• Final Glance: Pharmaceuticals companies May 18, 2012
• Healthcare Business Recap: Dendreon Attack Continues, Pfizer Recall May 18, 2012
• U.S. Suggests All Baby Boomers Should Get Tested for Hepatitis C May 18, 2012
  [at The Wall Street Journal] - U.S. Suggests All Baby Boomers Should Get Tested for Hepatitis C
• [$$] India's Proposals to Cap Drug Prices Sparks Debate May 18, 2012
• Sunscreen Labeling Delay Should Be Reversed, Senators Say May 18, 2012
• Pfizer recalls Advil bottles from distributors May 18, 2012
• Midday Glance: Pharmaceuticals companies May 18, 2012
• Test All Baby Boomers for Hepatitis C, CDC Urges May 18, 2012
• Report: Drug Makers Working on Emergency Supply Plan in Greece May 18, 2012
• Early Glance: Pharmaceuticals companies May 18, 2012

• Money, Money, Money Makes the World Go Round May 14, 2012
  First the bad news: salary budgets remain tight at many companies. Your annual raises may be modest at best. Some firms are under salary freezes. Now the good news: even under these conditions there are strategies you can use to receive more money from your employer. These are summarized below. Your 401(k) Plan Put enough [...]
• How do I Prepare for a Networking Conversation and What Do I Say When I Get There? May 7, 2012
  There are several job searching strategies, but  few as valuable as building strong networking contacts. That means meeting as many people as you can who are willing and able to provide job leads, resources, and other contacts.  When you do get a contact, you’ll want to make the most of the opportunity. That means treating [...]

[Perspectives] Dodging Drug-Resistant Cancer with Diamonds

Merkel, T. J., DeSimone, J. M

By Derek Lowe

Note: Other Chemistry blogs under “Panopharma”.

• The Genetic Diversity of Cancer Cells May 18, 2012
  For those of you interested in the recent work on the diversity of different cancer cell genotypes inside single tumors, there's a review out that covers the field well. The authors also go into some of the major unanswered questions: does having a tumor cell population with a lot of genetic diversity correlate with a poor prognosis for treatment? Can small populations of potentially troublesome cells be identified ahead treatments that might give them too free a field to work in? Can the huge genetic diversity be reduced to a more manageable set of practical phenotypes, to make therapeutic recommendations? This will keep everyone busy for a long time to come.
• Strangely Good Results in Diabetes and Cardiovascular Disease May 18, 2012
  I've read a couple of medical papers recently that show how tricky it is to draw conclusions on what patients would be best helped by a specific therapy. Many of you will have seen the paper in The Lancet on the use of statins in low-risk patients. This isn't something you'd necessarily think would do much good - it all depends on what the benefits are, at the margin, of lowering LDL. But the results appear surprisingly strong: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. A note to the conspiratorially minded, should any such come across this: it's worth noticing that this "maybe everyone should take statins" result comes after the major ones have gone off patent. Pfizer, Merck et al. would have greatly enjoyed this recommendation had it occurred ten years ago, but it didn't (and probably couldn't have, since we didn't have as much data as we do now). Now to another (often related) disease, type II diabetes. It's been found that bariatric surgery improves glycemic control in the very obese patients who are candidates for the procedure. And that makes sense - obesity is absolutely a risk factor for type II in the first place. But as more and more of these surgeries are being done, something odd is becoming apparent: Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward. Why this happens is a very good question indeed. Patients seem to benefit greatly within the first two weeks after gastric bypass surgery, well before any significant weight loss has occurred. My first guess is that it's something to do with secretion of hormones from the gut itself, and you'd also have to think that nutrient sensing gets profoundly altered. It's not going to be easy to turn this into an approved therapy, though. Running randomized clinical trials for dramatic surgical procedures (versus noninvasive care) is difficult, as you'd imagine: Despite these compelling clinical observations, RCTs of surgery versus nonsurgery are sorely needed. Ample precedents exist wherein RCTs reversed longstanding paradigms derived from nonrandomized clinical trials. Some of the best evidence in bariatric surgery, from the Swedish Obese Subjects study (a long-term observation of various operations versus conventional care), is prone to allocation bias because participants were not randomized. Subjects who actively chose surgery may be more motivated overall and generally take better care of themselves. The NIH is unlikely to reconsider its guidelines without pertinent RCTs, and insurance companies are unlikely to pay for operations that are not NIH-sanctioned. Both of these results point out the completely nonlinear nature of living systems. It can work for good, as in these cases, or for bad. Alzheimer's, the subject of yesterday's post, is a perfect example of the latter: one protein, out of perhaps a few million, has one of its hundreds of amino acids changed in one small way on its side chain. And it's a death sentence. Good to know that things can work in the other way once in a while.

