Miracle-dz/UniFAR-FTUs huggingface dataset:
Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes

In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (∼5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency.
Comparison of fingolimod and dimethyl fumarate in the treatment of multiple sclerosis: Two-year experience

Background Fingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively. Objective The objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years. Methods Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated. Results A total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At ≤24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23–2.37, p = 0.002), or 1.69 (1.16–2.46, p = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03–2.31, p = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67–1.90, p = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68–1.34, p = 0.783), were similar. Conclusions The odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs.
Aqueous and Ethanolic Extracts of Boswellia serrata Protect Against Focal Cerebral Ischemia and Reperfusion Injury in Rats

Oxidative stress and cell apoptosis play major roles in neuronal injury after ischemia–reperfusion (I‐R) injury. Boswellia serrata is a medicinal plant with antioxidant properties. Acetyl‐11‐keto‐β‐boswellic acid (AKBA) is an active triterpenoid compound from B. serrate. In the current study, the neuroprotective effects of aqueous and ethanolic extracts of B. serrata (named ABS and EBS, respectively) and AKBA were investigated against middle cerebral artery occlusion‐induced cerebral I‐R injury in rats. ABS and EBS with doses of 125, 250 and 500 and AKBA with a dose of 50 mg/kg were administered (intraperitoneally) just after middle cerebral artery occlusion induction for 30 min and reperfusion for 24 h. HPLC analysis suggested that ABS and EBS had AKBA of 8.8% and 9.5% (w/w), respectively. B. serrata and AKBA significantly improved neurological deficit and reduced brain infarction, neuronal cell loss and apoptosis and also attenuated lipid peroxidation while increasing glutathione content and superoxide dismutase activity in the cerebral cortex following a stroke. Apoptosis suppression was found to be mediated through regulating caspase‐3 and bax/bcl‐2 expressions. In conclusion, our results demonstrated that B. serrata and AKBA attenuate oxidative damage and inhibit cell apoptosis, subsequently protecting cerebral I‐R injury in rats. Copyright © 2016 John Wiley & Sons, Ltd.
Randomized clinical trial of Ligasure™ versus conventional surgery for extended gastric cancer resection

The Ligasure™ Vessel Sealing System is a haemostatic device designed primarily for use in abdominal surgery. Randomized trials have demonstrated that it is safe and quick for haemorrhoidectomy, but there is no evidence that it confers any advantage in complicated gastrointestinal surgery. The aim of the present study was to examine the value of the Ligasure™ system in extended lymph node dissection (D2) during gastrectomy for cancer in a randomized clinical trial.
Emerging Functions Of Gonadotropin‐Releasing Hormone II in Mammalian Physiology and Behaviour

Gonadotropin‐releasing hormone (GnRH) is the central neuroendocrine regulator of the hypothalamic‐pituitary‐gonadal axis. Multiple structural variants of GnRH are present in vertebrates. The first isoform isolated in the mammalian brain (GnRH I) was shown to regulate the release of pituitary gonadotropins. Recently, a second form has been discovered in mammals (GnRH II), both in the brain and periphery. Although it is unlikely to be a primary regulator of gonadotropin release, the highly conserved GnRH II variant appears to have a wide array of physiological functions. In the periphery, GnRH I and II have similar roles in regulating cell proliferation and mediating hormonal secretion from the ovary and placenta in an autocrine/paracrine manner. In the brain, GnRH I and II apparently modulate mammalian reproductive behaviours in different but complementary ways: GnRH I stimulates luteinizing hormone/follicle‐stimulating hormone secretion (and thus gonadal steroids) and promotes sexual behaviour in ad libitum fed animals. By contrast, GnRH II acts as a permissive regulator of female reproductive behaviour based on energy status, as well as a modifier of short‐term food intake. GnRH II has also been implicated in the regulation of calcium and potassium channels in nervous systems of amphibians, functions which may also be present in mammals. Increasing evidence suggests that the effects of GnRH II in both the periphery and brain may be mediated by GnRH receptor subtypes distinct from the type‐1 GnRH receptor. It is likely that this evolutionarily conserved peptide has been co‐opted over evolutionary time to possess multiple regulatory functions in a broad range of biological aspects, including, but not limited to, reproduction. Here, the proposed actions of both neural and peripheral GnRH II in affecting physiology and behaviour are summarized, and an outline of critical directions for future research is proposed.
Ascending projections to the inferior colliculus

