Genomics on Cancer Care @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
1:00PM – 1:15PM, January 26, 2015 – Clinical Methodologies of NGS – LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
10:30AM-12PM, January 26, 2015 – NGS Applications: Impact of Genomics on Cancer Care – LIVE @Silicon Valley 2015 Personalized Medicine World Conference, Mountain View, CA
1:00PM 11/13/2014 – Panel Discussion Genomics in Prenatal and Childhood Disorders @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:30AM 11/13/2014 – Role of Genetics and Genomics in Pharmaceutical Development @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:00AM 11/13/2014 – Welcome from Gary Gottlieb, M.D., Partners HealthCare @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
4:00PM 11/12/2014 – Panel Discussion Novel Approaches to Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
1:15PM 11/12/2014 – Keynote Speaker – International Genetics Health and Disease @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:30AM 11/12/2014 – Personalized Medicine Coalition Award & Award Recipient Speech @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
11:00AM 11/12/2014 – Keynote Speaker – Past, Present and Future of Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:50AM 11/12/2014 – Keynote Speaker – CEO, American Medical Association @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
8:20AM 11/12/2014 – Special Guest Keynote Speaker – The Future of Personalized Medicine @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston
10th Annual Personalized Medicine Conference at the Harvard Medical School, November 12-13, 2014, The Joseph B. Martin Conference Center at Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA
Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center
Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com
The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference,11/28-29, 2012, Harvard Medical School, Boston, MA
GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”
AGENDA – Personalized Diagnostics, February 16-18, 2015 | Moscone North Convention Center | San Francisco, CA Part of the 22nd Annual Molecular Medicine Tri-Conference
attn #3: Investors in HealthCare — Platforms in the Ecosystem of Regulatory & Reimbursement – Integrated Informational Platforms in Orthopedic Medical Devices, and Global Peer-Reviewed Scientific Curations: Bone Disease and Orthopedic Medicine –Draft
Multi-drug, Multi-arm, Biomarker-driven Clinical Trial for patients with Squamous Cell Carcinoma called the Lung Cancer Master Protocol, or Lung-MAP launched by NCI, Foundation Medicine, and Five Pharma Firms
Gene engineering and editing specifically are becoming more attractive. There are many applications derived from microbial origins to correct genomes in many organisms including human to find solutions in health.
There are four customizable DNA specific binding protein applications to edit the gene expression in translational genomics. The targeted DNA double-strand breaks (DSBs) could greatly stimulate genome editing through HR-mediated recombination events. We can mainly name these site-specific DNA DSBs:
meganucleases derived from microbial mobile genetic elements (Smith et al., 2006),
most recently the RNA-guided DNA endonuclease Cas9 from the type II bacterial adaptive immune system CRISPR (Cong et al., 2013;Mali et al., 2013a).
There is a new ground breaking study published in Science by Valentino Gantz and Ethan Bier of the University of California, San Diego, described an approach called mutagenic chain reaction (MCR).
This group developed a new technology for editing genes that can be transferable change to the next generation by combining microbial immune defense mechanism, CRISPR/Cas9 that is the latest ground breaking technology for translational genomics with gene therapy-like approach.
In short, this so-called “mutagenic chain reaction” (MCR) introduces a recessive mutation defined by CRISPR/Cas9 that lead into a high rate of transferable information to the next generation. They reported that when they crossed the female MCR offspring to wild type flies, the yellow phenotype observed more than 95 percent efficiency.
Structural and Metagenomic Diversity of Cas9 Orthologs
(A) Crystal structure of Streptococcus pyogenes Cas9 in complex with guide RNA and target DNA.
(B) Canonical CRISPR locus organization from type II CRISPR systems, which can be classified into IIA-IIC based on their cas gene clusters. Whereas type IIC CRISPR loci contain the minimal set of cas9, cas1, andcas2, IIA and IIB retain their signature csn2 and cas4 genes, respectively.
(C) Histogram displaying length distribution of known Cas9 orthologs as described in UniProt, HAMAP protein family profile MF_01480.
(D) Phylogenetic tree displaying the microbial origin of Cas9 nucleases from the type II CRISPR immune system. Taxonomic information was derived from greengenes 16S rRNA gene sequence alignment, and the tree was visualized using the Interactive Tree of Life tool (iTol).
(E) Four Cas9 orthologs from families IIA, IIB, and IIC were aligned by ClustalW (BLOSUM). Domain alignment is based on the Streptococcus pyogenes Cas9, whereas residues highlighted in red indicate highly conserved catalytic residues within the RuvC I and HNH nuclease domains.
There is a big difference between the new type of mutation and traditional mutation is expressivity of the character since previously mutations were passive and non-transferable at 100% rate. However, in classical Mendelian Genetics, only one fourth f the recessive traits can be presented in new generation. Yet, in this case this can be achieve about 97% plus transferred to new generation.
MCR alterations is active that is they convert matching sequences at the same target site so mutated sites took over the wild type character without degenerating by wild type alleles segregating independently during the breeding process
Therefore, the altered sequences routinely replace the wild type (original) sequences at that site. The data demonstrated that among 92 flies, only one female became wild type but remaining 41 females had yellow eyes yet all 50 males showed wild type eye coloring at the second generation.
The genetic engineering of the genome occurred in a single generation with high efficiency.
Their technique developed by Gantz and Bier had three basic parts:
Both somatic and germline cells expressed a Cas9 gene,
A guide RNA (gRNA) targeted to a genomic sequence of interest,
The Cas9/gRNA cassettes have the flanking homolog arms that matches the two genomic sequences immediately adjacent to either side of the target cut site
There are many applications in translational genomics that requires multiple steps to make it perfect for complicated organisms, such as plants, mosquitoes and human diseases.
Short Walk from Past to the Future of CRISPR/Cas9
The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats(CRISPR)adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA.
CRISPR/Cas systems are part of the adaptive immune system of bacteria and archaea, protecting them against invading nucleic acids such as viruses by cleaving the foreign DNA in a sequence-dependent manner.
The latest ground-breaking technology for genome editing is based on RNA-guided engineered nucleases, which already hold great promise due to their:
simplicity,
efficiency and
versality
Although CRISPR arrays were first identified in the Escherichia coli genome in 1987 (Ishino et al., 1987),
their biological function was not understood until 2005, when it was shown that the spacers were homologous to viral and plasmid sequences suggesting a role in adaptive immunity (Bolotin et al., 2005; Mojica et al., 2005; Pourcel et al., 2005).
Two years later, CRISPR arrays were confirmed to provide protection against invading viruses when combined with Cas genes (Barrangou et al., 2007).
The mechanism of this immune system based on RNA-mediated DNA targeting was demonstrated shortly thereafter (Brounset al., 2008; Deltcheva et al., 2011; Garneau et al., 2010; Marraffini and Sontheimer, 2008).
The most widely used system is the type II clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 (CRISPR-associated) system from Streptococcus pyogenes (Jinek et al., 2012).
