Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene-modified T lymphocytes in the setting of hematopoietic cell transplantation: potential benefits and possible risks

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is a consolidated treatment for several hematologic malignancies. Donor T lymphocytes can mediate a graft versus tumor (GVT) effect and control opportunistic infections but can also cause severe graft versus host disease (GVHD). Gene-transfer strategies are appealing tools to modulate T cell functions when infused after HCT. Areas covered: The current and potential future applications of T cell gene-transfer approaches to HCT. This review is not limited to GVHD control but covers the issues of GVT and immune reconstitution. Clinical data are used to discuss more general issues, perspectives and concerns common to gene-modification of T cells. An overview of the results and limitations emerging from clinical trials with herpes simplex virus-thymidine kinase (HSV-TK) engineered lymphocytes is provided. The review provides perspectives on additional gene-transfer strategies, currently at preclinical level or that have just entered clinical trials, to increase the efficacy and safety of HCT. Expert opinion: Gene-transfer can positively interfere with T cell functions after HCT. TK-lymphocytes have proven effective in controlling GVHD while retaining an acceptable GVT effect. Strategies exploiting new suicide molecules or engineered T cell receptors (TCRs) should be further explored to address current limitations with TK-lymphocytes and augment the efficacy and specificity of GVT and antiviral activity.
Evolving heuristics for Dynamic Vehicle Routing with Time Windows using genetic programming

Dynamic vehicle routing problem with time windows is an important combinatorial optimisation problem in many real-world applications. The most challenging part of the problem is to make real-time decisions (i.e. whether to accept the newly arrived service requests or not) during the execution of the routes. It is hardly applicable to use the optimisation methods such as mathematical programming and evolutionary algorithms that are competitive for static problems, since they are usually time-consuming, and cannot give real-time responses. In this paper, we consider solving this problem using heuristics. A heuristic gradually builds a solution by adding the requests to the end of the route one by one. This way, it can take advantage of the latest information when making the next decision, and give immediate response. In this paper, we propose a meta-algorithm to generate a solution given any heuristic. The meta-algorithm maintains a set of routes throughout the scheduling horizon. Whenever a new request arrives, it tries to re-generate new routes to include the new request by the heuristic. It accepts the new request if successful, and reject otherwise. Then we manually designed several heuristics, and proposed a genetic programming-based hyper-heuristic to automatically evolve heuristics. The results showed that the heuristics evolved by genetic programming significantly outperformed the manually designed heuristics.
Comparison of sampling techniques for measuring the antimicrobial susceptibility of enteric Escherichia coli recovered from feedlot cattle.

OBJECTIVE To evaluate the effectiveness of various sampling techniques for determining antimicrobial resistance patterns in Escherichia coli isolated from feces of feedlot cattle. SAMPLE POPULATION Fecal samples obtained from 328 beef steers and 6 feedlot pens in which the cattle resided. PROCEDURE Single fecal samples were collected from the rectum of each steer and from floors of pens in which the cattle resided. Fecal material from each single sample was combined into pools containing 5 and 10 samples. Five isolates of Escherichia coli from each single sample and each pooled sample were tested for susceptibility to 17 antimicrobials. RESULTS Patterns of antimicrobial resistance for fecal samples obtained from the rectum of cattle did not differ from fecal samples obtained from pen floors. Resistance patterns from pooled samples differed from patterns observed for single fecal samples. Little pen-to-pen variation in resistance prevalence was observed. Clustering of resistance phenotypes within samples was detected. CONCLUSIONS AND CLINICAL RELEVANCE Studies of antimicrobial resistance in feedlot cattle can rely on fecal samples obtained from pen floors, thus avoiding the cost and effort of obtaining fecal samples from the rectum of cattle. Pooled fecal samples yielded resistance patterns that were consistent with those of single fecal samples when the prevalence of resistance to an antimicrobial was > 2%. Pooling may be a practical altemative when investigating patterns of resistance that are not rare. Apparent clustering of resistance phenotypes within samples argues for examining fewer isolates per fecal sample and more fecal samples per pen.
The Efficacy of Systematic Active Conservative Treatment for Patients With Severe Sciatica: A Single-Blind, Randomized, Clinical, Controlled Trial

