Miracle-dz/UniFAR-FTUs huggingface dataset:
Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup

Introduction Most patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%–50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects. Methods and analysis RILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety. Ethics and dessimination The study was approved by a French ethics committee (ref:39/18_1, ‘Comité de Protection des Personnes’ Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov. Trial registration number N°2017-002320-25; NCT03722680
Time-Restricted Eating to Prevent and Manage Chronic Metabolic Diseases.

Molecular clocks are present in almost every cell to anticipate daily recurring and predictable changes, such as rhythmic nutrient availability, and to adapt cellular functions accordingly. At the same time, nutrient-sensing pathways can respond to acute nutrient imbalance and modulate and orient metabolism so cells can adapt optimally to a declining or increasing availability of nutrients. Organismal circadian rhythms are coordinated by behavioral rhythms such as activity-rest and feeding-fasting cycles to temporally orchestrate a sequence of physiological processes to optimize metabolism. Basic research in circadian rhythms has largely focused on the functioning of the self-sustaining molecular circadian oscillator, while research in nutrition science has yielded insights into physiological responses to caloric deprivation or to specific macronutrients. Integration of these two fields into actionable new concepts in the timing of food intake has led to the emerging practice of time-restricted eating. In this paradigm, daily caloric intake is restricted to a consistent window of 8-12 h. This paradigm has pervasive benefits on multiple organ systems. Expected final online publication date for the Annual Review of Nutrition Volume 39 is August 21, 2019. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Effect of Soluplus on the supersaturation and absorption of tacrolimus formulated as inclusion complex with dimethyl-β-cyclodextrin

Abstract The application of tacrolimus (FK506) is hampered by its poor solubility and dissolution, which can be promoted by the use of inclusion complex. However, in supersaturated environment, crystallization of the drug inclusion complex may occur, leading to reduced absorption in vivo. In this study, Soluplus, an amphiphilic copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol, was used to improve the supersaturated stability and absorption of FK506. Using dimethyl-β-cyclodextrin (DM-β-CD), the inclusion complex (FK506-CD) was prepared, which showed favorable dissolution profiles. But in supersaturated condition, the drug concentration was rapidly decreased, with 10.64 ± 0.69 μg/ml of FK506 at 12 h. Ternary complex (FK506-SCD) containing Soluplus contributed steadier drug concentration. The FK506-SCD with 1.2% Soluplus best promoted the supersaturated stability of the inclusion complex, with 62.90 ± 3.34 μg/ml of FK506 at 12 h. Soluplus also reduced the crystallization and degradation of FK506 in the stress test. In the single-pass intestinal perfusion test, the absorption of FK506 in the ileum and colon was significantly increased. Pharmacokinetic results showed that the bioavailability of FK506-SCD was 2.34-fold that of FK506-CD. Our data suggested that Soluplus had an excellent capability in improving the supersaturated stability and in vivo absorption of FK506 inclusion complex.
Protein Structure Prediction Using Population-Based Algorithm Guided by Information Entropy

Ab initio protein structure prediction is one of the most challenging problems in computational biology. Multistage algorithms are widely used in ab initio protein structure prediction. The different computational costs of a multistage algorithm for different proteins are important to be considered. In this study, a population-based algorithm guided by information entropy (PAIE), which includes exploration and exploitation stages, is proposed for protein structure prediction. In PAIE, an entropy-based stage switch strategy is designed to switch from the exploration stage to the exploitation stage. Torsion angle statistical information is also deduced from the first stage and employed to enhance the exploitation in the second stage. Results indicate that an improvement in the performance of protein structure prediction in a benchmark of 30 proteins and 17 other free modeling targets in CASP.
Aripiprazole for treating irritability associated with autism spectrum disorders

ABSTRACT Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a reported prevalence of 1 in 59 people. Its core features are persistent deficits in social communication and restricted, repetitive patterns of behavior or interests. Individuals with ASD have a high incidence of secondary problems with mood lability, tantrums, self-injurious behavior and aggressiveness toward others. Collectively, these behaviors are often referred to as irritability. Many medications have been used to treat irritability in autism, with aripiprazole one of only two medications approved in the USA for this purpose. Areas covered: Herein, the authors review the evidence supporting the use of aripiprazole for treating irritability in autism, including the pivotal trials leading to regulatory approval and long-term studies conducted post-approval. They utilized PubMed, searching all English language publications since 2000, using the terms aripiprazole, autism, autism spectrum disorder, pervasive developmental disorder, Asperger’s disorder, and irritability, and focused on clinical trials and review articles. Expert opinion: Multiple studies have shown the clear benefit of aripiprazole in the treatment of irritability in autism disorders compared to placebo. Often underemphasized are the metabolic effects, the proper monitoring for these effects, and the need for periodic reassessment to determine if ongoing treatment is needed.
Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Purpose: KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML. Experimental Design: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT−)] and mutation location (E8 vs. E17). Results: KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT− (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT− patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome. Conclusions: E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.
An engineered galactosylceramidase construct improves AAV gene therapy for Krabbe disease in twitcher mice.

