Miracle-dz/UniFAR-FTUs huggingface dataset:
Vorinostat, a possible alternative to metronidazole for the treatment of amebiasis caused by Entamoeba histolytica

AbbreviationsSAHA suberoylanilide hydroxamic acidEhHDAC Histone Deacetylase from Entamoeba histolyticaRg Radius of gyrationRMSD root-mean-square deviationRMSF root-mean-square fluctuationMDS molecular dynamics simulationVMD Visual Molecular DynamicsNAMD Nanoscale Molecular DynamicsPBC periodic boundary conditionsPME Particle Mesh Ewald3D three-dimensionalCα alpha carbonFDA Food and Drug Administrationns nanosecondsGPU CUDA Graphics Processing Unit Compute Unified Device Architecture Communicated by Ramaswamy H. Sarma
Diclofenac Sodium Topical Solution 1.5% w/w with Dimethyl Sulfoxide Compared with Placebo for the Treatment of Osteoarthritis: Pooled Safety Results

Abstract Oral nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2-selective inhibitors are frequently recommended for management of osteoarthritis (OA). However, serious gastrointestinal and cardiovascular systemic adverse events (AEs) are associated with oral NSAIDs and can be treatment limiting. The efficacy of diclofenac sodium topical solution 1.5% w/w with dimethyl sulfoxide (TDiclo) has been established as superior to placebo and comparable with oral NSAIDs in the management of OA. This study characterizes the safety and tolerability profile of TDiclo compared with placebo through a pooled analysis of data from 1252 patients in 7 randomized controlled trials across 61 centers in the United States and 97 centers in Canada. Patients received TDiclo (n = 911) or placebo (n = 341) for 4 to 12 weeks for management of OA of the hand or knee. The most frequently reported AE was dry skin, occurring in 33.0% of patients receiving TDiclo and 5.0% of patients receiving placebo (P < 0.001). Dyspepsia was the most common gastrointestinal reaction, reported by 7.7% of patients receiving TDiclo and 2.9% of patients receiving placebo (P = 0.002). Changes in vital signs and laboratory assessments of hepatic and renal function were similar between the 2 groups; TDiclo did not increase mean blood pressure, nor was it associated with hypertension. The rate of serious AEs favored placebo in both groups (0.9% for TDiclo vs 1.5% for placebo; P = 0.358), as did the rate of severe AEs (4.4% vs 7.6%; P = 0.023). The most common reason for study discontinuation was dry skin (2.5% vs 0.3%). Results from this analysis suggest that TDiclo is well tolerated in a large population and may offer an alternative to oral NSAID therapy for OA of the knee or hand, particularly for patients at increased risk for serious systemic AEs. Larger head-to-head, long-term, multicenter trials would be beneficial to further evaluate safety data comparing both topical and oral NSAIDs.
Etiology and Treatment Outcomes for Sural Neuroma

Background: Neuroma results from disorganized regeneration following nerve injury and may be symptomatic. The aim of this study was to investigate the causes, treatment, and outcomes of operatively treated sural neuromas, and to describe the factors associated with persistent or unchanged postoperative pain symptoms. Methods: Consecutive patients with surgically treated sural neuromas in a 14-year period were identified using Current Procedural Terminology (CPT) codes (n = 49), followed by a chart review to collect patient and treatment characteristics. Postoperative pain symptoms were categorized as complete resolution of pain, improvement of pain, no change in pain, or worse pain. The median patient age was 46.5 years (interquartile range [IQR], 39.1-51.3), and median follow-up was 4.0 years (IQR, 1.9-9.2). Results: Ninety percent of symptomatic sural neuromas developed as a result of previous lower extremity surgery. Initial surgery of sural neuroma led to improvement in pain in 63% of patients, and an additional 8.2% of the patients had improvement after secondary neuroma surgery. Pain relief after diagnostic injection showed a trend toward an association with postoperative pain improvement. Neuroma excision and implantation in muscle was the most common surgical technique used (67%). Four of the 7 patients that underwent a second neuroma operation reported symptom improvement. Conclusion: Sural neuromas may arise from prior surgery or trauma to the lower extremity. Surgical intervention resulted in either improvement or complete resolution of pain symptoms in 71% of patients, although occasionally more than one procedure was required to obtain symptomatic relief. Preoperative anesthetic injection may help identify patients that benefit from neuroma surgery. Level of Evidence: Level IV, retrospective case series.
Assessing the Likelihood of Recurrence during RNA Evolution in Vitro

