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Celebrating the First Anniversary of PharmaceuticalIntelligence.com, 4/30/2012 – 4/30/2013

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Health Economics and Outcomes Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged , , on April 30, 2013| 1 Comment »

Curator: Aviva Lev-Ari, PhD, RN

First post published on 4/30/2012

We went pretty far:

On 4/30/2013 – Great News to Share

News from the National Academy of Sciences

Date: April 30, 2013

FOR IMMEDIATE RELEASE

National Academy of Sciences Members and Foreign Associates Elected

The National Academy of Sciences announced today the election of 84 new members and 21 foreign associates from 14 countries in recognition of their distinguished and continuing achievements in original research.

Those elected today bring the total number of active members to 2,179 and the total number of foreign associates to 437. Foreign associates are nonvoting members of the Academy, with citizenship outside the United States.

Newly elected members and their affiliations at the time of election are:

We congratulate OUR BOARD MEMBER for being elected 

Feldman, Marcus W.

Director, Morrison Institute for Population and Resource Studies, and Burnet C. and Mildred Finley Wohlford Professor of Biological Sciences, department of biological sciences, Stanford University, Stanford, Calif.

http://www.nasonline.org/news-and-multimedia/news/2013_04_30_NAS_Election.html

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OUR BioMed e-BOOKS Series

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Target Market: CARDIOLOGISTS

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Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Posted in Biomarkers & Medical Diagnostics, Cell Biology, Signaling & Cell Circuits, Frontiers in Cardiology and Cardiovascular Disorders, Interviews with Scientific Leaders, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Pharmaceutical Analytics, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , on April 30, 2013| 6 Comments »

Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Reporter: Aviva Lev-Ari, PhD, RN

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Prostacyclin and Nitric Oxide: Adventures in vascular biology –  a tale of two mediators

The e-Readers are encouraged to review two additional Sources on this topic on this Open Access Online Scientific Journal

Perspectives on Nitric Oxide in Disease Mechanisms

 and

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

S Moncada*

The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK
* (Email: s.moncada@ucl.ac.uk)

Prof. Moncada:

I would like to thank the Royal Society for inviting me to deliver the Croonian Lecture. In so doing, the Society is adding my name to a list of very distinguished scientists who, since 1738, have preceded me in this task. This is, indeed, a great honour.

For most of my research career my main interest has been the understanding of the normal functioning of the blood vessel wall and the way this is affected in pathology. During this time, our knowledge of these subjects has grown to such an extent that many people now believe that the conquering of vascular disease is a real possibility in the foreseeable future.

My lecture concerns the discovery of two substances, prostacyclin and nitric oxide. I would like to describe the moments of insight and some of the critical experiments that contributed significantly to the uncovering of their roles in vascular biology. The process was often adventurous, hence the title of this lecture. It is the excitement of the adventure that I would like to convey in the text that follows.

Keywords: prostacyclin, aspirin, nitric oxide, oxidative stress, free radicals, cardiovascular pathology
Full article 
Philos Trans R Soc Lond B Biol Sci. 2006 May 29; 361(1469): 735–759.
Published online 2006 February 8. doi:  10.1098/rstb.2005.1775
PMCID: PMC1609404

9. THE TWO STORIES CONVERGE

Although the research fields of prostacyclin/thromboxane and NO are now mature, they have developed mostly as parallel research activities with few points of contact between them. Thus, our understanding of how both might operate in relation to each other in physiology and pathophysiology remains to be developed. Table 2 shows some of the similarities between prostacyclin and NO. Both mediators, from very different biochemical pathways, play a variety of roles in the modulation and protection of the vascular wall. The release of both mediators is dependent on constitutive enzymes, the activity of which seems to be regulated locally, predominantly by the shear stress caused by the blood passing over the endothelial surface (Grabowski et al. 1985; Frangos et al. 1985; for review see Boo & Jo 2003). However, while the constitutive eNOS—localized only in the vascular endothelium—is the enzyme that responds to shear stress, the generation of prostacyclin is dependent on the activity of two enzymes, COX-1 and COX-2, in relation to which several questions remain unanswered. These include whether COX-2 is a constitutive as well as an inducible enzyme, and whether COX-1 or COX-2, or both, respond to shear stress by increases in their mRNA, their activity, or both (Topper et al. 1996; Okahara et al. 1998;McCormick et al. 2000; Garcia-Cardena et al. 2001). Prostacyclin, unlike NO, is constitutively generated throughout the vessel wall (Moncada et al. 1977c) and at this stage we also do not know whether the ratio between COX-1 and COX-2 changes in the different layers. In addition, the similarities and differences between regulation of NO and prostacyclin by shear stress are only now being investigated (Osanai et al. 2000; McAllister et al. 2000; Walshe et al. 2005).

Table 2

Table 2

Comparison of the properties of nitric oxide and prostacyclin.

A clear synergism between NO and prostacyclin has been demonstrated in regard to inhibition of platelet aggregation; however, only one of them (NO) plays a role in inhibiting platelet adhesion. The significance of this difference remains to be understood. Many years ago a physiological role for platelets in repairing the vessel wall was investigated (for discussion see Higgs et al. 1978). This subject has not been re-evaluated in the light of all this new knowledge about the roles of NO and prostacyclin in platelet/vessel wall interactions. Both mediators also regulate vascular smooth muscle proliferation and white cell vessel wall interactions through similar mechanisms which include, at least in part, the activation of adenylate cyclase and the soluble guanylate cyclase. The interactions between NO and prostacyclin in the control of these functions are not fully understood.

Both mediators are further increased by inflammatory stimuli; however, while in the case of prostacyclin the same COX-2 which responds to shear stress responds to such stimuli by a further increase in its expression, NO is generated during inflammation by a specific ‘inducible’ NO synthase which is not normally present physiologically in the vessel wall. The induction of both is inhibited by anti-inflammatory glucocorticoids (Axelrod 1983; Knowles et al. 1990). It is remarkable that both compounds possess antioxidant properties (Wink et al. 1995; Egan et al. 2004) but are themselves affected by oxidative stress, which inhibits the synthesis of prostacyclin and decreases the bioavailability of NO. This mechanism might be relevant to the ‘malfunctioning’ of the constitutive generation of both mediators and therefore to the genesis of endothelial dysfunction. This, however, is an early phenomenon. In advanced disease the situation is far more complex, akin to chronic inflammation in other parts of the body and, as such, probably varies significantly in the different stages of the disease. A simple hypothesis would suggest that any amount of prostacyclin which is bioavailable, although pro-inflammatory, will provide anti-thrombotic protection, while in the case of NO the balance will vary between bioavailable NO which is protective and cytotoxic peroxynitrite formed from the interaction of NO with O2−. Currently, however, the results are not clear and on the crucial question of the role of both mediators in the progression of atherosclerosis, the information in relation to prostacyclin is contradictory (Burleigh et al. 2002; Olesen et al. 2002; Rott et al. 2003). The evidence in relation to NO, on the other hand, seems to suggest that, while constitutive NO generated by eNOS is protective (e.g. Kawashima & Yokoyama 2004), NO generated by the inducible enzyme favours the development of atherosclerosis (Chyu et al. 1999). Studies of genetically manipulated animals are providing some important clues. For example, knockout of the prostacyclin receptor (IP) leads to mice with normal blood pressure but an increased tendency to thrombosis when the endothelium is damaged (Murata et al. 1997) These animals also exhibit an increased platelet activation and proliferative response to injury that can be prevented by deletion or antagonism of the TXA2 receptor (Cheng et al. 2002). Furthermore, deletion of the IP receptor in animals prone to spontaneous atherosclerosis accelerates the development of the disease (Egan et al. 2004;Kobayashi et al. 2004). On the other hand, knocking out the thromboxane receptor or the thromboxane synthase gives rise to a mild bleeding tendency and a resistance to platelet aggregation and sudden death induced by arachidonic acid infusion (Thomas et al. 1998; Yu et al. 2004). Deletion of the thromboxane receptor also seems to retard atherogenesis in murine models of atherosclerosis (Cayatte et al. 2000;Egan et al. 2005).

Although the lack of either mediator has been shown to increase the risk of thrombosis and atherosclerosis, especially in animals with additional risk factors such as ApoE deficiencies (Kuhlencordtet al. 2001; Belton et al. 2003), there seems to be a certain specialization in their actions, so that NO has a more significant role in the regulation of blood pressure and blood flow, while prostacyclin has a clearer role in regulating platelet/vessel wall interactions. For example, inhibition of NO generation has an immediate and dramatic effect on blood flow and blood pressure and the eNOS−/− animal exhibits a clear hypertensive phenotype. On the other hand, inhibition of prostacyclin synthesis by the coxibs leads to a slow effect on blood pressure and apparently to a more thrombotic situation (Muscara et al. 2000;FitzGerald 2003). Similarly, COX-1−/− and COX-2−/− animals show no change in blood pressure (Norwood et al. 2000; Cheung et al. 2002) and manipulation of COX or IP results in a prothrombotic phenotype.

Protection against decreases in the generation of constitutive NO and prostacyclin in the vasculature may prevent the development of vascular disease. In relation to NO, the most often tried interventions relate to the use of antioxidants (see Carr & Frei 2000) and the manipulation of eNOS expression by genetic means (Von der Leyen & Dzau 2001). Each of these interventions has shown promise in both animal experiments and in humans. An unexpected and highly interesting development relates to the effects of statins which, in the last few years, have been shown to increase the production of endothelial NO in endothelial cell cultures and in animals (for review see Laufs 2003). Many mechanisms have been claimed for this action. However, of interest in the context of our discussion is the fact that statins have been claimed to reduce oxidative stress by increasing the synthesis of BH4 (Hattori et al. 2002), increasing the coupling of the eNOS (Brouet et al. 2001) or reducing the activation of NADPH oxidase (Wagner et al. 2000). Reduction of oxidative stress is likely to preserve the generation of prostacyclin, and to our knowledge there is at least one report suggesting that statins also increase prostacyclin in endothelial cell cultures of human coronary arteries (Mueck et al. 2001). Studies on the transfection of COX-1 or COX-2 into endothelial and other cells, on the other hand, are at an early stage and clear results are not conclusive (Murakami et al. 1999; Shyue et al. 2001). The full consequences of overexpression of both NO and prostacyclin in the vasculature remain to be investigated.

