Miracle-dz/UniFAR-FTUs huggingface dataset:
Modification of the Tumor Microenvironment as a Novel Target of Renal Cell Carcinoma Therapeutics

AbstractTo move forward with immunotherapy, it is important to understand how the tumor microenvironment generates systemic immunosuppression in patients with renal cell carcinoma (RCC) as well as in patients with other types of solid tumors. Even though antigen discovery in RCC has lagged behind melanoma, recent clinical trials have finally authenticated that RCC is susceptible to vaccine-based therapy. Furthermore, judicious coadministration of cytokines and chemotherapy can potentiate therapeutic responses to vaccine in RCC and prolong survival, as has already proved possible for melanoma. Although high-dose interleukin 2 immunotherapy has been superseded as first-line therapy for RCC by promiscuous receptor tyrosine kinase inhibitors (rTKIs) such as sunitinib, sunitinib itself is a potent immunoadjunct in animal tumor models. A reasonable therapeutic goal is to unite antiangiogenic strategies with immunotherapy as first-line therapy for RCC. This strategy is equally appropriate for testing in all solid tumors in which the microenvironment generates immunosuppression. A common element of RCC and pancreatic, colon, breast, and other solid tumors is large numbers of circulating myeloid-derived suppressor cells (MDSCs), and because MDSCs elicit regulatory T cells rather than vice versa, gaining control over MDSCs is an important initial step in any immunotherapy. Although rTKIs like sunitinib have a remarkable capacity to deplete MDSCs and restore normal T-cell function in peripheral body compartments such as the bloodstream and the spleen, such rTKIs are effective only against MDSCs, which are engaged in phospho-STAT3–dependent programming (pSTAT3+). Unfortunately, rTKI-resistant pSTAT3− MDSCs are especially apt to arise within the tumor microenvironment itself, necessitating strategies that do not rely exclusively on STAT3 disruption. The most utilitarian strategy to gain control of both pSTAT3+ and pSTAT3− MDSCs may be to exploit the natural differentiation pathway, which permits MDSCs to mature into tumoricidal macrophages (TM1) via such stimuli as Toll-like receptor agonists, interferon &ggr;, and CD40 ligation. Overall, this review highlights the mechanisms of immune suppression used by the different regulatory cell types operative in RCC as well as other tumors. It also describes the different therapeutic strategies to overcome the suppressive nature of the tumor microenvironment.
Baptism in the Holy Spirit

The sign of Christ Now, what was the first thing ever said about Jesus? It was this amazing prophecy: that he would baptize people in the Holy Spirit and fire (Matthew 3:11, Luke 3:16). John the Baptist was sent by God to announce that Jesus was coming and to tell people how they would be able to identify him. There are religions a-plenty, but Christ stands apart. Before he even began his ministry, people were told that he was to be recognisable as the person who baptizes in the Holy Spirit.
Inhibited Neurogenesis in JNK1-Deficient Embryonic Stem Cells

ABSTRACT The JNKs are components of stress signaling pathways but also regulate morphogenesis and differentiation. Previously, we invoked a role for the JNKs in nerve growth factor (NGF)-stimulated PC12 cell neural differentiation (L. Marek et al., J. Cell. Physiol. 201:459-469, 2004; E. Zentrich et al., J. Biol. Chem. 277:4110-4118, 2002). Herein, the role for JNKs in neural differentiation and transcriptional regulation of the marker gene, NFLC, modeled in mouse embryonic stem (ES) cells was studied. NFLC-luciferase reporters revealed the requirement for NFLC promoter sequences encompassing base pairs −128 to −98 relative to the transcriptional start site as well as a proximal cyclic AMP response element-activating transcription factor binding site at −45 to −38 base pairs for transcriptional induction in NGF-treated PC12 cells and neurally differentiated ES cells. The findings reveal common promoter sequences that integrate conserved signal pathways in both PC12 cell and ES cell systems. To test the requirement for the JNK pathway in ES cell neurogenesis, ES cell lines bearing homozygous disruptions of the jnk1, jnk2, or jnk3 genes were derived and submitted to an embryoid body (EB) differentiation protocol. Neural differentiation was observed in wild-type, JNK2−/−, and JNK3−/− cultures but not in JNK1−/− EBs. Rather, an outgrowth of cells with epithelial morphology and enhanced E-cadherin expression but low NFLC mRNA and protein was observed in JNK1−/− cultures. The expression of wnt-4 and wnt-6, identified inhibitors of ES cell neurogenesis, was significantly elevated in JNK1−/− cultures relative to wild-type, JNK2−/−, and JNK3−/− cultures. Moreover, the Wnt antagonist, sFRP-2, partially rescued neural differentiation in JNK1−/− cultures. Thus, a genetic approach using JNK-deficient ES cells reveals a novel role for JNK1 involving repression of Wnt expression in neural differentiation modeled in murine ES cells.
Telmisartan and Irbesartan Therapy in Type 2 Diabetic Patients Treated with Rosiglitazone: Effects on Insulin-Resistance, Leptin and Tumor Necrosis Factor-α