Cells that send ascending projections to the inferior colliculus were identified following injections of horseradish peroxidase into the colliculus. Labelled cells were found in all subcollicular auditory nuclei. Virtually all cells of the ipsilateral ventral nucleus of the lateral lemniscus and medial superior olive appear to project to the colliculus. Very few cells in these nuclei were labelled on the contralateral side. Heavy labelling on the contralateral side was found in the dorsal nucleus of the lateral lemniscus and cochlear nucleus, with less labelling being found ipsilaterally in these nuclei. The lateral superior olive was approximately evenly labelled on the two sides, with about half the cells from each side projecting to each colliculus. Cells in all periolivary cell groups were labelled, with most being found adjecent to the medial superior olive. An effort was made to identify individual cell types that were labelled and some 24 cell types were identified. In the cochlear nucleus there were marked differences between cell types in the extent of their labelling. Topographic projections matched previously described tonotopic organization of the colliculus and all major subcollicular nuclei except the ventral nucleus of the lateral lemniscus. A description of the cells in the nucleus is provided.
Impact of orlistat initiation on cardiovascular treatment use: a 6-year population-based cohort study

Background: Trials of weight-loss drugs indicate some benefits on lipids, blood glucose, or blood pressure levels. Since obesity is associated with increased cardiovascular (CV) medication use and pharmaceutical costs, weight-loss drug use could beneficially impact CV medication use. Objective: We examined the temporal associations between CV drugs use 3 years before and after the initiation of orlistat, a weight-loss drug. Design: An historical cohort study in the PHARMO pharmacy registry among new users of orlistat, who were in the database at least 3 years before and after such drug initiation. We assessed the prevalence of use of antihypertensive, antidiabetic, and lipid-lowering drugs within a 6-month period before and after orlistat initiation. Slopes and changes in slopes between these two periods were calculated using logistic generalized estimating equations and odds ratios (OR) with 95% confidence intervals (CI) are presented. Results: A total of 6139 subjects had a prescription of orlistat between January 1992 and May 2009. Mean ± SD age was 46.5 ± 12.5 years, with a majority of female (88.7%). Use of antihypertensive, antidiabetic, and lipid-lowering drugs increased over time, but after start of orlistat the slopes levelled-off. Initiation of orlistat resulted in a significant change in slope for antihypertensive (OR 0.79; 95% CI 0.77–0.81), antidiabetic (0.86; 0.83–0.90), and lipid-lowering drugs (0.84; 0.81–0.88). Conclusions: Our data suggest a potential cost-effectiveness of orlistat, with a reduction in any cardiovascular comedication use over time. By potentially reducing costs of other medications use, orlistat remains as a unique option for tackling the obesity epidemic.
The single neurofilament subunit of the lamprey forms filaments and regulates axonal caliber and neuronal size in vivo.

Neurofilaments (NFs) are composed of a heteropolymer of three related subunits in mammalian neurons, where they are a major component of the cytoskeleton in large neurons and are thought to regulate axonal diameter. NFs in the lamprey, while ultrastructurally and functionally indistinguishable from mammalian NFs, are polymers of a single subunit protein, NF180. In this study, we use the simplicity of lamprey NFs and the accessibility of the lamprey central nervous system (CNS) to examine the effects of overproducing NFs in an identified giant neuron in vivo, and thus to elucidate the role of NFs in regulating neuronal size and axonal caliber in the vertebrate CNS. We show that overexpression of NF180 tagged with a variant of Green Fluorescent Protein (EYFP) in identified lamprey neurons (ABCs) and in human neuroblastoma (NB2a) cells results in the assembly of exogenous NF180 into ultrastructurally normal NFs that are tightly packed and unphosphorylated. These accumulate in the somata of NB2a cells and produce somatic swelling by 3 days post-transfection. NF180 overexpression in lamprey ABCs in vivo causes exogenous NFs to accumulate in ABC axons, somata, and dendrites, and induces a significant increase in axonal diameter without increasing axonal NF packing density. Overexpression of EYFP alone has none of these effects. We conclude that NF180 normally plays a critical role in determining axonal caliber in ABCs and may influence neuronal size in situations where NFs accumulate in the soma, such as after axonal injury.
Molecular characterisation of Escherichia coli from dead broiler chickens with signs of colibacillosis and ready-to-market chicken meat in the West Bank

