Miracle-dz/UniFAR-FTUs huggingface dataset:
Estimation of the Optimal Cut Off Point in a New Immunological Faecal Occult Blood Test in a Corporate Colorectal Cancer Screening Programme

Objective –To estimate the optimal cut off point in a new immunological method (OC-Hemodia®) for faecal occult blood testing (FOBT). Setting –A corporate colorectal cancer screening programme in Japan. Method –The screening programme targeted colorectal cancer and adenomatous polyps ≥ 10 mm, and was conducted on 27 860 participants (age ⩾ 40) during 1991–92. The follow up consisted of diagnostic management by total colonoscopy on positive screened subjects exceeding the manufacturer recommended cut off level of 50 ng/ml faecal haemoglobin, and the identification of false negative cases by health insurance claims. The optimal cut off point was estimated by the positive predictive value, receiver operating characteristic (ROC) curve, and a cost effectiveness analysis. In this study evaluation was carried out only for cancer as the target disease. Results –At the current cut off level of 50 ng/ml the sensitivity and specificity were 86.5% and 94.9%. When the optimal cut off point was estimated the highest positive predictive value was obtained at 250–350 ng/ml. The ROC curve showed that the sum of sensitivity and specificity is maximised at 50 ng/ml, but evaluation of the ratio, change in sensitivity/change in false positive rate, pointed to higher optimal cut off points, showing marked changes occurring at about 200 ng/ml. The average cost per case was lowest at 250–300 ng/ml. Overall, the optimal cut off point was estimated to be about 200 ng/ml, at which the sensitivity and specificity of the test would be 77.5% and 98.9%, respectively. Conclusion –The optimal cut off point of the new immunological method of FOBT was estimated to be about 200 ng/ml, a value which, more than the current cut off value, favours specificity over sensitivity.
Induction of prostatic carcinomas and lower urinary tract neoplasms by combined treatment of intact and castrated rats with testosterone propionate and N-nitrosobis(2-oxopropyl)amine.

The effect of exogenous testosterone on prostatic carcinogenicity of N-nitrosobis(2-oxopropyl)amine (BOP) in intact and castrated rats was examined in Wistar-derived MRC rats. Daily administration of BOP (either s.c. or i.g.) for 3 days, at a dose of 20 mg/kg b.w. at the heights of prostatic cell proliferation induced by testosterone, led to development of a large number of prostatic tumors, the incidence of which, however, was dependent on the duration of testosterone administration. Testosterone given for life following BOP administration induced prostatic cancer in over 60% of rats, regardless of whether BOP was given orally or s.c. , or whether the rats were orchiectomized or not, whereas tumor incidence was significantly lower in rats treated with testosterone for only a short period of time. One (3%) orchiectomized rat, which received testosterone only during BOP treatment, and four (15%) of rats treated with testosterone only for life also developed carcinomas. Histologically, a large number of BOP + testosterone-induced prostatic tumors were adenocarcinomas of various histological patterns and arose primarily from the dorsal lobe, whereas the great majority of squamous cell carcinomas were found in the ventral lobe. Simultaneously induced tumors were papillomas and carcinomas of the urinary bladder and urethra. Testosterone appeared to enhance the incidence of urinary bladder tumors, but not of the urethral tumors, whereas orchiectomy inhibited urethral carcinogenesis, and, to much lesser extent, urinary bladder tumor development. Rats treated weekly for 20 weeks with BOP (10 mg/kg/week i.g.) did not develop any prostatic tumors and all rats died of rectal cancer. Of rats treated similarly with BOP and with testosterone pellets for life following the last injection of BOP, 17% of rats developed prostatic cancer, all of the squamous cell type. Simultaneous testosterone and BOP treatment for 20 weeks followed by testosterone pellets for life resulted in a 39% tumor incidence (three adenocarcinomas, one anaplastic carcinoma, and five squamous cell carcinomas). The overall results suggest that testosterone plays an important role in the initiation of prostatic carcinogenesis, whereas the promotional phase is governed by the interaction of testosterone with other factors.
Inhibition of 11 b-hydroxysteroid dehydrogenase type 1 ameliorates obesity-related insulin resistance