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56±5, treated with telmisartan; and 45 males and 48 females, aged 55±4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c, fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-α (TNF-α), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbA1c and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-α and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.
Genetic variation and genetic load due to the male reproductive component of fitness in Drosophila.

The genetic variation and genetic load due to virility, the male reproductive component of fitness, was measured in Drosophila melanogaster and D. pseudoobscura using males homozygous and heterozygous for the second chromosome of each species. Virility was determined in a female-choice, male mating competition experiment where both mating propensity and fertility were taken into account. --The mean virility of the homozygous D. melanogaster males relative to the heterozygous males was 0.50; the relative mean virility of the quasinormal homozygotes was 0.56. The mean virility of the homozygous D. pseudoobscura males relative to the heterozygous males was 0.70; the relative mean virility of the nonsterile homozygotes was 0.72, and of the quasinormal homozygotes, 0.68. --Depending on the species and chromosome sampled, fertile homozygous males had a mean virility 15 to 50% lower than the mean viability of individuals homozygous for a chromosome with quasinormal viability. The genetic load due to virility was also greater than that due to the female reproductive component. This higher level of hidden genetic variation (or genetic load) indicates that the results of Prout (1971a, b) and Bundgaard and Christian (1972), where the virility component of fitness dominated the dynamics of an artificial polymorphism, may be more general and that virility may dominate the dynamics of natural polymorphisms as well.
Activity Profile in Elite Italian Soccer Team

The purpose of this study was to analyse the activity profile of players in a top-class team in the Italian national football league over the course of a season (n=388). The effect of playing position and the two halves on the number and duration of short, intense bursts of effort and recovery phases was studied. The main results show that midfielders cover significantly more distance than players in other positions (p<0.001). For midfielders, the number of displacements of 2-40 m and the number of sprints covering between 2 and 9 m and between 30 and 40 m are considerably greater than for other positions (p<0.05). The distances covered in the second half compared to the first half are significantly lower for all categories of run (p<0.05). In the second half, the distance covered at very high intensity is significantly lower (p<0.01), whilst the number of recovery times greater than 120 s increases significantly compared to the first half (p<0.01). This study provides data which could be used as a basis for the work of scientists as well as football professionals.
Persistent at-Risk-of-Poverty Rate in Italy (2007-2010)

We propose an analysis of the persistent at-risk-of-poverty (PARP) rate in Italy at the onset of the Great Recession. Italy represents an interesting case study because it has one of the highest PARP rates in Europe, together with a flexible labour market and an inadequate social security system. A territorial dualism characterises the country, with the South witnessing worse off standards of living.Our main result is that male employees, the category most protected by the welfare system, are more likely to prevent their households from experiencing persistent poverty. Women, traditionally playing a secondary economic role, let their households more likely to be persistently poor, whatever their source income. The South disadvantage slightly decreases at the beginning of the crisis. This is due to the worsening economic conditions in the North-Centre, whose production was affected to a wider extent by the economic downturn. Analysing poverty and its underlying process may be useful in designing social policies aimed at reducing poverty and contrasting inequalities. The study of poverty studies and of related policy issues for targeted population would benefit from longer datasets. These would allow to analyse poverty transitions and their determinants, by taking explicitly into account poverty duration.
Improving Personalized Ranking in Recommender Systems with Topic Hierarchies and Implicit Feedback

The knowledge of semantic information about the content and user's preferences is an important issue to improve recommender systems. However, the extraction of such meaningful metadata needs an intense and time-consuming human effort, which is impractical specially with large databases. In this paper, we mitigate this problem by proposing a recommendation model based on latent factors and implicit feedback which uses an unsupervised topic hierarchy constructor algorithm to organize and collect metadata at different granularities from unstructured textual content. We provide an empirical evaluation using a dataset of web pages written in Portuguese language, and the results show that personalized ranking with better quality can be generated using the extracted topics at medium granularity.
Colorimetric Phage-Based Assay for Detection of Rifampin-Resistant Mycobacterium tuberculosis

