Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer

Simple Summary FL118 is a novel orally available small molecule anticancer drug. We found that bladder cancer cells with a mutant Kras is highly sensitive to FL118-induced cell growth inhibition and cell death induction through inhibiting the anti-cancer cell death and drug resistance factors (survivin, Mcl-1, XIAP). In the Kras-mutation bladder cancer cells, FL118 can stimulate the reactive oxygen species (ROS) over-production for killing bladder cancer cells and inhibiting bladder cancer cell-established tumor growth. Elimination of mutant Kras by Kras-specific shRNA technology in mutant Kras-containing bladder cancer cell-established tumor decreased FL118 effectiveness to inhibit bladder cancer tumor growth. In this regard, mutant Kras is a potential favorable biomarker for FL118. This finding is significant because mutant Kras is known to be a formidable challenge treatment resistant factor in various types of cancer. Thus, FL118 could use mutant Kras as favorable biomarker for patient selection to carry out precision medicine. Abstract Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment.
Tuberculosis among Children and Adolescents at HIV Treatment Centers in Sub-Saharan Africa

HIV-infected children and adolescents are at increased risk for tuberculosis (TB). Antiretroviral therapy (ART) reduces TB risk in HIV-infected adults, but its effectiveness in HIV-infected children and adolescents is unknown. We analyzed data from 7 integrated pediatric HIV/TB centers in 6 countries in sub-Saharan Africa. We used a Bayesian mixed-effect model to assess association between ART and TB prevalence and used adaptive lasso regression to analyze risk factors for adverse TB outcomes. The study period encompassed 57,525 patient-years and 1,160 TB cases (2,017 cases/100,000 patient-years). Every 10% increase in ART uptake resulted in a 2.33% reduction in TB prevalence. Favorable TB outcomes were associated with increased time in care and early ART initiation, whereas severe immunosuppression was associated with death. These findings support integrated HIV/TB services for HIV-infected children and adults and demonstrate the association of ART uptake with decreased TB incidence in high HIV/TB settings.
Desmoglein-2 as a prognostic and biomarker in ovarian cancer

ABSTRACT Greater than 80% of all cancer cases are carcinomas, formed by the malignant transformation of epithelial cells. One of the key features of epithelial tumors is the presence of intercellular junctions, which link cells to one another and act as barriers to the penetration of molecules. This study assessed the expression of desmoglein-2, an epithelial junction protein, as a prognostic and diagnostic biomarker for ovarian cancer. Ovarian cancer sections were stained for DSG2 and signal intensity was correlated to cancer type and grade. DSG2 immunohistochemistry signals and mRNA levels were analyzed in chemo-resistant and chemo-sensitive cases. Ovarian cancer patient serum levels of shed DSG2 were correlated to disease-free and overall survival. Primary ovarian cancer cells were used to study DSG2 levels as they changed in response to cisplatin treatment. DSG2 expression was found to be positively correlated with cancer grade. Ovarian cancer patients with high serum levels of shed DSG2 fared significantly worse in both progression-free survival (median survival of 16 months vs. 26 months, p = .0023) and general survival (median survival of 37 months vs. undefined, p < .0001). A subgroup of primary chemotherapy-resistant cases had stronger DSG2 IHC/Western signals and higher DSG2 mRNA levels. Furthermore, our in vitro studies indicate that non-cytotoxic doses of cisplatin can enhance DSG2 expression, which, in turn, can contribute to chemo-resistance. We suggest that DSG2 can be used in stratifying patients, deciding on where to use aggressive treatment strategies, predicting chemoresistance, and as a companion diagnostic for treatments targeting DSG2.
Comparative efficacy and acceptability of traditional Chinese medicine for adult major depression

Abstract Background: Major depression disorder (MDD) is a severe health threat characterized by persistent depression, loss of interests, lack of initiative, and even suicidal tendencies. Traditional Chinese medicine (TCM) is well tolerated and effective in treating adult MDD. However, research on the evaluation of efficacy and acceptability of different TCM strategies for adult MDD is insufficient. Consequently, it is high time to evaluate the efficacy of TCM strategies for adult MDD. Meanwhile, the acceptability of different TCM strategies is worth exploring. Methods: Comprehensively and systematically retrieve the literature in PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure Database (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese BioMedical Literature Database (CBM). The literature search will focus on randomized controlled trials (RCTs) with TCM in adult MDD. Two reviewers will search the literature and extract relevant data back-to-back. Once mismatched outcomes appear, arbitration will be conducted by a third reviewer. Based on the Bayesian framework, data analysis is carried out with STATA and WinBUGS software. Heterogeneity, transitivity, consistency test, bias risk assessment, subgroup and sensitivity analysis, evidence quality evaluation will be performed accordingly. Results: The efficacy and acceptability of different TCM strategies for adults with MDD will be compared and sorted. Conclusion: The study will facilitate the treatment options of adults MDD according to the supporting evidence. INPLASY registration number: INPLASY2020100028.
The amygdala instructs insular feedback for affective learning