Then, five independent groups demonstrated that the two-component system was functional in eukaryotes (human, mouse and zebrafish), indicating that the other functions of the CRISPR locus genes were supported by endogenous eukaryotic enzymes (Cho et al., 2013, Cong et al., 2013, Hwang et al., 2013, Jinek et al., 2013 and Mali et al., 2013).
Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified colonial cell lines can be derived within 2-3 weeks
Genome editing with site-specific nucleases.
Double-strand breaks induced by a nuclease at a specific site can be repaired either by non-homologous end joining (NHEJ) or homologous recombination (HR). In most cases, NHEJ causes random insertions or deletions (indels), which can result in frameshift mutations if they occur in the coding region of a gene, effectively creating a gene knockout.
Alternatively, when the DSB generates overhangs, NHEJ can mediate the targeted introduction of a double-stranded DNA template with compatible overhangs
Even though the generation of breaks in both DNA strands induces recombination at specific genomic loci, NHEJ is by far the most common DSB repair mechanism in most organisms, including higher plants, and the frequency of targeted integration by HR remains much lower than random integration.
Unlike its predecessors, the CRISPR/Cas9 system does not require any protein engineering steps, making it much more straightforward to test multiple gRNAs for each target gene
Unlike ZFNs and TALENs, the CRISPR/Cas9 system can cleave methylated DNA in human cells (Hsu et al., 2013), allowing genomic modifications that are beyond the reach of the other nucleases (Ding et al., 2013).
The main practical advantage of CRISPR/Cas9 compared to ZFNs and TALENs is the ease of multiplexing. The simultaneous introduction of DSBs at multiple sites can be used to edit several genes at the same time (Li et al., 2013; Mao et al., 2013) and can be particularly useful to knock out redundant genes or parallel pathways.
Finally, the open access policy of the CRISPR research community has promoted the widespread uptake and use of this technology in contrast, for example, to the proprietary nature of the ZFN platform.
The community provides access to plasmids (e.g., via the non-profit repository Addgene), web tools for selecting gRNA sequences and predicting specificity:
hosts active discussion groups (e.g.: https://groups.google. com/forum/#!forum/crispr).
Downside:
One area that will likely need to be addressed when moving to more complex genomes, for instance, is off-target CRISPR/Cas9 activity since fruit fly has only four chromosomes and less likely to have off-target effects. However, this study provided proof of principle.
Yet, this critics is not new since one of the few criticisms of the CRISPR/Cas9 technology is the relatively high frequency of off-target mutations reported in some of the earlier studies (Cong et al., 2013; Fu et al., 2013; Hsu et al., 2013; Jiang et al., 2013a; Mali et al., 2013; Pattanayak et al., 2013).
Several strategies have been developed to reduce off-target genome editing, the most important of which is the considered design of the gRNA.
fusions of catalytically inactive Cas9 and FokI nuclease have been generated, and these show comparable efficiency to the nickases but substantially higher (N140-fold) specificity than the wild-type enzyme (Guilinger et al., 2014; Tsai et al., 2014)
Altering the length of the gRNA can also minimize non-target modifications. Guide RNAs with two additional guanidine residues at the 5′ end were able to avoid off-target sites more efficiently than normal gRNAs but were also slightly less active at on-target sites (Cho et al., 2014)
What more:
The CRISPR/Cas9 system can be used for several purposes in addition to genome editing:
The ectopic regulation of gene expression, which can provide useful information about gene functions and can also be used to engineer novel genetic regulatory circuits for synthetic biology applications.
The external control of gene expression typically relies on the use of inducible or repressible promoters, requiring the introduction of a new promoter and a particular treatment (physical or chemical) for promoter activation or repression.
Disabled nucleases can be used to regulate gene expression because they can still bind to their target DNA sequence. This is the case with the catalytically inactive version of Cas9 which is known as dead Cas9 (dCas9).
Preparing the host for an immunotherapy is possible if it is combined with TLR mechanism:
On the other hand, the host mechanism needs to be review carefully for the design of an effective outcome.
The mechanism of microbial response and infectious tolerance are complex.
During microbial responses, Toll-like receptors (TLRs) play a role to differentiate and determine the microbial structures as a ligand to initiate production of cytokines and pro-inflammatory agents to activate specific T helper cells.
Uniqueness of TLR comes from four major characteristics of each individual TLR :
ligand specificity,
signal transduction pathways,
expression profiles and
cellular localization.
Thus, TLRs are important part of the immune response signaling mechanism to initiate and design adoptive responses from innate (naïve) immune system to defend the host.
TLRs are expressed cell type specific patterns and present themselves on APCs (DCs, MQs, monocytes) with a rich expression levels Specific TLR stimulat ion links innate and acquired responses through simple recognition of pathogen-associated molecular patterns (PAMPs) or co-stimulation of PAMPs with other TLR or non-TLR receptors, or even better with proinflammatory cytokines.
Some examples of ligand – TLR specificity shown in Table1, which are bacterial lipopeptides, Pam3Cys through TLR2, double stranded (ds) RNAs through TLR3, lipopolysaccharide (LPS) through TLR4, bacterial flagellin through TLR5, single stranded RNAs through TLR7/8, synthetic anti-viral compounds imiquinod through TLR 7 and resiquimod through TLR8, unmethylated CpG DNA motifs through TLR9.
The specificity is established by correct pairing of a TLR with its proinflammatory cytokine(s), so that these permutations influence creation and maintenance of cell differentiat ion.
Immunotherapy: The immune cells can be used as a sensor to scavenger the circulating malformed cells in vivo diagnostics or attack and remember them, for instance, relapse of cancer, re-infection with a same or similar agent (bacteria or virus) etc.
Not only using unique microbial and other model organism properties but also using the human host defense mechanism during innate immune responses may bring a new combat to create a new method of precision medicine. This can be a new type of immunotherapy, immune cell mediated gene therapy or vaccine even a step for an in vivo diagnostics.
Molecular Genetics took a long road from discovery of restriction enzymes, developing PCR assays, cloning were the beginning. Now, having technology to sequence and compare the sequences between organisms also help to design more sophisticated methods.
Generating mutant lines in Drosophila with the classical genetics methods relies on P elements, a type of transposon and balancers after crossing selected flies with specific markers. This fly pushing is a very tedious work but powerful to identify primary pathways, mechanisms and gene interactions in system and translational genomics.
Thus, Microbial Immunomodulation is an important factor not only using the microorganisms or their mechanisms but also modulating the immune cells based on the host interaction may generate new types of diagnostics and targeted therapy tools.
Microbial immunomodulation. Microbes from the environment, and from the various microbiota, modulate the immune system. Some of this is due to direct effects of defined microbial products on elements of the immune system. But modulation of the immune system also secondarily alters the host–microbiota relationship and leads to changes in the composition of the microbiota, and so to further changes in immunoregulation (shown as indirect pathways). At the end of the day balance is the key for survival.