Also relevant to this discussion are studies of the role that NO and prostacyclin play in the protection of the cardiovascular system provided by oestrogens, and therefore in the difference between genders in susceptibility to cardiovascular disease. Oestrogens increase the expression and the activity of eNOS (Weiner et al. 1994; Yang et al. 2000) and the activity of the COX-2 enzyme (Akarasereenont et al. 2000;Egan et al. 2004). They could therefore reduce oxidative stress by simply increasing both mediators. Alternatively, it has been claimed that oestrogens increase the efficiency of the NO synthase, thus reducing free radical formation (Barbacanne et al. 1999).

In summary, the concept of the balance between prostacyclin and TXA2 has to be expanded to include NO. Furthermore, although not discussed in this review, the way in which these compounds interact with many other systems known to be involved in vessel wall physiology and pathophysiology requires further investigation. Both prostacyclin and NO synergize in the protection of the vessel wall. TXA2, however, lies on the negative side of this balance being responsible for, among other things, platelet aggregation and vasoconstriction. The investigation into the interplay between these three molecules is just beginning. This is a sobering thought when one is contemplating probably close to 100 000 papers and over 30 years of research! However, it is clear that the discoveries of prostacyclin and NO have transformed our comprehension of vascular physiology and opened avenues for further understanding of pathophysiological processes. This knowledge has already benefited clinical medicine and no doubt will continue providing clues that will guide future therapy and prevention of vascular disease. I have had the good fortune to be intimately involved with both discoveries. More importantly, many of the colleagues that I have interacted with in the process of doing this work have become life-long personal friends. To those with whom I have managed to combine scientific excitement with friendship I owe a double debt of gratitude.

Philos Trans R Soc Lond B Biol Sci. 2006 May 29; 361(1469): 735–759.
Published online 2006 February 8. doi:  10.1098/rstb.2005.1775

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Colon Cancer

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , on April 30, 2013| 4 Comments »

Colon Cancer

Author/Editor: Tilda Barliya PhD

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Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy (1-4).

Courtesy WebMD site

In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC. The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.5 per 100,000 people. The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing. In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors. It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

Colon Cancer is divided into 5 types:

  1. Sporadic: 60-85%
  2. Familial: 10-30%
  3. Hereditary non-Polyposis Colon Cancer (HNPCC): 5%
  4. Familial Adenomatous Polyposis (FAP): 1%
  5. Autosomal Dominant Inheritance

The molecular defects are of two types:

  • alterations that lead to novel or increased function of oncogenes
  • alterations that lead to loss of function of tumor-suppressor genes (TSGs)

Multiple genes are associated with the initiation and progression of the different syndromes of colon cancer and are summarized by Fearon ER in Table 1 (6):

Table 1  Genetics of inherited colorectal tumor syndromesa
Syndrome Common features Gene defect(s)
FAP Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium APC (>90%)
Gardner syndrome Same as FAP; also, desmoid tumors and mandibular osteomas APC
Turcot’s syndrome Polyposis and colorectal cancer with brain tumors (medulloblastomas); colorectal cancer and brain tumors (glioblastoma) APC
MLH1, PMS2
Attenuated adenomatous polyposis coli Fewer than 100 polyps, although marked variation in polyp number (from 5 to >1,000 polyps) observed in mutation carriers within a single family APC(predominantly 5′ mutations)
Hereditary nonpolyposis colorectal cancer Colorectal cancer without extensive polyposis; other cancers include endometrial, ovarian and stomach cancer, and occasionally urothelial, hepatobiliary, and brain tumors MSH2
MLH1
PMS2
GTBP, MSH6
Peutz-Jeghers syndrome Hamartomatous polyps throughout the GI tract; mucocutaneous pigmentation; increased risk of GI and non-GI cancers LKB1, STK11(30–70%)
Cowden disease Multiple hamartomas involving breast, thyroid, skin, central nervous system, and GI tract; increased risk of breast, uterus, and thyroid cancers; risk of GI cancer unclear PTEN (85%)
Juvenile polyposis syndrome Multiple hamartomatous/juvenile polyps with predominance in colon and stomach; variable increase in colorectal and stomach cancer risk; facial changes DPC4 (15%)
BMPR1a(25%)
PTEN (5%)
MYH-associated polyposis Multiple adenomatous GI polyps, autosomal recessive basis; colon polyps often have somatic KRAS mutations MYH

aAbbreviations: FAP, familial adenomatous polyposis; GI, gastrointestinal.

Essentially all of the genes discussed above are conclusively implicated in subsets of CRC due to specific somatic defects that either activate or inactivate gene and protein function. It is hypothesized that essentially any gene with dysregulated expression in CRC—either increased or decreased expression—may have a functionally significant role as an oncogene or a TSG, respectively. The aggregate data on the mutations and function of any given gene must be carefully evaluated to establish whether the gene truly contributes to CRC pathogenesis and whether it should be designated as an oncogene or a TSG (5,6).

The first proposed genetic model of CRC assumed that most CRCs arise from preexisting adenomatous lesions and that the accumulation of multiple gene defects is required for CRCs.

Benign GI tumors are a varied group, but localized lesions that project above the surrounding mucosa are commonly termed polyps. In humans, most colorectal polyps, particularly small polyps less than 5 mm in size, are hyperplastic (6). Most data indicate that hyperplastic polyps are not a major precursor to CRC; rather, the adenomatous polyp, or adenoma, is probably the important precursor lesion (7).

” Adenomas arise from glandular epithelium and are characterized by dysplastic morphology and altered differentiation of the epithelial cells in the lesion. The prevalence of adenomas in the United States is approximately 25% by age 50 and approximately 50% by age 70 (8)”. Only a fraction of adenomas progress to cancer, and progression probably occurs over years to decades. Individuals affected by syndromes that strongly predispose to adenomas, such as FAP, invariably develop CRCs by the third to fifth decade of life if their colons are not removed”.

A more recent and modified version of the genetic model postulate that each gene defect described in the model occurs at high frequency only at particular stages of tumor development. This observation is the basis for assigning a relative order to the defects in a multistep pathway.

Colon Cancer and clinical Trails:

Mutations in the KRAS proto-oncogene are found in 40-45% of patients with CRC and occur mainly in exon 2 (codon 12 and 13) and to a lesser extent in exon 3 (codon 61) and exon 4 (codon 146). A number of studies have evaluated a potential prognostic role of KRAS  in clinical practice for the treatment of colorectal cancer. However, clinical study design, reproducibility, interpretation and reporting of the clinical data remain important challenges.

Laurent-Puig’s group was the first to show the negative predictive value of KRAS mutations for response to the EGFR monoclonal antibody (mAb) cetuximab (11, 12, 13). Ever since then, a number of large phase II-III randomized studies have confirmed the negative predictive value of KRAS mutations for response to cetuximab and panitumumab treatment.

The role of KRAS mutations in predicting response to other therapies remains unclear. A subset analysis of patients treated in the phase III study of bevacizumab plus IFL (irinotecan, bolus 5-FU, and folinic acid) versus IFL showed that the clinical benefit of bevacizumab is independent of KRAS mutational status (11, 14).

“The KRAS biomarker story is unique in several ways. It represents the first biomarker integrated into clinical practice in CRC“.

The high prevalence of KRAS mutations in CRC and its strong negative predictive value for EGFR mAb therapies, has led to its rapid acceptance as a valuable biomarker. The EMEA, FDA and ASCO47 now recommend that all patients with metastatic CRC who are candidates for anti-EGFR mAb therapy should be tested for KRAS mutations and, if a KRAS mutation in codon 12 or 13 is detected, then patients should not receive anti-EGFR antibody therapy.

More so, Data from the PETACC-3 trial, presented at ASCO 2010, have shown that KRAS and BRAF mutant CRC tumors induce different gene-expression profiles, further reiterating that these tumors have a distinct underlying biology. Despite intensive progress in the field of genomic research, none of these genomic markers are used routinely in clinical trials.  Only, nowadays, trials are starting to use specific gene-pathway” target in CRC clinical trials.

Samuel Constant et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Summary:

Early studies are underway to understand the role of DNA methylation, chromatin modification, changes in the patterns of mRNA and noncoding RNA expression, and changes in protein expression and posttranslational modification. However,  we do not yet have an indepth and comprehensive understanding of the pathogenesis of the biologically and clinically distinct subsets of CRC. Careful design of clinical trials end points and validation of the genes as potential prognostic markers will allow a better outcome for these patients.

Ref:

1. Sarah Popek, MD, and Vassiliki Liana Tsikitis, MD. Colorectal Cancer: A Review. OncLive  November 10, 2011. http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Colorectal-Cancer-A-Review

x. Martin Hefti.,  H.Maximilian Mehdorn., Ina Albert and Lutz Dörner. Fluorescence-Guided Surgery for Malignant Glioma: A Review on Aminolevulinic Acid Induced Protoporphyrin IX Photodynamic Diagnostic in Brain Tumors.  Current Medical Imaging Reviews, 2010, 6, 1-5. http://www.hirslanden.ch/content/global/en/startseite/gesundheit_medizin/mediathek_bibliothek/fachartikel/verschiedenes/fluorescence_guidedsurgeryformalignantglioma/_jcr_content/download/file.res/FluorescenceGuidedSurgeryforMalignantGlioma.pdf

2. Oguz Akin, Sandra B. Brennan., D. David Dershaw., Michelle S. Ginsberg., Marc J. Gollub., Heiko Sch€oder., David M. Panicek, and Hedvig Hricak. Advances in Oncologic Imaging: Update on 5 Common Cancers. CA CANCER J CLIN 2012;62:364–393. http://onlinelibrary.wiley.com/doi/10.3322/caac.21156/pdf

3. O’Donnell, Kevin et al. Nanoparticulate systems for oral drug delivery to the colon. International Journal of Nanotechnology, 2010, 8, 1/2, 4-20. “Colonic Navigation: Nanotechnology Helps Deliver Drugs to Intestinal Target”. http://www.sciencedaily.com/releases/2010/11/101104154553.htm

4. Perumal V. Molecular Therapy and Nanocarrier Based Drug Delivery to Colon Cancer: Targeted Molecular Therapy (AEE788 and Celecoxib) and Drug Delivery (Celecoxib) To Colon Cancer. http://www.amazon.com/Molecular-Therapy-Nanocarrier-Delivery-Cancer/dp/3659162558