Affective responses depend on assigning value to environmental predictors of threat or reward. Neuroanatomically, this affective value is encoded at both cortical and subcortical levels. However, the purpose of this distributed representation across functional hierarchies remains unclear. Using fMRI in mice, we mapped a discrete cortico-limbic loop between insular cortex (IC), central amygdala (CE), and nucleus basalis of Meynert (NBM), which decomposes the affective value of a conditioned stimulus (CS) into its salience and valence components. In IC, learning integrated unconditioned stimulus (US)-evoked bodily states into CS valence. In turn, CS salience in the CE recruited these CS representations bottom-up via the cholinergic NBM. This way, the CE incorporated interoceptive feedback from IC to improve discrimination of CS valence. Consequently, opto-/chemogenetic uncoupling of hierarchical information flow disrupted affective learning and conditioned responding. Dysfunctional interactions in the IC↔CE/NBM network may underlie intolerance to uncertainty, observed in autism and related psychiatric conditions.
Interindividual Differences in Human Intestinal Microbial Conversion of (−)-Epicatechin to Bioactive Phenolic Compounds

To quantify interindividual differences in the human intestinal microbial metabolism of (−)-epicatechin (EC), in vitro anaerobic incubations with fecal inocula from 24 healthy donors were conducted. EC-derived colonic microbial metabolites were qualitatively and quantitively analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-TQ-MS) and liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS). Quantitative microbiota characterization was achieved by 16S rRNA analysis. The results obtained show 1-(3′,4′-dihydroxyphenyl)-3-(2″,4″,6″-dihydroxyphenyl)-2-propanol (3,4-diHPP-2-ol) and 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (3,4-diHPV) to be key intermediate microbial metabolites of EC and also revealed the substantial interindividual differences in both the rate of EC conversion and the time-dependent EC metabolite pattern. Furthermore, substantial differences in microbiota composition among different individuals were detected. Correlations between specific microbial phylotypes and formation of certain metabolites were established. It is concluded that interindividual differences in the intestinal microbial metabolism of EC may contribute to interindividual differences in potential health effects of EC-abundant dietary foods or drinks.
Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain

Metallocarboxypeptidase Z (CPZ) is a secreted enzyme that is distinguished from all other members of the M14 metallocarboxypeptidase family by the presence of an N-terminal cysteine-rich Frizzled-like (Fz) domain that binds Wnt proteins. Here, we present a comprehensive analysis of the enzymatic properties and substrate specificity of human CPZ. To investigate the enzymatic properties, we employed dansylated peptide substrates. For substrate specificity profiling, we generated two different large peptide libraries and employed isotopic labeling and quantitative mass spectrometry to study the substrate preference of this enzyme. Our findings revealed that CPZ has a strict requirement for substrates with C-terminal Arg or Lys at the P1′ position. For the P1 position, CPZ was found to display specificity towards substrates with basic, small hydrophobic, or polar uncharged side chains. Deletion of the Fz domain did not affect CPZ activity as a carboxypeptidase. Finally, we modeled the structure of the Fz and catalytic domains of CPZ. Taken together, these studies provide the molecular elucidation of substrate recognition and specificity of the CPZ catalytic domain, as well as important insights into how the Fz domain binds Wnt proteins to modulate their functions.
Emotional-Behavioral Regulation, Temperament and Parent–Child Interactions Are Associated with Dopamine Transporter Allelic Polymorphism in Early Childhood: A Pilot Study

International research has highlighted the role played by individual genetic polymorphism, children’s emotional-behavioral functioning, and quality of parent–child feeding interaction in shaping children’s development. Few studies have focused on the dopamine transporter (DAT1) gene in these processes. In a community sample of 81 families with young children aged between 19 and 28 months (37 males and 44 females), this pilot study aimed to explore possible relationships between children’s DAT1 genotype (9/x: 9/9, 9/19 contrasted to 10/10), their own psychological profiles, parental psychopathological risk, and the quality of mother–child and father–child feeding interactions. Children’s DAT1 genotype was assessed collecting DNA through buccal; children’s temperament and emotional-behavioral regulation, and parental psychopathological risk were assessed, respectively, through report-form and self-report instruments; then, dyadic exchanges were videotaped during a mealtime, and coded based on the Scala di Valutazione dell′Interazione Alimentare (SVIA). Results showed significant differences in the variables under study based on children’s DAT1 genotype, with a higher risk associated with the 10/10. Our findings have provided preliminary new evidence on the relationship between a different child’s polymorphisms, their own emotional-behavioral functioning, and the quality of the family environment, with important implications for the planning of more targeted prevention programs.
Baseline prognostic nutritional index and changes in pretreatment body mass index associate with immunotherapy response in patients with advanced cancer