CRISPR-Cas9 mediated NHEJ in transient transfection experiments.
Table 1.
Species
Transformation method
Cas9 codon optimization
Promoters (Cas9, gRNA)
Target
Mutation frequency
Detection method
Off-target (no. of sites analyzed)
Detection method
Multiplex (deletion)
Reference
Arabidopsis thaliana
PEG-protoplast transfection
Arabidopsis (with intron)
CaMV35SPDK, AtU6
PDS3<comma> FLS2
1.1–5.6%
PCR + sequencing
Li et al. (2013)
A. thaliana
Leaf agroinfiltration
Arabidopsis (with intron)
CaMV35SPDK, AtU6
PDS3
2.70%
PCR + sequencing
Yes (48 bp)
Li et al. (2013)
A. thaliana
PEG-protoplast transfection
Arabidopsis (with intron)
CaMV35SPDK, AtU6
RACK1b<comma> RACK1c
2.5–2.7%
PCR + sequencing
No (1 site)
PCR + sequencing
Li et al. (2013)
A. thaliana
Leaf agroinfiltration
C. reinhardtii
CaMV35S, AtU6
Co-transfected GFP
n.a.
Pre-digested PCR + RE
Jiang et al. 2013a and Jiang et al. 2013b
Nicotiana benthamiana
PEG-protoplast transfection
Arabidopsis (with intron)
CaMV35SPDK, AtU6
PDS3
37.7–38.5%
PCR + sequencing
Li et al. (2013)
N. benthamiana
Leaf agroinfiltration
Arabidopsis (with intron)
CaMV35SPDK, AtU6
PDS3
4.80%
PCR + sequencing
Li et al. (2013)
N. benthamiana
Leaf agroinfiltration
Human
CaMV35S, AtU6
PDS
1.8–2.4%
PCR + RE
No (18 sites)
PCR + RE
Nekrasov et al. (2013)
N. benthamiana
Leaf agroinfiltration
C. reinhardtii
CaMV35S, AtU6
Co-transfected GFP
n.a.
pre-digested PCR + RE
Jiang et al. 2013a and Jiang et al. 2013b
N. benthamiana
Leaf agroinfiltration
Human
CaMV35S, CaMV35S
PDS
12.7–13.8%
Upadhyay et al. (2013)
Nicotiana tabacum
PEG-protoplast transfection
Tobacco
2xCaMV35S, AtU6
PDS<comma> PDR6
16.27–20.3%
PCR + RE
Yes (1.8 kb)
Gao et al. (2014)
Oryza sativa
PEG-protoplast transfection
Rice
2xCaMV35S, OsU3
PDS<comma> BADH2<comma> MPK2<comma> Os02g23823
14.5–38.0%
PCR + RE
Noa (3 sites)
PCR + RE
Shan et al. (2013)
O. sativa
PEG-protoplast transfection
Human
CaMV35S, OsU3 or OsU6
MPK5
3–8%
RE + qPCR and T7E1 assay
No (2 sites) Yes (1 site with a mismatch at position 12)
RE + PCR
Xie and Yang (2013)
O. sativa
PEG-protoplast transfection
Rice
CaMV35S, OsU6
SWEET14
n.a.
pre-digested PCR + RE
Jiang et al. 2013a and Jiang et al. 2013b
O. sativa
PEG-protoplast transfection
Rice
ZmUbi, OsU6
KO1 KOL5; CPS4 CYP99A2; CYP76M5 CYP76M6
n.a.
PCR + sequencing
Yes (115<comma> 170<comma> 245 kb)
Zhou et al. (2014)
Triticum aestivum
PEG-protoplast transfection
Rice
2xCaMV35S, TaU6
MLO
28.50%
PCR + RE
Shan et al. (2013)
T. aestivum
PEG-protoplast transfection
Plant
ZmUbi, TaU6
MLO-A1
36%
T7E1
Wang et al. 2014a and Wang et al. 2014b
T. aestivum
Agrotransfection of cells from immature embryos
Human
CaMV35S, CaMV35S
PDS<comma> INOX
18–22%
PCR + sequencing
Upadhyay et al. (2013)
T. aestivum
Agrotransfection of cells from immature embryos
Human
CaMV35S, CaMV35S
INOX
PCR + sequencing
No*
PCR + RE
Yes (53 bp)
Upadhyay et al. (2013)
Zea mays
PEG-protoplast transfection
Rice
2xCaMV35S, ZmU3
IPK
16.4–19.1%
PCR + RE
Liang et al. (2014)
Citrus sinensis
Leaf agroinfiltration
Human
CaMv35S, CaMV35S
PDS
3.2–3.9%
PCR + RE
No (8 sites)
PCR + RE
Jia et al. (2014)
References:
A brief overview of CRISPR-mediated immunity and explain how the emerging new properties of this defense system are being repurposed for genome engineering in bacteria, yeast, human cells, insects, fish, worms, plants, frogs, pigs, and rodents.
Cho SW, Kim S, Kim JM, Kim J. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol. 2013;31:230–2. doi: 10.1038/nbt.2507.
Cradick TJ, Fine EJ, Antico CJ, Bao G. CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res.2013;41:9584–92. doi: 10.1093/nar/gkt714.
Bassett AR, Tibbit C, Ponting CP, Liu J. Highly efficient targeted mutagenesis of Drosophila with the CRISPR/Cas9 system. Cell Rep. 2013;4:220–8. doi: 10.1016/j.celrep.2013.06.020.
Cho SW, Lee J, Carroll D, Kim J, Lee J. Heritable Gene Knockout in Caenorhabditis elegans by Direct Injection of Cas9-sgRNA Ribonucleoproteins.Genetics. 2013;195:1177–80. doi: 10.1534/genetics.113.155853.
Katic I, Großhans H. Targeted Heritable Mutation and Gene Conversion by Cas9-CRISPR in Caenorhabditis elegans. Genetics. 2013;195:1173–6. doi: 10.1534/genetics.113.155754.
Jiang W, Zhou H, Bi H, Fromm M, Yang B, Weeks DP. Demonstration of CRISPR/Cas9/sgRNA-mediated targeted gene modification in Arabidopsis, tobacco, sorghum and rice. Nucleic Acids Res. 2013;41:e188. doi: 10.1093/nar/gkt780.
Li W, Teng F, Li T, Zhou Q. Simultaneous generation and germline transmission of multiple gene mutations in rat using CRISPR-Cas systems. Nat Biotechnol.2013;31:684–6. doi: 10.1038/nbt.2652.