ABSTRACT Tests based on bacteriophage replication enable rapid screening of Mycobacterium tuberculosis for drug resistance. We describe a novel broth-based colorimetric method for detecting phage replication. When clinical isolates were tested by this novel method, high concordance was observed with both the traditional phage assay and gene mutation analysis for detection of resistance to rifampin.
Metamodel-based prediction of performance metrics for bilevel parameter tuning in MOEAs

We consider a bilevel parameter tuning problem where the goal is to maximize the performance of a given multi-objective evolutionary optimizer on a given problem. The search for optimal algorithmic parameters requires the assessment of several sets of parameters, through multiple optimization runs, in order to mitigate the effect of noise that is inherent to evolutionary algorithms. This task is computationally expensive and therefore, in this paper, we propose to use sampling and metamodeling to approximate the performance of the optimizer as a function of its parameters. While such an approach is not unheard of, the choice of the metamodel to be used still remains unclear. The aim of this paper is to empirically compare 11 different metamodeling techniques with respect to their accuracy and training times in predicting two popular multi-objective performance metrics, namely, the hypervolume and the inverted generational distance. For the experiments in this pilot study, NSGA-II is used as the multi-objective optimizer for solving ZDT problems, 1 through 4.
Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy

Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ADNFLE]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated α4 or β2 subunits. Fenofibrate, a common lipid‐regulating drug, is an agonist at peroxisome proliferator‐activated receptor alpha (PPARα) that is a ligand‐activated transcription factor, which negatively modulates the function of β2‐containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLE\NFLE patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype.
A New Antidiabetic Agent, BRL 49653, Reduces Lipid Availability and Improves Insulin Action and Glucoregulation in the Rat

Thiazolidinediones offer promise as oral insulin-sensitizing agents. The effects of a new, high-potency compound (BRL 49653, SmithKline Beecham, Epsom, U.K.) were examined in insulin-resistant (high-fat–fed, HF) and control (high-starch–fed, HS) rats. The diet period was 3 weeks, with a BRL 49653 (10 μmol · kg−1 · day−1) or vehicle gavage on the last 4 days. Then basal or euglycemic clamp studies were performed on animals in the conscious fasted state. In the basal state, BRL 49653 produced many similar metabolic responses in HF and HS rats (reduced insulin, glycerol, ketone body, and nonesterified fatty acid levels, reduced whole body glucose turnover, reduced brown adipose tissue glucose metabolism, and increased cardiac glucose metabolism and GLUT4 levels). In contrast, under euglycemic clamp conditions (500 pmol/l insulin), BRL 49653 only induced changes in the HF group (increased glucose infusion rate from 12.2 ± 0.9 to 21.6 ± 1.1 mg · kg−1 · min−1 [P < 0.001], increased insulin suppressibility of hepatic glucose production [P < 0.01], and increased glucose uptake in muscle [P < 0.01]). BRL 49653 significantly reduced liver but not muscle triglyceride content in HF rats. We conclude that the agent has a general effect on lowering circulating lipid and insulin levels, manifested similarly in normal and insulin-resistant rats, but that enhancement of peripheral insulin action is confined to insulin-resistant rats. Therefore, the hypoinsulinemic action of the thiazolidinediones is probably not related simply to improved peripheral insulin sensitivity. The pattern of individual tissue response to BRL 49653 suggests that altered lipid availability is an important mediator of its effects on glucose metabolism.
A Systematic Review of the Inclusion (or Exclusion) of Women in HIV Research: From Clinical Studies of Antiretrovirals and Vaccines to Cure Strategies

