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Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, Human Immune System in Health and in Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders, tagged anti-TNF, Crohn's disease, Cure, cytokine, endotoxin, immunomodulation, immunosuppression, inflammation, Inflammatory bowel disease, interleukins, lymphokines, Neutrophilia, Pfizer, Src family kinases, TLRs, Tofacitinib, Tumor necrosis factors, Ulcerative Colitis on September 13, 2012| 5 Comments »

Ulcerative colitis (Photo credit: Wikipedia)

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

Reporter: Larry Bernstein, MD

This is an overview of a recently published article about a new treatment for ulcerative colitis. It also reviews the use of a class of drug in inflammatory conditions, and introduces the problem of sepsis.

Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis.
WJ Sandborn, S Ghosh, J Panes, I Vranic, C Su, for the Study A3921063 Investigators
N Engl J Med 2012; 367:616-624 August 16, 2012
http://www.nejm.org/doi/full/10.1056/NEJMoa1112168?query=TOC

 

Ulcerative colitis  is a chronic inflammatory disease of the colon that belongs to a group of diseases lumped together as Inflammatory Bowel Disease (IBD). There is a distinction to be made between Crohn’s disease, which may be limited to the small intestine (regional enteritis), the terminal ileum, or a portion of the transverse colon, and ulcerative colitis.

In ulcerative colitis the inflammation is limited to the mucosa and submucosa, but in Crohn’s disease there is a deep penetration of the intestinal wall (fistula) that may extend to the peritoneum causing abscess, scarring, peritonitis and possibly volvulus, obstruction and gangrenous bowel, which necessitate surgical resection. IBD tends to occur in children and young adults, repeats in families, and requires dietary management (fluid intake, Metamucil, restriction of fiber) . It is characterized by abdominal pain, diarrhea, bleeding, weight loss, and episodic fever, but also may be associated with joint pain.
Conservative medical treatment focuses on suppressing the immune response using 5-ASA, azathioprine, 6-mercaptopurine. If severe, biologic therapy is used to treat patients with severe Crohn’s disease that does not respond to any other types of medication, such as a TNF (tumor necrosis factor) inhibitor which can have secondary effects, and they are not universally effective. The importance of immunity can’t be understated, it involves a large portion of immune system and primitive Toll-like receptors (TLRs) that trigger signaling pathways. TLRs represent an important mechanism by which the host detects a variety of microorganisms that colonize in the gut. Endothelial and epithelial cells, and resident macrophages are potent producers of inflammatory cytokines, interleukins, IL-1, IL-6, and TNF-α, which are distinguished from another set that is treated in this study. In addition, there is a balance that has to be achieved between suppression and upregulation in treatment, which is referred to as immunomodulation.
The opposite of immunosuppression is upregulation It is cental to recent advances in chemotherapy of melanolma, small cell carcinoma and NSCCL of lung, and treatment resistant prostate cancer. An example is ipilimumab, whic upregulates cytotoxic T-cells to destroy cancer cells, but it has runaway destructive effects on the GI tract.

This study investigates the use of tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain–containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.

The mechanism of drug action

Jak 1 and 3 inhibitor, which is targeted at blocking signaling involving gamma chain–containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. The result would be to block signaling involving (gamma chains)–suppressing “lymphokines” 2, 4, 7, 9, 15, and 21. The lymphocyte pool is regional, being the antibody mediated immune system of the Bursa of Fabricius (B-lymphocytes, as opposed to the thymic derived T-cells) that form the largest immune organ extending the length of the intestines and the stomach.  The family transmission suggests an epigenetic event.

• Gastrointestinal Tract
• Oropharynx – Tonsils
• Distal small intestine (ilieum) – Peyer’s Patches
• Appendix, cecum

However, this classification of the lymphocytes has much greater complexity than I indicate.  The so called B-cells have receptors that recognize foreign antigen, but the T-cells have similar receptors and are tied to both the innate and the adaptive immune response.  Lymphocytes are the predominant cells of the immune system, but macrophages and plasma cells are present also.  Lymphocytes circulate, alternating between the circulatory blood stream and the lymphatic channels.  The end result of the immune reaction is the production of specific antibodies and antigen-reactive cells. These cells are called lymphocytes and are found in the blood and in the lymphoid system.

See Appendix

Trial features: double-blind, placebo-controlled, phase 2 trial; Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks.
Study goal: evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis.

Primary outcome: a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.
Results and conclusion: The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo.
Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.
Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.)
Commentary: The study is only phase 2, and it is also limited to disease of the descending colon. The next phase will be necessary to determine the effect on a larger population at the selected dose, and will be necessary to determine both the size of the effect and identify unexpected adverse effects. We also have to keep in mind that the success of the study would limit the treatment to a subset of patients with IBD.

Efficacy of Proposed Treatment:

• it is effective at about 40% remission for 8 weeks compared to 10% for placebo, or an adjusted actual 30% for 8 weeks.
• A much larger study needs to be done to see how well the dose holds up, as well as the dosing interval. There are two factors that will affect the t1/2 of the drug so that 1/2 dose could be replaced at the end of t1/2.
• The dose of 15 mg was no better for clinical response.
• I would think that the next trial might give a loading dose of 15 mg, and then 7 mg (better that 3 mg) would be replaced every t1/2.  But this is more complicated than usual.

I identified two steps, not one direct effect.

• The inhibitor has to balance the production rate versus the removal rate of the T-cell population. The drug itself is not measured, only the effect. I know that albumin, the liver produced protein, has a half-life of removal of 21 days. Platelets are short shelf-life as well as rapid turnaround in plasma.
•  I don’t know what is the local production and removal rate of lymphocytes in the gut. That would be the key determinant for dosing.

The following may shed some light on what has been discussed:

Common characteristics of the lymphoid system.

• The lymphoid system involves organs and tissues where lymphocytic cells originate as lymphocyte precursors that mature and differentiate, and either lodge in the lymphoid organs or move throughout the body.
• Precursor cells originate in the yolk sac, liver, spleen, or bursa of Fabricius (or its mammalian equivalent, the bone marrow) in an embryo or fetus.
• Stem cells from bone marrow or embryonic tissues are deposited and mature into lymphocytes in the central or primary lymphoid organs, which include the thymus and the bursa or bone marrow. Upon maturation, the lymphocytes undergo further maturation toward immunocompetence and production of immunoglobulins or sensitized lymphocytes.

Adaptive immunity has 2 main classes:

• Antibody-mediated – B Lymphocyte
• Cell-mediated – T Lymphocyte

Lymph follicles are our point of reference:

• Organized concentrations of Lymphocytes
• No capsule, covered by epithelia
• Nodules are unit structure seen in a node
• Oval concentrations in meshwork of reticular cells

If pathogens initially evade constitutive defenses, they may yet be attacked by more specific inducible defenses. The inducible defenses are so-called because they are induced upon primary exposure to a pathogen or one of its products. The inducible defenses must be triggered in a host, take time to develop, and are a function of the immune response. The type of resistance thus developed in the host is called acquired immunity.