CRISPR-Cas9 Discovery and Development of Programmable Genome Engineering – Gabbay Award Lectures in Biotechnology and Medicine – Hosted by Rosenstiel Basic Medical Sciences Research Center, 10/27/14 3:30PM Brandeis University, Gerstenzang 121
Annual Margaret Pittman Lecture, honors the NIH’s first female lab chief, March 11, 2015, 3:00:00 PM by Jennifer Doudna, Ph.D., University of California, Berkeley
attn #1: Investors in HealthCare — Platforms in the Ecosystem of Regulatory & Reimbursement – Integrated Informational Platforms in Medical Devices, Global Oncology Drugs Market and Peer-Reviewed Curations: Cancer, Genomics and Cardiovascular – Draft
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New Frontiers in Gene Editing — Cambridge Healthtech Institute’s Inaugural, February 19-20, 2015 | The Inter Continental San Francisco | San Francisco, CA
Lecture Contents delivered at Koch Institute for Integrative Cancer Research, Summer Symposium 2014: RNA Biology, Cancer and Therapeutic Implications, June 13, 2014 @MIT
9:10 – 9:30, 6/13/2014, Phillip Sharp “Why RNA Biology?” Phillip Sharp, PhD Institute Professor, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Koch Institute for Integrative Cancer Research @MIT – Summer Symposium 2014: RNA Biology, Cancer and Therapeutic Implications, June 13, 2014 8:30AM – 4:30PM, Kresge Auditorium @MIT
Dr Sag has a Bachelor’s degree in Basic and Industrial Microbiology as a Sum cum Laude among 450 graduating class of Science faculty, an MSc in Microbial Engineering and Biotechnology (Bioprocessing improvement) and PhD in Molecular and Developmental Genetics (Functional Genome and Stem Cell Biology).
She is an translational functional genomic scientist to develop diagnostics and targeted therapies by non-invasive methods for personalized medicine from bench to bedside and engineering tools through clinical trials and regulatory affairs.
You may contact with her at 858-729-4942 or by demet.sag@gmail.com if you have questions.
Our body works a s a system even during complex diseases that is sometimes forgotten. From nutrition to basic immune responses since we are born we start to change how we respond and push the envelope to keep hemostasis in our body.
During this time additional factors also increase or decrease the rate of changes such as life style, environment, inherited as well acquired genetic make-up, types of infections, weight and stress only some of them. As a result we customized our body so deserve a personalized medicine for a treatment. Customized approach is its hype with developing technology to analyze data and compare functional genomics of individuals.
However, still we need the basic cell differentiation to solve the puzzle to respond well and connect the dots for physiological problems. At the stem of the changes there is a cell that respond and amplify its reaction to gain a support to defend at its best . Thus, in this review I like to make a possible connection for pancreatic cancer, obesity-diabetes and innate immune response through natural killer cells.
Pancreatic cancer is one of the most lethal malignancies. Pancreatic cancer is one of the most difficult cancers to treat. Fewer than 5% of patients survive more than 5 years after diagnosis. The 5-year survival rate is despite therapeutic improvements still only 6%. More than 80% of the pancreatic tumors are classified as pancreatic ductal adenocarcinoma (PDA).
When cells in the pancreas that secrete digestive enzymes (acinar cells) turn into duct-like structures, pancreatic cancer can develop. Oncogenic signaling – that which causes the development of tumors – can influence these duct-like cells to form lesions that are a cancer risk.
Crossing roads
The recent publication brought up the necessity to understand how pancreatic cancer and IL17 are connected.
Schematic diagram showing the central role of IL-17B–IL-17RB signaling in pancreatic cancer metastasis.
Adapted from an illustration by Heng-Hsiung Wu and colleagues
Simply, obesity and diabetes increases the risks of cancers, cardiovascular disease, hypertension, and type-2 DM. There is a very big public health concern as obesity epidemic, the incidence of diabetes is increasing globally, with an estimated 285 million people, or 6.6% of the population from 20 to 79 years of age, affected this is especially more alarming as child obesity is on the rise.
According to a World Health Organization (WHO) report showing that 400 million people are obese in the world, with a predicted increase to 700 million by 2015 and in the US, 30–35 percent of adults are obese. In addition, high BMI and increased risk of many common cancers, such as liver, endometrium, breast, pancreas, and colorectal cancers have a linear increasing relationship.
The BMI is calculated by dividing body weight in kilograms by height squared in meters kg/m2). The current standard categories of BMI are as follows: underweight, <18.5; normal weight, 18.5–24.9; overweight, 25.0–29.9; obese, 30.0–34.9; and severely obese, > or = 35.0).
Furthermore, natural killer cells not only control innate immune responses but have function in other immune responses that was not recognized well before.
Recently, there have been reports regarding Natural Killer cells on was about the function of IL17 that is produced by iNKT, a subtype of NK, for a possible drug target. In addition, regulation of receptors that are up or downregulated by NK cells for a precise determination between compromised cells and healthy cells.
Therefore, instead of sole reliance on SNPs, or GWAS for early diagnostics or only organ system base pathology, compiling the overall health of the system is necessary for a proper molecular diagnostics and targeted therapies.
What is Pancreas cancer
SNAP SHOT:
Incidence
It is a rare type of cancer.
20K to 200K US cases per year
Medically manageable
Treatment can help
Requires a medical diagnosis
lab tests or imaging
spreads rapidly and has a poor prognosis.
treatments may include: removing the pancreas, radiation, and chemotherapy.
Ages affected; even though person may develop this cancer from age 0 to 60+ there is a high rate of incidence after age 40.
People may experience:
Pain: in the abdomen or middle back
Whole body: nausea, fatigue, or loss of appetite
Also common: yellow skin and eyes, fluid in the abdomen, weight loss, or dark urine
The pancreas secretes enzymes that aid digestion and hormones that help regulate the metabolism of sugars.
Prescription
Chemotherapy regimen by injection: Irinotecan, Gemcitabine (Gemzar), Oxaliplatin (Eloxatin)
Other treatments: Leucovorin by injection, Fluorouracil by injection (Adrucil)
Procedures: Radiation therapy, Pancreatectomy, surgery to remove pancreatic tumors
Specialists
Radiologist: Uses images to diagnose and treat disease within the body.
Oncologist: Specializes in cancer.
Palliative medicine: Focuses on improving quality of life for terminally ill patients.
General surgeon: Performs a range of surgeries on the abdomen, skin, breast, and soft tissue.
Gastroenterologist: Focuses on the digestive system and its disorders.
What are the current and possible applications for treatment and early diagnosis
Diagnostics
Several imaging techniques are employed in order to see if cancer exists and to find out how far it has spread. Common imaging tests include:
Ultrasound – to visualize tumor
Endoscopic ultrasound (EUS) – thin tube with a camera and light on one end
Abdominal computerized tomography (CT) scans – to visualize tumor
Endoscopic retrograde cholangiopancreatography (ERCP) – to x-ray the common bile duct
Angiogram – to x-ray blood vessels
Barium swallows to x-ray the upper gastrointestinal tract
Magnetic resonance imaging (MRI) – to visualize tumor
Positron emission tomography (PET) scans – useful to detect if disease has spread
New solutions in Diagnostics;
The study, published in Nature Communications, suggests that targeting the gene in question – protein kinase D1 (PKD1) – could lead to new ways of halting the development of one of the most difficult tumors to treat.
