bluuebunny/crossref_metadata_2025_split huggingface dataset:
HPV-associated Vulvar Intraepithelial Carcinoma With Sebaceous Differentiation: Report of 2 Cases
Authors: Hamza Mugahed A. , Quick Charles M. , Williams Heather R. , Patil Ninad M. , Shalin Sara C. 
Published: November 2022

Sebaceous carcinoma (SC) is a malignant neoplasm demonstrating sebocytic differentiation, commonly in the periocular area. Sebocytic differentiation is recognized by multivesicular cytoplasmic clearing with frequent nuclear scalloping. The vesicles can be highlighted by immunohistochemical stains against the perilipin family proteins including adipophilin. Extraocular SC is uncommon but well reported, often in the setting of Muir-Torre syndrome; however, vulvar SC is exceptionally rare. The literature review yielded only 12 prior cases of vulvar SC, all of which showed invasion. Here we report 2 additional similar cases from 2 different institutions of an intraepithelial carcinoma with sebaceous differentiation. Histologic examination of multiple specimens from both patients showed similar features: a multifocal intraepithelial basaloid nodular neoplasm sparing the basal layer with occasional pagetoid spread. The tumor cells demonstrated a high nuclear to cytoplasmic ratio, mitoses, variably foamy vacuolated cytoplasm, and nuclear indentation. Multiple specimens from both patients showed evidence of sebaceous differentiation (substantiated by adipophilin positivity in a membranous vesicular pattern in case 1 and by androgen receptor and epithelial membrane antigen positivity in case 2), and squamous differentiation (substantiated by p63/p40 and weak CK 5/6 expression), as well as human papillomavirus (HPV) association (substantiated by p16 block positivity and detection of high-risk HPV by in situ hybridization). One case was a true in situ lesion without evidence of invasion, and the other case was predominantly an in situ carcinoma with prominent adnexal extension and focal superficial invasion of <1 mm seen in one of multiple specimens. To our knowledge, these 2 cases are the first to show a vulvar SC/carcinoma with sebaceous differentiation that is predominantly limited to the epidermis, and the first documentation of HPV infection in vulvar sebaceous neoplasms. Vulvar intraepithelial carcinoma with sebaceous differentiation is the umbrella term we chose for this entity. Whether this is a true SC in situ that is HPV positive/driven, or a vulvar intraepithelial neoplasia with sebaceous differentiation, is not entirely clear. We emphasize the importance of looking for this morphology to avoid misclassification. Due to the rarity of cases, optimal treatment at this site has not been established.
Tenofovir disoproxil fumarate/emtricitabine and severity of coronavirus disease 2019 in people with HIV infection
Authors: Del Amo Julia , Polo Rosa , Moreno Santiago , Martínez Esteban , Cabello Alfonso , Iribarren José Antonio , Curran Adria , Macías Juan , Montero Marta , Dueñas Carlos , Mariño Ana I. , de la Cámara Santiago Pérez , Díaz Asuncion , Arribas José Ramón , Jarrín Inma , Hernán Miguel A. 
Published: November 2022

Background:
Effective, safe, and affordable antivirals are needed for coronavirus disease 2019 (COVID-19). Several lines of research suggest that tenofovir may be effective against COVID-19, but no large-scale human studies with appropriate adjustment for comorbidities have been conducted.

Methods:
We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4+ cell count, HIV-RNA viral-load, comorbidities and the following outcomes: laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.

Results:
Of 51 558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% confidence interval) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88–6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals.

Discussion:
Compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.
Therapeutic Effects of Anti-PD1 Immunotherapy on Hepatocellular Carcinoma Under Administration of Tacrolimus
Authors: Hsu Yu-Chen , Chen Chien-Hung , Huang Hui-Fu , Lee Ying-Te , Wu Meng-Chuan , Su Chien-Wen , Chou Huei-Chi , Wang Li-Fang , Lee Hsuan-Shu , Lin Shu-Wha , Hsu Ping-Ning , Wu Yao-Ming , Sheu Jin-Chuan , Weng Meng-Tzu 
Published: November 2022

Background.
Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients.