Three important features of the immunological system relevant to host defense and/or “immunity are:

1. Specificity. An antibody or reactive T cell will react specifically with the antigen that induced its formation; it will not react with other antigens. Generally, this specificity is of the same order as that of enzyme-substrate specificity or receptor-ligand specificity.

• The specificity of the immune response is explained on the basis of the clonal selection hypothesis: during the primary immune response, a specific antigen selects a pre-existing clone of specific lymphocytes and stimulates exclusively its activation, proliferation and differentiation.

2.  Memory. The immunological system has a “memory”.

• Once the immunological response has reacted to produce a specific type of antibody or reactive T cell, it is capable of producing more of the antibody or activated T cell more rapidly and in larger amounts.

3. Tolerance. An animal generally does not undergo an immunological response to its own (potentially-antigenic) components.

• The animal is said to be tolerant, or unable to react to its own potentially-antigenic components.

Gene expression – CD28 signal transduction , λδ T repertoire and antigen reactivity

Efficient lymphokine gene expression appears to require both T-cell antigen receptor (TCR) signal transduction and an uncharacterized second or costimulatory signal. CD28 is a T-cell differentiation antigen that can generate intracellular signals that synergize with those of the TCR to increase T-cell activation and interleukin-2 (IL-2) gene expression.

• These investigators examined the effect of CD28 signal transduction on granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and gamma interferon (IFN-gamma) promoter activity.
• Stimulation of CD28 in the presence of TCR-like signals increases the activity of the GM-CSF, IL-3, and IFN-gamma promoters by three- to sixfold.
• As previously demonstrated for the IL-2 promoter, the IL-3 and GM-CSF promoters contain distinct elements of similar sequence which specifically bind a CD28-induced nuclear complex.
• Mutation of the CD28 response elements in the IL-3 and GM-CSF promoters abrogates the CD28-induced activity without affecting phorbol ester- and calcium ionophore-induced activity.
• These studies indicate that the TCR and CD28-regulated signal transduction pathways, coordinately regulate the transcription of several lymphokines, and the influence of CD28 signals on transcription is mediated by a common complex.

Fraser JD, Weiss A.  Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28. Mol Cell Biol. 1992 Oct;12(10):4357-63.

These investigators looked at the relevance λδ T repertoire and the antigen reactivity of clones isolated from CSF in multiple sclerosis (MS).

• they found an increased percentage of V delta 1+ cells as compared to peripheral blood of the same donors.
• Phenotypic analysis of cells from MS CSF with V gamma- and V delta-specific monoclonal antibodies (mAb) showed that the V delta 1 chain is most frequently associated with gamma chains belonging to the V gamma 1 family.
• Sequence analysis of TCR genes revealed heterogeneity of junctional regions in both delta and gamma genes indicating polyclonal expansion. gamma delta clones were established and some recognized glioblastoma, astrocytoma or monocytic cell lines.
• Stimulation with these targets induced serine esterase release and lymphokine expression characteristic of the TH0-like phenotype.
• Remarkably, these tumor-reactive gamma delta cells were not detected in the peripheral blood using PCR oligotyping, but were found in other CSF lines independently established from the same MS patient.
• in the CSF there is a skewed TCR gamma delta repertoire and suggest that gamma delta cells reacting against brain-derived antigens might have been locally expanded.

Nick S, Pileri P, Tongiani S, Uematsu Y, Kappos L, De Libero G. T cell receptor gamma delta repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive gamma delta clones. Eur J Immunol. 1995 Feb;25(2):355-63. PMID: 1328852 [PubMed – indexed for MEDLINE] PMCID: PMC360359 Free PMC Article

B Cells and T Cells:  Addendum

users.rcn.com/jkimball.ma.ultranet/…/B/B_and_Tcells.htmlShareAIDS; Building the T-cell Repertoire; Gamma/Delta T Cells … T cells specific for this structure (i.e., with complementary TCRs) bind the B cell and; secrete lymphokines that: … Each chain has a variable (V) region and a constant (C) region.

Although mature lymphocytes all look pretty much alike, they are extraordinarily diverse in their functions. The most abundant lymphocytes are:

• B lymphocytes (often simply called B cells) and
• T lymphocytes (likewise called T cells).
• B cells are produced in the bone marrow.
•  The precursors of T cells are also produced in the bone marrow but leave the bone marrow and mature in the thymus (which accounts for their designation).
• Each B cell and T cell is specific for a particular antigen. What this means is that each is able to bind to a particular molecular structure.

The specificity of binding resides in a receptor for antigen:

• the B cell receptor (BCR) for antigen and
• the T cell receptor (TCR) respectively.

Both BCRs and TCRs share these properties:

• They are integral membrane proteins.
• They are present in thousands of identical copies exposed at the cell surface.
• They are made before the cell ever encounters an antigen.
• They are encoded by genes assembled by the recombination of segments of DNA.

How antigen receptor diversity is generated.

• They have a unique binding site.
• This site binds to a portion of the antigen called an antigenic determinant or epitope.
  The binding, like that between an enzyme and its substrate depends on complementarity of the surface of the receptor and the surface of the epitope.
• The binding occurs by non-covalent forces (again, like an enzyme binding to its substrate).

Successful binding of the antigen receptor to the epitope, if accompanied by additional signals, results in:

• stimulation of the cell to leave G0 and enter the cell cycle.
• Repeated mitosis leads to the development of a clone of cells bearing the same antigen receptor; that is, a clone of cells of the identical specificity.

BCRs and TCRs differ in:

• their structure;
• the genes that encode them;
• the type of epitope to which they bind.

heavy (H) plus kappa (κ) or lambda (λ) chains for BCRs;

alpha (α) and beta (β) or gamma (γ) and delta (δ) chains for TCRs)

……is encoded by several different gene segments.

The genome contains a pool of gene segments for each type of chain. Random assortment of these segments makes the largest contribution to receptor diversity.

There are two types of T cells that differ in their TCR:

alpha/beta (αβ) T cells. Their TCR is a heterodimer of an alpha chain with a beta chain. Each chain has a variable (V) region and a constant (C) region. The V regions each contain 3 hypervariable regions that make up the antigen-binding site. [Link]

gamma/delta (γδ) T cells. Their TCR is also a heterodimer of a gamma chain paired with a delta chain.

The discussion that follows now concerns alpha/beta T cells. Gamma/delta T cells, which are less well understood, are discussed at the end [Link].

