Miracle-dz/UniFAR-FTUs huggingface dataset:
Phosphate Binder, Ferric Citrate, Attenuates Anemia, Renal Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in 5/6 Nephrectomized CKD Rats

Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder ferric citrate (FC) increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload resulting from excessive use of intravenous iron can accelerate CKD progression. The present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology, and inflammatory, oxidative, and fibrosis pathways in CKD rats. Male Sprague Dawley rats were randomized to sham-operated control (CTL) group and 5/6 nephrectomized (CKD) groups fed either regular or 4% FC-supplemented diets for 6 weeks. Animals were then sacrificed, and blood and target tissues were harvested and processed. The untreated CKD rats exhibited anemia, hypertension, upregulation of renal tissue inflammatory, oxidative, and fibrotic pathways, impaired nuclear translocation, and downregulation of Nrf2’s target gene products and depletion of colonic epithelial tight junction proteins. FC administration raised serum iron, improved anemia, attenuated hyperphosphatemia, partially improved renal function, reduced oxidative stress, inflammation, and fibrosis, and restored colonic epithelial zonula occludens-1 protein abundance. Tissue iron staining detected presence of iron in epithelial cells and subepithelium of colon and in renal proximal tubules. In conclusion ferric citrate administration resulted in modest amelioration of renal function and histology and partial improvements of fibrosis, inflammation, and oxidative stress in the kidney tissues of CKD rats.
Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma

Purpose: Lung squamous cell carcinoma (LUSC) is a major subtype of non–small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single-agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed. Experimental Design: PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds. Results: Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways. Conclusions: PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA-mutant LUSC.
Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.
NADPH–Cytochrome P450 Reductase Mediates the Resistance of Aphis (Toxoptera) citricidus (Kirkaldy) to Abamectin

NADPH-cytochrome P450 reductase (CPR) plays an essential role in the cytochrome P450 enzyme system, which aids in the metabolism of endogenous and exogenous compounds including the detoxification of insecticides. In this study, the CPR transcript in Aphis (Toxoptera) citricidus (Kirkaldy) was cloned, and the deduced amino acid sequence contained an N-terminal membrane anchor, three conserved binding domains (flavin mononucleotide, flavin adeninedinucleotide, and nicotinamide adenine dinucleotide phosphate), a flavin adeninedinucleotide-binding motif, and catalytic residues. Based on phylogenetic analysis, AcCPR was grouped in the hemipteran branch. AcCPR was ubiquitously expressed at all developmental stages and was most abundant in the adults and least abundant in third instar nymphs. Compared with other tested tissues of adults, the expression level of AcCPR was significantly high in the gut. Feeding double-stranded RNA of AcCPR reduced the AcCPR mRNA level and the activity of AcCPR in aphids, and the treated insects exhibited higher susceptibility to abamectin than the control group. Furthermore, the heterologous overexpression of AcCPR in Sf9 cells resulted in a greater viability than control cells when treated with abamectin. All results demonstrated that AcCPR may contribute to the resistance of A. citricidus to abamectin, and CPR may be a potential target for novel insecticide design or a new factor in the development of insecticide resistance.
miR‐182‐5p overexpression inhibits chondrogenesis by down‐regulating PTHLH

Human bone marrow mesenchymal stem cells (hBM‐MSC) have the ability of differentiating into chondrocytes and osteoblasts. miR‐182‐5p promotes osteoclastogenesis and bone metastasis by up‐regulating the expression of parathyroid hormone‐like hormone (PTHLH). However, the function of miR‐182‐5p in chondrogenesis is still unknown. Mimic or inhibitor of miR‐182‐5p was used to upregulate or knock‐down miR‐182‐5p expression, respectively. We analyzed chondrogenesis by Safranin O staining and Blyscan™ Sulfated Glycosaminoglycan Assay. Immunohistochemistry, real‐time PCR, and Western bolts were used to detect related makers. miR‐182‐5p overexpression inhibited chondrogenesis. Dual‐luciferase reporter assay indicated that PTHLH was one of the target genes of miR‐182‐5p. Further studies showed that miR‐182‐5p overexpression down‐regulated the expression of SOX‐9 and COL2A1, but up‐regulated COL1A1 and COL10A1. Consistently, miR‐182‐5p knock‐down had the opposite effects. This effect of miR‐182‐5p in BM‐MSCs can be rescued by PTHLH overexpression. miR‐182‐5p may play a negative role in chondrogenesis by down‐regulating PTHLH.
Reduced Cooling Redundancy: A New Security Vulnerability in a Hot Data Center