Recurrence is the possibility of resulting in the same endpoint multiple times when a living system is allowed to evolve repeatedly starting from a given initial point. This concept is of concern to both evolutionary theoreticians and molecular biologists who use nucleic acid selection techniques to mimic biotic and computorial processes in the test tube. Using the continuous in vitro evolution methodology, many replicate experimental evolutionary lineages with populations of catalytic RNA were performed to gain insight into the parameters that could affect recurrence. The likelihood that the same genotype will result in parallel trials of an evolution experiment in vitro depends on several factors, including the phenotype under selection, the size and composition of the initial diverse pool of nucleic acids used in the experiment, the degree of mutation possible during the experiment, the shape of the fitness landscape through which the population evolves, and the strategies used to invoke selection and to search the landscape, among others. By considering these factors, it can be predicted that recurrence is more likely when a small, wild-type-based starting pool is used with efficient selection and search strategies involving little online mutagenesis within a rugged adaptive landscape with a strong local optimum. The recurrence experiments performed here on the 150-nucleotide ligase ribozyme demonstrate that it repeatedly jumps from one peak in a fitness landscape to another, apparently hurdling a deep fitness valley. These predictions can and should be tested by additional multiple replicates of actual evolution experiments in the laboratory.
The discovery and characterization of K‐563, a novel inhibitor of the Keap1/Nrf2 pathway produced by Streptomyces sp

Keap1/Nrf2 pathway regulates the antioxidant stress response, detoxification response, and energy metabolism. Previous reports found that aberrant Keap1/Nrf2 pathway activation due to Kelch‐like ECH‐associated protein 1 (Keap1) mutations or Nuclear factor E2‐related factor 2 (Nrf2) mutations induced resistance of cancer cells to chemotherapy and accelerated cell growth via the supply of nutrients. Therefore, Keap1/Nrf2 pathway activation is associated with a poor prognosis in many cancers. These previous findings suggested that inhibition of Keap1/Nrf2 pathway could be a target for anti‐cancer therapies. To discover a small‐molecule Keap1/Nrf2 pathway inhibitor, we conducted high‐throughput screening in Keap1 mutant human lung cancer A549 cells using a transcriptional reporter assay. Through this screening, we identified the novel Keap1/Nrf2 pathway inhibitor K‐563, which was isolated from actinomycete Streptomyces sp. K‐563 suppressed the expression of Keap1/Nrf2 pathway downstream target genes or the downstream target protein, which induced suppression of GSH production, and activated reactive oxygen species production in A549 cells. K‐563 also inhibited the expression of downstream target genes in other Keap1‐ or Nrf2‐mutated cancer cells. Furthermore, K‐563 exerted anti‐proliferative activities in these mutated cancer cells. These in vitro analyses showed that K‐563 was able to inhibit cell growth in Keap1‐ or Nrf2‐mutated cancer cells by Keap1/Nrf2 pathway inhibition. K‐563 also exerted synergistic combinational effects with lung cancer chemotherapeutic agents. An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K‐563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors. K‐563, a novel Keap1/Nrf2 pathway inhibitor, may be a lead compound for development as an anti‐cancer agent.
Prostate Cancer Disparity, Chemoprevention, and Treatment by Specific Medicinal Plants

Prostate cancer (PC) is one of the most common cancers in men. The global burden of this disease is rising. Its incidence and mortality rates are higher in African American (AA) men compared to white men and other ethnic groups. The treatment decisions for PC are based exclusively on histological architecture, prostate-specific antigen (PSA) levels, and local disease state. Despite advances in screening for and early detection of PC, a large percentage of men continue to be diagnosed with metastatic disease including about 20% of men affected with a high mortality rate within the African American population. As such, this population group may benefit from edible natural products that are safe with a low cost. Hence, the central goal of this article is to highlight PC disparity associated with nutritional factors and highlight chemo-preventive agents from medicinal plants that are more likely to reduce PC. To reach this central goal, we searched the PubMed Central database and the Google Scholar website for relevant papers. Our search results revealed that there are significant improvements in PC statistics among white men and other ethnic groups. However, its mortality rate remains significantly high among AA men. In addition, there are limited studies that have addressed the benefits of medicinal plants as chemo-preventive agents for PC treatment, especially among AA men. This review paper addresses this knowledge gap by discussing PC disparity associated with nutritional factors and highlighting the biomedical significance of three medicinal plants (curcumin, garlic, and Vernonia amygdalina) that show a great potential to prevent/treat PC, as well as to reduce its incidence/prevalence and mortality, improve survival rate, and reduce PC-related health disparity.
Services satisfaction of type 2 diabetic patients attending Arar’s diabetic center, Saudi Arabia