The TCR (of alpha/beta T cells) binds a bimolecular complex displayed at the surface of some other cell called an antigen-presenting cell (APC).

Most of the T cells in the body belong to one of two subsets. These are distinguished by the presence on their surface of one or the other of two glycoproteins designated:

• CD8+ T cells bind epitopes that are part of class I histocompatibility molecules. Almost all the cells of the body express class I molecules.
• CD4+ T cells bind epitopes that are part of class II histocompatibility molecules. Only specialized antigen-presenting cells express class II molecules.

These include:

• dendritic cells
• phagocytic cells like macrophages and
• B cells!

Building the T-cell Repertoire

T cells have receptors (TCRs) that bind to antigen fragments nestled in MHC molecules. But,

• all cells express class I MHC molecules containing fragments derived from self proteins;
• many cells express class II MHC molecules that also contain self peptides.

This presents a risk of the T cells recognizing these self-peptide/self-MHC complexes and mounting an autoimmune attack against them. Fortunately, this is usually avoided by a process of selection that goes on in the thymus (where all T cells develop).

Appendix

FDA approves Abbott Humira as Ulcerative Colitis therapy
PBR Staff Writer Published 01 October 2012
The USFDA has approved Abbott’s Humira (adalimumab) for the treatment of adult patients with moderate to severe Ulcerative Colitis (UC) when certain other medicines have not worked well enough.
Humira, which works by inhibiting tumour necrosis factor-alpha (TNF-alpha), was previously approved for the treatment of moderate to severe Crohn’s disease.

Abbott Global Pharmaceutical Research and Development senior vice president John Leonard said, “Since the first FDA approval of HUMIRA in late 2002, Abbott has continued to investigate the medication in multiple conditions with the goal of bringing this treatment option to more patients who may benefit from it.”

The approval was based on the data from two phase 3 studies, ULTRA 1 and ULTRA 2, both of which enrolled adult patients who had moderately to severely active UC despite concurrent or prior treatment with immunosuppressants.  This should have special significance in view of the past history, which may be explainable, but also keep in mind the serious risks of complications.

It is worthy of comment that anti-TNF treatment was previously rejected in trials for use in sepsis leading to Multiple Organ Dysfunction Syndrome and cardiovascular collapse (shock).  More recently an anti-Factor Xa drug, Xygris,  to prevent hypercoagulability only in severe sepsis was withdrawn.

Anti TNF for sepsis

1.   In a group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively.

Panacek EA, Marshall JC, Albertson TE, Johnson DH, at al.  Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004 Nov;32(11):2173-82.

2. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p =.003), but TNF levels were not found to be a prognostic indicator. TNFlevels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p <.001) and outcome was poor (41% vs. 71% survival; p =.007) in patients who were in shock at study entry when compared with septic patients not in shock.

Fisher CJ Jr, Opal SM, Dhainaut JF, Stephens S, et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group.  Critical Care Medicine [1993, 21(3):318-327] (PMID:8440099)

3.  Large clinical trials involving anti-TNF-alpha MAb have proven to be less conclusive and less successful than clinicians had hoped. The International Sepsis Trial (INTERSEPT), reported by Cohen and Carlet,^[14] was designed to assess the safety and efficacy of Bay x 1351, a murine MAb to recombinant human TNF-alpha in patients with sepsis. The INTERSEPT trial was an international, multicenter trial involving 564 patients, 420 of whom were in septic shock. The main study end point — 28-day survival — showed no significant benefit for the treatment group vs controls. Prospectively, the researchers identified 2 secondary variables: shock reversal and frequency of organ failure. Post-28-day survival, treatment groups showed a more rapid reversal of shock compared with placebo, as well as a significant delay in time to first organ failure. The researchers concluded that the anti-TNF-alpha antibody may have a role as adjunctive therapy, but that such a putative role requires more in the way of clinical trial confirmation.

In the TNF-alpha MAb Sepsis Study Group trial, also called the North American Sepsis Trial I (NORASEPT I), Abraham and associates^[15] evaluated the efficacy and safety of an anti-TNF-alpha MAb in the treatment of patients with sepsis syndrome. A total of 994 patients in 31 hospitals were enrolled in a randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Patients were stratified into shock/nonshock subgroups, then randomized to receive a single infusion of 15 mg/kg of anti-TNF-alpha MAb, 7.5 mg/kg of anti-TNF-alpha MAb, or placebo. The researchers found that among all infused patients, there was no difference in mortality among those receiving therapy and those on placebo. In septic shock patients (n = 478), however, there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion. At day 3, 25 of 162 patients treated with the 15 mg/kg dose died; 22 of 156 treated with 7.5 mg/kg died, but 44 of 160 placebo-treated patients died (15 mg/kg: 44% mortality reduction vs placebo, P = .01; 7.5 mg/kg: 48% reduction vs placebo, P = .004). However, at day 28, the reduction in mortality of shock patients was not significant for either dose of the anti-TNF-alpha MAb relative to placebo.

All studies of MAb against TNF in septic patients and found an absolute risk reduction of 3.5%. The most recently published clinical trial found an absolute reduction in mortality of 3.7%.

Of note, therapy with MAb against TNF has been proven efficacious for treatment of rheumatoid arthritis and is approved by the US Food and Drug Administration for this purpose.

New directions in research on severe sepsis. Human trials with TNF alpha.  Medscape.

4. Why the poor results with sepsis?

This would be sufficient for another discussion.  That can be left for another day.

Sepsis

Sepsis syndrome, or sepsis, is an adverse systemic response to infection that includes fever, rapid heartbeat and respiration, low blood pressure and organ dysfunction associated with compromised circulation.

LPS is a major constituent of Gram-negative bacterial cell walls (see section 3-0) and is essential for membrane integrity. The portion of LPS that causes shock is the innermost and most highly conserved phosphoglycolipid, lipid A. Lipid A is a phosphoglycolipid consisting of a core hexosamine disaccharide with ester- and amide-linked acylated fatty acid tails arranged in either asymmetric or symmetric arrays that anchor the structure in the membrane. It acts by potently inducing inflammatory responses that are life-threatening when systemic, and is known as bacterial endotoxin.  Mice deficient in any of the LPS receptor components are more
susceptible to Gram-negative bacterial infection but, at the same time, are less susceptible to the sepsis syndrome.

TLRs have a lethal function in the septic shock syndrome. The physiological function of signaling through phagocyte TLRs is to induce the release of the cytokines TNF, IL-1, IL-6, IL-8 and IL-12 and trigger the inflammatory response, which is critical to containing bacterial infection in the tissues. However, if infection disseminates in the blood, the widespread activation of phagocytes in the bloodstream is catastrophic. Increase in the numbers of circulating neutrophils, or neutrophilia, is driven by effects of colony stimulating factors, such as G-CSF.