5. Xiaoyun Liao, Paul Lochhead, Reiko Nishihara, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Zhi Rong Qian, Yoshifumi Baba, Kaori Shima, Ruifang Sun, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Andrew T. Chan, Shuji Ogino. Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival. New England Journal of Medicine, 2012; 367 (17): 1596 DOI:10.1056/NEJMoa1207756. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532946/

Gene Mutation Identifies Colorectal Cancer Patients Who Live Longer With Aspirin Therapy. http://www.sciencedaily.com/releases/2012/10/121024175357.htm

6. Fearon ER. Molecular Genetics of Colorectal Cancer. Annual Review of Pathology: Mechanisms of Disease 2011; 6: 479-507.http://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130235

7.  Jass JR. 2007. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Hisopathology 50:113–130. http://www.amedeoprize.com/ap/pdf/histopathology.pdf

8.  Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, et al.  Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am. J. Gastroenterol 1993. 88:825–831.http://www.ncbi.nlm.nih.gov/pubmed/8503374

9. Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer 2005; 4:239–44. http://www.ncbi.nlm.nih.gov/pubmed/16136384

10. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996: 87:159–170. http://users.ugent.be/~fspelema/les%204-5%20HMG/kinzler%20clon.pdf

11. Sandra Van Schaeybroeck, Wendy L. Allen, Richard C. Turkington & Patrick G. Johnston. Implementing prognostic and predictive biomarkers in CRC clinical trials.(colorectal cancer)(Clinical report). Nature Reviews Clinical Oncology 2011: 8; 222-232. http://www.nature.com/nrclinonc/journal/v8/n4/abs/nrclinonc.2011.15.html

12. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66 2006: 3992-3995. http://hwmaint.cancerres.aacrjournals.org/cgi/content/full/66/8/3992

13. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008: 26, 374-379. http://jco.ascopubs.org/content/26/3/374.full.pdf

14. Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F. & Rosen, O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist  2009: 14, 22-28. http://theoncologist.alphamedpress.org/content/14/1/22.full

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Aviva Lev-Ari, PhD, RN. Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. http://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. http://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.D. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. http://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.D. In Focus: Targeting of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. http://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. http://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. http://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

Other posts by the group: Please see http://pharmaceuticalintelligence.com/?s=colon+cancer

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Genetics of Disease: More Complex is How to Creating New Drugs

Posted in Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, tagged , , , , , , on April 30, 2013| 2 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

The reader is encourage to review the following ANALYSIS of this subject matter:

Genomics & Genetics of Cardiovascular DiseaseDiagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

and

10 Years On, Still Much To Be Learned From Human Genome Map

Advances made in genetics of disease, but creating new drugs more complex than first thought

By Amanda Gardner
HealthDay Reporter

FRIDAY, April 12 (HealthDay News) — As scientists mark the 10th anniversary Sunday of the completion of the Human Genome Project, they will note how that watershed effort has led to the discovery of the genetic underpinnings of almost 5,000 diseases.

And it has made it possible to develop personalized treatments that have prolonged the lives of many.

But the scientists will also acknowledge that, while the project has unlocked many mysteries that once shrouded diseases, there’s still much to be learned before new drugs can be developed to target illness-causing mutations in human DNA.

“What we’ve learned over the past 10 years is that we’re still far from really understanding the complexity of the human genome,” said Eric Schadt, chairman of genetics and genomic sciences at Mount Sinai Icahn School of Medicine in New York City. “Human disease is way more complicated than the old view that single hits to single genes cause diseases.

“In most forms of diseases, it’s whole constellations of genes operating in networks,” Schadt explained. “That becomes a much harder problem. How do you target networks with a single drug?

“We keep learning how much we really don’t know and how much further we need to go,” he added. “That’s the big story.”

A decade ago, the Human Genome Project was hailed as a major milestone because researchers identified all of the nearly 25,000 genes in human DNA and sequenced the 3 billion chemical base pairs comprising that DNA.

The feat took 13 years and cost close to $3 billion, but the genetic information gleaned from the project gave scientists the tools needed to pinpoint how changes in specific genes could kick-start some diseases.

One of the most tangible benefits of the project has been the development of ever more sophisticated sequencing technology and a dramatic lowering of the cost of using that technology.

Today, the cost of sequencing one human genome is closer to $5,000 and can be done in a day or two, said Dr. Eric Green, director of the National Human Genome Research Institute in Bethesda, Md.

What that means is that the pace of research, and its attendant discoveries, has been accelerated.

When the project first began, scientists knew the genetic basis of about 53 diseases. Today, that number is close to 5,000, Green noted. That means doctors can now test patients to see if they carry gene mutations that raise their risk for certain diseases, and counsel them accordingly on ways they might prevent or delay illness. There are currently almost 2,000 genetic tests for specific diseases or conditions, according to the U.S. National Institutes of Health.

There have also been breakthroughs with some rare diseases.

In 2011, 6-year-old Nicholas Volker became the first child to be saved by the new technology. He had undergone a hundred surgeries, including the removal of his colon, as doctors tried to identify his mysterious bowel disease. Genomic sequencing uncovered a genetic mutation that could be treated with a bone marrow transplant consisting of cells from umbilical cord blood.

“Knowing more of the basic genetics that makes up an individual has allowed us to diagnose far more genetic diseases,” said Dr. Barbara Pober, a medical geneticist at the Frank H. Netter, M.D. School of Medicine at Quinnipiac University in North Haven, Conn.

Once a diagnosis has been made, doctors can now use gene sequencing to determine treatment for some diseases. For instance, breast cancer patients can be tested to see how they will respond to the drug Herceptin. HIV patients can be tested to determine their response to the drug abacavir. And those on the widely used blood thinner warfarin can be tested to determine the most effective dose, according to the NIH.

The field of pharmacogenetics, still in its infancy, enables doctors to use a patient’s genetic information to figure out which cancer drugs the patient will best respond to before treatment even starts.

The U.S. Food and Drug Administration now includes genetic information on labeling for more than 100 drugs, up from just four 10 years ago, Green said.

The goal of developing new drugs to target diseases with genetic roots, however, will take much longer to realize.

Although the NIH states that there are roughly 350 biotechnological products currently being tested in clinical trials, new drugs take a decade or more to develop. Not only that, the knowledge gained from the Human Genome Project has actually made the field of genetic medicine even more complex. Scientists are finding that many diseases are triggered by interaction involving multiple gene variants, making it difficult to design a treatment that targets all the culprits in a particular illness.

And the complexities don’t end there.

Not long ago, scientists discovered that so-called “junk” DNA, which makes up 98 percent of the genome, is not junk at all but serves critical regulatory functions.

What’s more, about 10 percent of the human genome still hasn’t been sequenced and can’t be sequenced by existing technology, Green added. “There are parts of the genome we didn’t know existed back when the genome was completed,” he said.

More information

For more on developments over the past 10 years, visit the Human Genome Projectwebsite.

SOURCES: Eric Green, M.D., Ph.D., director, National Human Genome Research Institute, Bethesda, Md.; Barbara Pober, M.D., professor, medical sciences, Frank H. Netter, M.D., School of Medicine, Quinnipiac University, North Haven, Conn.; Eric Schadt, Ph.D., professor and chairman, department of genetics and genomic sciences, Mount Sinai Icahn School of Medicine, New York City

Last Updated: April 12, 2013

Health News Copyright © 2013 HealthDay. All rights reserved.

http://consumer.healthday.com/Article.asp?AID=675381

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Francois Jacob, Nobelist with Monod and Lwoff, dies an octogenarian

Posted in Biological Networks, Gene Regulation and Evolution, Scientist: Career considerations, tagged , , , , , , , , , on April 29, 2013| 5 Comments »

Larry H Bernstein, MD, FCAP, Repost
Leaders in Pharmaceutical  Intelligence
http://pharmaceuticalintelligence.com/2013/04/29/francois-jacob…-lwoff/

Dr. Francois Jacob dies at 92; Nobel-winning biologist
A biologist who shared a Nobel Prize in 1965, Dr. Francois Jacob helped unlock the mysteries of RNA.
April 24, 2013, 7:21 p.m.
When James Watson and Francis Crick deciphered the structure of DNA in 1953, their discovery answered a crucial question in biology: How is genetic information passed down from parent to child?
Their work also created conundrums, however. They and others showed that every cell of an organism contains all of its genetic material. How, then, does an individual cell know which genes to use and when? And how does information from DNA get to the cell’s protein-making machinery?
The seminal insight into those questions came from three biologists at the Pasteur Institute in Paris — Dr. Francois Jacob, Jacques Monod and Andre Lwoff. They identified messenger RNA which, as the name implies, carries the blueprint for a protein from cellular DNA to the ribosome, where proteins are built. They also identified the complex system of regulatory genes that turn protein-making genes on and off.
Their achievement ushered in the modern age of molecular biology. It also won them the 1965 Nobel Prize in Medicine or Physiology, only five years after Watson and Crick received theirs.
Jacob died Friday in Paris at 92. His death was announced by the French government, but no details were released.
The inspiration for Jacob’s achievements came in the early 1950s, while he was working in Lwoff’s laboratory studying bacteriophages, viruses that infect only bacteria. They studied a bacteriophage, or phage, that infected the common bacterium Escherichia coli. They observed that the phage could infect bacterial cells and lie dormant in its genes until something triggered explosive replication that caused the cell to split open.
In related experiments with male and female bacteria, they found that male DNA that was infected with a dormant phage could be transferred to a female cell, but not vice versa. They concluded that something in the cells was suppressing the activity of the phage genes.
Nobel-winner Dr. Francois Jacob dies
That led Jacob and Monod to study E. coli that normally live on the sugar glucose. But if the bacteria are deprived of glucose and placed in a medium containing the more complicated sugar lactose, they suddenly begin producing three enzymes that: 1) take lactose into the cell; 2) break it down into its constituents glucose and galactose; and 3) break galactose down into glucose.
Through an elegant series of experiments, the researchers showed that the genes that serve as the blueprints for those three enzymes are each accompanied by another gene called the operator. In this system, glucose acts as a repressor, binding to the operator and physically preventing the blueprint gene from being copied into messenger RNA.
In other words, when the gene is not needed, it is shut off.
But when lactose is present, it binds more strongly to the operator than does glucose, pushing out the latter and allowing the structural gene to be copied. The researchers called this system of two genes an “operon” and the specific system for lactose the lactose or lac operon. They submitted their findings to the Journal of Molecular Biology on Christmas Eve in 1960 and it was published the next year.
In a review in the journal Science, molecular biologist Gunther S. Stent called it “one of the monuments in the literature of molecular biology.” Introducing the three biologists at the Nobel awards ceremony, Sven Gard of the Royal Karolinska Institute proclaimed that the French workers “opened up a field of research which in the truest sense of the word can be described as molecular biology.”
Francois Jacob was born June 17, 1920, in Nancy, France, the son of a merchant. He began studying medicine at the University of Paris with the intention of becoming a surgeon, but the war intervened after his first two years. At the age of 20, he caught one of the last vessels to England, where he joined the Free French forces.
With his two years of medical training, he served as a doctor with the Free French armored forces throughout North Africa. After the Allies’ 1944 Normandy invasion, as his armored brigade was nearing Paris, Jacob was severely wounded in a German attack when he used his own body to protect his lieutenant. He spent seven months in a hospital, missing the Free French forces’ grand reentry into the city. Damage to his hand ended his hopes of becoming a surgeon.
For his service, he received the Companion of the Liberation, the country’s highest World War II decoration for valor. He was also awarded the Legion d’Honneur and the Croix de Guerre.
After he received his medical degree in 1947, he joined a company that was attempting to make a French version of penicillin and helped in the development of a related antibiotic called tyrothrycin. In 1950, at the age of 30, he decided he was interested in cellular genetics and obtained a fellowship at the Pasteur Institute, receiving his doctor of science degree in 1954.
He later studied mechanisms of cell division and the early development of the mouse embryo.
In addition to his many research papers, he authored four books, including the 1988 autobiography “The Statue Within.”
He married the pianist Lysiane “Lise” Bloch in 1947, and they had four children. After her death, he married Genevieve Barrier in 1999. Information about survivors was unavailable.
news.obits@latimes.com
Related articles