Introduction:The effect of clinical interventions can differ because of sex/gender. Studies have shown that women are often under-represented in medical research. The aim of this systematic literature review was to characterize women's participation in HIV clinical studies of antiretroviral drugs (ARV), prophylactic vaccines (VAX), and curative strategies (CURE). Methods:Systematic PubMed searches were conducted to identify ARV, VAX, and CURE studies. Data were extracted on the number of women, date of publication, sources of funding, country of study, and trial phase. Correlates of female participation were assessed. Results:Women represented a median of 19.2% participants in ARV studies (387), 38.1% in VAX studies (53), and 11.1% in CURE studies (104). Funding source was not correlated with the proportion of female participants in VAX and CURE studies but was for ARV studies (P = 0.03). ARV trials funded by private noncommercial sources had the highest proportion of women, whereas publicly funded trials had the lowest female participation (median 16.7%). The median proportion of women in ARV trials that were fully or partially funded by the National Institutes of Health was significantly lower than the median in trials funded by other sources (19.6% vs. 22.3%, P = 0.001). Conclusions:Although women comprise nearly half of people living with HIV, they continue to be under-represented in clinical studies. Despite federal policies that have been established to address this, our study shows that publicly funded ARV trials recruit even fewer women than other trials. There is an urgent need to ensure that HIV clinical studies consider sex/gender dimensions.
Action Recognition Scheme Based on Skeleton Representation With DS-LSTM Network

Skeleton-based human action recognition has been a popular research field during the past few years. With the help of cameras equipping deep sensors, such as the Kinect, human action can be represented by a sequence of human skeleton data. Inspired by the skeleton descriptors based on Lie group, a spatial–temporal skeleton transformation descriptor (ST-STD) is proposed in this paper. The ST-STD describes the relative transformations of skeletons, including the rotation and translation during movement. It gives a comprehensive view of the skeleton in both spatial and temporal domain for each frame. To capture the temporal connections in the skeleton sequence, a denoising sparse long short term memory (DS-LSTM) network is proposed in this paper. The DS-LSTM is designed to deal with two problems in action recognition. First, to decrease the intra-class diversity, the spatial–temporal auto-encoder (STAE) is proposed in this paper to generate representations with higher abstractness. The denoising constraint and the sparsity constraint are applied on both spatial and temporal domain to enhance the robustness and to reduce action misalignment. Second, to model the action sequence, a three-layer LSTM structure is trained with STAE representations for temporal modeling and classification. The experiments are carried out on four popular datasets. The results show that our approach performs better than several existing skeleton-based action recognition methods, which prove the effectiveness of our method.
Forecasting Stock Index Movement: A Comparison of Support Vector Machines and Random Forest

There exists vast research articles which predict the stock market as well pricing of stock index financial instruments but most of the proposed models focus on the accurate forecasting of the levels (i.e. value) of the underlying stock index. There is a lack of studies examining the predictability of the direction/sign of stock index movement. Given the notion that a prediction with little forecast error does not necessarily translate into capital gain, this study is an attempt to predict the direction of S&P CNX NIFTY Market Index of the National Stock Exchange, one of the fastest growing financial exchanges in developing Asian countries. Random forest and Support Vector Machines (SVM) are very specific type of machine learning method, and are promising tools for the prediction of financial time series. The tested classification models, which predict direction, include linear discriminant analysis, logit, artificial neural network, random forest and SVM. Empirical experimentation suggests that the SVM outperforms the other classification methods in terms of predicting the direction of the stock market movement and random forest method outperforms neural network, discriminant analysis and logit model used in this study.
Large scale screening of the mitochondrial DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians

We report the first large‐scale screening of mitochondrial (mt) DNA in 77 Caucasian patients with relapsing‐remitting or secondary progressive form of multiple sclerosis (MS) and in 84 Caucasian controls by using the method of restriction site polymorphism and haplotype analysis. No pathogenic mtDNA mutation was found in association with MS. However, mtDNA haplotypes K* and J* defined by the simultaneous presence of DdeI restriction sites at nucleotides 10,394 and 14,798 of the mtDNA in haplogroups K and J showed association with MS at a P‐value of 0.001. A relative increase of MS patients compared to controls either with the J* or with the K* haplotype (+ 10,394DdeI/+14,798DdeI in haplogroup J or K) also was detected (each with a P<0.05). No distinct phenotypic characteristics of MS were observed when clinical data of patients with haplotypes K* or J* were analyzed. In addition to previous complete sequencing in several MS patients, the population screening of mtDNA presented here suggests that mtDNA point mutations are not likely to be involved in the pathogenesis of typical forms of MS. However, the mitochondrial genetic background (haplotype K* and J*) may moderately contribute to MS susceptibility. The reported association between MS and Leber's hereditary optic nerve atrophy, a disease caused by mtDNA point mutations preferentially occurring in haplogroup J, may be at least in part related to the overlapping mitochondrial genetic background of the two diseases.