Excess 11behydroxysteroid dehydrogenase type 1 (11b-HSD1) may be implicated in the development of obesity related metabolic disorders. The present study measured the expression level of 11b-HSD1 in visceral adipose tissues from 23 patients undergoing abdominal operation. Correlation of 11b-HSD1 expression with BMI, waist-to-hip ratio (WHR), HOMA-IR, and serum lipids was evaluated by spearman correlation analysis. High-fat diet-induced obese (DIO) rats were orally dosed with BVT.2733 for 4 weeks. Weight, plasma insulin, and lipids were detected at the end of the treatment. The effects of 11b-HSD1 inhibition on the key insulin-signaling cascade and adipocytokines were measured by western blot and ELISA respectively. 11b-HSD1 was increased in patients with central obesity, the expression level of which was closely related with WHR (r 1⁄4 0.5851), BMI (r 1⁄4 0.4952), and HOMA-IR (r 1⁄4 0.4637). Obesity related insulin resistance in high-fat DIO rats, as reflected by a marked decrease in IRS-1, IRS-2, GLUT4, and PI3K, could be attenuated by 11b-HSD1 inhibition. Furthermore, the down-regulation of 11b-HSD1 could correct the disordered profiles of adipocytokines including adiponectin, IL-6, and TNF-a. These findings indicated that 11b-HSD1 inhibition can give a potential benefit in reducing obesity and lowering insulin resistance by modulating the insulin-signaling pathway and adipocytokine production. © 2016 Published by Elsevier Inc.
Conservation Status and Abundance of the Crowned Sifaka (Propithecus coronatus)

Abstract: The crowned sifaka (Propithecus coronatus) is Endangered. It has a large but highly fragmented distribution; its known range extends from the Betsiboka River in the north of Madagascar, to the Mahavavy River in the north-west, and down to the Tsiribihina River in the south-west. The species lives in forest habitats that are highly and increasingly fragmented and are continuously suffering perturbations and destruction. In order to carry out effective conservation measures targeting P. coronatus, its conservation status needs to be updated so that measures can be taken before anthropogenic or natural environmental changes lead to the extirpation of the species in most of its forests. We (i) identified forest fragments where the species is still present and (ii) using the line-transect “Distance” sampling method, estimated the population size and density in the principal remaining forest fragments in the northern part of its range, including both protected and unprotected areas. We visited most of the forests in the northern part of its range in order to update the current area of occupancy, and to rate the state of its forests using a qualitative “forest quality index. ” Our survey results have shown that (i) a large number of forests have disappeared or decreased in size in the last 10 years, and (ii) population densities vary considerably among forest fragments (ranging from 49 to 309 individuals per km2), with some very high densities in forests located along the Mahavavy River and in the Antrema area. Their abundance in the area surveyed is likely to be between 4,226 and 36,672 individuals, and most probably above 10,000. It is difficult to extrapolate from these estimates to the total abundance across the species' entire range, but we estimate that it is likely to be large, probably between 130,000 and 220,000 individuals. Unfortunately, many field observations suggest that its populations continue to decline at a high rate due to habitat loss and hunting, and we argue for the re-evaluation of the conservation status from Endangered A2cd to Endangered A4acd, and the need to survey the rest of the range of P. coronatus.
Ammonium Assimilation Requires Mitochondrial Respiration in the Light : A Study with the Green Alga Selenastrum minutum.