Study Design. Prospective single-blind, randomized, clinical, controlled trial. Objective. To evaluate the efficacy of active conservative treatment and to compare 2 active conservative treatment programs for patients with severe sciatica. Summary of Background Data. Reviews have demonstrated little or no efficacy for passive conservative treatment modalities in patients suffering from sciatica. The results for surgery are conflicting. Cohort studies have shown excellent results for active treatment modalities in patients with sciatica. Methods. One hundred eighty-one consecutive patients with radicular pain below the knee were examined at the baseline, at 8 weeks, and at 1 year after the treatment. Participants were randomized into 2 groups: (1) symptom-guided exercises + information + advice to stay active and (2) sham exercises + information + advice to stay active. Symptom-guided exercises consisted of a variety of back-related exercises given in accordance with a written algorithm in which symptoms or response to exercises determined the exercises given (http://www.sygehuslillebaelt.dk/wm345075, click exercises). Sham exercises were optional, designed to increase general blood circulation, and had no targeted effect on the back. The information was comprehensive and included anatomy, pathogenesis, and how discs heal without surgery. The advice included encouragement to stay as active as possible but to reduce activity if leg pain increased. The use of medication was optional, but only paracetamol and nonsteroidal anti-inflammatory drugs were recommended. Results. A mean of 4.8 treatment sessions were provided. All patients experienced statistically significant and clinically important improvements in global assessment, functional status, pain, vocational status, and clinical findings. The symptom-guided exercise group improved significantly more than the sham exercise group in most outcomes. Conclusion. Active conservative treatment was effective for patients who had symptoms and clinical findings that would normally qualify them for surgery. Although participating patients had greater faith in the sham exercises before treatment, the symptom-guided exercises were superior for most outcomes.
Breast cancer stem cells are involved in Trastuzumab resistance through the HER2 modulation in 3D culture

Breast cancer human cells culture as spheroids develop autophagy and apoptosis, which promotes Trastuzumab resistance in HER2 overexpressing cells. Our aim was to study the association of the hostile environment developed in 3D with the breast cancer stem cells population and the HER2 modulation. Human mammary adenocarcinoma cell lines were cultured as spheroids using the hanging drop method. We generated hypoxia conditions by using a hypoxic chamber and CoCl2 treatment. Breast cancer stem cells were measured with mammosphere assays, the analysis of CD44 + CD24low population by flow cytometry and the pluripotent gene expression by RT‐qPCR. HER2 expression was evaluated by flow cytometry and Western blot. MTS assays were conducted to study cell viability. Hostil environment developed in spheroids, defined by hypoxia and autophagy, modulated the response to Trastuzumab. In HER2+ cells with acquired resistance, we observed an increase in the breast cancer stem cell population. In BT474 spheroids, Trastuzumab induced the acquisition of resistance, along with an increase in breast cancer stem cells. Also, in 3D culture conditions we determined a modulation in the HER2 expression. Moreover, breast cancer stem cells showed enhanced HER2 expression. Finally, cells without HER2 gene amplification cultured as spheroids were sensitive to Trastuzumab, diminishing HER2 expression and cancer stem cells. Our findings show that 3D architecture is able to modulate breast cancer stem cell population and HER2 distribution, modifying the cell response to Trastuzumab.
Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells

Ectonucleotide pyrophosphatase/PDE1 (NPP1) is an ectoenzyme, which plays a role in several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack potency and specificity. Quinazoline‐4‐piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated.
Improved Amplification of Genital Human Papillomaviruses

ABSTRACT Genital human papillomaviruses (HPVs) are commonly detected from clinical samples by consensus PCR methods. Two commonly used primer systems, the MY09-MY11 (MY09/11) primers and the GP5+-GP6+ (GP5+/6+) primers, amplify a broad spectrum of HPV genotypes, but with various levels of sensitivity among the HPV types. Analysis of the primer-target sequence homology for the MY09/11 primers showed an association between inefficient amplification of HPV types and the number and position of mismatches, despite accommodation of sequence variation by inclusion of degenerate base sites. The MY09/11 primers were redesigned to increase the sensitivity of amplification across the type spectrum by using the same primer binding regions in the L1 open reading frame. Sequence heterogeneity was accommodated by designing multiple primer sequences that were combined into an upstream pool of 5 oligonucleotides (PGMY11) and a downstream pool of 13 oligonucleotides (PGMY09), thereby avoiding use of degenerate bases that yield irreproducible primer syntheses. The performance of the PGMY09-PGMY11 (PGMY09/11) primer system relative to that of the standard MY09/11 system was evaluated with a set of 262 cervicovaginal lavage specimens. There was a 91.5% overall agreement between the two systems (kappa = 0.83; P < 0.001). The PGMY09/11 system appeared to be significantly more sensitive than the MY09/11 system, detecting an additional 20 HPV-positive specimens, for a prevalence of 62.8% versus a prevalence of 55.1% with the MY09/11 system (McNemar's χ2 = 17.2; P < 0.001). The proportion of multiple infections detected increased with the PGMY09/11 system (40.0 versus 33.8% of positive infections). HPV types 26, 35, 42, 45, 52, 54, 55, 59, 66, 73, and MM7 were detected at least 25% more often with the PGMY09/11 system. The PGMY09/11 primer system affords an increase in type-specific amplification sensitivity over that of the standard MY09/11 primer system. This new primer system will be useful in assessing the natural history of HPV infections, particularly when the analysis requires HPV typing.
Regulation of Arabinose and Xylose Metabolism in Escherichia coli