Time course of sepsis. The clinical manifestations of sepsis are manifested by successive waves of the serum cytokine cascade. In humans injected with purified LPS, TNF rises almost immediately and peaks at 1.5 h; the sharp decline of TNF may be due to modulation by its soluble receptor sTNFR. A second wave of cytokines that peaks at 3 h activates the acute-phase response
in the liver, the systemic pituitary response (via IL-6 and IL-1), and the activation and chemotaxis of neutrophils (via IL-6, IL-8 and  G-CSF). Neutrophil activation results in the release of lactoferrin from neutrophil secondary granules; the activation of endothelial procoagulants with the rise of tissue plasminogen activator (t-PA). Pituitary-derived adrenocorticotropic hormone (ACTH)  and migration inhibition factor (MIF) peak at 5 h and coincide with peak levels of the regulatory cytokines IL-Ra and IL-10 that counteract the release or activity of inflammatory cytokines. Diffuse endothelial activation is shown by the appearance of soluble E-selectin that peaks at about 8 h and remains elevated for several days.

Susceptibility to LPS Toxicity in Gene Knockout Mice

Defect:
High LPS; Low LPS/D-Gal

Proteins

 

LPS recognition
CD14
LBP
TLR4
MD-2
MyD88
SR-A

phagocyte function
Hck/Fgr
CAM-1
L-selectin
GM-CSF
TNFR1

inflammation
TNFR2
IL-1Ra
IL-1β
IFN-γR
caspase 1
The proteins encoded by the deleted genes are listed. SR-A is scavenger receptor A; Hck and Fgr are Src-family kinases with an essential role in integrin-mediated migration of neutrophils out of the bloodstream.

The Immune Response to Bacterial Infection. Sepsis Syndrome: Bacterial Endotoxin
Chapter 9-3.  2007. p 232-233. New Science Press Ltd

Related articles

• Oral Drug Shows Clinical Response And Remission In Some Patients With Ulcerative Colitis (medicalnewstoday.com)
• Abbott’s Humira May Not Be Effective in Colitis, FDA Says (bloomberg.com)
• New Way to Ease Ulcerative Colitis? (webmd.com)
• Abbott’s Humira Backed by FDA Advisory Panel for Colitis – Bloomberg (bloomberg.com)
• Pfizer’s Experimental Drug Works in Ulcerative Colitis – Bloomberg (bloomberg.com)
• Study Identifies Potential New Class Of Drug For Treating Ulcerative Colitis (bioresearchonline.com)
• New Ulcerative Colitis Medications (answers.com)
• Promising colitis data build blockbuster case for Pfizer’s tofacitinib (fiercebiotech.com)
• Study finds potential drug for ulcerative colitis (universityofcalifornia.edu)
• Crohn’s disease driven by inflammation – not genetics (PharmaceuticalIntell)

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Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

Posted in Bio Instrumentation in Experimental Life Sciences Research, Computational Biology/Systems and Bioinformatics, Genome Biology, International Global Work in Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Uncategorized, tagged Biomedical Research Workforce, Biotechnology Industry Organization, GlaxoSmithKline, Johnson, MD/PhDs in US labor market, Pfizer, PhDs, Polaris Venture Partners, Sage Bionetworks, Structural Genomics Consortium on June 27, 2012| 3 Comments »