Objectives: To determine type 2 diabetic patients’ satisfaction with the services provided by the Diabetic Center, Arar, Saudi Arabia, and to assess the relationship between patients’ satisfaction and their diabetic control. Methods: An observational cross-sectional study, carried out in 322 patients at the Arar Diabetic Center, Arar, Kingdom of Saudi Arabia between January and April 2018. A systematic random sampling technique was applied to include every second type 2 diabetic patient attending the center. We interviewed the type 2 diabetic patients using a predesigned questionnaire tested for validity and reliability. Results: The mean age of the studied population was 48.5±13.05. The overall satisfaction rate was 65.8%. There was a significant association between patient satisfaction to both self-reported health status (p=0.001) and mode of treatment (p=0.02). Regarding service related factors: 78% of patients were satisfied with the time spent during consultation; 58.7% were satisfied with information given regarding the disease; 58.7% were dissatisfied with dietary advice; and 44.7% were dissatisfied with information given regarding medications. Hemoglobin A1c (HbA1c) was controlled in 64% of patients. There was a statistically significant association between patients’ dissatisfaction and poor diabetic control. Conclusion: Two-thirds of the patients were satisfied with the services provided by the Diabetic Centres of Arar city, Saudi Arabia. The study recommends emphasis on patient education and addressing patient needs and worries.
Expression of a Novel Long Noncoding RNA (lncRNA), GASL1, is Downregulated in Patients with Intracranial Aneurysms and Regulates the Proliferation of Vascular Smooth Muscle Cells In Vitro

Background Preliminary microarray data in our laboratory indicated that the novel long noncoding RNA (lncRNA), GASL1, was downregulated in patients with intracranial aneurysms. This study aimed to investigate the expression of lncRNA GASL1 in patients with intracranial aneurysms and its role in the regulation of vascular smooth muscle cell (VSMC) proliferation by transforming growth factor-β1 (TGF-β1). Material/Methods The study included 68 patients with unruptured intracranial aneurysms and 56 healthy volunteers. In both groups, serum levels of TGF-β1 were measured using an enzyme-linked immunoassay (ELISA) and Western blot. Human VSMCs in vitro underwent lncRNA GASL1 overexpression using the insertion of an EcoRI-EcoRI fragment into the pIRSE2 vector. Cell viability and proliferation were measured by a cell counting kit-8 (CCK-8) assay. RNA extraction and quantitative real-time polymerase chain reaction (qRT-PCR) determined GASL1 expression. Results The lncRNA, GASL1, was significantly downregulated, while TGF-β1 was significantly upregulated in the serum of patients with an intracranial aneurysm compared with healthy controls, which was confirmed by receiver operating characteristic (ROC) curve analysis. In human VSMCs, lncRNA GASL1 overexpression increased cell proliferation and downregulated TGF-β1 expression, while treatment with TGF-β1 reduced VSMC proliferation but showed no effects on GASL1 expression. Conclusions Expression of the novel lncRNA, GASL1, was downregulated in patients with intracranial aneurysms and regulated the proliferation of VSMCs in vitro by targeting TGF-β1.
The impact of the introduction of a toxicology service on the intensive care unit

Abstract Objective: To examine the impact of a clinical toxicology service on toxicology patients admitted to an intensive care department Methods: The authors performed a retrospective chart audit of all patients presenting to Cairns Emergency Department (ED) over a five-year period from 2011 to 2016 with a toxicology diagnosis requiring Intensive Care Unit (ICU) admission. They were divided into two groups: pre-toxicology (1 April 2011 to 30 September 2012), and post-toxicology service (1 October 2012 to 31 of March 2016) introduction. Patients were identified using ED and ICU databases. Patient charts were manually searched, and data entered on a preformatted data extraction tool. The data were statistically compared pre- versus post-toxicology service introduction using univariate (t-tests and Pearson’s Chi Square) and multivariate modelling. Where appropriate, continuous variables were log transformed to enable parametric analyses. Results: There were 37 patients in the pre-toxicology and 102 in the post-toxicology group, with an increased median APACHE III J score in the post toxicology group (39 vs. 49). The introduction of a toxicology service was associated with statistically significant reductions in median ICU length of stay (LOS) (32.9 vs. 20.6 h), median duration of mechanical ventilation (29.1 vs. 20.6 h) and median time to psychiatry review (19.4 vs. 6.7 h). The reduction in ICU LOS remained statistically significant (p = 0.036) when adjusted by sex, age and duration of mechanical ventilation. There was neither increase in mortality, nor readmissions from EDSSU to ICU. Conclusions: This study has demonstrated that the introduction of a toxicology service was associated with a reduction in median ICU LOS, duration of mechanical ventilation and time to psychiatric review in patients with a toxicology diagnosis admitted to our ICU.
Early-onset Alzheimer Disease and Its Variants