http://pgabiram.scientificlegacies.org/doc/7_nobelist_abs_1991.pdf

Stained glass window in the dining hall of Gon...

Stained glass window in the dining hall of Gonville and Caius College, in Cambridge (UK), commemorating Francis Crick, who co-discovered the molecular structure of DNA, received a Nobel Prize and was an honorary fellow of the college. The window represents a double helix; the text on the windows reads: F.H.C. CRICK, HONORARY FELLOW 1976. (Photo credit: Wikipedia)

Diagram of a eukaryotic gene

Diagram of a eukaryotic gene (Photo credit: Wikipedia)

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Importance of Omega-3 Fatty Acids in Reducing Cardiovascular Disease

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Frontiers in Cardiology and Cardiovascular Disorders, Metabolomics, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, tagged , , , , , , , , , on April 29, 2013| 5 Comments »

Importance of Omega-3 Fatty Acids in Reducing Cardiovascular Disease

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

UPDATED on 7/24/2018

Omega-3 fats Supplements Effect on Cardiovascular Health: EPA and DHA has little or no effect on Mortality or Cardiovascular Health

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/07/24/omega-3-fats-supplements-effect-on-cardiovascular-health-epa-and-dha-has-little-or-no-effect-on-mortality-or-cardiovascular-health/

 

The available evidence for cardiovascular effects of n-3 polyunsaturated fatty acid (PUFA) consumption has been reviewed here, focusing on long chain (seafood) n-3 PUFA, including their principal dietary sources, effects on physiological risk factors, potential molecular pathways and bioactive metabolites, effects on specific clinical endpoints, and existing dietary guidelines. Major dietary sources include fatty fish and other seafood. n-3 PUFA consumption lowers plasma triglycerides, resting heart rate, and blood pressure and might also improve myocardial filling and efficiency, lower inflammation, and improve vascular function. Experimental studies demonstrate direct anti-arrhythmic effects, which have been challenging to document in humans. n-3 PUFA affect a myriad of molecular pathways, including alteration of physical and chemical properties of cellular membranes, direct interaction with and modulation of membrane channels and proteins, regulation of gene expression via nuclear receptors and transcription factors, changes in eicosanoid profiles, and conversion of n-3 PUFA to bioactive metabolites. In prospective observational studies and adequately powered randomized clinical trials, benefits of n-3 PUFA seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on other cardiovascular outcomes are less-well-established, including conflicting evidence from observational studies and/or randomized trials for effects on nonfatal myocardial infarction, ischemic stroke, atrial fibrillation, recurrent ventricular arrhythmias, and heart failure. Research gaps include the relative importance of different physiological and molecular mechanisms, precise dose-responses of physiological and clinical effects, whether fish oil provides all the benefits of fish consumption, and clinical effects of plant-derived n-3 PUFA. Overall, current data provide strong concordant evidence that n-3 PUFA are bioactive compounds that reduce risk of cardiac death. National and international guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFA or at least 2 servings / week of oily fish.

Source References:

http://content.onlinejacc.org/article.aspx?articleid=1146941

http://www.ncbi.nlm.nih.gov/pubmed/17047219

http://www.ncbi.nlm.nih.gov/pubmed/18614744

http://www.ncbi.nlm.nih.gov/pubmed/19364995

http://www.ncbi.nlm.nih.gov/pubmed/16172267

Other articles related to this topic were published on this Open Access Online Scientific Journal, including the following:

Reversal of Cardiac mitochondrial dysfunction

Larry H Bernstein, MD, FACP, RN 04/14/2013

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Can resolvins suppress acute lung injury?

Larry H Bernstein, MD, FACB, RN 03/06/2013

http://pharmaceuticalintelligence.com/2013/03/06/can-resolvins-suppress-acute-lung-injury/

Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

Aviva Lev-Ari, PhD., RN 02/19/2013

http://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FCAP, Pathologist, Contributor, RN 10/25/2012

http://pharmaceuticalintelligence.com/2012/10/25/endothelial-function-and-cardiovascular-disease/

Mediterranean Diet is BEST for patients with established Heart Disorders

Aviva Lev-Ari, PhD, RN 10/15/2012

http://pharmaceuticalintelligence.com/2012/10/15/mediterranean-diet-is-best-for-patients-with-established-heart-disorders/

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Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Biomarkers & Medical Diagnostics, Cell Biology, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Population Health Management, Proteomics, tagged , , , , , , , , , , , on April 28, 2013| 20 Comments »

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 6/13/2013

with a CASE of  Anti-Ro Antibodies and Reversible Atrioventricular Block

N Engl J Med 2013; 368:2335-2337 June 13, 2013 DOI: 10.1056/NEJMc1300484

As an Introduction to the Genetics of Conduction Disease, we selected the following article which represents the MOST comprehensive review of the Human Cardiac Conduction System presented to date:

Circulation.2011; 123: 904-915 doi: 10.1161/​CIRCULATIONAHA.110.942284

The Cardiac Conduction System

  1. David S. Park, MD, PhD;
  2. Glenn I. Fishman, MD

+Author Affiliations


  1. From the Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
  1. Correspondence to Glenn I. Fishman, MD, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, Smilow 801, New York, NY 10016. E-mail glenn.fishman@med.nyu.edu

Key Words:

The human heart beats 2.5 billion times during a normal lifespan, a feat accomplished by cells of the cardiac conduction system (CCS). The functional components of the CCS can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. Human diseases of the conduction system have been identified that alter impulse generation, impulse propagation, or both. CCS dysfunction is primarily due to acquired conditions such as myocardial ischemia/infarct, age-related degeneration, procedural complications, and drug toxicity. Inherited forms of CCS disease are rare, but each new mutation provides invaluable insight into the molecular mechanisms governing CCS development and function. Applying a multidisciplinary approach, which includes human genetic screening, biophysical analysis, and transgenic mouse technology, has yielded a broad array of gene families involved in maintaining normal CCS physiology (Figure 1). In this review, we discuss gene families that have been implicated in human CCS diseases of rhythm, conduction block, accessory conduction, and development (Table). We also investigate evolving therapeutic strategies that may serve as adjuvant or replacement therapy to current implantable pacemakers.

Figure 1.

View larger version:

Figure 1.

Cardiac conduction system cell. Genes identified in human cardiac conduction system disease are highlighted.

Table.

Genetic Basis of Conduction System Disease

Diseases of Automaticity

The human sinoatrial node (SAN) is a crescent-shaped, intramural structure with its head located subepicardially at the junction of the right atrium and the superior vena cava and its tail extending 10 to 20 mm along the crista terminalis.26 The SAN has complex 3-dimensional tissue architecture with central and peripheral components made up of distinct ion channel and gap junction expression profiles.27 Central and peripheral cells have different action potential characteristics and conduction properties (Figure 2).27Experimental and computational models have demonstrated that SAN heterogeneity is necessary to maintain normal automaticity and impulse conduction.28,–,30

Figure 2.

Figure 2.

Electrophysiological heterogeneity of the sinoatrial node (SAN). The central SAN, the site of dominant pacemaking, is electronically insulated from the hyperpolarizing atrial myocardium through the differential expression of connexins and ion channels. Peripheral SAN cells are electrophysiologically intermediate between central cells and atrial cardiomyocytes. SR indicates sarcoplasmic reticulum.

Pacemaker automaticity is due to spontaneous diastolic depolarization of phase 4, which depolarizes the membrane to threshold potential generating rhythmic action potentials. The current paradigm of SAN automaticity has been modeled as 2 clocks that function in concert, the “membrane voltage clock” and the “calcium clock.” The membrane voltage clock is produced by the net disequilibrium between the decay of outward potassium currents (IK) and the activation of inward currents that include, but are not limited to, background sodium-sensitive current (Ib Na), L- and T-type calcium currents (ICa,L,ICa,T), sustained inward (Ist) current, and hyperpolarization-activated current (If) (Figure 2).27,31,–,33

The subsarcolemmal calcium clock contributes to SAN diastolic depolarization through the spontaneous, rhythmic release of Ca2+ from the sarcoplasmic reticulum (SR) via the ryanodine type 2 receptor (RYR2).34 The local intracellular calcium (Cai) elevations drive the sodium-calcium exchange current (INCX) to substitute 1 intracellular Ca2+ for 3 extracellular Na+. The net gain in positive charge results in membrane depolarization.35The elevation of intracellular Ca2+ occurs in the latter third of diastolic depolarization and is sensitive to β-adrenergic stimulation.36

Human mutations affecting the voltage clock

  • (SCN5A and HCN4),

  • calcium clock (RYR2 and CASQ2), or both mechanisms

  • (ANKB) have been identified that negatively affect sinus node function.37,38

Diseases of Conduction BlockConduction block can occur at any level of the CCS and can manifest as sinoatrial exit block, atrioventricular block, infra-Hisian block, or bundle branch block. Impaired conduction can be caused by ion channel defects that alter action potential shape or by defective coupling between cardiomyocytes. Inherited defects in cardiac conduction have been linked to mutations in SCN5A and SCN1B (both affect phase 0) and KCNJ2 (affects phase 3 and 4). 