Reporter: Aviva Lev-Ari, PhD, RN The Price of Togetherness Is togetherness the latest drug? Will touchy feeliness be the answer to the pharmaceutical industry’s crisis of productivity? Collaboration certainly isn’t anything new in the life sciences, but the nature and structure of partnerships is evolving to the point that many companies are now contemplating pooling their resources…and diluting their returns. Certainly the past decade has been marked by more partnerships between industry and academia, where there has been an effort to find a win-win solution to academia’s funding deficits and pharma’s desire to get more helping hands in early innovation. Out of this have grown “open-source” research efforts that use pharma’s financial backing to create or aggregate data any researcher can use. Sage Bionetworks, a three-year-old Seattle-based non-profit, offers a “commons” of pooled data and resources. Merck has contributed many human and mouse disease models for open consumption. Eli Lilly has opened up its doors to compounds created at academic labs through its PD2 and other Open Innovation Drug Discovery efforts. In 2008, GlaxoSmithKline released over 300 cell lines to the National Cancer Institute’s Cancer Bioinformatics Grid, open for academics to mine. The Structural Genomics Consortium is an open-access database of 3-D protein structures that counts Lilly, GSK, Novartis, Pfizer, and most recently Takeda among its members and financial backers. While these kinds of open efforts come with a series of challenges concerning ownership, consent and disclosure, and many other issues, they exist because industry increasingly recognizes that biology is too complex for any one company, even a large one, to tackle on its own. Major drug companies have also started to innovate the way they work with venture capitalists to help nurture early research. Johnson & Johnson announced back in January that it is partnering with Polaris Venture Partners to scout out and co-invest in biotech startups–presumably structuring deals such that venture backers can find an exit without relying on the lousy IPO market. And they’re hardly alone–as I highlighted a few months ago.. But now drug companies are starting to do the unthinkable–work directly with each other. They’ve taken baby steps in this direction before, often with a focus on emerging markets and diseases not viewed as critical profit-drivers. For example, 13 major drug companies joined the Bill and Melinda Gates Foundation earlier this year to combat tropical diseases. But rather than just contributing medicine, some of the companies– Abbott, Johnson & Johnson and Pfizer–are actually collaborating on research as part of the Drugs for Neglected Diseases Initiative. All the companies are sharing compound libraries. That’s not entirely unprecedented, but companies that have wanted to work closely together in the past have formally launched joint ventures, like the HIV-focused ViiV Healthcare venture between Pfizer and GlaxoSmithKline. Now these cooperative efforts are broadening. One announcement made at the recent Biotechnology Industry Organization (BIO)convention is the formation of a consortium for neuroscience research between seven companies including Biogen, Abbott Labs and Merck. The stakes a fairly small, at least money-wise–each company is only pledging $250,000 at this point. But it is symbolically important that they are sharing all the costs of basic research, as well as their expertise, to try to quickly and efficiently get R&D off the ground. While some of this newfound camaraderie might be difficult for companies dreaming of developing blockbusters and keeping all the profits to themselves, there is a silver lining. The growing demand for drugs in emerging markets means that some of these collaboratively developed drugs may eventually reach much broader audiences–meaning larger populations over which to recoup development costs, bigger opportunities for rare disease indications, and acceptable profits even if prices are forced lower. That should be some consolation. -Karl Thiel http://www.biospace.com/news_story.aspx?NewsEntityId=264902&type=email&source=BE_062712 More by Karl Thiel http://www.biospace.com/news_subject_all_results.aspx?CatagoryId=40094 Picturing US-Trained PhDs’ Paths While the US National Institutes of Health Advisory Committee to the Director’s Biomedical Workforce Working Group issued a draft report this month, detailing data it collected as well as its recommendations for the federal agency, Sally Rockey really breaks it down at her NIH Office of Extramural Research blog. “I plan to highlight some of the specific data in future posts, but first, I’d like to discuss the outcome — the conceptual framework that presents a snapshot of the biomedical research workforce, incorporating the latest available data,” she says. And she does, in an infographic that follows the career paths of the 9,000 biomedical PhDs who graduated in the US in 2009. Seventy percent of them went on to do postdoctoral research, Rockey notes. Down the line, “looking at the career paths taken by these US-trained biomedical PhDs, we can see that fewer than half end up in academia, either in research or in teaching, and only 23 percent of the total are in tenured or tenure-track positions,” she adds. “Many other people are conducting research, however, with 18 percent in industry and 6 percent in government.” Overall, Rockey says, the non-academic biomedical workforce is huge. “If you’re a graduate student or postdoc looking at these numbers, particularly the proportion of people in industry and government settings, it makes sense to learn as much about these career paths as possible,” she writes at Rock Talk. http://www.genomeweb.com/careers NIH Advisory Committee to the Director’s Biomedical Workforce Working Group Issues Draft Report  The US National Institutes of Health Advisory Committee to the Director’s Biomedical Workforce Working Group issued a draft report this week that summarizes data it has collected and includes recommendations “that can inform decisions about training the optimal number of people for the appropriate types of positions that will advance science and promote health,” it reads.In its report, the working group emphasizes the overall purpose of its research efforts and resulting recommendations, namely “to ensure future US competitiveness and innovation in biomedical research” through proper undergraduate, graduate, and postdoctoral training and to “attract and retain the best and most diverse scientists, engineers, and physicians from around the world,” as well as domestically.When it comes to graduate education, the working group suggests that NIH cap the total number of years a grad student can be supported by NIH funds, in order to encourage timely completion of PhD studies.As for graduate career training, the working group says that because around 30 percent of biomedical PhDs work in the biotech and pharmaceutical industries — in both research and non-research positions — “their transition would be more effective if their training was better aligned with the required skill-sets for these careers.” In addition, “institutions also could be encouraged to develop other degree programs — e.g. master’s degrees designed for specific science-oriented career outcomes, such as industry or public policy … as stand-alone programs or provide sound exit pathways for PhD students who do not wish to continue on the research career track,” the group continues.For PhDs who do wish to continue on with a postdoctoral fellowship, the working group suggests that NIH “create a pilot program for institutional postdoctoral offices to compete for funding to experiment in enriching and diversifying postdoctoral training,” and adjust the current stipends for the postdocs it supports to better reflect their years of training.In addition, the group recommends that NIH double the number of Pathway to Independence (K99/R00) awards it issues and shorten the eligibility period for applying to this program from five to three years of postdoc experience to encourage more PhDs to swiftly move into independent research positions. Likewise, the group suggests that NIH also double the number of NIH Director’s Early Independence awards “to facilitate the skip-the-postdoc career path for those who are ready immediately after graduate school.”More generally, the Biomedical Workforce Working Group recommends that institutions receiving NIH funds ramp up their efforts to collect information on career outcomes of the grad students and postdocs supported by federal research grants. Finally, the group suggests that NIH create a permanent unit in the Office of the Director that would work with the extramural research community, the National Science Foundation, and the agency’s other institutes and centers “to coordinate data collection activities and provide ongoing analysis of the workforce and evaluation of NIH policies so that they better align with the workforce needs.” http://www.genomeweb.com/nih-advisory-committee-directors-biomedical-workforce-working-group-issues-draft Rock Talk Helping connect you with the NIH perspective So, What Does the Biomedical Research Workforce Look Like? Posted on June 22, 2012 by Sally Rockey Update 6/27/12: The full report is now posted on the ACD website. As I blogged last week, and most of you have heard by now, a working group of the Advisory Committee to the NIH Director (ACD) that I co-chaired with Shirley Tilghman from Princeton just completed a study of the biomedical research workforce. We reported our findings to the ACD last Thursday (you can find a link to the videocasthere). We gathered a lot of data during this study, which are included in the report (see the ACD site for the executive summary and instructions for obtaining a copy of the full report). The data also are posted on an accompanying website. I plan to highlight some of the specific data in future posts, but first, I’d like to discuss the outcome—the conceptual framework that presents a snapshot of the biomedical research workforce, incorporating the latest available data. The framework of the PhD workforce is presented below, and a companion framework for MDs and MD/PhDs in the biomedical research workforce can be seen in the report and on the website. First, 9,000 biomedical PhDs graduated in the US in 2009 (including basic biomedical and clinical sciences), and 70% of these went on to do postdoctoral research. As we conducted our analysis, it became clear that there are few reliable data on the number of biomedical postdoctoral researchers in the US. We lack solid information on foreign-trained postdoctoral researchers, and many postdoctoral researchers change their title as they proceed through their training, complicating the data collection. That’s why the estimate of postdoctoral researchers ranges from 37,000 to 68,000. Looking at the career paths taken by these US-trained biomedical PhDs, we can see that fewer than half end up in academia, either in research or in teaching, and only 23% of the total are in tenured or tenure-track positions. Many other people are conducting research, however, with 18% in industry and 6% in government. The science related non-research box includes individuals working in industry, government, or other settings who do not conduct research but are part of the scientific enterprise. Many of the career paths represented by this box contribute