Alphabetical by University Name:

A  *  B  * C  * D  *  E  * F  *  G *  H 

I  * J  *   K  *  L  *  M  *  N  *  O  *  P   

Q *  R  *  S  *  T  *  U  *  V  *  W  *  X  * Y

By State:

Dynamic Periodic Table – An interactive periodic table

Visual Elements Periodic Table - A striking representation of the chemical elements drawing on the symbolism that surrounds them from the commonplace to the mythological

• Senate Dips Toe Into STEM Immigration Reform Stream May 18, 2012
  Two bills would make it easier for those with U.S. graduate degrees to gain green cards
• Alzheimer's Research Strategy Announced May 18, 2012
  Recommendations will help guide U.S. plan to develop treatments by 2025
• ScienceShot: Disposable Keypads May 18, 2012
  High-tech paper gets buttons
• Supervolcano Drilling Plan Gets Go-Ahead May 18, 2012
  Some scientists believe the international project puts lives at risk in Naples
• Researchers Meet Protesters in TV Debate May 18, 2012
  Opponents of genetically modified crops unclear on their plans to destroy test field of GM wheat
• Roots of Racism May 18, 2012
  Humans everywhere divide the world into "us" and "them." Why are we so tribal?
• ScienceShot: The Secret History of the Domesticated Apple May 17, 2012
  Genetic analysis reveals new clues to the origin of one of our favorite fruits
• U.S.-China Research Projects Draw Congressman's Ire May 17, 2012
  Rohrabacher questions U.S. spending on projects in China
• CPRIT Leaders Defend $20 Million Incubator Grant May 17, 2012
  Contrary to scientists' views, MD Anderson drug discovery institute is "not a research program"
• Barely Breathing Microbes Still Living in 86-Million-Year-Old Clay May 17, 2012
  Organisms deep beneath the sea floor survive on minuscule amounts of oxygen

• Cage, Book, and Prism
  The array of hydrogen bonds governing the extended structure of liquid water is so intricate that chemists have often sought to understand it by studying simpler clusters. Even so, it … [Read more]
• Water-Assisted Proton Diffusion
  Proton diffusion on metal oxide surfaces can play an important role in many catalytic processes. The presence of water is thought to accelerate proton diffusion. Merte et al. (p. 889) … [Read more]
• Mechanisms in Methanol Catalysis
  The industrial production of methanol from hydrogen and carbon monoxide depends on the use of copper and zinc oxide nanoparticles on alumina oxide supports. This catalyst is “structure sensitive”; its … [Read more]
• Radioactive Resonance
  Nuclear magnetic resonance (NMR) spectroscopy and its spatially sensitive cousin, magnetic resonance imaging, have found widespread application in chemical and biological characterization studies. For the most part, these studies take … [Read more]
• Keep Your Distance
  Conspecific negative density dependence (CNDD), whereby the abundance of a species is limited by negative interactions between individuals of the same species, is thought to have an important influence on … [Read more]
• Bring In the Inspectors
  In order to assess the impact of occupational and health practices in the state of California, Levine et al. (p. 907) compared more than 400 uninspected firms with a matched … [Read more]
• Ultimate Blockade
  A Rydberg atom has an electron in a highly excited energy state, close to being set free, but not quite. Ensembles of such atoms interact strongly, sometimes leading to blockade … [Read more]
• Accounting for Lac
  When Escherichia coli expresses the lac operon, it needs to balance the potential increase in growth rate conferred through having the encoded proteins (which help it to take up and … [Read more]
• The Hibernating Ribosome
  When bacteria enter stationary phase, their ribosomes are inactivated. In Escherichia coli, ribosome modulation factor (RMF) causes dimerization of the 70S ribosome and the dimer is stabilized by, hibernation promotion … [Read more]
• An Aspirin a Day?
  The protein kinase AMPK (adenosine monophosphate–activated protein kinase) directly monitors cellular energy stores as reflected by changes in cellular concentrations of AMP, adenosine diphosphate (ADP), and adenosine triphosphate (ATP). Through … [Read more]