Data centers have been growing rapidly in recent years to meet the surging demand of cloud services. However, the expanding scale and powerful servers generate a great amount of heat, resulting in significant cooling costs. A trend in modern data centers is to raise the temperature and maintain all servers in a relatively hot environment. While this can save on cooling costs given benign workloads running in servers, the hot environment increases the risk of cooling failure. In this paper, we unveil a new vulnerability of existing data centers with aggressive cooling energy saving policies. Such a vulnerability might be exploited to launch thermal attacks that could severely worsen the thermal conditions in a data center. Specifically, we conduct thermal measurements and uncover effective thermal attack vectors at the server, rack, and data center levels. We also present damage assessments of thermal attacks. Our results demonstrate that thermal attacks can (1) largely increase the temperature of victim servers degrading their performance and reliability, (2) negatively impact on thermal conditions of neighboring servers causing local hotspots, (3) raise the cooling cost, and (4) even lead to cooling failures. Finally, we propose effective defenses to prevent thermal attacks from becoming a serious security threat to data centers.
The OhioT1DM Dataset for Blood Glucose Level Prediction: Update 2020

This paper documents the OhioT1DM Dataset, which was developed to promote and facilitate research in blood glucose level prediction. It contains eight weeks' worth of continuous glucose monitoring, insulin, physiological sensor, and self-reported life-event data for each of 12 people with type 1 diabetes. An associated graphical software tool allows researchers to visualize the integrated data. The paper details the contents and format of the dataset and tells interested researchers how to obtain it. The OhioT1DM Dataset was first released in 2018 for the first Blood Glucose Level Prediction (BGLP) Challenge. At that time, the dataset was half its current size, containing data for only six people with type 1 diabetes. Data for an additional six people is being released in 2020 for the second BGLP Challenge. This paper subsumes and supersedes the paper which documented the original dataset.
Impact of MAGNET hospital designation on nursing culture: an integrative review

Background: Organisational culture is a critical part of a positive and productive working environment and often presents as an area of ongoing development. The MAGNET recognition program awards recognition to organisations that have positive organisational cultures that meet the standards and criteria. However, the broad impact of MAGNET on hospital culture outside of America remains unclear. Objective: In this study, we explore the impact of MAGNET designation on organisational culture within the nursing context. Methods: An integrative literature review was performed using a systematic search of Medline (Ovid), Embase (Elsevier) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL Ebsco) databases and a combination of subject headings and key words for organizational culture, organizational change and MAGNET hospital, as well as reference chaining was conducted. Using a constant comparative process key categories, themes and subthemes emerged. Results: Twenty-nine key studies were identified and were evaluated utilising two study quality appraisal tools; National Health and Medical Research Council (NH&MRC) levels of evidence and the Polit and Beck critical appraisal tool. Three key categories emerged from the data: (1) nurse practice environment; (2) structure and process models; (3) measurement scales. A key finding was that MAGNET designation appears to enhance organisational culture for nurses and the framework used to introduce MAGNET helps to empower nurses to direct organisational culture in their facility. Conclusion and Implications for Nursing and Health Policy: MAGNET appears to have a positive impact on organisational culture, particularly for nurses. However, lack of standardised evaluation tools used to assess organisational culture associated with MAGNET designation limits comparability of the studies. Generally, the quality of evidence used to develop recommendations was poor to very poor. More, well designed studies undertaken outside of the USA are required. Impact Statement: An in-depth integrative review exploring the impact of MAGNET designation on organisational culture has not been undertaken. In this paper, we have used an integrative review methodology to identify, examine, thematically group and critically evaluate published literature around the impact of MAGNET designation on organisational culture within designated hospitals.
Monitoring of colonoscopy quality indicators in an academic endoscopy facility reveals adherence to international recommendations.

