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Scientists, public servants, and patient advocates alike increasingly question the validity of published scientific results, endangering the public’s acceptance of science. Here, I argue that emerging flaws in the integrity of the peer review system are largely responsible. Distortions in peer review are driven by economic forces and enabled by a lack of accountability of journals, editors, and authors. One approach to restoring trust in the validity of published results may be to establish basic rules that render peer review more transparent, such as publishing the reviews (a practice already embraced by some journals) and monitoring not only the track records of authors but also of editors and journals. [ABSTRACT FROM AUTHOR]

There are currently over 2.5 million breast cancer survivors in the United States and, according to the American Cancer Society, 10 to 20 percent of these women will develop recurrent breast cancer. Early detection of recurrence can avoid unnecessary radical treatment. However, self-examination or mammography screening may not discover a recurring cancer if the number of surviving cancer cells is small, while biopsy is too invasive and cannot be frequently repeated. It is therefore important to identify non-invasive biomarkers that can detect early recurrence. The present paper develops a mathematical model of cancer recurrence. The model, based on a system of partial differential equations, focuses on tissue biomarkers that include the plasminogen system. Among them, only uPAR is known to have significant correlation to its concentration in serum and could therefore be a good candidate for serum biomarker. The model includes uPAR and other associated cytokines and cells. It is assumed that the residual cancer cells that survived primary cancer therapy are concentrated in the same location within a region with a very small diameter. Model simulations establish a quantitative relation between the diameter of the growing cancer and the total uPAR mass in the cancer. This relation is used to identify uPAR as a potential serum biomarker for breast cancer recurrence. [ABSTRACT FROM AUTHOR]

Background: We investigated the correlation between pancreatic ductal adenocarcinoma patient prognosis and the presence of tumour infiltrating lymphocytes and expression of 521 immune system genes. Methods: Intratumoural CD3+, CD8+, and CD20+ lymphocytes were examined by immunohistochemistry in 12 PDAC patients with different outcomes who underwent pancreaticoduodenectomy. The results were correlated with gene expression profile using the digital multiplexed NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA). Results: Twenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NFκB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37. Discussion: Tumour infiltrating lymphocytes were present at higher levels in samples from patients with better prognosis. Our findings indicate that tumour infiltrating lymphocyte levels and expression level of the immune system genes listed above influence pancreatic ductal adenocarcinoma prognosis. This information could be used to improve selection of best responders to immune inhibitors. [ABSTRACT FROM AUTHOR]

Reports of American shad fecundity identify two important themes regarding egg production in fishes. First, geographic variation occurs and is biologically meaningful. Shad annual fecundity decreases with increasing latitude, but predicted lifetime fecundity does not, because of a counter-gradient of survival probability, all of which can explain the adaptive significance of natal homing. Second, the appropriate method of measuring fecundity depends on the pattern of oocyte development. Historically, the relatively simple determinate-fecundity method was used; however, a recent study in a Virginia river indicates that this method may be biased, requiring the more complicated indeterminate method. We address both themes with collections from the 2015 shad spawning run in the Connecticut River, USA. Criteria for using a determinate method were satisfied for this northern population: 1) a size gap evident in the oocyte size frequency distribution, indicating group-synchronous development of yolked oocytes; 2) a decline, early in spawning, in the standing stock of yolked oocytes; and 3) low levels of atresia at the end of spawning. The determinate-method estimate of American shad annual (2015) fecundity (303,000 ± 73,400; mean ± sd) overlapped historic estimates for this and a neighboring river. The indeterminate-method estimate of annual (2015) fecundity (311,500 ± 4,500 sd) was not significantly different from the determinate-method estimate (Student’s t-test, P > 0.05). In contrast, indeterminate-method estimates of annual fecundity for a Virginia population were twice as high as that measured by the determinate method in the past. This can all be explained by fundamentally different patterns of oogenesis (i.e., group synchrony versus asynchrony with respect to yolk development) at different latitudes. American shad, which is distributed within its native range from the Canadian maritimes to Florida, USA (50–30°N), may be particularly well suited to evaluate intra-specific variation in oocyte development, a relatively unexplored life history trait. [ABSTRACT FROM AUTHOR]