Krabbe disease is an inherited neurodegenerative disease caused by mutations in the galactosylceramidase gene. In the infantile form, patients die before 3 years of age. Systemic adeno-associated virus serotype 9 (AAV9) gene therapy was recently shown to reverse the disease course in human patients in another lethal infantile neurodegenerative disease. To explore AAV9 therapy for Krabbe disease, we engineered a codon-optimized AAV9 galactosylceramidase vector. We further incorporated features to allow AAV9-derived galactosylceramidase to more efficiently cross the blood-brain-barrier and be secreted from transduced cells. We tested the optimized vector by a single systemic injection in the twitcher mouse, an authentic Krabbe disease model. Untreated twitcher mice showed characteristic neuropathology and motion defects. They died prematurely with a median lifespan of 41 days. Intravenous injection in 2-day-old twitcher mice reduced central and peripheral neuropathology, significantly improved the gait pattern and body weight. Noticeably, the median lifespan was extended to 150 days. Intraperitoneal injection in 6 to 12-day-old twitcher mice also significantly improved the motor function, body weight, and median life span (to 104 days). Our results far exceed the ≤70 days median lifespan seen in all reported standalone systemic AAV therapies. Our study highlights the importance of vector engineering for Krabbe disease gene therapy. The engineered vector warrants further development.
Associations Between Linoleic Acid Intake and Incident Type 2 Diabetes Among U.S. Men and Women

OBJECTIVE To investigate the association between intakes of n-6 polyunsaturated fatty acids (PUFAs) and type 2 diabetes risk in three prospective cohort studies of U.S. men and women. RESEARCH DESIGN AND METHODS We followed 83,648 women from the Nurses’ Health Study (NHS) (1980–2012), 88,610 women from NHSII (1991–2013), and 41,771 men from the Health Professionals Follow-Up Study (HPFS) (1986–2012). Dietary data were collected every 2–4 years by using validated food-frequency questionnaires. Self-reported incident diabetes, identified biennially, was confirmed by using a validated supplementary questionnaire. RESULTS During 4.93 million person-years of follow-up, 18,442 type 2 diabetes cases were documented. Dietary n-6 PUFAs accounted for 4.4–6.8% of total energy, on average, and consisted primarily of linoleic acid (LA) (≥98%). In multivariate-adjusted models, hazard ratios (95% CIs) of type 2 diabetes risk comparing extreme n-6 PUFA quintiles (highest vs. lowest) were 0.91 (0.85, 0.96) (Ptrend = 0.002) for total n-6 PUFAs and 0.92 (0.87, 0.98) (Ptrend = 0.01) for LA. In an isocaloric substitution model, diabetes risk was 14% (95% CI 5%, 21%) (P = 0.002) lower when LA isocalorically replaced saturated fats (5% of energy), 17% (95% CI 9%, 24%) (P < 0.001) lower for trans fats (2% of energy), or 9% (95% CI 17%, 0.1%) (P = 0.047) lower for carbohydrates (5% of energy). Replacing n-3 PUFAs or monounsaturated fats with LA was not significantly associated with type 2 diabetes risk. CONCLUSIONS Our study provides additional evidence that LA intake is inversely associated with risk of type 2 diabetes, especially when replacing saturated fatty acids, trans fats, or carbohydrates.
Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine

Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.
Evolutionary origin of O-acetyltransferases responsible for glucomannan acetylation in land plants.

• Mannans are an abundant cell wall polysaccharide in bryophytes, seedless vascular plants and gymnosperms. A previous study has shown that mannan acetylation in Arabidopsis and konjac is mediated by mannan O-acetyltransferases belonging to the DUF (Domain of Unknown Function) 231 family. However, little is known about the acetylation patterns of mannans in bryophytes and seedless vascular plants and the evolutionary origin of mannan O-acetyltransferases in land plants has not yet been studied. • Phylogenetic analysis of the DUF231 family revealed that DUF231 members were present in the charophycean green algae and they evolved to form overlapped and divergent phylogenetic groups in different taxa of land plants. • Acetyltransferase activity assays of recombinant proteins demonstrated that a number of group II DUF231 members from moss, Selaginella, pine, spruce, rice and poplar were mannan 2-O- and 3-O-acetyltransferases, whereas the two group I DUF231 members from the alga Klebsormidium nitens were not. Structural analysis of mannans from moss and Selaginella showed that they were composed of mannosyl and glucosyl residues and the mannosyl residues were acetylated at O-2 and O-3. • These findings indicate that although the DUF231 genes originated in algae, their recruitment as mannan O-acetyltransferases likely occurred in bryophytes and the biochemical functions of these O-acetyltransferases are evolutionarily conserved throughout land plants. This article is protected by copyright. All rights reserved.
In silico based unraveling of New Delhi metallo-β-lactamase (NDM-1) inhibitors from natural compounds: a molecular docking and molecular dynamics simulation study

