Miracle-dz/UniFAR-FTUs huggingface dataset:
Tumorigenesis and Neoplastic Progression Stat3 Promotes Metastatic Progression of Prostate Cancer

There are currently no effective therapies for metastatic prostate cancer because the molecular mechanisms that underlie the metastatic spread of primary prostate cancer are unclear. Transcription factor Stat3 is constitutively active in malignant prostate epithe-lium, and its activation is associated with high histo-logical grade and advanced cancer stage. In this work, we hypothesized that Stat3 stimulates metastatic progression of prostate cancer. We show that Stat3 is active in 77% of lymph node and 67% of bone metastases of clinical human prostate cancers. Importantly, adenoviral gene delivery of wild-type Stat3 (AdWTStat3) to DU145 human prostate cancer cells increased the number of lung metastases by 33-fold in an experimental metastasis assay compared with controls. Using various methods to inhibit Stat3, we demonstrated that Stat3 promotes human prostate cancer cell migration. Stat3 induced the formation of lamellipodia in both DU145 and PC-3 cells, further support-ing the concept that Stat3 promotes a
Intensive follow-up strategies after radical surgery for nonmetastatic colorectal cancer: A systematic review and meta-analysis of randomized controlled trials

Background Intensive follow-up after surgery for colorectal cancers is common in clinical practice, but evidence of a survival benefit is limited. Objective To conduct a systematic review and meta-analysis on the effects of follow-up strategies for nonmetastatic colorectal cancer. Data sources We searched Medline, Embase, and CENTRAL databases through May 30, 2018. Study selection We included randomized clinical trials evaluating intensive follow-up versus less follow-up in patients with nonmetastatic colorectal cancer. Interventions Intensive follow-up Main outcomes measures Overall survival. Results The analyses included 17 trials with a total of 8039 patients. Compared with less follow-up, intensive follow-up significantly improved overall survival in patients with nonmetastatic colorectal cancer after radical surgery (HR 0.85, 95% CI 0.74–0.97, P = 0.01; I2 = 30%; high quality). Subgroup analyses showed that differences between intensive-frequency and intensive-test follow-up (P = 0.04) and between short interval and long interval of follow-up (P = 0.02) in favor of the former one. Limitations Clinical heterogeneity of interventions Conclusions For patients with nonmetastatic colorectal cancer after curative resection, intensive follow-up strategy was associated with an improvement in overall survival compared with less follow-up strategy. Intensive-frequency follow-up strategy was associated with a greater reduction in mortality compared with intensive-test follow-up strategy.
Differences in Self-Reported Trauma Symptomatology Between Individuals With and Without Disability

In this study, the authors examined whether individuals with disabilities report higher levels of trauma symptoms than their nondisabled counterparts. Based on trauma theory and prior research regarding the incidence rate of posttraumatic stress disorder, the authors hypothesized that individuals with disabilities would report higher levels of trauma symptoms. Results partially supported the hypothesis, with women with disabilities reporting significantly higher levels of recalled trauma symptomatology when compared with men with disabilities and with men and women without disabilities. Men with disabilities did not report significantly higher levels of trauma symptoms when compared with men and women without disabilities. Effect sizes and confidence intervals were also computed for each analysis.
Spatial heterogeneity and hydrological fluctuations drive bacterioplankton community composition in an Amazon floodplain system

Amazonian floodplains form complex hydrological networks that play relevant roles in global biogeochemical cycles, and bacterial degradation of the organic matter in these systems is key for regional carbon budget. The Amazon undergoes extreme seasonal variations in water level, which produces changes in landscape and diversifies sources of organic inputs into floodplain systems. Although these changes should affect bacterioplankton community composition (BCC), little is known about which factors drive spatial and temporal patterns of bacterioplankton in these Amazonian floodplains. We used high-throughput sequencing (Illumina MiSeq) of the V3-V4 region of the 16S rRNA gene to investigate spatial and temporal patterns of BCC of two size fractions, and their correlation with environmental variables in an Amazon floodplain lake (Lago Grande do Curuai). We found a high degree of novelty in bacterioplankton, as more than half of operational taxonomic units (OTUs) could not be classified at genus level. Spatial habitat heterogeneity and the flood pulse were the main factors shaping free-living (FL) BCC. The gradient of organic matter from transition zone-lake-Amazon River was the main driver for particle-attached (PA) BCC. The BCC reflected the complexity of the system, with more variation in space than in time, although both factors were important drivers of the BCC in this Amazon floodplain system.
Categorising trajectories and individual item changes of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy

Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to ≤ 5 at age ~10y), 35% were in cluster 2 (NSAA ≤ 5 ~12y), 21% in were cluster 3 (NSAA≤ 5 ~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement–or static behavior–by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease progression; this will be invaluable for future DMD clinical trial design and interpretation of findings.
Transience effect in capture-recapture studies: The importance of its biological meaning

Capture–recapture (CR) models are an essential tool for estimating demographic parameters in most animal and some plant populations. To avoid drawing incorrect conclusions in any statistical inference, a crucial prerequisite is to assess the goodness of fit of a general model to the data. In CR models, a frequent cause of lack of fit, is the so-called transience effect, which is due to a lower expectation of re-observation of individuals marked for the first time as compared to other individuals. The transience effect may result either from different biological causes or from the sampling procedure. A transience effect is usually treated by distinguishing at least two age-classes in the survival probability, but other approaches may be more suitable. Here we develop a conceptual and analytical framework for including a transience effect in capture-recapture models. We show the implementation of two additional parametrizations that incorporate a transience effect. With these parametrizations, we can directly estimate the “transience probability” defined as the probability that a newly caught individual disappear from the population beyond what is expected based on the behavior of the previously caught individuals in the same sample. Additionally, these parametrizations allow testing biological hypotheses concerning drivers affecting this probability. Results from our case study show differences between parametrizations, with the parametrization most currently used giving different estimates, especially when including covariates. We advocate for a unifying framework for treating a transience effect, that helps clarifying the ideas and terminology, and where the biological reasons should be the rule for choosing the appropriate analytical procedure. This framework will also open new and powerful ways for the detection and exploration of ecological processes such as the costs of the first reproduction or the deleterious effects of some types of marking.
Geographical location influences the composition of the gut microbiota in wild house mice (Mus musculus domesticus) at a fine spatial scale

The composition of the mammalian gut microbiota can be influenced by a multitude of environmental variables such as diet and infections. Studies investigating the effect of these variables on gut microbiota composition often sample across multiple separate populations and habitat types. In this study we explore how variation in the gut microbiota of the house mouse (Mus musculus domesticus) on the Isle of May, a small island off the east coast of Scotland, is associated with environmental and biological factors. Our study focuses on the effects of environmental variables, specifically trapping location and surrounding vegetation, as well as the host variables sex, age, body weight and endoparasite infection, on the gut microbiota composition across a fine spatial scale in a freely interbreeding population. We found that differences in gut microbiota composition were significantly associated with the trapping location of the host, even across this small spatial scale. Sex of the host showed a weak association with microbiota composition. Whilst sex and location could be identified as playing an important role in the compositional variation of the gut microbiota, 75% of the variation remains unexplained. Whereas other rodent studies have found associations between gut microbiota composition and age of the host or parasite infections, the present study could not clearly establish these associations. We conclude that fine spatial scales are important when considering gut microbiota composition and investigating differences among individuals.
Extracellular matrix turnover and inflammation in chemically-induced TMJ arthritis mouse models

The temporomandibular joint (TMJ) is a fibrocartilaginous tissue critical for chewing and speaking. In patients with temporomandibular disorders (TMDs), permanent tissue loss can occur. Recapitulating the complexity of TMDs in animal models is difficult, yet critical for the advent of new therapies. Synovial fluid from diseased human samples revealed elevated levels of tumor necrosis factor alpha (TNF-alpha). Here, we propose to recapitulate these findings in mice by subjecting murine TMJs with TNF-alpha or CFA (Complete Freund’s Adjuvant) in mandibular condyle explant cultures and by local delivery in vivo using TMJ intra-articular injections. Both TNF-alpha and CFA delivery to whole mandibular explants and in vivo increased extracellular matrix deposition and increased cartilage thickness, while TNF-alpha treated explants had increased expression of inflammatory cytokines and degradative enzymes. Moreover, the application of TNF-alpha or CFA in both models reduced cell number. CFA delivery in vivo caused soft tissue inflammation, including pannus formation. Our work provides two methods of chemically induced TMJ inflammatory arthritis through a condyle explant model and intra-articular injection model that replicate findings seen in synovial fluid of human patients, which can be used for further studies delineating the mechanisms underlying TMJ pathology.
Tumorigenesis and Neoplastic Progression Transmembrane Interactions Are Needed for KAI 1 / CD 82-Mediated Suppression of Cancer Invasion and Metastasis