to the scientific research enterprise and require graduate training in biomedical science. For example, program and review officers at NIH and managers in many biotechnology companies would be included in this group. This is my box too. It’s interesting to note the 18% included in this group is made up of PhDs employed in industry (13% of the total workforce), in government (2.5%), and in other settings (2.5%). This means that all individuals working in industry (research plus non-research occupations) represent about 30% of the workforce, and all those working in government represent about 9% (more than 10,000 individuals). That leaves 13% in non-science related occupations and 2% unemployed (this does not include retirees or those who choose not to work). These are 2008 data, the latest available from the NSF Survey of Doctoral Recipients. If you’re a graduate student or postdoc looking at these numbers, particularly the proportion of people in industry and government settings, it makes sense to learn as much about these career paths as possible. I’m very proud that we were able to develop this framework, as it seems that for the first time we have an idea of where domestically trained biomedical researchers are going. I was quite surprised by the idea that the majority of our trainees do not end up in academia. Did this surprise you? Notes on the figure The main sources of the original data, from which the graphs in the report were made and these numbers were derived, come from three NSF surveys: the Survey of Graduate Students and Postdoctorates, the Survey of Earned Doctorates, and the Survey of Doctorate Recipients. You can see the specific sources of each number by clicking on the relevant box on the website. The color of the numbers reflects our confidence in the accuracy of the data: high (green), medium (yellow), or low (red). For more details see colors. In this case, the red numbers in the post-training workforce box are accurate, but the color reflects the fact that we know almost nothing about the distribution of foreign-trained PhDs in the workforce, so the overall picture is an under-estimate. The post-training workforce boxes are color coded, with light blue denoting those in research positions and academic teaching positions. The science related non-research box is colored dark blue to indicate that many of the careers represented in this box are closely related to the conduct of biomedical research. http://nexus.od.nih.gov/all/2012/06/22/so-what-does-the-biomedical-research-workforce-look-like/ Live Chat: Are We Training Too Many Scientists? by Jocelyn Kaiser on 27 June 2012, 8:30 AM | Too many graduate students and postdocs chasing too few academic jobs has led to a dysfunctional biomedical research system. That’s the conclusion of a draft report on the biomedical workforce released this month by an advisory panel to the National Institutes of Health (NIH). The panel urged taking steps to shorten young scientists’ career paths, including capping how long graduate students can receive NIH support and better preparing them for non-academic careers. The report also encourages university labs to rely more on staff scientists rather than trainees. But is it a good idea to tinker with the research system at a time when NIH funding is tighter than ever? And given that most biomedical Ph.D.s will find a job, are there really too many?  http://news.sciencemag.org/sciencenow/2012/06/live-chat-are-we-training-too-ma.html NIH Panel Urges Steps to Control Growth in Biomedical Research Trainees by Jocelyn Kaiser on 14 June 2012, 5:50 PM | A glut of trainees and a dearth of academic positions in the United States is creating a dysfunctional biomedical research system, an advisory group to the National Institutes of Health (NIH) concluded today. It urged several steps be taken to bring the problem under control. NIH should cap how many years it will support graduate students, pay postdoctoral researchers more, and encourage universities to fund staff scientist positions. The changes may appear to make research labs less productive, but in the long run will result in “a more vibrant workforce,” said Shirley Tilghman, president of Princeton University and co-chair of the panel that delivered the draft report. The widely anticipated report comes from a working group of the NIH Advisory Committee to the Director (ACD) co-led by NIH Deputy Director for Extramural Research Sally Rockey. The panel spent a year examining available data on the number and fate of biomedical researchers through different stages of their careers, focusing on the slow pace of advancement and the often-cited fact that the average age for an investigator winning the first independent grant from NIH is 42. (The panel’s economists abandoned a plan to model the workforce—there wasn’t time or sufficient data.)  Live Chat: Are We Training Too Many Scientists?  In the executive summary of their draft report, the panel found that a steep rise in U.S. biomedical Ph.D.s in the past decade, more foreign postdocs, and the aging of academic faculty members make it increasingly hard for young biomedical researchers to find academic jobs. Biomedical researchers are paid less than scientists in other fields, and the low pay and long training period may make the field unattractive to the best and brightest. To address the problem, NIH needs to make some changes, the panel says. The agency should provide supplements to training grants that help students prepare for alternatives to academic careers, such as a master’s degree geared toward an industry position. It should cap how long a graduate student can receive NIH funding at 6 years (the average length of a biomedical Ph.D. including all funding is now 6.5 years, says Rockey). NIH should find ways to shift the funding source for graduate students, most of whom are now paid out of investigators’ grants, to training grants and fellowships. The reason: such programs provide higher quality training, and their graduates tend to be more successful than those funded from grants. Postdoctoral researchers should also be supported to a greater extent by fellowships and training grants, the panel says. And postdoc stipends should be increased—starting with the entry level, now $39,264, which should rise to $42,000—and they should receive better benefits. “We think it is scandalous how [little] postdoctoral fellows are paid,” Tilghman said. NIH should also encourage study sections to look favorably upon research projects that employ staff scientists, and institutions should create more of these positions. There is an “urban myth” that staff scientists are less productive than graduate students, Tilghman said. In fact, she said, graduate students are productive for a couple of years but are otherwise a “drain on the system.” Staff scientists, by contrast, are “often the glue that holds your lab together.” Although the panel did not say the overall number of trainees should decline, the recommendations, if adopted, should make the growth in the number of trainees at least slow down because “we’re making it more expensive to have those individuals,” Tilghman said. The recommendations drew concern from at least one ACD member. Biologist Robert Horvitz, of the Massachusetts Institute of Technology in Cambridge, questioned whether NIH should make “risky” changes to the system at a time when NIH is struggling with flat budgets and record-low success rates. “Some of this makes me very nervous,” he said. But Tilghman, who headed a National Research Council panel 14 years ago that she said came to “identical conclusions,” disagreed. “The only time it’s possible to make hard decisions … is actually during tough times,” she said. NIH Director Francis Collins said he would like see some “experiments” before making “more systemically disruptive” changes to the funding system. But, he added, this time the Tilghman panel’s recommendations “will go somewhere. I promise you that.” Tomorrow, ScienceInsider will post a story on another draft report presented later in the ACD meeting on diversity in the biomedical research workforce. http://news.sciencemag.org/scienceinsider/2012/06/nih-panel-urges-steps-to-control.html Can NIH Renovate the Biomedical Workforce? By Michael Price June 22, 2012 “The most effective training dollars that the NIH has to expend are those in their training grants.” —Shirley Tilghman When molecular biologist and Princeton University President Shirley M. Tilghman first sounded the alarm about the need for major overhauls to the way the United States trains its biomedical workforce in the 1998 National Academies of Science report Trends in the Early Careers of Life Scientists, many of her proposals fell on deaf ears. Fourteen years later, Tilghman is arguing again for training reform, this time as chair of the National Institutes of Health (NIH) Biomedical Research Workforce Working Group. Last week, Tilghman presented a draft of her group’s latest report to NIH’s Advisory Committee to the Director (ACD) at NIH headquarters in Bethesda, Maryland. In the report, the group calls on NIH to divert funding from research grants to training grants for graduate students, support more postdocs on training grants, increase pay and improve benefits for postdocs, and boost the prestige and remuneration of staff scientist positions in academic labs. At the presentation, Tilghman and the other members of the working group argued that in its present state, the graduate training system at our nation’s universities and the workforce that graduates enter into are dysfunctional and unsustainable. At the root of that dysfunction, Tilghman said, is a mismatch between the training most graduate students receive and the careers most Ph.D. graduates end up in. The number of academic jobs has shrunk dramatically compared to the number of new graduates. NIH estimates that 26% of biomedical Ph.D. recipients end up in tenure-track academic positions, down from 34% in 1993; meanwhile, the proportion of nontenure-track academic positions has remained constant. The growth in jobs for Ph.D. biomedical scientists, the working group concluded, is outside academia, so new graduates must be prepared to work in other roles: in industry, in government, or in positions tangentially related to their degrees, such as science writing or policy, Tilghman said. Shifting funds toward training How can universities prepare graduate students better for the careers they’re most likely to wind up in? One way, Tilghman said, would be for NIH to shift funding from R01 research grants, which currently support the majority of graduate students in biomedical sciences, to NIH training grants, which are peer-reviewed by NIH for their training-related virtues. The total number of graduate students supported by NIH, the report says, should remain constant. While the number of graduate students supported by research grants has been higher than the number supported on training grants since the early 1980s, the gap steadily widened as NIH’s research budget grew—then shot up in the early 2000s when NIH’s budget doubled over 5 years (see graph below). CREDIT: National Institutes of Health Research grants are far and away the most common source of funding for graduate students today. Click here to enlarge image. The report’s authors argue that many graduate students are ill-served by this approach because it limits the ability of NIH to hold principal investigators (PIs) accountable in their roles as mentors. Without oversight, Tilghman argued, it’s easy for PIs to see and treat their graduate students as laborers rather than scientists in training. If a larger proportion of the graduate student population were supported on training grants, she said, NIH could better monitor students’ training and ensure broader exposure to careers outside of academia—and better training in the skills needed to perform well in those careers. The members of the working group “are, I think, unanimously of the view that the most effective training dollars that the NIH has to expend are those in their training grants,” Tilghman said. “Training grants are immensely effective at inducing good behavior on the part of graduate programs. … It is the only mechanism we have to really peer review the quality of graduate training.” Some members of the ACD weren’t buying it. Biologist Robert Horvitz of the Massachusetts Institute of Technology in Cambridge argued that shifting funding away from R01s takes away too much autonomy from PIs. “One wants to be sure that the principal investigators, who are supposed to be doing the research, continue to have enough flexibility to be able to support the research they want to do,” he said. Taking away that flexibility, he argued, could reduce research productivity. Other ACD members, including Haile Debas, director of the University of California Global Health Institute in San Francisco, were more supportive of the recommendations. While such a shift would be bold, Debas said, “you can also do harm by doing nothing.” He proposed that NIH launch experiments to determine whether graduate students who get industry experience during their traineeships, for example, go on to have successful careers in industry. Judith Bond, incoming president of the Federation of American Societies for Experimental Biology (FASEB) and a biochemist at Pennsylvania State University, Hershey, also disagrees with this recommendation, saying in an interview with Science Careers that “oversight of student training should be left to the universities, not the federal government.” Bond is not a member of the ACD. Upping postdoc pay The situation is equally grim, if not grimmer, for postdoctoral researchers, Tilghman and her colleagues argue in the report. The report recommends that more postdocs be supported by training grants and fewer by PIs’ research grants, with the total number of NIH-supported postdocs remaining constant or perhaps decreasing. One way of reducing the number of postdocs—and decreasing the intense competition for jobs—would be to increase postdoc salaries from $39,264 to $42,000 and provide benefits equal to those of employees at their institutions, the report says. It also recommends that NIH mandate a 4% raise before the third year of postdoctoral work and a 6% raise before the seventh. The idea, Tilghman said, would be to motivate PIs to help their postdocs move as quickly as possible into jobs rather than toil away as a postdoc. “One of the things the committee really grappled with is: To what degree are these [people] trainees … and to what extent are they worker bees who are the producers of the research in our lab?” Tilghman said. The working group felt strongly, she said, that emphasizing training is the best way to produce well-trained future PIs. Cato Laurencin, an ACD member and CEO of the Connecticut Institute for Clinical and Translational Science in Farmington, agreed with the working group’s postdoc recommendations. “We’ve gotten into a mindset where postdocs last 5, 6, 7 years,” he said. “After 5 or 6 years of Ph.D. training, people are spending their careers in training. I am very concerned about that.” Bond, too, agreed with the postdoc salary recommendation. “In general, FASEB is in favor of increasing postdoc salaries. … Postdocs are essential to work in the lab, and they should be paid a living wage,” she said. But ACD member Horvitz was skeptical. The money to raise postdoc salaries “has to come from somewhere,” he said, and given NIH’s current budget woes, it might be impractical to raise postdoc pay. If PIs were forced to make do with fewer (but better paid) postdocs, he argued, lab productivity would probably decline. Improving the staff scientist position One way to provide more job opportunities for Ph.D. scientists would be to increase the number and stature of staff scientists in university labs. (See “A Hidden Academic Workforce.”) One way this could be accomplished would be to have universities shoulder a larger percentage of researcher salaries than most currently do, Tilghman said. That would make the positions more stable and less vulnerable to changes in NIH budgets and competitive grant renewals. Those salaries should also be increased, the report argues, to be commensurate with the training levels of staff scientists and their value to the lab. If the number of postdocs drops as a result of raising postdoc salaries, staff scientists could fill the gap, which should help attract talented scientists to these positions. Finally, Tilghman recommended that NIH award grants preferentially to PIs who employ staff scientists. “When I think about the tradeoff of a graduate student for a staff scientist who is already extremely well trained, who can work without constant supervision, who can really help train the younger people in the laboratory, … I actually think we’ll be more productive,” she said. Tough times afford opportunity Two of the key recommendations of the report—shifting funding away from R01s to create more training grants and increasing postdoc pay and benefits—met with resistance from members of the ACD. Yet Tilghman believes that these recommendations will gain more traction with NIH leadership than when she proposed similar reforms in 1998. Times are much tougher now, she said, which makes it easier to make larger changes. “The only time when it’s going to be possible to make hard decisions that would … have a long-term, beneficial effect on all the players in the biomedical workforce is … during tough times,” Tilghman said. “Doing nothing, in my view, is not an option.” NIH Director Francis Collins said that the ACD appeared generally supportive of the report and that NIH would collect more data, build models, and run pilot programs so that they can better predict the impact of implementing the report’s recommendations. “I do think the NIH will want to take some action here,” he said. “I like the idea of doing some experiments to get some early indications of whether the interventions are achieving the goals that we hope for. It would be a very good thing before we do something more systematically disruptive in ways that we didn’t intend.” Michael Price is a staff writer for Science Careers.http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/201206_22/caredit.a1200069 A Hidden Academic Workforce  By Siri Carpenter June 08, 2012 The staff scientist role is not just a boon for universities. It is also a career destination for some of the tens of thousands of highly trained researchers who wish to remain in or close to academic research—a cadre that’s far too large for the number of available faculty positions. On university campuses, students, postdocs, and professors are so ubiquitous that it would be easy not to notice the other Ph.D.-level professional scientists—often dubbed staff scientists—who roam the halls. Some of them work as lab managers or project directors; others direct or help operate university core facilities. Despite their low profile, staff scientists are numerous and make a major contribution to their institutions. At the University of Wisconsin (UW), Madison, between 700 and 800 members of the academic staff are Ph.D.-level scientists, estimates Heather Daniels, chair of the university’s Academic Staff Executive Committee. For comparison, the university has 2137 faculty members in all disciplines, with a number of staff scientists comparable to the number of science faculty members. The same may well be true at other, similar universities. Many staff scientists write grants. In fact, UW Madison staff scientists brought in $120 million to the university last year, out of a total grant portfolio worth just over $1 billion. When you include grants on which staff scientists serve as co–principal investigators (co-PIs), that figure rises to $240 million. The staff scientist role is not just a boon for universities. It is also a career destination for some of the tens of thousands of highly trained researchers who wish to remain in or close to academic research—a cadre that’s far too large for the number of available faculty positions. Such positions typically pay better than postdocs and sometimes about as well as assistant professor positions. At UW Madison, the minimum starting salary for an academic staff scientist is $40,055. Unfortunately, there is no mechanism for annual merit-based increases, so staff scientists typically receive raises only when the state pay plan calls for an across-the-board increase. As a result, “the longer you’re here, the more your salary tends to fall behind,” Daniels says. Most staff scientists are grant supported, a fact that, in addition to creating job insecurity, limits the ability of staff-scientist PIs to perpetuate their own careers. According to federal rules, researchers are not allowed to use time supported by federal grants to write grants. Government auditors have interpreted the rules to stipulate that grant-funded researchers are on the clock 100% of the time, Daniels says, even if they work much longer weeks than the 40-hour standard. So whenever a staff scientist’s salary comes entirely from federal grants, federal grant writing is effectively forbidden. The solution, usually, is to find non-federal money to pay part of that salary. “It’s been a struggle for a lot of universities,” she says, “to come up with non-grant dollars to give folks time to write grants. I think researchers are feeling really constrained by this.” On the positive side, the role of staff scientist has several benefits. Staff scientists typically travel less, work fewer nights and weekends, spend less time writing grants, and have fewer administrative responsibilities than faculty members. They seldom have formal teaching responsibilities, which some staff scientists consider a perk. Much more than postdocs, staff scientists tend to have a hand in more than one scientific project at a time. A nonfaculty career path can also provide geographic stability, notes Alexander Pico, a staff research scientist at the Gladstone Institutes, a group of research institutes closely affiliated with the University of California, San Francisco (UCSF). “If you go with the traditional route, you have to move a lot. You have to prove yourself as a Ph.D. student in one institution, then prove yourself in another as a postdoc, and then you’re expected to continue that as faculty, proving yourself in one environment after another before you get tenure,” Pico says. “The staff position is a little more stable. I really like the working culture at Gladstone, and I would really hate to have to leave just because it’s a convention in the career path.” Here, we profile a sampling of staff scientists from two universities—UW Madison and UCSF—who have foregone the tenure track while remaining deeply rooted in university life.  http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2012_06_08/caredit.a1200065