“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Dr. Peter Storz.
Do we have new markers?
Is it possible check the cancer along with glucose levels or insulin at the point of care or companion diagnostics?
Therapy
New Solutions in Therapies
ABRAXANE (paclitaxel formulated as albumin bound nanoparticles; nab-paclitaxel), in combination with gemcitabine, has been recommended for use within NHS Scotland by the Scottish Medicines Consortium (SMC) for the treatment of metastatic adenocarcinoma of the pancreas.
The SMC decision is based on results from the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, published in the October 2013 edition of the New England Journal of Medicine, which demonstrated an increase in median overall survival of 1.8 months when compared to gemcitabine alone [(8.5 months vs. 6.7 months respectively) (HR 0.72; 95% CI 0.62 to 0.83 P<0.001)].
Updated results from post-hoc analysis of the MPACT trial based on an extended data cut-off (8 months) at the time the trial was closed demonstrated an increase in the median overall survival benefit of 2.1 months when compared to gemcitabine alone [(8.7 months vs. 6.6 months respectively) (HR 0.72,95% CI = 0.62 to 0.83, P<.001)].
Targeting stroma is another approached that is followed by TGen to potentially extend patient survival in all cases including advanced cases based on a report at Clinical Cancer Research, published online by the American Association for Cancer Research. Thus this eliminates one of the limiting factor to reach tumor cells and destroying the accumulation of stroma — the supporting connective tissue that includes hyaluronan and few other collagen types.
One of the study leaders, Andrew Biankin, a Cancer Research UK scientist at the University of Glasgow in the UK said that “Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients.”
In the journal Nature, the international team- including scientists from Cancer Research UK showed the evidence of large chunks of DNA being shuffled around, which they were able to classify according to the type of disruption they created in chromosomes.
The study concludes there are four subtypes of pancreatic cancer, depending on the frequency, location and types of DNA rearrangement. It terms the subtypes: stable, locally rearranged, scattered and unstable.
Can we develop an immunotherapy?
Genetics of Pancreatic Cancer
There are many ongoing studies to develop diagnostics technologies and treatments. However, the etiology of PC is not well understood. Pancreas has dual functions that include 2% of endocrine hormone secretion and 98% exocrine secretion, enzymes, to help digestion. As a result, pancreatic cancer is related to obesity, overweight, diabetes.
First, eliminating the risk factors can be the simplest path. Next approach is dropping the obesity and diabetes to prevent the occurrence of cancers since in the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Tobacco smoking, alcohol consumptions, chronic pancreatitis, and genetic risk factors, have been recognized as potential risk factors for the development and progression of PC.
Many studies showed that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers. Thus, these agents are thought to be the target to diagnose or cure PC.
Type 2 diabetes mellitus has been associated with an increased risk of several human cancers, such as liver, pancreatic, endometrial, colorectal, breast, and bladder cancer. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes.
Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Type 2 diabetes mellitus accounts for more than 95% of the cases.
In PDA these cells have been reported to express specific genes such as Aldh1 or CD133. To date, more than 20 case-control studies and cohort and nested case-control studies with information on the association between diabetes and pancreatic cancer, BMI and cancer, and obesity and cancer have been reported.
Meta analysis and cohort studies:
Meta studies for Diabetes and PC
Most of the diabetes and PC studies were included in two meta-analyses, in 1995 and in 2005, investigating the risk of pancreatic cancer in relation to diabetes.
The first meta-analysis, conducted in 1995, included 20 of these 40 published case-control and cohort studies and reported an overall estimated relative risk (RR) of pancreatic cancer of 2.1 with a 95% confidence interval (CI) of 1.6-2.8. These values were relatively unchanged when the analyses were restricted to patients who had diabetes for at least 5 years (RR, 2.0 [95% CI, 1.2-3.2]).
The second meta-analysis, which was conducted in 2005, included 17 case-control and 19 cohort and nested case-control studies published from 1996 to 2005 and demonstrated an overall odds ratio (OR) for pancreatic cancer of 1.8 and 95% CI of 1.7-1.9 . Individuals diagnosed with diabetes within 4 years before their pancreatic cancer diagnosis had a 50% greater risk of pancreatic cancer than did those diagnosed with diabetes more than 5 years before their cancer diagnosis (OR, 2.1 [95% CI, 1.9-2.3] versus OR, 1.5 [95% CI, 1.3-1.8]; P = 0.005).
In a recent pooled analysis of 2192 patients with pancreatic cancer and 5113 cancer-free controls in three large case-control studies conducted in the United States (results of two of the three studies were published after 2005),
Risk estimates decreased as the number of years with diabetes increased.
Individuals with diabetes for 2 or fewer, 3-5, 6-10, 11-15, or more than 15 years had ORs (95% CIs) of 2.9 (2.1-3.9), 1.9 (1.3-2.6), 1.6 (1.2-2.3), 1.3 (0.9-2.0), and 1.4 (1.0-2.0), respectively (P < 0.0001 for trend).
Meta Studies between BMI and PC
Meta studies in 2003 and 2008 showed a week positive association between BMI and PC. In 2003, a meta-analysis of six case-control and eight prospective studies including 6,391 PC cases 2% increase in risk per 1 kg/m2 increase in BMI. In 2008, 221 datasets, including 282,137 incidence of cancer cases with 3,338,001 subjects the results were similar RR, 1.12; CI, 1.02–1.22.
In 2007, 21 prospective studies handled , 10 were from the United States, 9 were from Europe, and 2 were from Asia and studies was conducted including 3,495,981 individuals and 8,062 PC cases. There was no significant difference between men and women and the estimated summary risk ratio (RR) per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17) in men and women combined.
This study concluded that concluded that there was a positive association between BMI and risk of PC, per a 5 kg/m2 increase in BMI may be equal to a 12% increased risk of PC.
The location and type of the obesity may also signal for a higher risk. The recent Women’s Health Initiative study in the United States among 138,503 postmenopausal showed that women central obesity in relation to PC (n=251) after average of 7.7 years of follow-up duration demonstrated that central adiposity is related to developing PC at a higher risk. Based on their result “women in the highest quintile of waist-to-hip ratio have a 70 percent (95% CI, 10–160%) greater risk of PC compared with women in the lowest quintile”
Age of obesity or being overweight versus risk of developing PC was also examined.
Regardless of their DM status they were at risk and decreased their survival even more so among men than women between age of 14-59.
overweight 14 to 39 years (highest odds ratio [OR], 1.67; 95% CI, 1.20–2.34) or
obese 20 to 49 years (highest OR, 2.58; 95% CI, 1.70–3.90) , independent of DM status.
This association was different between men and women from the ages of 14 to 59:
stronger in men (adjusted OR, 1.80; 95% CI, 1.45–2.23)
weaker in women (adjusted OR, 1.32; 95% CI, 1.02–1.70).