ABSTRACT Bacteria such as Escherichia coli will often consume one sugar at a time when fed multiple sugars, in a process known as carbon catabolite repression. The classic example involves glucose and lactose, where E. coli will first consume glucose, and only when it has consumed all of the glucose will it begin to consume lactose. In addition to that of lactose, glucose also represses the consumption of many other sugars, including arabinose and xylose. In this work, we characterized a second hierarchy in E. coli, that between arabinose and xylose. We show that, when grown in a mixture of the two pentoses, E. coli will consume arabinose before it consumes xylose. Consistent with a mechanism involving catabolite repression, the expression of the xylose metabolic genes is repressed in the presence of arabinose. We found that this repression is AraC dependent and involves a mechanism where arabinose-bound AraC binds to the xylose promoters and represses gene expression. Collectively, these results demonstrate that sugar utilization in E. coli involves multiple layers of regulation, where cells will consume first glucose, then arabinose, and finally xylose. These results may be pertinent in the metabolic engineering of E. coli strains capable of producing chemical and biofuels from mixtures of hexose and pentose sugars derived from plant biomass.
Long-term natalizumab treatment is associated with sustained improvements in quality of life in patients with multiple sclerosis

Background Multiple sclerosis (MS) patients experience lower health-related quality of life (HRQoL) than the general population. In clinical trials, natalizumab significantly improved HRQoL and reduced relapse rates and disability progression in patients with relapsing MS. In a 1-year analysis of patients included in the current study, HRQoL improvement occurred within 3 months of natalizumab initiation and continued for 1 year thereafter. However, natalizumab’s long-term efficacy in improving HRQoL has not been studied. Methods In this longitudinal, observational, single-arm US study, HRQoL and treatment satisfaction were evaluated in MS patients receiving intravenous natalizumab 300 mg every 4 weeks in clinical settings. Patients completed surveys at baseline and every 6 months for 3 years and reported the following measures: Short Form-12 Version 2 (SF-12v2), Multiple Sclerosis Impact Scale (MSIS-29), and Treatment Satisfaction Questionnaire for Medication. Results In this study, 120 patients completed ≥3 years of natalizumab treatment. Significant HRQoL improvements were evident from baseline to year 3 by increases in SF-12v2 Physical Component Summary (PCS) and Mental Component Summary scores (P<0.01) and decreases in MSIS-29 physical and psychological scores (P<0.0001). Patients with less physical disability (baseline Disease Steps [DS] 0–2) had significant improvement from baseline to year 3 in SF-12v2 PCS (P<0.05) and MSIS-29 physical scores (P<0.05). Physical HRQoL outcomes in patients with baseline DS 3–6 remained stable over 3 years. Treatment satisfaction increased significantly from baseline to year 1 (P<0.0001) and was maintained in the following 2 years. Conclusion Patients reported physical and psychological HRQoL improvements over 3 years of natalizumab treatment, supporting the long-term efficacy of natalizumab in real-world settings. Lower baseline disease activity and earlier treatment were related to better outcomes, indicating the importance of starting natalizumab early in the disease course. Treatment satisfaction increased after natalizumab initiation and remained high over 3 years of treatment.
RIP: the regulatory interaction predictor - a machine learning-based approach for predicting target genes of transcription factors