In transmembrane (TM) domains, tetraspanin KAI1/ CD82 contains an Asn, a Gln, and a Glu polar residue. A mutation of all three polar residues largely disrupts the migration-, invasion-, and metastasis-suppressive activities of KAI1/CD82. Notably, KAI1/CD82 inhibits the formation of microprotrusions and the release of microvesicles, while the mutation disrupts these inhibitions, revealing the connections of microprotrusion and microvesicle to KAI1/CD82 function. The TM polar residues are needed for proper interactions between KAI1/CD82 and tetraspanins CD9 and CD151, which also regulate cell movement, but not for the association between KAI1/CD82 and 3 1 integrin. However, KAI1/CD82 still efficiently inhibits cell migration when either CD9 or CD151 is absent. Hence, KAI1/CD82 interacts with tetraspanin and integrin by different mechanisms and is unlikely to inhibit cell migration through its associated proteins. Moreover, without significantly affecting the glycosylation, homodimerization, and global folding of KAI1/CD82, the TM interactions maintain the conformational stability of KAI1/CD82, evidenced by the facts that the mutant is more sensitive to denaturation and less associable with tetraspanins and supported by the modeling analysis. Thus, the TM interactions mediated by these polar residues determine a conformation either in or near the tightly packed TM region and this conformation and/or its change are needed for the intrinsic activity of KAI1/CD82. In contrast to immense efforts to block the signaling of cancer progression, the perturbation of TM interactions may open a new avenue to prevent cancer invasion and metastasis. (Am J Pathol 2009, 174:647–660; DOI: 10.2353/ajpath.2009.080685)
Transforming growth factor beta 1 induces methylation changes in lung fibroblasts

Idiopathic pulmonary fibrosis is a complex disease of unknown etiology. Environmental factors can affect disease susceptibility via epigenetic effects. Few studies explore global DNA methylation in lung fibroblasts, but none have focused on transforming growth factor beta-1 (TGF-β1) as a potential modifier of the DNA methylome. Here we analyzed changes in methylation and gene transcription in normal and IPF fibroblasts following TGF-β1 treatment. We analyzed the effects of TGF-β1 on primary fibroblasts derived from normal or IPF lungs treated for 24 hours and 5 days using the Illumina 450k Human Methylation array and the Prime View Human Gene Expression Array. TGF-β1 induced an increased number of gene expression changes after short term treatment in normal fibroblasts, whereas greater methylation changes were observed following long term stimulation mainly in IPF fibroblasts. DNA methyltransferase 3 alpha (DMNT3a) and tet methylcytosine dioxygenase 3 (TET3) were upregulated after 5-days TGF-β1 treatment in both cell types, whereas DNMT3a was upregulated after 24h only in IPF fibroblasts. Our findings demonstrate that TGF-β1 induced the upregulation of DNMT3a and TET3 expression and profound changes in the DNA methylation pattern of fibroblasts, mainly in those derived from IPF lungs.
Educational achievement at age 9.5 years of children born to mothers maintained on methadone during pregnancy

Recent research shows that preschool children born to opioid-dependent mothers are at increased risk for cognitive, psychomotor, attention, and social-emotional adjustment problems. But very little is known about their school-age functioning, particularly their educational achievement. This analysis examined the educational outcomes of a regional cohort of 100 prenatally methadone-exposed children who were prospectively studied from birth to age 9.5 years alongside a comparison group of 110 randomly identified non-exposed children born between 2003 and 2008. At age 9.5, as part of a comprehensive neurodevelopmental evaluation, children’s teachers rated their achievement across the school curriculum, and children completed the Woodcock Johnson-III Tests of Achievement (WJ-III). Detailed information about the birth mother’s social background, pregnancy substance use, and mental health was also collected during pregnancy/at term. Infant clinical data were collected after birth. Methadone-exposed children performed less well than non-exposed children across seven school curriculum areas rated by teachers (ps ≤.001), performed less well than non-exposed children on all reading and mathematics subtests of the WJ-III, and had higher rates of any educational delay on the WJ-III (57% vs. 15%), OR = 7.47 (3.71–15.02). Results were similar when children with severe intellectual impairment were excluded. After adjusting for confounding factors, methadone-exposed children had increased odds of educational delay, but this was only marginally significant (OR = 3.62, [1.01–13.01], p = .049). Maternal educational attainment level (OR = 0.69, [0.50–0.89], p = .006), and maternal benzodiazepine use during pregnancy (OR = 2.70 [1.03–7.12], p = .044) were also associated with later educational risk. Findings suggest that children born to opioid-dependent women enrolled in methadone maintenance are at high risk of educational delay by age 9.5 years. Children’s academic difficulties appeared to reflect the effects of both adverse prenatal exposures and postnatal social risk.
Vascular Biology , Atherosclerosis and Endothelium Biology Epstein-Barr Virus-Induced Gene-3 Is Expressed in Human Atheroma Plaques