Mass spectrometric analysis of O(2) and CO(2) exchange in the green alga Selenastrum minutum (Naeg. Collins) provides evidence for the occurrence of mitochondrial respiration in light. Stimulation of amino acid synthesis by the addition of NH(4)Cl resulted in nearly a 250% increase in the rate of TCA cycle CO(2) efflux in both light and dark. Ammonium addition caused a similar increase in cyanide sensitive O(2) consumption in both light and dark. Anaerobiosis inhibited the CO(2) release caused by NH(4)Cl. These results indicated that the cytochrome pathway of the mitochondrial electron transport chain was operative and responsible for the oxidation of a large portion of the NADH generated during the ammonium induced increase in TCA cycle activity. In the presence of DCMU, ammonium addition also stimulated net O(2) consumption in the light. This implied that the Mehler reaction did not play a significant role in O(2) consumption under our conditions. These results show that both the TCA cycle and the mitochondrial electron transport chain are capable of operation in the light and that an important role of mitochondrial respiration in photosynthesizing cells is the provision of carbon skeletons for biosynthetic reactions.
Validation of Reference Genes for the Determination of Platelet Transcript Level in Healthy Individuals and in Patients with the History of Myocardial Infarction

RT-qPCR is the standard method for studying changes in relative transcript level in different experimental and clinical conditions and in different tissues. No validated reference genes have been reported for the normalization of transcript level in platelets. The very low level of platelet RNA and the elimination of leukocyte contamination represented special methodological difficulties. Our aims were to apply a simple technique to separate platelets for transcript level studies, and select the most stable reference genes for platelets from healthy individuals and from patients with the history of myocardial infarction. We developed a simple, straightforward method of platelet separation for RNA isolation. Platelet activation was inhibited by using acid-citrate-dextrose for anticoagulation and by prostaglandin E1. Leukocyte contamination was eliminated by three consecutive centrifugations. Samples prepared by this method were free of leukocytes, showed no inhibition in PCR reaction and no RNA degradation. The assay demands low blood volume, which complies with the requirements of everyday laboratory routine. Seventeen potential reference genes were investigated, but eight of them were excluded during optimization. The stability of the remaining genes, EEF2, EAR, ACTB, GAPDH, ANAPC5, OAZ1, HDGF, GNAS, and CFL1, were determined by four different descriptive statistics. GAPDH, GNAS, and ACTB were shown to be the most stable genes in platelets of healthy individuals, while HDGF, GNAS, and ACTB were the most stable in platelets of patients with the history of myocardial infarction. The results confirm that data normalization needs assessment of appropriate reference genes for a particular sample set.
Three‐dimensional nanofabrication of polystyrene by focused ion beam

Focused ion beam micromachining provides a maskless and resistless technique for prototyping of structures from thermoplastic polymers, an example being the production of polystyrene microcantilevers with potential applications as micro/nanoelectromechanical systems sensors and actuators. The applicability of FIB technology is, however, often restricted by the damage created by high energy gallium ion bombardment and local beam heating, which can affect the desired properties and limit the minimum achievable size of the fabricated structure. To investigate the ion‐induced damage and determine the limitations of the technique for polymer nanofabrication, we have exposed thin polystyrene film to the ion beam at varying ion doses, ion energies and specimen temperatures. Ion doses ranging from 1016 to 1018 ions cm−2 show significant gallium implantation, redeposition of sputtered material and chemical degradation in the polymer. Raman results show that the local heating in polymer during milling is severe at room temperature, damaging the aromatic carbon bonding (C = C) in particular. These observations are supported by the results of a beam heating model and Monte Carlo simulations. The chemical degradation caused by local beam heating is found to be significantly reduced by cooling the specimen to −25°C during milling. This is consistent with observations that reversible and repeatable thermal actuation of a fabricated polystyrene–platinum microcantilever is only observed when the cantilever is prepared at low temperature milling. Using this cooling approach, polymer structures can be fabricated with dimensions as low as 200 nm and still retain a sufficient volume of material unaffected by the ion beam.
Schisandra chinensis Stem Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity via Activation of the Nrf2 Pathway and Inhibition of the MAPKs and NF-κB Pathways