Abstract 1. The aim of this work was to compare a group of virulence-associated characteristics of Escherichia coli isolates from broiler chickens that had died with signs of colibacillosis against E. coli isolates from ready-to-market chicken meat in the West Bank. 2. The isolates were investigated to determine the virulence factor (VF) profile, phylogenetic group and the presence of extended-spectrum beta-lactamase (ESBL). A total of 66 avian pathogenic E. coli (APEC) strains from different affected broiler farms and 21 E. coli isolates from ready-to-market chicken carcasses (hereinafter called meat strains) from 8 slaughter houses were analysed. 3. The overall content of VFs was significantly higher (P < 0.05) among APEC strains, with over 75% of APEC strains having ≥4 VFs, while over 75% of the meat strains had <4 VFs. The VFs iss, astA and iucD were frequently detected in APEC and meat strains, whereas cvi, papC, vat, tsh and irp2 occurred more significantly in APEC strains. Phylogenetic typing showed that 67% of the meat strains belonged to group B2. Phylogroup D was predominant (50%) in the APEC strains. Using double disc diffusion and polymerase chain reaction (PCR), 10.6% of the APEC and 9.5% of the meat strains were determined to be ESBL positive. 4. Our findings show that the VFs papC, vat, irp2 and to a lesser extent tsh and cvi are significantly more prevalent in APEC strains. The results demonstrate that chicken meat can be contaminated with APEC strains (≥4 VF). A significant percentage of the meat strains fall in the B2 group, which is a phylogroup largely associated with human pathogenic ExPEC strains. The results of ESBL screening indicated that broiler chicken products in Palestine represent a potential reservoir of ESBL genes and therefore could be considered a possible public health risk.
Averted HIV infections due to expanded antiretroviral treatment eligibility offsets risk of transmitted drug resistance: a modeling study

Background:Earlier antiretroviral therapy initiation can reduce the incidence of HIV-1. This benefit can be offset by increased transmitted drug resistance (TDR). We compared the preventive benefits of reducing incident infections with the potential TDR increase in East Africa. Methods:A mathematical model was constructed to represent Kampala, Uganda, and Mombasa, Kenya. We predicted the effect of initiating treatment at different immunological thresholds (<350, <500 CD4+ cells/&mgr;l) on infections averted and mutation-specific TDR prevalence over 10 years compared to initiating treatment at CD4+ cell count below 200 cells/&mgr;l. Results:When initiating treatment at CD4+ cell count below 350 cells/&mgr;l, we predict 18 [interquartile range (IQR) 11–31] and 46 (IQR 30–83) infections averted for each additional case of TDR in Kampala and Mombasa, respectively, and 22 (IQR 17–35) and 32 (IQR 21–57) infections averted when initiating at below 500. TDR is predicted to increase most strongly when initiating treatment at CD4+ cell count below 500 cells/&mgr;l, from 8.3% (IQR 7.7–9.0%) and 12.3% (IQR 11.7–13.1%) in 2012 to 19.0% (IQR 16.5–21.8%) and 19.2% (IQR 17.1–21.5%) in 10 years in Kampala and Mombasa, respectively. The TDR epidemic at all immunological thresholds was comprised mainly of resistance to non-nucleoside reverse transcriptase inhibitors. When 80–100% of individuals with virological failure are timely switched to second-line therapy, TDR is predicted to decline irrespective of treatment initiation threshold. Conclusion:Averted HIV infections due to the expansion of antiretroviral treatment eligibility offset the risk of transmitted drug resistance, as defined by more infections averted than TDR gained. The effectiveness of first-line non-nucleoside reverse transcriptase inhibitor-based therapy can be preserved by improving switching practices to second-line therapy.
Preoperative and postoperative lower-extremity joint and pelvic kinematics during maximal squatting of patients with cam femoro-acetabular impingement.