Atherosclerosis is characterized by a complex immune response in the vessel wall , involving both inflammation and autoimmune processes. EpsteinBarr virus-induced gene 3 (Ebi3) is a member of the interleukin (IL)-12 heterodimeric cytokine family, which has important immunomodulatory functions. To date, little is known about the role of Ebi3 in vascular disease. We examined the expression of Ebi3 in human atheromatous lesions and analyzed its transcriptional regulation in vascular cells. The in situ expression of Ebi3 in human endarterectomy specimens was analyzed by immunohistochemistry. In these lesions, smooth muscle cells expressed Ebi3 as well as the IL-27 /p28 and IL-12 /p35 subunits. Primary aortic smooth muscle cells up-regulated Ebi3 in response to proinflammatory stimuli like tumor necrosis factorand interferon. Interestingly , pretreatment of these cells with the peroxisome proliferator-activated receptoragonist rosiglitazone strongly reduced Ebi3 induction. Chromatin immunoprecipitation experiments revealed that this inhibition is due to interference with p65/RelA recruitment to the Ebi3 promoter. Our data support a possible role of Ebi3 in atherogenesis either as homodimer or as IL-27/IL-35 heterodimer, and suggest that Ebi3 could be an interesting target for therapeutic manipulation in atherosclerosis. (Am J Pathol 2009, 175:440–447; DOI: 10.2353/ajpath.2009.080752)
A flexible formula for incorporating distributive concerns into cost-effectiveness analyses: Priority weights

Background Cost effectiveness analyses (CEAs) are widely used to evaluate the opportunity cost of health care investments. However, few functions that take equity concerns into account are available for such CEA methods, and these concerns are therefore at risk of being disregarded. Among the functions that have been developed, most focus on the distribution of health gains, as opposed to the distribution of lifetime health. This is despite the fact that there are good reasons to give higher priority to individuals and groups with a low quality adjusted life expectancy from birth (QALE). Also, an even distribution of health gains may imply an uneven distribution of lifetime health. Methods We develop a systematic and explicit approach that allows for the inclusion of lifetime health concerns in CEAs, by creating a new priority weight function, PW = α+(t-γ)·C·e-β·(t-γ), where t is the health measure. PW has several desirable properties. First, it is continuous and smooth, ensuring that people with similar health characteristics are treated alike. For example, those who achieve 50 QALE should be treated similarly to those who achieve 49.9 QALE. Second, it is flexible regarding shape and outcome measure (i.e., caters to other measures than QALE), so that a broad range of values may be modelled. Third, the coefficients have distinct roles. This allows for the easy manipulation of the PW’s shape. In order to demonstrate how PW may be applied, we use data from a previous study and estimated the coefficients of PW based on two approaches. Conclusions Equity concerns are important when conducting CEAs, which means that suitable PWs should be developed. We do not intend to determine which PW is the most appropriate, but to illustrate how a flexible general PW can be estimated based on empirical data.
Tumorigenesis and Neoplastic Progression Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation

From the Divisions of Cancer-Related Genes,* and Cancer Biology, Institute for Genetic Medicine, and the Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan; and the Departments of Molecular and Cellular Oncology, GI Medical Oncology, Pathology, Endocrine Neoplasia and Hormonal Disorders,** and General Internal Medicine, Ambulatory Treatment and Emergency Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Therapeutic Efficacy of Antibodies Lacking FcγR against Lethal Dengue Virus Infection Is Due to Neutralizing Potency and Blocking of Enhancing Antibodies

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.