• [Editorial] APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield
  Gandy, S., DeKosky, S. T.
• [Perspectives] Drug-Based Optical Agents: Infiltrating Clinics at Lower Risk
  Fluorescent agents with specificity to cellular and subcellular moieties present promise for enhancing diagnostics and theranostics, yet challenges associated with regulatory approvals of experimental agents stifle the clinical translation. As a result, targeted fluorescent agents have remained predominantly as preclinical imaging tools. We discuss the potential of using optically labeled drugs to accelerate the clinical acceptance of optical and optoacoustic agents, in analogy to nuclear medicine approaches. This strategy, corroborated with microdosing studies, outlines a promising approach for overcoming bottlenecks and advancing photonic clinical imaging.
  Scheuer, W., van Dam, G. M., Dobosz, M., Schwaiger, M., Ntziachristos, V.
• [Research Articles] Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model
  Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.
  Goldstein, L. E., Fisher, A. M., Tagge, C. A., Zhang, X.-L., Velisek, L., Sullivan, J. A., Upreti, C., Kracht, J. M., Ericsson, M., Wojnarowicz, M. W., Goletiani, C. J., Maglakelidze, G. M., Casey, N., Moncaster, J. A., Minaeva, O., Moir, R. D., Nowinski, C. J., Stern, R. A., Cantu, R. C., Geiling, J., Blusztajn, J. K., Wolozin, B. L., Ikezu, T., Stein, T. D., Budson, A. E., Kowall, N. W., Chargin, D., Sharon, A., Saman, S., Hall, G. F., Moss, W. C., Cleveland, R. O., Tanzi, R. E., Stanton, P. K., McKee, A. C.
• [Research Articles] Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency
  Aromatic l-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector–mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[18F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.
  Hwu, W.-L., Muramatsu, S.-i., Tseng, S.-H., Tzen, K.-Y., Lee, N.-C., Chien, Y.-H., Snyder, R. O., Byrne, B. J., Tai, C.-H., Wu, R.-M.
• [Research Articles] CD25 Blockade Depletes and Selectively Reprograms Regulatory T Cells in Concert with Immunotherapy in Cancer Patients
  Regulatory T cells (Tregs) are key mediators of immune tolerance and feature prominently in cancer. Depletion of CD25+ FoxP3+ Tregs in vivo may promote T cell cancer immunosurveillance, but no strategy to do so in humans while preserving immunity and preventing autoimmunity has been validated. We evaluated the Food and Drug Administration–approved CD25-blocking monoclonal antibody daclizumab with regard to human Treg survival and function. In vitro, daclizumab did not mediate antibody-dependent or complement-mediated cytotoxicity but rather resulted in the down-regulation of FoxP3 selectively among CD25high CD45RAneg Tregs. Moreover, daclizumab-treated CD45RAneg Tregs lost suppressive function and regained the ability to produce interferon-, consistent with reprogramming. To understand the impact of daclizumab on Tregs in vivo, we performed a clinical trial of daclizumab in combination with an experimental cancer vaccine in patients with metastatic breast cancer. Daclizumab administration led to a marked and prolonged decrease in Tregs in patients. Robust CD8 and CD4 T cell priming and boosting to all vaccine antigens were observed in the absence of autoimmunity. We conclude that CD25 blockade depletes and selectively reprograms Tregs in concert with active immune therapy in cancer patients. These results suggest a mechanism to target cancer-associated Tregs while avoiding autoimmunity.
  Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell, D. J., Colligon, T. A., Trosko, J. A., Leinbach, L. I., Pletcher, C. H., Tweed, C. K., DeMichele, A., Fox, K. R., Domchek, S. M., Riley, J. L., Vonderheide, R. H.
• [Research Articles] High-Throughput Sequencing Detects Minimal Residual Disease in Acute T Lymphoblastic Leukemia
  High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.
  Wu, D., Sherwood, A., Fromm, J. R., Winter, S. S., Dunsmore, K. P., Loh, M. L., Greisman, H. A., Sabath, D. E., Wood, B. L., Robins, H.
• [Editors' Choice] A Tinier Target for B Cell Therapy in Multiple Sclerosis
  Obhrai, J. S.
• [Editors' Choice] Coming Unglued: The Potential to Break Apart Biofilms
  Shrout, J. D.
• [Editors' Choice] You May Feel Some Discomfort--or Not!
  Skarke, C.
• [Editors' Choice] Of Bugs and Men: Antibiotics, the Gut Microbiota, and Risk of Developing Allergic Asthma
  Zeki, A. A.