The cardiac sodium channel consists of the pore-forming α-subunit (encoded by SCN5A) and a modulatory β-subunit (encoded by SCN1B). The α-subunit contains a voltage sensor that allows for rapid activation in response to membrane depolarization. After depolarization, the sodium channel undergoes a period of inactivation, in which it is refractory to further impulses. SCN5A requires membrane repolarization to relieve the inactivated state. The inward rectifier potassium channel, Kir2.1, encoded by KCNJ2, maintains the resting membrane potential. Therefore, proper functioning of Nav1.5 and Kir2.1 is necessary for normal cardiac excitability.

SCN5A

Progressive cardiac conduction defect, or Lev-Lenègre disease, is characterized by age-related, fibrosclerotic degeneration of the His-Purkinje system.6 Impulse propagation through the proximal ventricular conduction system progressively declines, resulting in bundle branch blocks and eventually complete atrioventricular block. An inherited form of Lev-Lenègre disease is associated with loss of function mutations in SCN5A and can exist alone or as overlap syndromes with Brugada or long QT syndrome 3.6 Inherited progressive cardiac conduction defect is associated with a high risk of complete atrioventricular block and Stoke-Adams syncope without ventricular dysrhythmia.7 Schott et al8 identified a mutation in SCN5A that cosegregates with Lenègre disease in a large French family. Affected individuals had variable degrees of conduction block requiring pacemaker implantation in 4 family members because of syncope or complete heart block. Linkage analysis and candidate gene sequencing identified a T>C substitution at position +2 of the donor splice site of intron 22 (IVS22+2 T>C), which results in a mutant lacking the voltage-sensitive segment.8 Functional analysis demonstrated no transient inward sodium current in response to depolarization, consistent with a loss-of-function mutation.6

SCN1B

The majority of patients with Brugada and conduction disease do not have SCN5Amutations. Therefore, modifiers of Nav1.5 expression or function have become the target of candidate gene sequencing approaches. Watanabe et al9 identified SCN1B mutations in 3 families with conduction disease with or without Brugada syndrome. Coexpression of mutant β-subunits with Nav1.5 resulted in diminished sodium current.

KCNJ2

Mutations in KCNJ2 have been found in a rare autosomal dominant condition called Andersen-Tawil syndrome, characterized by periodic paralysis, dysmorphic features, polymorphic ventricular tachycardia, and cardiac conduction disease.10,11 ECG evaluation of 96 patients with Andersen-Tawil syndrome from 33 unrelated kindreds revealed conduction defects at multiple levels from the atrioventricular node to the distal conduction system.55 Cardiomyocytes expressing a dominant-negative subunit of Kir2.1 exhibited a 95% reduction in IK1, resulting in significant action potential prolongation. Mouse models of Andersen-Tawil syndrome exhibited a slower heart rate and significant slowing of conduction.56,57

Diseases of Accessory Conduction

Wolff-Parkinson-White (WPW) syndrome is characterized by preexcitation of ventricular myocardium via an accessory pathway (bundle of Kent) that bypasses the normal slow conduction through the atrioventricular node. Ventricular preexcitation is common, with a disease prevalence of 1.5 to 3 per 1000 people.22,58 Histological evaluation of Kent bundles resected from human subjects displayed features of typical ventricular myocytes with expression of connexin 43 (Cx43).59 The expression of high-conductance gap junctions in bypass tracts enables them to preexcite ventricular myocardium, manifesting as a short PR and a slurred QRS complex, or “delta wave,” on the ECG. The vast majority of WPW cases are sporadic, and the underlying mechanism remains unknown; however, rare inherited forms have been reported. Vidaillet et al60 determined that 3.4% of probands with WPW had 1 or more first-degree relatives with accessory conduction.

PRKAG2

A familial form of WPW with an autosomal dominant mode of transmission was identified in 2 families. Thirty-one affected individuals had evidence of preexcitation and cardiac hypertrophy. A missense mutation in PRKAG2 was identified that results in a constitutively active form of the γ2 regulatory subunit of AMP-activated protein kinase.22,23 Under normal conditions, AMP-activated protein kinase responds to energy-depleted states by increasing glucose uptake and promoting glycolysis. Transgenic mice expressing a heart-restricted, constitutively active mutant, PRKAG2N488I, recapitulated the human WPW phenotype of cardiac hypertrophy, preexcitation, and conduction defects. The predominant histological finding was ventricular myocyte engorgement with glycogen-laden vacuoles. The disruption of the annulus fibrosus by vacuolated ventricular myocytes resulted in the preexcitation phenotype.61 Using a mouse model of reversible glycogen-storage defect, Wolf et al62 demonstrated that the cardiomyopathy and CCS degeneration seen in PRKAG2N488I mice were reversible processes.

BMP2

Lalani et al24 reported a novel WPW syndrome associated with microdeletion of the bone morphogenetic protein-2 (Bmp2) region within 20p12.3 that is characterized by variable cognitive deficits and dysmorphic features. The BMPs are members of the transforming growth factor-β superfamily and play a critical role in cardiac development. Mice with cardiac deletion of BMP receptor type Ia (Bmpr1a) were embryonic lethal before E18.5 because of abnormal development of trabecular and compact myocardium, interventricular septum, and endocardial cushion.63 More restricted deletion of Bmpr1a in the atrioventricular canal resulted in defective atrioventricular valve formation and maturation defects in the annulus fibrosus, resulting in preexcitation.64,65

 

Diseases of CCS Development

Congenital heart disease is the most common form of birth defect, affecting 1% to 2% of live births.66 Arrhythmias may result from defective CCS specification/patterning, malformation or displacement of the conduction system, altered hemodynamics, prolonged hypoxic states, or postoperative sequelae.67,68 Developmentally, the conduction system derives from myocardial precursor cells within the fetal heart.69,–,71The process by which conduction cells are specified or recruited into a “conduction” versus “working myocyte” lineage is determined by the regional expression of transcription factors.69,–,74 The main transcription factors identified in human CCS development are the T-box and homeobox factors.

TBX5

Holt-Oram syndrome is an autosomal dominant condition characterized by preaxial radial ray limb deformities (defects of the radius, carpal bones, and/or thumbs) and cardiac septation defects. The septal defects are typically ostium secundum atrial septal defects, muscular ventricular septal defects, and atrioventricular canal defects. Patients with Holt-Oram syndrome manifest variable degrees of CCS dysfunction, such as sinus bradycardia and atrioventricular block, even in the absence of overt structural heart disease. In 1997, Basson et al18 screened 2 families with Holt-Oram syndrome and identified mutations in the T-box transcription factor, TBX5. The T-box transcription factors can function as transcriptional activators or repressors and are known to be critical regulators of cardiac specification and differentiation. Seven TBX family members are expressed in the developing heart, 3 of which (TBX1, TBX5, TBX20) have been linked to human congenital heart disease.75

Mice deficient in Tbx5 were embryonic lethal at E10.5 because of arrested development of the atria and left ventricle. Tbx5+/− mice recapitulated the upper limb and cardiac manifestations of human Holt-Oram syndrome, including the conduction abnormalities.72,76 Significant maturation defects in the atrioventricular canal and ventricular conduction system were present.76 Moskowitz et al76 demonstrated thatTbx5+/− mice have maturation failure of the atrioventricular canal manifesting as persistent atrioventricular rings around the tricuspid and mitral valves. Patterning defects were noted in the His bundle and bundle branches, including complete absence of right bundle branch formation in some cases. Expression of CCS-enriched markers, such as atrial natriuretic factor and Cx40, were found to be significantly downregulated, implicating TBX5 as a transcriptional activator of these genes. TBX5 and the homeobox transcription factor NKX2-5 were found to act synergistically in upregulating atrial natriuretic factor and Cx40 expression.76

Conduction Disease Associated With Neuromuscular Disorders

Neuromuscular disorders represent a diverse collection of diseases that commonly present with cardiac involvement. Mutations have been identified in genes involved in the cytoskeleton, nuclear envelope, and mitochondrial function. Cardiac involvement typically manifests as dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, and atrial and ventricular dysrhythmias.82

EMD and LMNA

Mutations affecting the nuclear envelope have been associated with significant CCS dysfunction. The inner membrane of the nuclear envelope is a highly organized structure, composed of integral membrane proteins and nuclear cytoskeletal proteins that function together in higher-order chromatin structure and transcriptional regulation. The lamins (A, B, and C) are an integral part of an intermediate filament network that imparts structural rigidity to the inner nuclear membrane. Emerin, a member of the nuclear lamina-associated protein family, putatively mediates anchoring of chromatin to the cytoskeleton. Mutations in emerin (EMD) or lamin A/C (LMNA) result in X-linked Emery-Dreifuss muscular dystrophy and autosomal dominant Emery-Dreifuss muscular dystrophy,20respectively. Individuals with Emery-Dreifuss muscular dystrophy develop progressive skeletal muscle weakness in the first decade of life and cardiac involvement (dilated cardiomyopathy and atrioventricular block) in the second decade.82,83

Arimura et al84 engineered a mouse model of autosomal dominant Emery-Dreifuss muscular dystrophy by knocking-in an Lmna missense mutation (H222P) previously identified from a family with typical autosomal dominant Emery-Dreifuss muscular dystrophy. The mouse model faithfully recapitulated the human disease with LmnaH222P/H222P mice exhibiting locomotive defects, dilated cardiomyopathy, and CCS dysfunction. Telemetric evaluation of the mutant mice revealed PR prolongation and QRS complex widening. A similar CCS defect was seen in mice haploinsufficient in the Lmna gene. Lmna+/− mice exhibited sinus bradycardia with variable degrees of atrioventricular block. Histological evaluation of these mice revealed nuclear deformation and apoptosis in atrioventricular node cells.85 Another engineered mouse line expressing LmnaN195K, known to cause autosomal dominant dilated cardiomyopathy with conduction disease in humans,86 exhibited high-grade atrioventricular block and complete heart block. Biochemical evaluation revealed reduced expression and mislocalization of Cx40 and Cx43 in mutant atrial tissue.87 Desmin staining also revealed structural defects of the sarcomere and intercalated discs.87