The beneficial value of the stems of Schisandra chinensis (SSC) in neurological diseases is unclear. We examined whether SSC aqueous extract (SSCE) alleviates striatal toxicity in a 3-nitropropionic acid (3-NPA)-induced mouse model of Huntington's disease (HD). SSCE (75, 150, or 300 mg/kg/day, p.o.) was given daily before or after 3-NPA treatment. Pre- and onset-treatment with SSCE displayed a significant protective effect and pretreatment was more effective as assessed by neurological scores and survival rate. These effects were related to reductions in mean lesion area, cell death, succinate dehydrogenase activity, microglial activation, and protein expression of inflammatory factors including interleukin (IL)−1β, IL-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NPA treatment. Pretreatment with SSCE stimulated the nuclear factor erythroid 2-related factor 2 pathway and inhibited phosphorylation of the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways in the striatum after 3-NPA treatment. The gomisin A and schizandrin components of SSCE significantly reduced the neurological impairment and lethality induced by 3-NPA treatment. These results indicate for the first time that SSCE may effectively prevent 3-NPA-induced striatal toxicity during a wide therapeutic time window through anti-oxidative and anti-inflammatory activities. SSCE has potential value in preventive and therapeutic strategies for HD-like symptoms.
Evolving spectrum and incidence of non-AIDS-defining malignancies

Purpose of reviewNon-AIDS defining cancer (NADC) has emerged as an important cause of morbidity and mortality in the HIV-infected population. Insight into the incidence, spectrum, risk factors, management, and outcome of these cancers has continued to emerge. The recent literature on this topic is reviewed. Recent findingsSeveral recent studies have explored the shifting spectrum of NADC in both developed and underdeveloped regions of the world. Investigators have shown only a minor difference in the geographic spectrum of NADC. Although several NADC have continued to occur at rates significantly higher than expected, a noticeable decline was observed in other cancers despite antiretroviral therapy. Factors other than HIV and immunosuppression proved to be important in the risk, treatment response, and outcome of these neoplasms. Studies dealing with the management of several NADC were published, including the role of highly active antiretroviral therapy (HAART). SummaryAn increased overall relative risk of developing NADC continues to be reported in the HIV-infected population worldwide. The development of NADC appears to be multifactorial. Although control of HIV viremia has proven to be beneficial, the impact of HAART on NADC incidence rates and survival is not uniform. Further effort is needed to resolve the direct and indirect effects of HIV on NADC in order to guide effective prevention and treatment strategies of these malignancies.
Assessing the Costs and Cost-Effectiveness of Genomic Sequencing

Despite dramatic drops in DNA sequencing costs, concerns are great that the integration of genomic sequencing into clinical settings will drastically increase health care expenditures. This commentary presents an overview of what is known about the costs and cost-effectiveness of genomic sequencing. We discuss the cost of germline genomic sequencing, addressing factors that have facilitated the decrease in sequencing costs to date and anticipating the factors that will drive sequencing costs in the future. We then address the cost-effectiveness of diagnostic and pharmacogenomic applications of genomic sequencing, with an emphasis on the implications for secondary findings disclosure and the integration of genomic sequencing into general patient care. Throughout, we ground the discussion by describing efforts in the MedSeq Project, an ongoing randomized controlled clinical trial, to understand the costs and cost-effectiveness of integrating whole genome sequencing into cardiology and primary care settings.
Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension

Background— It has been proposed that activation of endothelial SK3 (KCa2.3) and IK1 (KCa3.1) K+ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding of the precise function of SK3 and IK1 in the EDHF dilator response and in blood pressure control remains incomplete. To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels. Methods and Results— Expression and function of endothelial SK3 and IK1 in IK1−/−/SK3T/T mice was characterized by patch-clamp, membrane potential measurements, pressure myography, and intravital microscopy. Blood pressure was measured in conscious mice by telemetry. Combined IK1/SK3 deficiency in IK1−/−/SK3T/T (+doxycycline) mice abolished endothelial KCa currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHF-mediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine-induced EDHF-mediated vasodilation, whereas SK3 deficiency impaired NO-mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1-deficient mice exhibited an elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of SK3 in IK1−/−/SK3T/T mice partially restored EDHF- and nitric oxide–mediated vasodilation and lowered elevated blood pressure. The IK1-opener SKA-31 enhanced EDHF-mediated vasodilation and lowered blood pressure in SK3-deficient IK1+/+/SK3T/T (+doxycycline) mice to normotensive levels. Conclusions— Our study demonstrates that endothelial SK3 and IK1 channels have distinct stimulus-dependent functions, are major players in the EDHF pathway, and significantly contribute to arterial blood pressure regulation. Endothelial KCa channels may represent novel therapeutic targets for the treatment of hypertension.
Genomewide DNA Methylation Analysis Identifies Novel Methylated Genes in Non–Small-Cell Lung Carcinomas