The effect of BMI , obesity and overweight had reduced overall survival of PC regardless of disease stage and tumor resection status
high BMI (= or > 25) 20 to 49 years , an earlier onset of PC by 2 to 6 years.
Being overweight or obese during early adulthood was associated with a greater risk of PC and a younger age of disease onset, whereas obesity at an older age was associated with a lower overall survival in patients diagnosed with PC.
More recently, several large prospective cohort studies with a long duration of follow-up has been conducted in the U.S. showing a positive association between high BMI and the risk of PC (adjusted RR 1.13–1.54), suggesting the role of obesity and overweight with higher risk in the development and eventual death due to PC.
Although the role of smoking and gender in the association of obesity and PC is not clear, the new evidence strongly supports a positive association of high BMI with increased risk of PC, consistent with the majority of early findings; however, all recent studies strongly suggest that obesity and overweight are independent risk factor of PC.
Diabetes was associated with a 1.8-fold increase in risk of pancreatic cancer (95% CI, 1.5-2.1).
How pancreatic cancer is related to obesity, overweight, BMI, diabetes
Connections in Physiology and Pathology:
Altogether cumulative data suggest that DM has a three-fold increased risk for the development of PC and a two-fold risk for biliary cancer insulin resistance and abnormal glucose metabolism, even in the absence of diabetes, is associated with increased risk for the development of PC. Obesity alters the metabolism towards insulin resistance through affecting gene expression of inflammatory cytokines, adipose hormones such as adipokines, and PPAR-γ.
Furthermore, adiponectin also pointed out to be a negative link factor for cancers such as colon, breast, and PC. Therefore, insulin resistance is one of the earliest negative effects of obesity, early altered glucose metabolism, chronic inflammation, oxidative stress and decreased levels of adipose hormone adiponectin and PPAR-γ, key regulators for adipogenesis.
Potential pathways directly linking obesity and diabetes to pancreatic cancer. Obesity and diabetes cause mutiple alterations in glucose and lipid hemastasis, microenvironments, and immune responses, which result in the activation of several oncogenic signaling pathways.
These deregulations increase cell survival and proliferation, eventually leading to the development and progression of pancreatic cancer. ROS, reactive oxygen species; IGF-1, insulin-like growth factor-1; IR, insulin receptors; IGF-1R, insulin-like growth factor-1 receptors; TNFR, tumor necrosis factor receptors; TLR, Toll-like receptors; HIF-1α, hypoxia-inducible factor-α1; AMPK, AMP kinase; IKK, IκB kinase; PPAR-γ, peroxisome proliferator-activated receptor-γ; VEGF, vascular endothelial growth factor; MAPK, MAP kinase; mTOR, mammalian target of rapamycin; TSC, tuberous sclerosis complex; Akt, protein kinase B. PI3K, phosphoinositide-3-kinase; STAT3, activator of transcription-3; JNK, c-Jun NH2-terminal kinase.
Top six pathways interacting with obesity or diabetes in modifying the risk of pancreatic cancer are Chemokine Signaling, Pathways in cancer, Cytokine-cytokine receptor interaction, Calcium signaling pathway. MAPK signaling pathway.
This analysis showed
GNGT2,
RELA,
TIAM1,
CBLC,
IFNA13,
IL22RA1,
IL2RA
GNAS,
MAP2K7,
DAPK3,
EPAS1 and
FOS as contributor genes.
Furthermore, top overrepresented canonical pathways, including
Role of RIG1-like Receptors in Antiviral Innate Immunity,
Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, and
Molecular Mechanisms of Cancer
in genes interacting with risk factors (P < 10−8) are
aNumber of genes making up the pathway/ number of genes survived the PCA-LRT (P ≤ 0.10).
bNumber of SNPs in the “reconstructed” pathways/number of principal components for LRT.
cP value was estimated by LRT in logistic regression model with adjustment of age, sex, study site, pack years(continuous), obesity or diabetes as appropriate, and five principal components for population structure.
dGenes with PG x E ≤ 0.05 in logistic regression and P ≤ 0.10 in PCA-LRT.
ePathways remained significant after Bonferroni correction (P < 1.45 × 10−4)
Top overrepresented canonical pathways in genes interacting with risk factors (P < 10−8)
aCalculated using Fisher’s exact test (right-tailed).
bNumber of genes interacting with a risk factor of interest (P ≤ 0.05) in a given pathway divided by total number of genes making up that pathway.
Pancreatic Cancer and Diabetes:
We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.
Diabetes increases tumor size and proliferation of carcinoma cells
Diabetes does not decrease cell death in carcinomas
Diabetes II like syndrome reduces the number of Aldh1+cells within the tumor
Metformin decreases tumor size and proliferation of carcinoma cells
Much is known about factors increasing the likelihood to develop PDA. Identified risk factors include among others chronic pancreatitis, long lasting diabetes, and obesity. Patients with chronic and especially hereditary pancreatitis have a very high relative risk of developing pancreatic cancer of 13.3 and 69.0, respectively. Patients with diabetes and obesity have a moderately increased relative risk of 1.8 and 1.3. These studies indicate that a substantial number of patients with PDA also suffer from local inflammation or diabetes.
Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking and obesity. The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients.
Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5-fold to 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies.
Insulin resistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be the underlying mechanisms contributing to development of diabetes-associated pancreatic cancer.
“A study by Permert et al.using glucose tolerance tests in patients with newly diagnosed pancreatic cancer showed that 75% of patients met criteria for diabetes. Pannala et al. used fasting blood glucose values or previous use of antidiabetic medications to define diabetes in patients with pancreatic cancer (N.=512) and age-matched control non-cancer subjects attending primary care clinics (N.=933) “
Distribution of fasting blood glucose among pancreatic cancer cases and controls. From Pannala et al.
“ They reported a nearly seven-fold higher prevalence of diabetes in pancreatic cancer patients compared to controls (47% vs. 7%). In a retrospective study using similar criteria, Chari et al. found the prevalence of diabetes in pancreatic cancer patients to be 40%. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/”
Relationship between type 2 diabetes and risk of pancreatic cancer in case-control and nested case control studies. “Diamond: point estimate representing study-specific relative risks or summary relative risks with 95% CIs. Horizontal lines: represent 95% confidence intervals (CIs). Test for heterogeneity among studies: P<0.001, I2=93.6%. 1, cohort studies (N.=27) use incidence or mortality rate as the measurements of relative risk; 2, cohort studies (N.=8) use standardized incidence/mortality rate as the measurement of relative risk. From Benet al.”
PART II: Targets for Immunomodulation to develop a therapy
Natural Killer Cells:
Natural Killer cells usually placed under non-specific immune response as a first defend mechanism during innate immunity. NKs responses to innate immune reactions but not only viruses but also bacteria and parasitic infections develop a new line of defense. These reactions involve amplification of many cytokines based on the specific infection or condition. Thus, these activities help NKs to evolve.