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Zithromax – likely to ‘max’ Heart Attack

Posted in Cardiovascular Pharmacogenomics, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, tagged Azithromycin, health, Heart disease, medicine, New England Journal of Medicine, Pfizer, research, science, sudden cardiac death, University of Washington, Vanderbilt University, Wayne Ray, Zithromax on May 18, 2012| 4 Comments »

A Word of Caution especially to Cardiacs’

Zithromax (azithromycin), is not only a more expensive antibiotic than other antibiotics but also seems to be an expensive one at Heart. Doctors should weigh other options for people already prone to heart problems, the researchers and other experts suggested. It is a popular antibiotic because it often can be taken for a fewer days compared to other antibiotics, for example: about 10 days for amoxicillin and other antibiotics and five-day course will suffice in case of Zithromax.

Azithromycin (Photo credit: Wikipedia)

It is widely used for bronchitis, sinus infections and pneumonia, and other common infections but seems to increase chances for sudden deadly heart problems. A rare but surprising risk found in a 14-year study. Also, antibiotics in the same class as Zithromax have been linked with sudden cardiac death. In the current study, patients those on Zithromax were about as healthy as those on other antibiotics, making it unlikely that an underlying condition might explain the increased death risk, researchers said.

Researchers analysis at Vanderbilt University indicates that there were 29 heart-related deaths among those who took Zithromax during five days of treatment. Their risk of death while taking the drug was more than double that of patients on another antibiotic, amoxicillin, or those who took none.

To compare risks, the researchers calculated that the number of deaths per 1 million courses of antibiotics would be about 85 among Zithromax patients versus 32 among amoxicillin patients and 30 among those on no antibiotics. The highest risks were in Zithromax patients with existing heart problems. Patients in each group started out with comparable risks for heart trouble, the researchers said. The results suggest there would be 47 extra heart-related deaths per 1 million courses of treatment with Zithromax. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.

Dr. Harlan Krumholz, a Yale University health outcomes specialist who was not involved in the study said that “People need to recognize that the overall risk is low,”. More research is needed to confirm the findings, but still, he said patients with heart disease “should probably be steered away” from Zithromax for now.

At the same time, Dr. Bruce Psaty, a professor of medicine at the University of Washington, of opinion that doctors and patients need to know about the potential risks. He said the results also raise concerns about long-term use of Zithromax, which other research suggests could benefit people with severe lung disease. Additional research is needed to determine if that kind of use could be dangerous, he said.

The study appears in the New England Journal of Medicine. The National Heart, Lung and Blood Institute helped pay for the research. Wayne Ray, a Vanderbilt professor of medicine, studied the drug’s risks because of evidence linking it with potential heart rhythm problems.

Pfizer is committed to patients safety and issued a statement saying it would thoroughly review the study and “Patient safety is of the utmost importance to Pfizer and we continuously monitor the safety and efficacy of our products to ensure that the benefits and risks are accurately described,” the company said.

Source

Additional info on Zithromax

Reported by Dr. Venkat Karra, Ph.D

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  • 2026 Grok Multimodal Causal Reasoning on Proprietary Cariovascular Corpus: From 2021 Wolfram NLP Baseline to Thousands of Novel Relationships – A Second Head-to-Head Validation of LPBI’s Domain-Aware Training Advantage January 6, 2026
  • Workflow for Dynamic Linkage and Transition between two Authoring Systems: LPBI Group’s WordPress.com Multi-Authors Authoring System and Microsoft PowerPoint product for Slide show presentation – Part 10.1 in Composition of Methods January 6, 2026

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