Abstract The development of pathogenic microbial resistance toward antibiotics has become a global clinical concern. New Delhi metallo-β-lactmase-1 (NDM-1) and its variants have recently drawn immense attention for its biological ability to catalyze the hydrolysis of almost all of β-lactam antibiotics including the Carbapenems which are generally considered as the last-resort antibiotics. Also, the horizontal gene transfer is expediting the rapid spread of NDM-1 in bacteria. In the wake of this serious antibiotic resistance problem it becomes imperative to find inhibitors which can render the present antibiotics functional and useful. In the present study, we have used Molecular docking and Molecular Dynamics (MD) simulation approach to find out suitable inhibitors against NDM-1 from an array of different natural compounds. We have screened unique natural compounds from ZINC database and also a set of standard antibiotics and inhibitors. Based upon the highest binding affinity demonstrated by docking with NDM-1, the best binding antibiotic Meropenem and the top five natural compounds, viz., Withaferin A, Beta-Sitosterol, Aristolochic acid, Diosgenin and Guggulsterone E were selected and subjected to MD simulations study. The docked NDM-1 complex with withaferin A, beta-sitosterol and diosgenin were found to be more stable as compared to the one with meropenem throughout the MD simulation process with the relative RMSD and RMSF in acceptable range. In conclusion, these compounds can be readily tested in vitro and in vivo to fully establish and confirm their inhibition potentiality and can also serve as lead molecules for the development of future functional inhibitors. Communicated by Ramaswamy H. Sarma
Lineage tracing and targeting of IL17RB+ tuft cell-like human colorectal cancer stem cells

Significance Cancer stem cells, capable of self-renewing and giving rise to progeny cells in the tumor, have attracted attention as potential therapeutic targets. In this study, using genetically engineered mouse models, we showed that IL17RB, a tuft cell marker in the intestine, does not mark normal stem cells but marks tumor stem cells of mouse intestinal adenomas. Furthermore, using CRISPR-Cas9–mediated IL17RB-CreERT2 knockin human organoids, we showed that IL17RB marks human colorectal cancer stem cells by lineage tracing, and that long-term targeting of IL17RB+ cells strongly suppressed the tumor growth in vivo. This study identifies IL17RB+ cancer stem cells and preclinically validates them as a cancer therapeutic target. Cancer stem cell (CSC)-specific markers may be potential therapeutic targets. We previously identified that Dclk1, a tuft cell marker, marks tumor stem cells (TSCs) in mouse intestinal adenomas. Based on the analysis of mouse Dclk1+ tumor cells, we aimed to identify a CSC-specific cell surface marker in human colorectal cancers (hCRCs) and validate the therapeutic effect of targeting it. IL17RB was distinctively expressed by Dclk1+ mouse intestinal tumor cells. Using Il17rb-CreERT2-IRES-EGFP mice, we show that IL17RB marked intestinal TSCs in an IL13-dependent manner. Tuft cell-like cancer cells were detected in a subset of hCRCs. In these hCRCs, lineage-tracing experiments in CRISPR-Cas9–mediated IL17RB-CreERT2 knockin organoids and xenograft tumors revealed that IL17RB marks CSCs that expand independently of IL-13. We observed up-regulation of POU2F3, a master regulator of tuft cell differentiation, and autonomous tuft cell-like cancer cell differentiation in the hCRCs. Furthermore, long-term ablation of IL17RB-expressing CSCs strongly suppressed the tumor growth in vivo. These findings reveal insights into a CSC-specific marker IL17RB in a subset of hCRCs, and preclinically validate IL17RB+ CSCs as a cancer therapeutic target.
Pericentrin-mediated SAS-6 recruitment promotes centriole assembly

The centrosome is composed of two centrioles surrounded by a microtubule-nucleating pericentriolar material (PCM). Although centrioles are known to regulate PCM assembly, it is less known whether and how the PCM contributes to centriole assembly. Here we investigate the interaction between centriole components and the PCM by taking advantage of fission yeast, which has a centriole-free, PCM-containing centrosome, the SPB. Surprisingly, we observed that several ectopically-expressed animal centriole components such as SAS-6 are recruited to the SPB. We revealed that a conserved PCM component, Pcp1/pericentrin, interacts with and recruits SAS-6. This interaction is conserved and important for centriole assembly, particularly its elongation. We further explored how yeasts kept this interaction even after centriole loss and showed that the conserved calmodulin-binding region of Pcp1/pericentrin is critical for SAS-6 interaction. Our work suggests that the PCM not only recruits and concentrates microtubule-nucleators, but also the centriole assembly machinery, promoting biogenesis close by.
PIN2 Polarity Establishment in Arabidopsis in the Absence of an Intact Cytoskeleton

Cell polarity is crucial for the coordinated development of all multicellular organisms. In plants, this is exemplified by the PIN-FORMED (PIN) efflux carriers of the phytohormone auxin: The polar subcellular localization of the PINs is instructive to the directional intercellular auxin transport, and thus to a plethora of auxin-regulated growth and developmental processes. Despite its importance, the regulation of PIN polar subcellular localization remains poorly understood. Here, we have employed advanced live-cell imaging techniques to study the roles of microtubules and actin microfilaments in the establishment of apical polar localization of PIN2 in the epidermis of the Arabidopsis root meristem. We report that apical PIN2 polarity requires neither intact actin microfilaments nor microtubules, suggesting that the primary spatial cue for polar PIN distribution is likely independent of cytoskeleton-guided endomembrane trafficking.