Genome-wide expression profiling of Lmna H222P mouse hearts revealed significant increases in mitogen-activated protein kinase (MAPK) signaling pathways.88Hyperactivation of MAPK pathways is associated with cardiomyopathy and CCS dysfunction. A significant increase of the activated forms of 2 MAPKs, JNK and ERK1/2, was noted in mutant hearts that predated the onset of overt or molecularly defined cardiomyopathy.88 Treatment of Lmna H222P mice with an inhibitor of ERK phosphorylation abrogated the increase in biomarkers of cardiomyopathy and restored ejection fraction to normal levels. These findings directly link MAPK hyperactivation to the cardiomyopathic phenotype in Lmna H222P mice.89

On the basis of the phenotypes of these mouse models, lamin A/C appears to maintain the functional integrity of the CCS in 2 ways: (1) protection of the nucleus against mechanical stress and (2) maintenance of proper chromatin organization to ensure accurate gene expression, such as in connexin expression and MAPK signaling pathways.83

Future Directions

Linkage analysis with positional cloning has been a highly effective means of identifying gene mutations within kindreds of monogenic disease. More than 1000 genes have been identified with this approach, including those in this review. With the sequencing of the human genome, the promise of identifying genetic causes of complex, multifactorial diseases is becoming more of a reality. One major step in this direction was the development of genome-wide association studies.94

The genome-wide association study is a test of association between a disease and genetic markers that span the entire genome. The technique relies on the fact that variance at one locus predicts with high probability variance of an adjacent locus because of linkage disequilibrium. In other words, there is nonrandom cosegregation of a series of genetic markers that are close together in the genome. This cluster of linked markers is known as a haplotype. The first study of haplotype structure within 4 populations (Yoruban, Northern/Western Europeans, Chinese, and Japanese) was published in Naturein 2005 by the International HapMap Consortium. Their work reported that individual genetic markers (single nucleotide polymorphisms) predict adjacent markers typically with a resolution of ≈30 000 bp. Considering that the human genome is ≈3×109 bp, they projected that <500 000 single nucleotide polymorphisms would be needed to survey the entire genome for all common genetic variants.94,95

Genome-wide association studies have now been used to identify genetic variants that influence ECG parameters in different populations. Intermediate parameters, such as heart rate or PR interval, were used as surrogate markers of disease for 2 reasons: (1) They have an association with cardiovascular morbidity and atrial fibrillation, and (2) they have tighter associations with gene variants than the actual disease. Holm et al96reported several genome-wide associations using a cutoff P value <1.6×10−9. One locus harboring MYH6 was associated with heart rate, 4 loci (TBX5, SCN10A, CAV1, andARHGAP24) were associated with PR interval, and 4 loci (TBX5, SCN10A, 6p21, and10q21) were associated with QRS duration. They went on to test these associations with individuals manifesting different arrhythmias in an Icelandic and Norwegian population. Correlations were found between atrial fibrillation and TBX5 and CAV1 (P=4.0×10−5 andP=0.00032, respectively), between advanced atrioventricular block and TBX5 (P=0.0067), and between pacemaker implantation and SCN10A (P=0.0029).

Similar loci were identified by 2 additional independent genome-wide association studies in a European population and an Indian Asian population. Pfeufer et al97 reported 9 loci that were highly associated with PR interval (P<5×10−8) from a meta-analysis of the CHARGE Consortium with >28 000 European subjects. One locus had associations with 2 sodium channels (SCN10A and SCN5A), and 6 loci were near genes involved in cardiac development (CAV1-CAV2, NKX2-5, SOX5, WNT11, MEIS1, and TBX5-TBX3). Of these,SCN10A, SCN5A, CAV1-CAV2, NKX2-5, and SOX5 were found to be associated with atrial fibrillation. Chambers et al98 also reported the association between SCN10A and PR interval in 6543 Indian Asians. Physiological testing of Scn10a-deficient mice revealed shortened PR intervals in knockout mice with no significant difference in all other ECG and echocardiographic parameters.

The discovery of novel gene families associated with human conduction and arrhythmic diseases with the use of genome-wide association studies is well under way. Identification of SCN10A by 3 independent groups studying different populations confirms the fidelity of this approach. Further experiments confirming the significance of these associations will need to be performed. In addition to identifying novel gene targets, this technique will also aid in the discovery of new associations with noncoding regions in which new epigenetic modifiers and transcriptional/translational regulators, such as microRNAs, will be identified.

Therapeutic Strategies

The current standard of care for symptomatic bradycardia due to conduction system disease is the implantation of an electronic pacemaker. Despite their success, electronic pacemakers have limitations, which include lead complications, finite battery life, potential for infection, lack of autonomic responsiveness, and size restriction in younger patients. These limitations have spurred on the development of biological pacemakers, the premise of which is to restore pacemaking activity with the use of viral-based or stem cell–based gene delivery systems.99 The identification and characterization of genes involved in generating pacemaker currents have allowed biological pacemaker technology to become a reality.

The restoration of sinus pacing rates can be achieved by modulating inward and outward currents to establish or increase the slope of diastolic depolarization in cardiac tissue. Increasing inward currents and/or decreasing outward currents increase the slope of diastolic depolarization and therefore the pacing rate. Genes that have been investigated or are under current investigation include the following: (1) β2-adrenergic receptor,100,101(2) dominant-negative Kir2.1 mutants,102 (3) adenylate cyclase type VI (ACVI),103,104and (4) HCN channels.105 The β2-adrenergic receptor and adenylate cyclase type VI both increase cAMP levels, leading to activation of endogenous HCN channels and calcium clock mechanisms. Although initial animal models using the β2-adrenergic receptor showed promise with transient increases in heart rate, the potential for proarrhythmia and the inability of this approach to establish de novo pacemaker activity limited its efficacy.101

Another approach focused on modifying ionic currents that convert working myocardial cells, which have relatively stable diastolic potentials, into cells with phase 4 diastolic depolarization. It was postulated that atrial and ventricular myocytes have the potential for automaticity, but that hyperpolarizing currents, such as IK1, prevent diastolic depolarization by stabilizing the resting membrane potential. Miake et al102 confirmed this hypothesis when they demonstrated that adenoviral delivery of a dominant-negative Kir2.1 construct into the left ventricle of guinea pigs resulted in conversion of quiescent myocytes into pacemaker cells. Unfortunately, significant action potential prolongation limited the clinical utility of this treatment strategy.102

Rosen and colleagues105,106 demonstrated that automaticity could be induced in quiescent myocardium with the use of heterologous expression of HCN channels that produce the pacemaker current If. Qu and Plotnikov et al demonstrated that stable autonomous rhythms could be generated when adenovirus encoding HCN2 was injected into the left atrium105 or left bundle branch106 of a canine heart. To bypass the limitations of viral-based systems, such as host immune response, several groups reported the successful use of cell-based delivery systems. Plotnikov et al107 reported the successful implantation of human mesenchymal stem cells expressing HCN2 in the left ventricle of a canine model of atrioventricular block. Dogs maintained stable ectopic pacemaker activity for >6 weeks without the use of immunosuppression.107 Human mesenchymal stem cells electronically couple to host myocardium through gap junctions; therefore, conditions with significant gap junction remodeling may affect the efficacy of this method.

Although standalone biological pacemakers may be far into the future, adjuvant biological pacemakers may find real-world utility for current deficiencies of electronic pacemakers, such as limited battery life and device infections. For example, biological preparations used in conjunction with device therapy may be used to extend battery life, decreasing the frequency of generator changes. Transient injectable pacemakers may also function as bridge therapy after lead extraction of an infected device. The need for adjuvant biological pacemakers is clear, but continued refinement of gene- and cell-based delivery systems will be necessary to make this technology a reality.99

Conclusion

Although rare, inherited arrhythmias have become an invaluable tool in identifying the genetic determinants of CCS function. Each new mutation enhances our understanding and appreciation of the biochemical and structural complexity needed for cardiac impulse generation and propagation. This methodology is hampered, however, by the relative scarcity of inherited conditions affecting the CCS. The addition of genome-wide association studies has broadened this search for novel genes beyond rare familial afflictions to include common, multifactorial conditions. It is hoped that this exciting new frontier will bring to light the complex interplay of genes and genetic/epigenetic modifiers that influence the prevalence of common diseases. These genetic screens will ultimately yield a bevy of new gene targets for pharmaceutical or gene-based therapeutics of the future.

Sources of Funding

Studies in the Fishman laboratory are supported by National Institutes of Health grants HL64757, HL081336, and HL82727 and a New York State STEM award (to Dr Fishman) and a Heart Rhythm Foundation Fellowship (to Dr Park).

Genetics of Atrioventricular Conduction Disease in Humans.

Benson DW.

Source

Division of Cardiology, ML7042, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. woody.benson@cchmc.org

Abstract

Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.

http://www.ncbi.nlm.nih.gov/pubmed/15372490

Additional Studies on Genetic Congenital AV Block

1) 12738236
Na+ channel mutation leading to loss of function and non-progressive cardiac conduction defects.
BACKGROUND: We previously described a Dutch family in which congenital cardiac conduction disorder has clinically been identified. The ECG of the index patient showed a first-degree AV block associated with extensive ventricular conduction delay. Sequencing of the SCN5A locus coding for the human cardiac Na+ channel revealed a single nucleotide deletion at position 5280, resulting in a frame-shift in the sequence coding for the pore region of domain IV and a premature stop codon at the C-terminus. METHODS AND RESULTS: Wild type and mutant Na+ channel proteins were expressed in Xenopus laevis oocytes and in mammalian cells. Voltage clamp experiments demonstrated the presence of fast activating and inactivating inward currents in cells expressing the wild type channel alone or in combination with the beta1 subinut (SCN1B). In contrast, cells expressing the mutant channels did not show any activation of inward current with or without the beta1 subunit. Culturing transfected cells at 25 degrees C did not restore the Na+ channel activity of the mutant protein. Transient expression of WT and mutant Na+ channels in the form of GFP fusion proteins in COS-7 cells indicated protein expression in the cytosol. But in contrast to WT channels were not associated with the plasma membrane. CONCLUSIONS: The SCN5A/5280delG mutation results in the translation into non-function channel proteins that do not reach the plasma membrane. This could explain the cardiac conduction defects in patients carrying the mutation.
2) 12956334
The genetic origin of atrioventricular conduction disturbance in humans.
Atrioventricular (AV) conduction disturbance (block) describes impairment of the electrical continuity between the atria and ventricles. Clinical classification of AV block has utilized biophysical characteristics, usually the extent (1st, 2nd, 3rd degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is not known. In some casesAV block occurrence is associated with intrauterine exposure to maternal antibody (anti-Ro, anti-La), and other cases are associated with injury (e.g. surgery). Based on familial clustering of idiopathic AV block, a genetic cause has also been suspected. Published pedigrees show autosomal dominant inheritance, and associated heart disease is common (e.g. congenital heart malformation, cardiomyopathy, etc.). The latter finding is not unexpected given the common origin of working myocytes and elements of the specialized conduction system. Using genetic models incorporating reduced penetrance (presence of disease genotype in absence of phenotype), variable expressivity (presence of a disease genotype with variable phenotypes) and genetic heterogeneity (similar phenotypes, different disease genotypes), molecular genetic causes of AV block are being identified. These findings are significant as they provide insight into the molecular basis of a clinical condition previously defined only by biophysical characteristics.
3) 15372490
Genetics of atrioventricular conduction disease in humans.
Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV blockhas unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.

