Are scientists really doing science? : Personal reflections on the NIH grant system

This brief essay summarizes some personal thoughts on the NIH grant system. The thoughts arise in part from my experience as a dissenter from scientific orthodoxy, and in part from my experience as a member of several workshops convened to assess and fix problems with the NIH and NSF grant systems.Sociedad Argentina de Fisiologí

Are scientists really doing science? : Personal reflections on the NIH grant system

This brief essay summarizes some personal thoughts on the NIH grant system. The thoughts arise in part from my experience as a dissenter from scientific orthodoxy, and in part from my experience as a member of several workshops convened to assess and fix problems with the NIH and NSF grant systems.Sociedad Argentina de Fisiologí

A Genome-Wide Screen for Promoter Methylation in Lung Cancer Identifies Novel Methylation Markers for Multiple Malignancies

BACKGROUND: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. METHODS AND FINDINGS: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. CONCLUSIONS: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention

Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study

Treatment decisions after diagnosis of clinically localised prostate cancer are difficult due to variability in tumour behaviour. We therefore examined one of the most promising biomarkers in prostate cancer, Ki-67, in a cohort of 808 patients diagnosed with prostate cancer between 1990 and 1996 and treated conservatively. Ki-67 expression was assessed immunohistochemically, in two laboratories, by two different scoring methods and the results compared with cancer-specific and overall survival. The power of the biomarker was compared with Gleason score and initial serum prostate-specific antigen (PSA). Both methods showed that Ki-67 provided additional prognostic information beyond that available from Gleason score and PSA: for the semi-quantitative method, Δχ2 (1 d.f.)=24.6 (P<0.0001), overall survival χ2=20.5 (P<0.0001), and for the quantitative method, Δχ2 (1 d.f.)=15.1 (P=0.0001), overall survival χ2=10.85 (P=0.001). Ki-67 is a powerful biomarker in localised prostate cancer and adds to a model predicting the need for radical or conservative therapy. As it is already in widespread use in routine pathology, it is confirmed as the most promising biomarker to be applied into routine practice

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Water, Energy and Life: Fresh Views from the Water's Edge

The impact of surfaces on the contiguous aqueous phase is generally thought to extend no more than a few water-molecule layers. We find, however, that colloidal and molecular solutes are profoundly excluded from the vicinity of hydrophilic surfaces, to distances typically several hundred micrometers. Such large zones of exclusion have been observed next to many different hydrophilic surfaces, and many diverse solutes are excluded. Hence, the exclusion phenomenon appears to be quite general. To test whether the physical properties of the exclusion zone differ from those of bulk water, several methods have been applied. NMR, infrared, and birefringence imaging, as well as measurements of electrical potential, viscosity, and UV-VIS and infrared-absorption spectra, collectively reveal that the solute-free zone is a physically distinct, more ordered phase of water. It can co-exist essentially indefinitely with the contiguous solute-containing phase. Indeed, this unexpectedly extensive zone may be a candidate for the long-postulated “fourth phase” of water considered by earlier scientists. The energy responsible for building this charged, low entropy zone comes from light. We found that incident radiant energy including all visible and near-infrared wavelengths induce exclusion-zone growth in a spectrally sensitive manner. IR is particularly effective. Five-minute exposure to radiation at 3.1 µm (corresponding to OH stretch) causes exclusion-zone-width increase up to three times. Apparently, incident photons cause some change in bulk water that predisposes constituent molecules to reorganize and build the charged, ordered exclusion zone. Photons from ordinary sunlight, then, may have an unexpectedly powerful effect that goes beyond mere heating. It may be that solar energy builds order and separates charge between the near-surface exclusion zone and the bulk water beyond — the separation effectively creating a battery. The resemblance to the first steps of photosynthesis is evident. Indeed, this light-induced action would seem relevant not only for photosynthesis, but also for all realms of nature and engineering involving water and interfaces, and also for biology, where much or all of the cell’s water may be structured. The implications are amply discussed in: http://uwtv.org/programs/displayevent.aspx?rID=22222 and http://www.i-sis.org.uk/liquidCrystallineWater.php and will be presented in the lecture. Dr. Pollack's 2008 UW Annual Faculty Lecture is available on-line. (See the archived video of the lecture: http://uwtv.org/programs/displayevent.aspx?rID=22222) This "Insider: UWTV e-news" article also gives more information about his revolutionary water theory: http://www.uwtv.org/newsletter/insider_0408.as

Why Hydrogels Don’t Dribble Water

Hydrogels contain ample amounts of water, with the water-to-solid ratio sometimes reaching tens of thousands of times. How can so much water remain securely lodged within the gel? New findings imply a simple mechanism. Next to hydrophilic surfaces, water transitions into an extensive gel-like phase in which molecules become ordered. This “fourth phase” of water sticks securely to the solid gel matrix, ensuring that the water does not leak out