However, their functions proven to be more than innate immune response since from keeping the pregnancy term to prevent recurrent abortions to complex diseases such as cancer, diabetes and cardiovascular conditions they have roles thorough awakening chemokines and engaging them specifically with their receptors to activate other immune cells. For example, there is a signaling mechanism connection between NKs and DCs to respond attacks. Furthermore, there are interactions between various types of immune cells and they are specific for example between NK and Tregs.
During pregnancy there is a special kind of interaction between NK cells and Tregs.
There can be several reasons such as to protect pregnancy from the immunosuppressive environment so then the successful implantation of the embryo and tolerance of the mother to the embryo can be established. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation.
During cancer development tumors want to build a microenvironment through an array of highly orchestrated immune elements to generate a new environment against the host. In normal pregnancy, decidua, the uterine endometrium, is critical for the development of placental vasculature.
This is the region gets thicks and thin during female cycles to prevent or accept pregnancies. As a result, mother nature created that 70% of all human decidual lymphocytes are NK cells, defined as uterine or decidual NK (dNK) cells.
The NK cell of decidua (dNK) and peripheral blood NK cells are different since dNK cells are characterized as CD56brightCD16−CD3−, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules, and a higher frequency of CD4+CD25bright
The lesson learn here is that pregnancy and mammary tissue are great examples of controlling cellular differentiation and growth since after pregnancy all these cells go back to normal state.
Understanding these minute differences and relations to manipulate gene expression may help to:
Develop better biomaterials to design long lasting medical devices and to deliver vaccines without side effects.
Generate safer vaccines as NKcells are the secret weapons in DC vaccination and studying their behavior together with T-cell activation in vaccinated individuals might predict clinical outcome.
Establish immunotherapies based on interactions between NK cells and Tregs for complex diseases not only cancer, but also many more such as autoimmune disorder, transplants, cardiovascular, diabetes.
Trascription factors are the silence players of the gene expression that matches input to output as a cellular response either good or bad but this can be monitored and corrected with a proper meical device or diagnostics tool to provide successful treatment regimen.
Therefore, the effects of Tregs on NK during gene regulation analyzed and compared among other living organisms for concerved as well as signature sequence targets even though the study is on human.
Unfortunatelly we can’t mutate the human for experimental purposes so comparative developmental studies now its widely called stem cell biology with a system biology approach may help to establish the pathway.
NK and T reg regulation share a common interest called T box proteins. These proteins are conserved and also play role in development of heart at very early development, embryology. What is shared among all T-box is simply lie behind the capacity for DNA binding through the T-box domain and transcriptional regulatory activity, which plays a role in controlling the expression of developmental gene in all animal species.
The Special T box protein: T-bet
The first identified T-box protein was Brachyury (T). in a nut shell
The T-box domain is made up of about 180 amino-acid residues that includes a specific sequence of DNA
called T-box domain, TCACACCT between residues 135 and 326 in mouse.
However, T-bet which is the T-box protein expressed in T cells and also called as TBX21 is quite conserved in 18 members of the T-box protein (TBX) family
since it has a crucial dual role during development and for coordination of both innate and adaptive immune responses.
T-Bet was originally cloned for its role in Th1 lineage, it has a role in Th2 development, too.
The whole mechanism based on direct activation and modulation mechanisms in that T-Bet directly activates IFN-γ gene transcription and enhances development of Th1 cells at the same time modulates IL-2 and Th2 cytokines in an IFN-γ-independent manner that creates an attenuation of Th2 cell development.
Thus, certain lipids ligands or markers can be utilized during vaccine design to steer the responses for immune therapies against autoimmune diseases. As a result, tumors can be removed and defeated by manipulating NKs action.
INKT:
NKT has functions in diabetes, asthma. One cell type that has been proposed to contribute immensely to the development of asthma is NKT cells, which constitute a small population of lymphocytes that express markers of both T cells (T-cell receptor, TCR) and NK cells (e.g., NK1.1, NKG2D). NKT cells can be subdivided into at least three subtypes, based on their TCR. Type I NKT cells or invariant NKT (iNKT) cells express invariant TCR chains (V14–J18 in mice and V24–J18 in humans) coupled with a limited repertoire of V chains (V8, V7 and V2 in mice and V11 in humans).
The studies in the past decade showed the protective mechanism of NKT cells during the development of Type 1 diabetes can be complex.
First, NKT cells can impair the differentiation of anti-islet reactive T cells into Th1 effector cells in a cell–cell contact dependent manner, which did not require Th2 cytokine production or CD1d recognition.
Second, NKT cells accumulating in the pancreas can indirectly suppress diabetogenic CD4+T cells via IFN-γ production.
Last, anergic iNKT cells induced by protracted αGalCer stimulation can induce the production of noninflammatory DCs, which inhibit diabetes development in an Ag-specific fashion.
These findings point to an important protective role for NKT cells during autoimmune pathogenesis in the pancreas.
A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR).
iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and adaptive immunity.
IL17:
Terashima A et al (2008) identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of Airway hypersensitive reaction (AHR). IL-17RB is preferentially expressed on a fraction of CD4(+) NKT cells but not on other splenic leukocyte populations tested.
They strongly suggested that IL-17RB(+) CD4(+) NKT cells play a crucial role in the pathogenesis of asthma.
NKT connection can be established between through targeting IL17 and IL17RB. There is a functional specialization of interleukin-17 family members. Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F).
Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses.
There is no one easy answer for the role of IL-17 in pancreatic cancer as there are a number of unresolved issues and but it can be only suggested that pro-tumorigenic IL-17 activity is confined to specific subsets of patients with pancreatic cancer since there is a increased expression of IL-17RB in these patients about ∼40% of pancreatic cancers presented on their histochemical staining (IHC- immunohistochemistry.
IL17 and breast cancer:
In addition, during breast cancer there is an increased signaling of interleukin-17 receptor B (IL-17RB) and IL-17B. They promoted tumor formation in breast cancer cells in vivo and even created acinus formation in immortalized normal mammary epithelial cells in vitro cell culture assays.
Furthermore, the elevated expression of IL-17RB not only present itself stronger than HER2 for a better prognosis but also brings the shortest survival rate if patients have increased IL-17RB and HER2 levels.
However, decreased level of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumor growth. This may prompt a different independent role for IL-17RB and HER2 in breast cancer development.
In addition, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells.
These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.
IL 17 and Asthma:
A requirement for iNKT cells has also been shown in a model of asthma induced with air pollution, ozone and induced with respiratory viruses chronic asthma studied in detail. In these studies specific types of NKT cells found to that specific types of NK and receptors trigger of asthma symptoms. Taken together, these studies indicate that both Th2 cells (necessary for allergen-specific responses) and iNKT cells producing IL-4 and IL-13 are required for the development of allergen-induced AHR.