Introduction: DNA methylation is part of the epigenetic regulatory mechanism present in all normal cells. It is tissue-specific and stably maintained throughout development, but often abnormally changed in cancer. Non–small-cell lung carcinoma (NSCLC) is the most deadly type of cancer, involving different tumor subtypes. This heterogeneity is a challenge for correct diagnosis and patient treatment. The stability and specificity make of DNA methylation a very suitable marker for epigenetic phenotyping of tumors. Methods: To identify candidate markers for use in NSCLC diagnosis, we used genomewide DNA methylation maps that we had previously generated by MethylCap and next-generation sequencing and listed the most significant differentially methylated regions (DMRs). The 25 DMRs with highest significance in their methylation scores were selected. The methylation status of these DMRs was investigated in 61 tumors and matching control lung tissues by methylation-specific polymerase chain reaction. Results: We found 12 novel DMRs that showed significant differences between tumor and control lung tissues. We also identified three novel DMRs for each of the two most common NSCLC subtypes, adenocarcinomas and squamous cell carcinomas. We propose a panel of five DMRs, composed of novel and known markers that exhibit high specificity and sensitivity to distinguish tumors from control lung tissues. Conclusion: Novel markers will aid the development of a highly specific epigenetic panel for accurate identification and subtyping of NSCLC tumors.
Neural activation dependent on reading speed during covert reading of novels

We measured the dependence of activation on reading speed with fMRI in a wide range that spanned two orders of magnitude. We used four trained subjects who were capable of a technique of rapid reading, and another four who were untrained, to investigate the neural mechanism during the covert reading of novels. This revealed that activation decreased for trained subjects during extremely rapid reading in the left superior and middle temporal gyri or near Wernicke's area, and in Broca's area. These results suggest that the trained subjects read sentences with fewer phonological processes. The decrease in activation might also be due to fewer semantic and syntactic processes, although the subjects understood the story lines in the novels.
Short Telomeres in Hatchling Snakes: Erythrocyte Telomere Dynamics and Longevity in Tropical Pythons

Background Telomere length (TL) has been found to be associated with life span in birds and humans. However, other studies have demonstrated that TL does not affect survival among old humans. Furthermore, replicative senescence has been shown to be induced by changes in the protected status of the telomeres rather than the loss of TL. In the present study we explore whether age- and sex-specific telomere dynamics affect life span in a long-lived snake, the water python (Liasis fuscus). Methodology/Principal Findings Erythrocyte TL was measured using the Telo TAGGG TL Assay Kit (Roche). In contrast to other vertebrates, TL of hatchling pythons was significantly shorter than that of older snakes. However, during their first year of life hatchling TL increased substantially. While TL of older snakes decreased with age, we did not observe any correlation between TL and age in cross-sectional sampling. In older snakes, female TL was longer than that of males. When using recapture as a proxy for survival, our results do not support that longer telomeres resulted in an increased water python survival/longevity. Conclusions/Significance In fish high telomerase activity has been observed in somatic cells exhibiting high proliferation rates. Hatchling pythons show similar high somatic cell proliferation rates. Thus, the increase in TL of this group may have been caused by increased telomerase activity. In older humans female TL is longer than that of males. This has been suggested to be caused by high estrogen levels that stimulate increased telomerase activity. Thus, high estrogen levels may also have caused the longer telomeres in female pythons. The lack of correlation between TL and age among old snakes and the fact that longer telomeres did not appear to affect python survival do not support that erythrocyte telomere dynamics has a major impact on water python longevity.