Background Recent research suggests that baseline body mass index (BMI) is associated with response to immunotherapy. In this study, we test the hypothesis that worsening nutritional status prior to the start of immunotherapy, rather than baseline BMI, negatively impacts immunotherapy response. Methods We studied 629 patients with advanced cancer who received immune checkpoint blockade at New York University. Patients had melanoma (n=268), lung cancer (n=128) or other primary malignancies (n=233). We tested the association between BMI changes prior to the start of treatment, baseline prognostic nutritional index (PNI), baseline BMI category and multiple clinical end points including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results Decreasing pretreatment BMI and low PNI were associated with worse BOR (p=0.04 and p=0.0004), ORR (p=0.01 and p=0.0005), DCR (p=0.01 and p<0.0001), PFS (p=0.02 and p=0.01) and OS (p<0.001 and p<0.001). Baseline BMI category was not significantly associated with any treatment outcomes. Conclusion Standard of care measures of worsening nutritional status more accurately associate with immunotherapy outcomes than static measurements of BMI. Future studies should focus on determining whether optimizing pretreatment nutritional status, a modifiable variable, leads to improvement in immunotherapy response.
High nitrogen concentration alter microbial community in Allium fistulosum rhizosphere

Welsh onion (Allium fistulosum L.) constitutes an important plant species cultivated in China due the benefits and applications in different areas. Moreover, nitrogen is an essential nutrient during the growth and development of plant. Here, we present the effects of nitrogen on soil microbiome in welsh onion plants. We used High-throughput sequencing analysis to determine the diversity and abundances of microbes associated to soil rhizosphere in welsh onion under the influence of nitrogen application. Nitrogen application significantly influenced in the diversity of fungal community. The relative abundance of Orbiliomycetes increased with the nitrogen concentration. Nitrogen application did not affect the diversity of bacterial community, whereas the relative abundance of Acidobacteria_Gp2, Verrucomicrobiae and Sphingobacteriia decreased with the nitrogen condition. In this work, we introduced evidences of the effect of nitrogen fertilization on microbial community in welsh onion rhizosphere, and the change of microbial community may interfere the growth and development of welsh onion.
Automated detection of Crohn's disease intestinal strictures on capsule endoscopy images using deep neural networks.

BACKGROUND AND AIMS Passable intestinal strictures are frequently detected on capsule endoscopy (CE). Such strictures are a major component of inflammatory scores. Deep neural network technology for CE is emerging. However, the ability of deep neural networks to identify intestinal strictures on CE images of Crohn's disease (CD) patients has not yet been evaluated. METHODS We tested a state-of-the-art deep learning network for detecting CE images of strictures. Images of normal mucosa, mucosal ulcers, and strictures of Crohn's disease patients were retrieved from our previously described CE image bank. Ulcers were classified as per degree of severity. We performed ten cross validation experiments. A clear patient-level separation was maintained between training and testing sets. RESULTS Overall, the entire dataset included 27,892 CE images; 1,942 strictures images, 14,266 normal mucosa images, and 11,684 ulcer images (mild: 7,075, moderate: 2,386, severe: 2,223). For classifying strictures versus non-strictures, the network exhibited an average accuracy of 93.5% (±6.7%). The network achieved excellent differentiation between strictures and normal mucosa (AUC 0.989), strictures and all ulcers (AUC 0.942), and between strictures and different grades of ulcers (for mild, moderate and severe ulcers - AUCs 0.992, 0.975, and 0.889, respectively). CONCLUSIONS Deep neural networks are highly accurate in the detection of strictures on CE images in Crohn's disease. The network can accurately separate strictures from ulcers across the severity range. The current accuracy for the detection of ulcers and strictures by deep neural networks may allow for automated detection and grading of Crohn's disease-related findings on CE.
ANK2 Hypermethylation in Canine Mammary Tumors and Human Breast Cancer