Although CD4+ IL-4/IL-13-producing iNKT cells (in concert with antigen-specific Th2 cells) are crucial in allergen-induced AHR, NK1.1–IL-17-producing iNKT cells have a major role in ozone-induced AHR.
A main question in iNKT cell biology involves the identification of lipid antigens that can activate iNKT cells since this allow to identify which microorganisms to attack as a result, the list of microorganisms that produce lipids that activate iNKT cells is rapidly growing.
Invariant natural killer T cells (iNKT) cell function in airway hyperreactivity (AHR). iNKT cells secrete various cytokines, including Th2 cytokines, which have direct effects on hematopoietic cells, airway smooth muscle cells, and goblet cells. Alternatively, iNKT cells could regulate other cell types that are known to be involved in asthma pathogenesis, e.g., neutrophils and alveolar macrophages.
Chemokines have a crucial role in organogenesis of various organs including lymph nodes, arising from their key roles in stem cell migration. Moreover, most homeostatic chemokines can control the movement of lymphocytes and dendritic cells and eventually adaptive immunity. Chemokines are heparin-binding proteins with 4 cysteine residues in the conserved positions.
The human chemokine system has about 48 chemokines. They are subgrouped based on:
Number of cysteines
Number of amino acid separating cysteines
Presence or absence of ELR motif includes, 3-amino acid sequence, glutamic acid-leucine-arginine
functionally classified as inflammatory, homeostatic, or both, based on their expression patterns
Chemokines are structurally divided into 4 subgroups :CXC, CC, CX3C, and C. X represent an aminoacid so the first 2 cysteines are separated by 1 is grouped as CXC and 3 amino acids is called CX3C chemokines but in CC the first 2 cysteines are adjacent. In the C chemokines there is no second and fourth cysteines.
Various types of inflammatory stimuli induce abundantly the expression of inflammatory chemokines to induce the infiltration of inflammatory cells such as granulocytes and monocytes/macrophages.
inflammatory chemokines are CXC chemokines with ELR motif and CCL2.
homeostatic chemokines are expressed constitutively in specific tissues or cells.
Chemokines exert their biological activities by binding their corresponding receptors, which belong to G-protein coupled receptor (GPCR) with 7-span transmembrane portions. Thus, the target cell specificity of each chemokine is determined by the expression pattern of its cognate receptor .
Moreover, chemokines can bind to proteoglycans and glycosaminoglycans with a high avidity, because the carboxyl-terminal region is capable of binding heparin.
Consequently, most chemokines are produced as secretory proteins, but upon their secretion, they are immobilized on endothelium cells and/or in extracellular matrix by interacting with proteoglycans and glycosaminoglycans. The immobilization facilitates the generation of a concentration gradient, which is important for inducing the target cells to migrate in a directed way.
The human chemokine system.
Chemokine receptor
Chemokines
Receptor expression in
Leukocytes
Epithelium
Endothelium
CXCR1
CXCL6, 8
PMN
+
−
CXCR2
CXCL1, 2, 3, 5, 6, 7, 8
PMN
+
+
CXCR3
CXCL4, 9, 10, 11
Th1, NK
−
+
CXCR4
CXCL12
Widespread
+
+
CXCR5
CXCL13
B
−
−
CXCR6
CXCL16
Activated T
+
−
CXCR7 (ACKR3)
CXCL12, CXCL11
Widespread
+
+
Unknown
CXCL14 (acts on monocytes)
CCR1
CCL3, 4, 5, 7, 14, 15, 16, 23
Mo, Mϕ, iDC, NK
+
+
CCR2
CCL2, 7, 8, 12, 13
Mo, Mϕ, iDC, NK
activated T, B
+
+
CCR3
CCL5, 7, 11, 13, 15, 24, 26, 28
Eo, Ba, Th2
−
+
CCR4
CCL2, 3, 5, 17, 22
iDC, Th2, NK, T, Mϕ
−
−
CCR5
CCL3, 4, 5, 8
Mo, Mϕ, NK, Th1
activated T
+
−
CCR6
CCL20
iDC, activated T, B
+
−
CCR7
CCL19, 21
mDC, Mϕ, naïve T
activated T
+
−
CCR8
CCL1, 4, 17
Mo, iDC, Th2, Treg
−
−
CCR9
CCL25
T
+
−
CCR10
CCL27, 28
Activated T, Treg
+
−
Unknown
CCL18 (acts on mDC and naïve T)
CX3CR1
CX3CL1
Mo, iDC, NK, Th1
+
−
XCR1
XCL1, 2
T, NK
−
−
Miscellaneous
Scavenger receptors for chemokines
Duffy antigen (ACKR1)
CCL2, 5, 11, 13, 14
CXCL1, 2, 3, 7, 8
D6 (ACKR2)
CCL2, 3, 4, 5, 7, 8, 12
CCL13, 14, 17, 22
CCRRL1 (ACKR4)
CCL19, CCL21, CCL25
Leukocyte anonyms are as follows. Ba: basophil, Eo: eosinophil, iDC: immature dendritic cell, mDC: mature dendritic cell, Mo: monocyte, Mϕ: macrophage, NK: natural killer cell, Th1: type I helper T cell, Th2: type II helper T cell, and Treg: regulatory T cell.
There are differences between human liver and peripheral NK cells. Regulation of NK cell functions by CD226, CD96 and TIGIT.close. CD226 binding to CD155 or CD112 at the cell surface of transformed or infected cells triggers cytotoxic granule exocytosis and target cell lysis by natural killer (NK) cells. TIGIT, CD226, CD96 and CRTAM ligand specificity and signalling.close.
Regulation of NK cell-mediated cancer immunosurveillance through CD155 expression.close. CD155 is frequently overexpressed by cancer cells.
In conclusion, having to develop precise early diagnostics is about determining the overlapping genes as key among diabetes, obesity, overweight and pancreas functions even pregnancy can be suggested.
It seems feasible to develop an immunotherapy for pancreatic cancer with the focus on chemokines and primary signaling between iNKT and Tregs such as one of the recent plausable target IL-17 and IL17 RB.
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Key Papers:
These papers, Gilfian et all and Iguchi-Manaka et al, were the first to show the role of CD226 in NK cell- and CD8+ T cell-mediated tumour immunosurveillance using Cd226−/− mice.
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Pradeu, T., Jaeger, S. & Vivier, E. The speed of change: towards a discontinuity theory of immunity? Nature Rev. Immunol.13, 764–769 (2013). This is an outstanding review on the formulation of a new immune paradigm ‘the discontinuity theory’
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
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Thymoquinone, an extract of nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.
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Pancreatic Cancer Diagnosis: Four Novel Histo-pathologies Screening Characteristics offers more Reliable Identification of Cellular Features associated with Cancer
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
Synchronous Triple Cancers of the Pancreas, Stomach, and Cecum Treated with S-1 Followed by Pancrelipase Treatment of Pancreatic Exocrine Insufficiency