BACKGROUND Understanding how the function of the lower extremity joints during everyday movements following surgery to treat cam femoro-acetabular impingement is essential to assess whether surgical intervention effectively restores the normal biomechanics of the hip. The purpose of this study was to compare preoperative and postoperative lower-extremity joint and pelvic angular displacements during maximal depth squatting of patients with unilateral symptomatic cam femoro-acetabular impingement. METHODS Ten participants were compared with respect to their preoperative and postoperative test results. The participants were between eighteen and fifty years of age and had a positive impingement test and visible cam deformity on anteroposterior and Dunn view radiographs. Postoperative testing for each participant occurred between eight and thirty-two months following surgical intervention. Three-dimensional lower-limb joint and pelvic kinematics of participants were collected during maximal depth squats. RESULTS Postoperatively, participants squatted to a greater mean maximal depth than they did preoperatively. Postoperative knee flexion and ankle dorsiflexion angles of the affected extremity at maximal depth were significantly greater than preoperative values. The postoperative sum of all joint angles of the affected limb at maximal squat depth was significantly larger than the preoperative sum. No significant differences were detected between the preoperative and postoperative measurements of the patients with cam impingement with respect to the kinematics of the affected hip at maximal squat depth, the pelvic angular displacements at maximal squat depth, or the overall pelvic range of motion during maximal deep squatting (p > 0.05). CONCLUSIONS The squat performance improved postoperatively, likely because of the combined effects of increased knee and ankle angles as well as a greater acetabular opening and thus reduced anterior femoral head coverage, allowing increased posterior pelvic pitch during the descent phase of the squat. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.
Managing Belief States for Service Robots : Dynamic Scene Perception and Spatio-temporal Memory

Unstructured information management (UIM) has proven itself as a powerful paradigm for scaling intelligent information and question answering systems towards real-world complexity. Complexity in UIM is handled by identifying (or hypothesizing) pieces of structured information in unstructured documents, by applying ensembles of experts for annotating information pieces, and by testing and integrating these isolated annotations into a comprehensive interpretation of the document. In this thesis the paradigm of unstructured information management is applied to the problem of robot perception of realistic scenes containing objects of daily use. In this view, the documents in UIM correspond to camera and depth images taken by the robot, the structured information pieces such as furniture pieces and objects to be manipulated to object hypotheses, and the ensembles of experts to sets of object perception methods. We believe that the application of the UIM principle to robot perception can achieve similar scaling effects as it did for intelligent information systems. We will present ROBOSHERLOCK, an open source software framework for unstructured information processing in robot perception and sketch a feasibility study of a perception system built on top of the framework that indicates the potential of the paradigm for real-world scene perception. A large number of perception methods have been implemented or integrated into ROBOSHERLOCK that span detection of different kinds of objects, annotators that compute appearance or spatial feature descriptors, shape classification, and object reconstruction as well as tracking and entity resolution methods. Web services have been incorporated to provide additional, visual or non-visual information such as text and logo recognition, or product matches from online stores.
Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A‐HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC‐prone microenvironment. Here, we have identified and validated an A‐HSC‐specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue‐related, A‐HSC‐specific gene expression is associated with recurrence and poor survival. Analyses of A‐HSC‐specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A‐HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A‐HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. Conclusion: A‐HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse. (Hepatology 2015;62:481–495
Evaluation of Attentional Demands During Motor Learning: Validity of a Dual-Task Probe Paradigm

ABSTRACT The aim of this study was to examine the validity of a 2-choice audio-vocal reaction time (RT) probe task for measuring the changes in attentional demand during practice and learning of a discrete motor task. Twenty participants practiced the motor task across 3 days and were probed with the RT task during either the preparation or execution phase of the primary task. As practice progressed, participants improved in the primary task performance and shortened the RTs to the probe task. This indicated that less attention was required to plan and execute the movement and suggested that the RT probe task was a sensitive and valid tool to measure changes in attentional demands across practice. The authors implemented several additional experimental controls to address possible confounders including unintentional learning of the probe task, primary-secondary task trade-off effects, and compliance with task priority instructions. These experimental controls further ensured the validity of the probe paradigm and interpretability of the dual-task cost findings. Our experimental methods provided confirmatory evidence for the validity of the 2-choice RT task as a means to assess attentional demands during motor learning.