Canine mammary tumors (CMT) constitute the most common tumor types found in female dogs. Understanding this cancer through extensive research is important not only for clinical veterinary applications, but also in the scope of comparative oncology. The use of DNA methylation as a biomarker has been noted for numerous cancers in the form of both tissue and liquid biopsies, yet the study of methylation in CMT has been limited. By analyzing our canine methyl-binding domain sequencing (MBD-seq) data, we identified intron regions of canine ANK2 and EPAS1 as differentially methylated regions (DMGs) in CMT. Subsequently, we established quantitative methylation specific PCR (qMSP) of ANK2 and EPAS1 to validate the target hypermethylation in CMT tissue, as well as cell free DNA (cfDNA) from CMT plasma. Both ANK2 and EPAS1 were hypermethylated in CMT and highlighted as potential tissue biomarkers in CMT. ANK2 additionally showed significant hypermethylation in the plasma cfDNA of CMT, indicating that it could be a potential liquid biopsy biomarker as well. A similar trend towards hypermethylation was indicated in HBC at a specific CpG of the ANK2 target on the orthologous human region, which validates the comparative approach using aberrant methylation in CMT.
Gancao Xiexin decoction combined with mesalazine in the treatment of ulcerative colitis

Abstract Backgroud: Ulcerative colitis (UC) is a chronic inflammatory disease that involves the rectum, colon and ileum. Gancao Xiexin decoction (GCXXD) is a classic herbal formula in Shanghanlun. More and more research evidence shows that GCXXD has a certain therapeutic effect on UC. Therefore, we designed this study protocol aim to evaluate the efficacy and safety of GCXXD combine with mesalazine for UC. Methods: We will systematically search 6 databases, including PubMed, the Cochrane Library, EMBASE, CNKI, VIP, Wang-fang database up to July 2020 to obtain eligible studies. The primary outcomes will focus on the clinical effectiveness. Review Manager 5.3 software will be used for data analysis. Results: This study will provide the systematic evidence of UC treated with GCXXD combine with mesalazine. Conclusion: The findings of this meta-analysis will provide evidence to judge whether GCXXD combine with mesalazine is a more effective intervention compare to mesalazine only for patient of UC. INPLASY registration number: INPLASY202080008.
Curcumin Formulations and Trials: What’s New in Neurological Diseases

Curcumin’s pharmacological properties and its possible benefits for neurological diseases and dementia have been much debated. In vitro experiments show that curcumin modulates several key physiological pathways of importance for neurology. However, in vivo studies have not always matched expectations. Thus, improved formulations of curcumin are emerging as powerful tools in overcoming the bioavailability and stability limitations of curcumin. New studies in animal models and recent double-blinded, placebo-controlled clinical trials using some of these new formulations are finally beginning to show that curcumin could be used for the treatment of cognitive decline. Ultimately, this work could ease the burden caused by a group of diseases that are becoming a global emergency because of the unprecedented growth in the number of people aged 65 and over worldwide. In this review, we discuss curcumin’s main mechanisms of action and also data from in vivo experiments on the effects of curcumin on cognitive decline.
Residual low HDV viraemia is associated HDV RNA relapse after PEG‐IFNa‐based antiviral treatment of hepatitis delta: Results from the HIDIT‐II study

The role of low levels of HDV‐RNA during and after interferon therapy of hepatitis D is unknown. We re‐analysed HDV RNA in 372 samples collected in the HIDIT‐2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in‐house assay (IA). We detected HDV‐RNA in one‐third of samples previously classified as undetectable using the highly sensitive RA. Low HDV viraemia detectable at week 48 or week 96 was associated with a high risk for post‐treatment relapse, defined as HDV RNA positivity in both assays at week 120. HDV RNA relapses occurred in 10/15 (67%) patients with detectable low HDV RNA at week 48 and in 10/13 (77%) patients with low viraemia samples at week 96. In contrast, the post‐treatment relapse rate was lower in patients with undetectable HDV RNA in both assays during treatment.
Multipath TCP-Based IoT Communication Evaluation: From the Perspective of Multipath Management with Machine Learning

With the development of wireless networking technology, current Internet-of-Things (IoT) devices are equipped with multiple network access interfaces. Multipath TCP (MPTCP) technology can improve the throughput of data transmission. However, traditional MPTCP path management may cause problems such as data confusion and even buffer blockage, which severely reduces transmission performance. This research introduces machine learning algorithms into MPTCP path management, and proposes an automatic learning selection path mechanism based on MPTCP (ALPS-MPTCP), which can adaptively select some high-quality paths and transmit data at the same time. This paper designs a simulation experiment that compares the performance of four machine learning algorithms in judging path quality. The experimental results show that, considering the running time and accuracy, the random forest algorithm has the best performance in judging path quality.