Studies of gene flow between crops and their wild relatives have implications for both management practices for cultivation and understanding the risk of transgene escape. These types of studies may also yield insight into population dynamics and the evolutionary consequences of gene flow for wild relatives of crop species. Moreover, the comparison of genetic markers with different modes of inheritance, or transmission, such as those of the nuclear and chloroplast genomes, can inform the relative risk of transgene escape via pollen versus seed. Here we investigate patterns of gene flow between crop and wild carrot, Daucus carota (Apiaceae) in two regions of the United States. We employed 15 nuclear simple sequence repeat (SSR) markers and one polymorphic chloroplast marker. Further, we utilized both conventional population genetic metrics along with Shannon diversity indices as the latter have been proposed to be more sensitive to allele frequency changes and differentiation. We found that populations in both regions that were proximal to crop fields showed lower levels of differentiation to the crops than populations that were located farther away. We also found that Shannon measures were more sensitive to differences in both genetic diversity and differentiation in our study. Finally, we found indirect evidence of paternal transmission of chloroplast DNA and accompanying lower than expected levels of chloroplast genetic structure amongst populations as might be expected if chloroplast DNA genes flow through both seed and pollen. Our findings of substantial gene flow for both nuclear and chloroplast markers demonstrate the efficiency of both pollen and seed to transfer genetic information amongst populations of carrot. [ABSTRACT FROM AUTHOR]

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h. [ABSTRACT FROM AUTHOR]

Differences in prognosis in HPV-positive and HPV-negative oral (oropharyngeal and oral cavity) squamous cell carcinomas (OSCCs) and increasing incidence of HPV-related cancers have spurred interest in demographic and temporal trends in OSCC incidence. We leverage multistage clonal expansion (MSCE) models coupled with age—period—cohort (APC) epidemiological models to analyze OSCC data in the SEER cancer registry (1973–2012). MSCE models are based on the initiation—promotion—malignant conversion paradigm in carcinogenesis and allow for interpretation of trends in terms of biological mechanisms. APC models seek to differentiate between the temporal effects of age, period, and birth cohort on cancer risk. Previous studies have looked at the effect of period and cohort on tumor initiation, and we extend this to compare model fits of period and cohort effects on each of tumor initiation, promotion, and malignant conversion rates. HPV-related, HPV-unrelated except oral tongue, and HPV-unrelated oral tongue sites are best described by placing period and cohort effects on the initiation rate. HPV-related and non-oral-tongue HPV-unrelated cancers have similar promotion rates, suggesting similar tumorigenesis dynamics once initiated. Estimates of promotion rates at oral tongue sites are lower, corresponding to a longer sojourn time; this finding is consistent with the hypothesis of an etiology distinct from HPV or alcohol and tobacco use. Finally, for the three subsite groups, men have higher initiation rates than women of the same race, and black people have higher promotion than white people of the same sex. These differences explain part of the racial and sex differences in OSCC incidence. [ABSTRACT FROM AUTHOR]

Background: The possibility of incorporating generics into combination antiretroviral therapy and breaking apart once-daily single-tablet regimens (STRs), may result in less efficacious medications and/or more complex regimens with the expectation of marked monetary savings. A modeling approach that assesses the merits of such policies in terms of lifelong costs and health outcomes using adherence and effectiveness data from real-world U.S. settings. Methods: A comprehensive computer-based microsimulation model was developed to assess the lifetime health (life expectancy and quality adjusted life-years—QALYs) and economic outcomes in HIV-1 infected patients initiating STRs compared with multiple-table regimens including generic medications where possible (gMTRs). The STRs considered included tenofovir disoproxil fumarate/emtricitabine and efavirenz or rilpivirine or elvitegravir/cobicistat. gMTRs substitutions included each counterpart to STRs, including generic lamivudine for emtricitabine and generic versus branded efavirenz. Results: Life expectancy is estimated to be 1.301 years higher (discounted 0.619 QALY gain) in HIV-1 patients initiating a single-tablet regimen in comparison to a generic-based multiple-table regimen. STRs were associated with an average increment of $26,547.43 per patient in medication and $1,824.09 in other medical costs due to longer survival which were partially offset by higher inpatients costs ($12,035.61) with gMTRs treatment. Overall, STRs presented incremental lifetime costs of $16,335.91 compared with gMTRs, resulting in an incremental cost-effectiveness ratio of $26,383.82 per QALY gained. Conclusions: STRs continue to represent good value for money under contemporary cost-effectiveness thresholds despite substantial price reductions of generic medications in the U. S. [ABSTRACT FROM AUTHOR]