Methods.
We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment.

Results.
Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8+ T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8+ T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model.

Conclusions.
Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.
Determinants of Eye Care Service Utilization Among Malawian adults; A Secondary Analysis of the Malawi fifth Integrated Household Survey 2019-2020
Authors: Mzumara Thokozani 
Published: November 2022

AbstractPurposeThe aim of the study was to assess the self-reported Eye Care Utilization (ECU) and associated demographic factors among Malawians adults.MethodsThis study utilized secondary data from the Malawi Integrated Health Survey (IHS) 5 2019-2020. We entered age, sex, level of education, residency(urban/rural) and having chronic disease into a logistic regression model and used a confusion matrix to predict the accuracy of the model.ResultsThe prevalence of ECU was 60.6% (95% CI [60.0,61.2]). The model was statistically significant and correctly classified 72 % of the cases. A logistic regression showed that ECU was positively associated with education compared to none (OR=3.6, 95 % CI [3.104-4.097], p<0.001, (OR =6.6), CI [5.927,7.366], p<0.001), male gender compared to females (OR= 1.2, 95% CI [1.104,1.290], p<0.001), urban residence compared to rural areas (OR= 1.2, 95% CI [1.118,1.375], p<0.001). But It was negatively associated with age compared to young adults, middle age (OR =7.5, 95% CI [6.782,8.476], p<0.001), older age (OR=0.9, 95 % CI [0.866,1.035], p<0.001), and having chronic diseases (OR=0.6, 95 % CI= [0.547,0.708], p<0.001).ConclusionSocial support, women empowerment, education, and mobile clinics are key strategic areas that would increase Access to eye care in Malawi. Further studies can investigate ECU among the pediatric population.
Networks of placental DNA methylation correlate with maternal serum PCB concentrations and child neurodevelopment
Authors: Mouat Julia S. , Li Xueshu , Neier Kari , Zhu Yihui , Mordaunt Charles E. , Merrill Michele A. La , Lehmler Hans-Joachim , Jones Michael P. , Lein Pamela J. , Schmidt Rebecca J. , LaSalle Janine M. 
Published: November 2022

ABSTRACTBackgroundGestational exposure to polychlorinated biphenyls (PCBs) has been associated with elevated risk for neurodevelopmental disorders. The mechanism of risk is unclear but may involve placental epigenetics. Prior studies have associated differential placental DNA methylation with maternal PCB exposure or with increased risk of autism spectrum disorder (ASD). However, sequencing-based placental methylomes have not previously been tested for simultaneous associations with maternal PCB levels and child neurodevelopmental outcomes.ObjectivesWe aimed to identify placental DNA methylation patterns associated with maternal PCB levels and child neurodevelopmental outcomes in the high-risk ASD MARBLES cohort.MethodsWe measured 209 PCB congeners in 104 maternal serum samples collected at delivery. We identified networks of DNA methylation from 147 placenta samples using the Comethyl R package, which performs weighted gene correlation network analysis for whole genome bisulfite sequencing data. We tested placental DNA methylation modules for association with maternal serum PCB levels, child neurodevelopment, and other participant traits.ResultsPCBs 153 + 168, 170, 180 + 193, and 187 were detected in over 50% of maternal serum samples and were highly correlated with one another. Consistent with previous findings, maternal age was the strongest predictor of serum PCB levels, alongside year of sample collection, pre-pregnancy BMI, and polyunsaturated fatty acid levels. Twenty seven modules of placental DNA methylation were identified, including five which significantly correlated with one or more PCBs, and four which correlated with child neurodevelopment. Two modules associated with maternal PCB levels as well as child neurodevelopment, and mapped toCSMD1andAUTS2, genes previously implicated in ASD and identified as differentially methylated regions in mouse brain and placenta following gestational PCB exposure.ConclusionsPlacental DNA co-methylation modules were associated with maternal PCBs and child neurodevelopment. Methylation ofCSMD1andAUTS2could potentially be mechanistically involved in ASD risk following maternal PCB exposure.GRAPHICAL ABSTRACT
Targeted high throughput mutagenesis of the human spliceosome reveals itsin vivooperating principles
Authors: Beusch Irene , Rao Beiduo , Studer Michael , Luhovska Tetiana , Šukytė Viktorija , Lei Susan , Oses-Prieto Juan , SeGraves Em , Burlingame Alma , Jonas Stefanie , Madhani Hiten D. 
Published: November 2022