SOURCE:

Anti-Ro Antibodies and Reversible Atrioventricular Block

N Engl J Med 2013; 368:2335-2337 June 13, 2013DOI: 10.1056/NEJMc1300484

To the Editor:

Transplacental transfer of anti-Ro antibodies is a well-known cause of conduction defects and permanent atrioventricular block in newborns.1 In adults, conduction disturbances related to these antibodies are rare.2

We report a case of a 26-year-old woman with no history of this condition who was admitted to the hospital through the emergency department after having several syncopal episodes. Electrocardiography (ECG) performed while the patient was at rest showed complete atrioventricular block and ventricular escape rhythm associated with left bundle-branch block (Figure 1AFIGURE 1Electrocardiographic Findings.). Laboratory evaluation included a positive test for antinuclear antibodies (with the HEp-2 cell substrate) at a titer of 1:320, with a speckled pattern and specificity for extractable nuclear antigens, including antibodies against Ro52 confirmed by means of immunoblot and enzyme-linked immunosorbent assays (first measurement of antibodies, 1.2 U per milliliter). No clinical manifestations of rheumatologic disease were present. Other causes of reversible atrioventricular block were ruled out. The patient had no history of cardiac surgery, ablation procedures, or drug use. There was no evidence of infiltrative diseases (e.g., sarcoidosis or amyloidosis) or myocardial ischemia, nor was there clinical suspicion of infectious diseases that cause conduction disturbances (e.g., Lyme disease or Chagas’ disease). Levels of electrolytes and thyrotropin were normal. Transthoracic echocardiography and magnetic resonance imaging were unremarkable.

During the first 4 days after admission, the patient had varying degrees of atrioventricular block. An electrophysiological study showed a mildly prolonged HV interval of 62 msec during sinus rhythm (normal values, 35 to 55 msec) and a pathologic response to atrial pacing, with atrioventricular block occurring after the deflection of the bundle of His during continuous stimulation at a fixed cycle length of 490 msec (Figure 1B). Intravenous methylprednisolone was initiated at a dose of 1 mg per kilogram of body weight per day, and 1:1 atrioventricular conduction was subsequently maintained on surface ECG. A second electrophysiological study during treatment showed normal atrioventricular conduction.

Maintenance immunosuppressive therapy with azathioprine (at a dose of 100 mg daily) and methylprednisolone (at a dose of 4 mg daily) was initiated and continued for 12 months. Serial anti-Ro (SS-A) levels fluctuated during follow-up and became negative after 1 year. Because of the uncertainty of the outcome, a backup pacemaker was implanted. The patient remained completely asymptomatic for 12 months with sustained normal atrioventricular conduction.

In this case of atrioventricular block in an adult patient with positive anti-Ro antibodies, we used electrophysiological testing to localize the conduction defect below the atrioventricular node. This finding, together with left bundle-branch block detected on ECG, suggests specific involvement of the Purkinje fibers. The pathogenesis of cardiac conduction disturbances in adults with positive anti-Ro (SS-A) antibodies remains unclear.3 Experimental studies suggest that anti-Ro antibodies interact with calcium channels and cause reversible inhibition of calcium currents. In fetal hearts, the internalization of these channels leads to apoptosis and fibrosis of the conduction tissue. The presence of a fully developed sarcoplasmic reticulum and the apparent lack of antibody-induced apoptosis in adult cardiomyocytes may explain the differential susceptibility of adult hearts to anti-Ro antibodies2 and, conceivably, the reversibility of the conduction disease in such persons.

Irene Santos-Pardo, M.D.
Melania Martínez-Morillo, M.D.
Roger Villuendas, M.D.
Antoni Bayes-Genis, M.D., Ph.D.
Hospital Universitari Germans Trias i Pujol, Badalona, Spain
abayes.germanstrias@gencat.cat

REFERENCES

1

Chameides L, Truex RC, Vetter V, Rashkind WJ, Galioto FM Jr, Noonan JA. Association of maternal systemic lupus erythematosus with congenital complete heart block. N Engl J Med 1977;297:1204-1207
Full Text | Web of Science | Medline

Lazzerini PE, Capecchi PL, Laghi-Pasini F. Anti-Ro/SSA antibodies and cardiac arrhythmias in the adult: facts and hypotheses. Scand J Immunol 2010;72:213-222
CrossRef | Web of Science | Medline

Costedoat-Chalumeau N, Georgin-la-Vialle S, Amoura Z, Piette J-C. Anti-SSA/Ro and anti-SSB/La antibody-mediated congenital heart block. Lupus 2005;14:660-664
CrossRef | Web of Science | Medline

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMc1300484?query=TOC

New Research on the Genetics of Conduction Disease
2010  
Heart failure clinics

  
conduction diseases (CD) include defects in impulse generation and conduction. Patients with CD may manifest a wide range of clinical presentations, from asymptomatic to potentially life-threatening arrhythmias. The pathophysiologic mechanisms underlying CD are diverse and may have implications for diagnosis, treatment, and prognosis. Known causes of functional CD include cardiac ion channelopathies or defects in modifying proteins, such as cytoskeletal proteins. Progress in molecular biology and genetics along with development of animal models has increased the understanding of the molecular mechanisms of these disorders. This article discusses the genetic basis for CD and its clinical implications.
(Beinart et al. 2010)
Beinart R, Ruskin J, et al. (2010). The genetics of conduction disease. Heart Fail Clin 6 (2): 201-14.
PMID: 20347788  DOI: 10.1016/j.hfc.2009.11.006  PII: S1551-7136(09)00108-1
2012  
PLoS genetics

  
(Curran and Mohler 2012)
Curran J and Mohler PJ (2012). Defining the Pathways Underlying the Prolonged PR Interval in Atrioventricular Conduction Disease. PLoS Genet. 8 (12): e1003154.
PMID: 23236297  DOI: 10.1371/journal.pgen.1003154  PII: PGENETICS-D-12-02668
2003  
BMC medical genetics

  
BACKGROUND: Mutations in the gene encoding the nuclear membrane protein lamin A/C have been associated with at least 7 distinct diseases including autosomal dominant dilated cardiomyopathy withconduction system disease, autosomal dominant and recessive Emery Dreifuss Muscular Dystrophy, limb girdle muscular dystrophy type 1B, autosomal recessive type 2 Charcot Marie Tooth, mandibuloacral dysplasia, familial partial lipodystrophy and Hutchinson-Gilford progeria.METHODS: We used mutation detection to evaluate the lamin A/C gene in a 45 year-old woman with familial dilated cardiomyopathy and conduction system disease whose family has been well characterized for this phenotype 1.RESULTS: DNA from the proband was analyzed, and a novel 2 base-pair deletion c.908_909delCT in LMNA was identified.CONCLUSIONS: Mutations in the gene encoding lamin A/C can lead to significant cardiac conductionsystem disease that can be successfully treated with pacemakers and/or defibrillators. Genetic screening can help assess risk for arrhythmia and need for device implantation.
(MacLeod et al. 2003)
MacLeod HM, Culley MR, et al. (2003). Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med. Genet. 4: 4.
PMID: 12854972  DOI: 10.1186/1471-2350-4-4
2012  
Heart (British Cardiac Society)

  
(MacRae 2012)
MacRae CA (2012). Pattern recognition: combining informatics and genetics to re-evaluate conduction disease. Heart 98 (17): 1263-4.
PMID: 22875820  DOI: 10.1136/heartjnl-2012-302408  PII: heartjnl-2012-302408
2004  
The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology

  
Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with diseasegene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.
(Benson 2004) – ORIGINAL FIRST PAPER on the Subject
Benson DW (2004). Genetics of atrioventricular conduction disease in humans. Anat Rec A Discov Mol Cell Evol Biol 280 (2): 934-9.
PMID: 15372490  DOI: 10.1002/ar.a.20099
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Other related articles published on this Open Access Online Scientific Journal, include the following:

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

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Ultrasound-based Screening for Ovarian Cancer

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Ecosystems & Industrial Concentration in the Medical Device Sector, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Medical Devices R&D and Inventions, tagged , , , , , , , , , , , , , , , , , , on April 28, 2013| 6 Comments »

Ultrasound-based Screening for Ovarian Cancer

Author: Dror Nir, PhD

Article 11.2.10 Ultrasound based Screening for Ovarian Cancer

Occasionally, I check for news on ovarian cancer screening. I do that for sentimental reasons; I started the HistoScanning project aiming to develop an effective ultrasound-based screening solution for this cancer.

As awareness for ovarian cancer is highest in the USA, I checked for the latest news on the NCI web-site. I found that to-date: “There is no standard or routine screening test for ovarian cancer. Screening for ovarian cancer has not been proven to decrease the death rate from the disease.

Screening for ovarian cancer is under study and there are screening clinical trials taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI Web site.”

I also found that:

Estimated new cases and deaths from ovarian cancer in the United States in 2013:

  • New cases: 22,240
  • Deaths: 14,030

To get an idea on the significance of these numbers, lets compare them to the numbers related to breast cancer:

Estimated new cases and deaths from breast cancer in the United States in 2013:

  • New cases: 232,340 (female); 2,240 (male)
  • Deaths: 39,620 (female); 410 (male)

Death rate of ovarian cancer patients is almost 4 times higher than the rate in breast cancer patients!