Background We monitor colonoscopy service quality biannually, by measuring sedation administration, colonoscopy completion, adenoma detection and early complications rates (CR). We herein present our audit results for the years 2013 and 2015. Methods In our endoscopy facility, five rotating senior gastroenterologists perform colonoscopies, on a daily basis. We measured the quality indicators in three cohorts: A, intention for total colonoscopy cases; B, cohort A excluding bowel obstruction cases; C, colorectal cancer (CRC) screening cases. Results In 2015, overall sedation administration rate (SAR) was 93.0% (91.6-94.4%), achieving our target to give conscious sedation to >90% of patients undergoing colonoscopy in all three cohorts. Colonoscopy completion rate (CCR) increased significantly (P<0.0001) from 94.8% (93.4-96.2%) to 98.1% (97.3-98.9%) in cohort B and numerically from 96.6% (94.4-98.8%) to 98.6% (97.4-99.7%) in cohort C, at the same periods. In cohort C, adenoma detection rates (ADR) were similar-27.1% (21.7-32.5%) and 27% (22.7-31.3%)-in the two periods. There were only two serious early complications: one cardiorespiratory event and one perforation in 2013 and 2015, respectively. While significant variability regarding SAR (ranging from 80% to 100%) was detected among the participating endoscopists, all but one of them constantly achieved [judged by the lower confidence interval (CI) of the quality indicator] CCRs higher than the recommended by international guidelines. On the contrary ADR was variable among endoscopists during the studied periods. Conclusions Although there is certain variability in endoscopists' performance, the overall colonoscopy quality indicators meet or exceed the internationally recommended standards, in our endoscopy facility.
Evaluation of Sustained-Release Steroid Hydrogels in a Guinea Pig Model for Noise-Induced Hearing Loss

The otoprotective effects of thermoreversible poloxamer 407 hydrogels containing dexamethasone or triamcinolone acetonide were evaluated in an animal model of noise-induced hearing loss. Seven days after noise exposure, hearing threshold shifts at 16 kHz were significantly reduced in the 6% dexamethasone group (p < 0.05). Even though no significant differences in hair cell counts were found, histological analysis revealed a significantly higher spiral ganglion cell density in the first turn of the cochlea in this group (p < 0.05). No otoprotective effects were observed after the application of the triamcinolone acetonide hydrogels. As the findings of this study indicate potential otoprotective effects of sustained topical dexamethasone delivery in the setting of noise-induced hearing loss, this strategy merits further evaluation.
Evaluating the Diagnostic Accuracy of Reflectance Confocal Microscopy to Diagnose Skin Cancer: Protocol for a Prospective, Multicenter Study