MOTIVATION Understanding transcriptional gene regulation is essential for studying cellular systems. Identifying genome-wide targets of transcription factors (TFs) provides the basis to discover the involvement of TFs and TF cooperativeness in cellular systems and pathogenesis. RESULTS We present the regulatory interaction predictor (RIP), a machine learning approach that inferred 73 923 regulatory interactions (RIs) for 301 human TFs and 11 263 target genes with considerably good quality and 4516 RIs with very high quality. The inference of RIs is independent of any specific condition. Our approach employs support vector machines (SVMs) trained on a set of experimentally proven RIs from a public repository (TRANSFAC). Features of RIs for the learning process are based on a correlation meta-analysis of 4064 gene expression profiles from 76 studies, in silico predictions of transcription factor binding sites (TFBSs) and combinations of these employing knowledge about co-regulation of genes by a common TF (TF-module). The trained SVMs were applied to infer new RIs for a large set of TFs and genes. In a case study, we employed the inferred RIs to analyze an independent microarray dataset. We identified key TFs regulating the transcriptional response upon interferon alpha stimulation of monocytes, most prominently interferon-stimulated gene factor 3 (ISGF3). Furthermore, predicted TF-modules were highly associated to their functionally related pathways. CONCLUSION Descriptors of gene expression, TFBS predictions, experimentally verified binding information and statistical combination of this enabled inferring RIs on a genome-wide scale for human genes with considerably good precision serving as a good basis for expression profiling studies. CONTACT r.koenig@dkfz.de SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
angsd‐wrapper: utilities for analysing next‐generation sequencing data

High‐throughput sequencing has changed many aspects of population genetics, molecular ecology and related fields, affecting both experimental design and data analysis. The software package angsd allows users to perform a number of population genetic analyses on high‐throughput sequencing data. angsd uses probabilistic approaches which can directly make use of genotype likelihoods; thus, SNP calling is not required for comparative analyses. This takes advantage of all the sequencing data and produces more accurate results for samples with low sequencing depth. Here, we present angsd‐wrapper, a set of wrapper scripts that provides a user‐friendly interface for running angsd and visualizing results. angsd‐wrapper supports multiple types of analyses including estimates of nucleotide sequence diversity neutrality tests, principal component analysis, estimation of admixture proportions for individual samples and calculation of statistics that quantify recent introgression. angsd‐wrapper also provides interactive graphing of angsd results to enhance data exploration. We demonstrate the usefulness of angsd‐wrapper by analysing resequencing data from populations of wild and domesticated Zea. angsd‐wrapper is freely available from https://github.com/mojaveazure/angsd-wrapper.
Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause

Introduction: The recent concept that estrogen agonist–antagonists, often referred to as selective estrogen receptor modulators, can be combined with an estrogen has led to the development of a novel form of menopausal therapy called Tissue-Selective Estrogen Complex (TSEC). This paper reviews the TSEC bazedoxifene and conjugated equine estrogens (BZA/CE). Areas covered: This review is based on clinical trials and a PubMed search. The pharmacokinetics and pharmacodynamics of BZA in BZA plus CE are reviewed. This review outlines the effects of this particular TSEC, which maintains or increases bone mineral density in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. The potential adverse effects of BZA/CE combinations are summarized. Expert opinion: A TSEC that contains CE and BZA that has both estrogen agonist and antagonist effects has reached clinical development. Phase III clinical trials show this TSEC relieves hot flashes, improves vulvo-vaginal atrophy and its symptoms, does not stimulate the endometrium, and prevents bone loss. In the trials so far it appears to have a good safety and tolerability profile. The optimum combination of BZA/CE combination is 20 mg BZA with CE 0.45 and 0.625 mg daily.
Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction.

BACKGROUND The benefits of vessel recanalization in acute myocardial infarction (AMI) are limited by reperfusion damage. In animal models, adenosine limits reperfusion injury, reducing infarct size and improving ventricular function. The aim of this study was to evaluate the safety and feasibility of adenosine adjunct to primary PTCA in AMI. METHODS AND RESULTS Fifty-four AMI patients undergoing primary PTCA were randomized to intracoronary adenosine or saline. The 2 groups were similar for age, sex, and infarct location. Adenosine administration was feasible and well tolerated. PTCA was successful in all patients and resulted in TIMI 3 flow in all patients given adenosine and in 19 given saline (P<0.05). The no-reflow phenomenon occurred in 1 adenosine patient and in 7 saline patients (P=0.02). Creatine kinase was lower in the adenosine group, and a Q-wave MI developed in 16 adenosine patients and in 23 saline patients (P=0.04). Sixty-four percent of dyssynergic segments improved in the adenosine group and 36% in the saline group (P=0. 001). Function worsened in 2% of dysynergic segments in the adenosine group and in 20% in the saline group (P=0.0001). Adverse cardiac events occurred in 5 patients in the adenosine group and in 13 patients in the saline group (P=0.03). CONCLUSIONS Intracoronary adenosine administration is feasible and well tolerated in AMI. Adenosine adjunct to primary PTCA ameliorates flow, prevents the no-reflow phenomenon, improves ventricular function, and is associated with a more favorable clinical course.