Therefore, I decided to raise awareness to the results achieved for ovarian HistoScanning in a double-blind multicenter European study that was published in European Radiology three years ago. The gynecologists who recruited patients to this study used standard ultrasound machines of GE-Medical. I would like as well to disclose that I am one of the authors of this paper:

A new computer-aided diagnostic tool for non-invasive characterisation of malignant ovarian masses: results of a multicentre validation study, Olivier Lucidarme et.al., European Radiology, August 2010, Volume 20, Issue 8, pp 1822-1830

Abstract

Objectives

To prospectively assess an innovative computer-aided diagnostic technology that quantifies characteristic features of backscattered ultrasound and theoretically allows transvaginal sonography (TVS) to discriminate benign from malignant adnexal masses.

Methods

Women (n = 264) scheduled for surgical removal of at least one ovary in five centres were included. Preoperative three-dimensional (3D)-TVS was performed and the voxel data were analysed by the new technology. The findings at 3D-TVS, serum CA125 levels and the TVS-based diagnosis were compared with histology. Cancer was deemed present when invasive or borderline cancerous processes were observed histologically.

Results

Among 375 removed ovaries, 141 cancers (83 adenocarcinomas, 24 borderline, 16 cases of carcinomatosis, nine of metastases and nine others) and 234 non-cancerous ovaries (107 normal, 127 benign tumours) were histologically diagnosed. The new computer-aided technology correctly identified 138/141 malignant lesions and 206/234 non-malignant tissues (98% sensitivity, 88% specificity). There were no false-negative results among the 47 FIGO stage I/II ovarian lesions. Standard TVS and CA125 had sensitivities/specificities of 94%/66% and 89%/75%, respectively. Combining standard TVS and the new technology in parallel significantly improved TVS specificity from 66% to 92% (p < 0.0001).

table 3

table 4

An example of an ovary considered to be normal with TVS.

An example of an ovary considered to be normal with TVS.

The same TVS false-negative ovary with OVHS-detected foci of malignancy. The presence of an adenocarcinoma was confirmed histologically.

The same TVS
false-negative ovary with OVHS-detected foci of malignancy. The presence of an
adenocarcinoma was confirmed histologically.

Conclusions

Computer-aided quantification of backscattered ultrasound is  highly sensitive for the diagnosis of malignant ovarian masses.

 Personal note:

Based on this study a promising offer for ultrasound-based screening method for ovarian cancer was published in:  Int J Gynecol Cancer. 2011 Jan;21(1):35-43. doi: 10.1097/IGC.0b013e3182000528.: Mathematical models to discriminate between benign and malignant adnexal masses: potential diagnostic improvement using ovarian HistoScanning. Vaes E, Manchanda R, Nir R, Nir D, Bleiberg H, Autier P, Menon U, Robert A.

Regrettably, the results of these studies were never transformed into routine clinical products due to financial reasons.

Other research papers related to the management of Prostate cancer were published on this Scientific Web site:

Beta-Blockers help in better survival in ovarian cancer

Ovarian Cancer and fluorescence-guided surgery: A report

Role of Primary Cilia in Ovarian Cancer

Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Warning signs may lead to better early detection of ovarian cancer

 

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T-helper cell recruitment governed by bystander B cells

Posted in Uncategorized, tagged , , , on April 26, 2013| Leave a Comment »

Reporter: Aviva Lev-Ari, PhD, RN

Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility

Nature 496, 523–527 (25 April 2013)

 

24 April 2013

Germinal centres support antibody affinity maturation and memory formation1. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle2, 3. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects4, 5, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program2, 6, 7. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

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#1 Amazon best seller among cell biology books: Secrets of Your Cells: Discovering Your Body’s Inner Intelligence by Sondra Barrett

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Interviews with Scientific Leaders, tagged , , , , on April 26, 2013| Leave a Comment »

#1 Amazon best seller among cell biology books: Secrets of Your Cells: Discovering Your Body’s Inner Intelligence by Sondra Barrett

Reporter: Aviva Lev-Ari, PhD, RN

This image has an empty alt attribute; its file name is ArticleID-44.png

WordCloud Image Produced by Adam Tubman

UPDATED on 5/9/2013 – based on Sondra’s e-mail to me on 5/9/2013

Sondra’s Voice on 5/9

I was SHOCKED and ecstatic to discover that the book hit #1 Amazon best seller among cell biology books.  It was also in the top 100 of “new thought” books.

Thank you so much for helping it get there.  If you already purchased a book, please take the time to write a review at Amazon,  GoodReads, Sounds True, wherever you enjoy reading about books.

If you haven’t yet received a copy, here’s an opportunity to win a free copy.

As mentioned last time, Tami Simon, founder and publisher of Sounds True, interviewed me recently for her Insights at the Edge series -Part 1:  YOUR CELLS ARE LISTENING.  If you’d like a candid look at my current and controversial interpretation of our cells’ intelligence, please listen.  You can also read the transcript of the interview. You may even discover for yourself, what your cells know to help you thrive.

Part two of the interview is now out.  It was fun to do.  You can download a file, read the transcript, enjoy!

I’m keeping this short and to the point.  You’ve helped make the book reach one goal – it can now be called an Amazon best-seller.  However an even bigger goal is to share the helpful information inside the book to folks who can use it – healers, people challenged by illness, stress, spiritual seekers, thinkers and tinkerers.

To that end, I am once again ‘out in the world’ doing book signings (July, August), workshops (August), and talks (September-November). I’d like to offer experential programs also to children so if you have any ideas or leads for that possibility, please let me know.

We’re also working on radio interviews and other media outreach.  What I am discovering – it’s as much work, if not more, promoting the book as it was to write it.  It is not so much just about the book, it’s what’s  inside.  Just like you and me, it’s what’s inside that is the most important to other people.

Stretch Your Self

One of the core themes in Secrets of Your Cells is the fact that tensions and stresses on our cells’ inner matrix  influence their actions and health.  When we extrapolate what has been learned by science about this structure of our cells, we find that it is a place where yoga, walking, stretching, dancing, singing, qigong, can have their beneficial effects.

A profound scientific discovery, first by Harvard scientist Dr. Donald Ingber, showed that stretching  and releasing tensions by the cell affects genetic expression. In other words, the simple practice of contracting and releasing physical tensions reverberates to our tiniest cells and even to our invisible consciousness.

Take your cells for a walk.  They will show their thanks in many ways.

Most promising forthcoming book by my friend, another University of California, Berkeley Alumna, Sondra Barett, PhD

Her acclaimed gift in Photography adorns the Cover Page of our forthcoming e-Book on Genomics, scroll down for the second image by Sondra Barett, PhD

http://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

Sondra’s Voice:

I’m writing to tell you about a forthcoming book, Secrets of Your Cells: Discovering

Your Body’s Inner Intelligence (Sounds True, on sale May 1, 2013) by Sondra Barrett,

PhD, biochemist, mind-body medicine teacher, and author.

About the book:

Secrets of Your Cells: Discovering Your Body’s Inner Intelligence puts cutting-edge

biology into practice for healing body, mind, and spirit. Bringing together a powerful

synthesis of easy-to understand science and ancient wisdom

traditions, “Secrets” offers a compelling and controversial new

look at our cells as our hidden teachers.

Researching children’s cancers brought medical scientist Sondra

Barrett, PhD into real life issues of families suffering, life, and

death. It also catapulted her into a spiritual quest to discover

more about healing.

In Secrets of Your Cells, Dr. Barrett takes an expansive

approach to our cellular universe. As she moves from our

molecular creation, she frames our cells’ roles in human health

and culture in a completely new and fresh way. By exploring the

development, design, and intelligence of human cells and working with people with lifethreatening

illnesses, Dr. Barrett became intrigued that perhaps the inner life of our cells

could add value to our own personal lives.

Beyond their biochemical abilities and knowledge for living, listening and thriving, our

cells carry powerful intelligence to assist us in letting go, diminishing stress and finding

deeper meaning in life.

• What can cells teach us about letting go that may influence genetic expression?

• What 5 things do our cells reveal about thriving physically and spiritually?

• What and where is cellular intelligence?

Willingly embracing the deep-rooted conflict between science and spirituality, Dr. Barrett

offers new controversial ideas that ancient sacred traditions may, in fact, have roots in

our cells and molecules. By searching for the sacred within our cells we might well find

the divine within ourselves.

One tip from your cells: Remembering gratitude with your heart, senses and mind of

your cells brings peacefulness to all of you.

For fans of Dr. Bruce Lipton (Biology of Belief) or Dr. Candace Pert (Molecules of

Emotion), Dr. Barrett’s provocative ideas and practical strategies will further inspire and

educate them.

Author’s BIO

Sondra Barrett, PhD, is a medical scientist and teacher with a degree in biochemistry

from the University of Illinois Medical School followed by a post-doctoral fellowship in

immunology and hematology at the University of California Medical School (UCSF). She

was on the faculty at UCSF for a decade engaged in basic cancer research, which led

her to bridge medical science and healing strategies for children and adults with lifethreatening

illnesses.

She has delivered programs throughout the United States as well as for University of

California, California Pacific Medical Center, Sonoma State, Apple Computer, Esalen,

California Institute of Integral Studies and numerous institutions throughout the Bay

Area. An award-winning photographer and long-time student of qigong and shamanism,

Sondra also explores the inner world of wine and our senses and is the author of book

Wine’s Hidden Beauty.

Book Title: SECRETS OF YOUR CELLS: Discovering Your Body’s Inner Intelligence

Author: Sondra Barrett, PhD

ISBN: 978-1-60407-626-4

ebook ISBN: 978-1-60407-819-0

Publication date: May 1, 2013

Publisher: Sounds True

Books are available online at Sounds True, Amazon, Barnes and Noble, Indie Books

and bookstores.

Additional Links

Online Interviews – “Insights at the Edge” – Sounds True publisher Tami Simon

Part 1 Your Cells are listening.

PART 2: Your Cells are listening. (Imagery, genetic expression, sacred symbols in our

cells

Press Room

Author’s website:

PRESS CONTACT: Wendy Gardner, WendyG@soundstrue.com,

303.665.3151 x114

CONTACT:

Sondra Barrett 707-799-0833

sondra@sondrabarrett.com

3171 Ross Rd. #305, Graton, CA 95444

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