PURPOSE OF REVIEW Early-onset Alzheimer disease (AD) is defined as having an age of onset younger than 65 years. While early-onset AD is often overshadowed by the more common late-onset AD, recognition of the differences between early- and late-onset AD is important for clinicians. RECENT FINDINGS Early-onset AD comprises about 5% to 6% of cases of AD and includes a substantial percentage of phenotypic variants that differ from the usual amnestic presentation of typical AD. Characteristics of early-onset AD in comparison to late-onset AD include a larger genetic predisposition (familial mutations and summed polygenic risk), more aggressive course, more frequent delay in diagnosis, higher prevalence of traumatic brain injury, less memory impairment and greater involvement of other cognitive domains on presentation, and greater psychosocial difficulties. Neuroimaging features of early-onset AD in comparison to late-onset AD include greater frequency of hippocampal sparing and posterior neocortical atrophy, increased tau burden, and greater connectomic changes affecting frontoparietal networks rather than the default mode network. SUMMARY Early-onset AD differs substantially from late-onset AD, with different phenotypic presentations, greater genetic predisposition, and differences in neuropathologic burden and topography. Early-onset AD more often presents with nonamnestic phenotypic variants that spare the hippocampi and with greater tau burden in posterior neocortices. The early-onset AD phenotypic variants involve different neural networks than typical AD. The management of early-onset AD is similar to that of late-onset AD but with special emphasis on targeting specific cognitive areas and more age-appropriate psychosocial support and education.
Endobronchial Manifestation of Methotrexate-induced Lymphoproliferative Disorder

Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of MTX-LPD are diverse, little attention is paid to endobronchial involvement. We herein describe two patients with MTX-LPD who presented with parenchymal pulmonary tumors and endobronchial involvement of LPD; one had lymphomatoid gramulomatosis and the other LPD. The patients had no tumors adjacent to the endobronchial lesions. The endobronchial findings included multiple protruded mucosal lesions covered with white material, which was pathologically consistent with LPD. Recognition of the findings may help in making an earlier diagnosis of MTX-LPD in appropriate settings.
Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam

Abstract 1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1′-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CLtot) and elimination rate constant (ke) between the control and 5-FU-treated rats. Lack of alteration in the metabolic clearance of MDZ may be attributable to the induction of CYP3A protein with reduced affinity for the substrate of CYP3A enzymes. 4. Our findings provide novel information regarding the manifestation of inductive and interfering actions of 5-FU toward hepatic CYP3A to help in assessing the pharmacokinetics of CYP3A substrate drugs.
The role of intestinal microbiota in cardiovascular disease

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.
Hoping for optimality or designing for inclusion: Persistence, learning, and the social network of citizen science

The explosive growth in citizen science combined with a recalcitrance on the part of mainstream science to fully embrace this data collection technique demands a rigorous examination of the factors influencing data quality and project efficacy. Patterns of contributor effort and task performance have been well reviewed in online projects; however, studies of hands-on citizen science are lacking. We used a single hands-on, out-of-doors project—the Coastal Observation and Seabird Survey Team (COASST)—to quantitatively explore the relationships among participant effort, task performance, and social connectedness as a function of the demographic characteristics and interests of participants, placing these results in the context of a meta-analysis of 54 citizen science projects. Although online projects were typified by high (>90%) rates of one-off participation and low retention (<10%) past 1 y, regular COASST participants were highly likely to continue past their first survey (86%), with 54% active 1 y later. Project-wide, task performance was high (88% correct species identifications over the 31,450 carcasses and 163 species found). However, there were distinct demographic differences. Age, birding expertise, and previous citizen science experience had the greatest impact on participant persistence and performance, albeit occasionally in opposite directions. Gender and sociality were relatively inconsequential, although highly gregarious social types, i.e., “nexus people,” were extremely influential at recruiting others. Our findings suggest that hands-on citizen science can produce high-quality data especially if participants persist, and that understanding the demographic data of participation could be used to maximize data quality and breadth of participation across the larger societal landscape.