Background In the United Kingdom, 350,000 patients per year are referred to hospital clinics with suspicious moles, and approximately half undergo a biopsy to identify the 5%-10% who require further treatment. If cancer cannot be ruled out clinically and on the basis of biopsy results, the lesion is surgically removed. One type of precancerous mole, called lentigo maligna, is particularly challenging to delineate and treat. Reflectance confocal microscopy (VivaScope, Caliber Imaging & Diagnostics) is an imaging technique that can supplement dermoscopy in identifying whether a clinically suspicious mole is malignant and can better assess lentigo maligna margins for excision. It allows clinicians to visualize the skin lesion to a depth of 200 microns with subcellular resolution, described as quasi-histological, and therefore better guide more accurate diagnoses. Objective The aim of this paper is to describe a prospective, single blinded, multicenter study to examine patients with clinically suspicious moles or lentigo maligna to determine whether confocal microscopy can both reduce the number of unnecessary biopsies of moles and more accurately guide the surgical excision margins of lentigo maligna. Methods This study will prospectively recruit adults into the following two cohorts: diagnostic accuracy and margin delineation. The diagnostic accuracy cohort will assess people with clinically suspicious lesions suspected of being diagnosed with melanoma and having an equivocal finding on dermoscopy or persistent clinical suspicion despite normal dermoscopy. Diagnostic accuracy will include the sensitivity and specificity of VivaScope in comparison with the histological diagnosis as the gold standard for patients. The margin delineation cohort will assess the ability of VivaScope to accurately delineate the margins of lentigo maligna compared with that of dermoscopy alone using margins taken during Mohs micrographic surgery as the gold standard. The primary study outcomes will be the diagnostic accuracy of VivaScope for the first cohort of patients and margin agreement between VivaScope and the final pathology report for the second cohort of patients. Results Funding for this proposed research is being secured. Conclusions The outcomes of the proposed study will indicate how many biopsies of nonmelanoma lesions, which are potentially unnecessary, could be prevented. This would reduce patient anxiety and cost to the National Health Service (NHS) in the United Kingdom. Improved margin delineation of lentigo maligna could also improve the surgical clearance rates and decrease overall cost. The results would demonstrate whether the adoption of VivaScope would potentially benefit patients and the NHS. Registered Report Identifier RR1-10.2196/9296
Unraveling the Interaction between Carboxylesterase 1c and the Antibody–Drug Conjugate SYD985: Improved Translational PK/PD by Using Ces1c Knockout Mice

Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody–drug conjugates (ADC) in mice, but not in monkeys or humans. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of humans and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc-seco-DUBA, is also sensitive to CES1c. In the present studies, we first focused on the interaction between CES1c and SYD985 by size- exclusion chromatography, Western blotting, and LC/MS-MS analysis, using recombinant CES1c and plasma samples. Intriguingly, CES1c activity not only results in release of the active toxin DUBA but also in formation of a covalent bond between CES1c and the linker of vc-seco-DUBA. Mass spectrometric studies enabled identification of the CES1c cleavage site on the linker-drug and the structure of the CES1c adduct. To assess the in vivo impact, CES1c−/− SCID mice were generated that showed stable PK for SYD985, comparable to that in monkeys and humans. Patient-derived xenograft (PDX) studies in these mice showed enhanced efficacy compared with PDX studies in CES1c+/+ mice and provided a more accurate prediction of clinical efficacy of SYD985, hence delivering better quality data. It seems reasonable to assume that CES1c−/− SCID mice can increase quality in ADC development much broader for all ADCs that carry linker-drugs susceptible to CES1c, without the need of chemically modifying the linker-drug to specifically increase PK in mice. Mol Cancer Ther; 17(11); 2389–98. ©2018 AACR.
The positioning of the asymmetric septum during sporulation in Bacillus subtilis

Probably one of the most controversial questions about the cell division of Bacillus subtilis, a rod-shaped bacterium, concerns the mechanism that ensures correct division septum placement–at mid-cell during vegetative growth but closer to one end during sporulation. In general, bacteria multiply by binary fission, in which the division septum forms almost exactly at the cell centre. How the division machinery achieves such accuracy is a question of continuing interest. We understand in some detail how this is achieved during vegetative growth in Escherichia coli and B. subtilis, where two main negative regulators, nucleoid occlusion and the Min system, help to determine the division site, but we still do not know exactly how the asymmetric septation site is determined during sporulation in B. subtilis. Clearly, the inhibitory effects of the nucleoid occlusion and Min system on polar division have to be overcome. We evaluated the positioning of the asymmetric septum and its accuracy by statistical analysis of the site of septation. We also clarified the role of SpoIIE, RefZ and MinCD on the accuracy of this process. We determined that the sporulation septum forms approximately 1/6 of a cell length from one of the cell poles with high precision and that SpoIIE, RefZ and MinCD have a crucial role in precisely localizing the sporulation septum. Our results strongly support the idea that asymmetric septum formation is a very precise and highly controlled process regulated by a still unknown mechanism.