SUMMARYThe spliceosome is a staggeringly complex machine comprising, in humans, 5 snRNAs and >150 proteins. We scaled haploid CRISPR-Cas9 base editing to target the entire human spliceosome and interrogated the mutants using the U2 snRNP/SF3b inhibitor, pladienolide B. Hypersensitive substitutions define functional sites in the U1/U2-containing A-complex but also in components that act as late as the second chemical step after SF3b is dissociated. Viable resistance substitutions map not only to the pladienolide B binding site but also to the G-patch (ATPase activator) domain of SUGP1, which lacks orthologs in yeast. We used these mutants and biochemical approaches to identify the spliceosomal disassemblase DHX15/hPrp43 as the ATPase ligand for SUGP1. These and other data support a model in which SUGP1 promotes splicing fidelity by triggering early spliceosome disassembly in response to kinetic blocks. Our approach provides a template for the analysis of essential cellular machines in humans.
Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma 3D organoids and identify matrix-activated therapeutic targets
Authors: Cruz-Acuña Ricardo , Kariuki Secunda W. , Sugiura Kensuke , Loebel Claudia , Karakasheva Tatiana , Gabre Joel T. , Burdick Jason A. , Rustgi Anil K. 
Published: November 2022

AbstractIncreased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying pro-tumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevantin vitro3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the contributions of matrix stiffness to EAC pathogenesis. Here, we describe a modular, tumor ECM-mimetic hydrogel platform with tunable mechanical properties, defined presentation of cell-adhesive ligands, and protease-dependent degradation that supports robustin vitrogrowth and expansion of patient-derived EAC 3D organoids (EAC PDOs). Hydrogel mechanical properties control EAC PDO formation, growth, proliferation and activation of tumor-associated pathways that elicit stem-like properties in the cancer cells, as highlighted throughin vitroandin vivoenvironments. We also demonstrate that the engineered hydrogel serves as a platform to identify potential therapeutic targets to disrupt the contribution of pro-tumorigenic increased matrix mechanics in EAC. Together, these studies show that an engineered PDO culture platform can be used to inform the development of therapeutics that target ECM stiffness in EAC.
Using Genome Sequence Data to Predict SARS-CoV-2 Detection Cycle Threshold Values
Authors: Duesterwald Lea , Nguyen Marcus , Christensen Paul , Long S. Wesley , Olsen Randall J. , Musser James M. , Davis James J. 
Published: November 2022

AbstractThe continuing emergence of SARS-CoV-2 variants of concern (VOCs) presents a serious public health threat, exacerbating the effects of the COVID19 pandemic. Although millions of genomes have been deposited in public archives since the start of the pandemic, predicting SARS-CoV-2 clinical characteristics from the genome sequence remains challenging. In this study, we used a collection of over 29,000 high quality SARS-CoV-2 genomes to build machine learning models for predicting clinical detection cycle threshold (Ct) values, which correspond with viral load. After evaluating several machine learning methods and parameters, our best model was a random forest regressor that used 10-mer oligonucleotides as features and achieved an R2score of 0.521 ± 0.010 (95% confidence interval over 5 folds) and an RMSE of 5.7 ± 0.034, demonstrating the ability of the models to detect the presence of a signal in the genomic data. In an attempt to predict Ct values for newly emerging variants, we predicted Ct values for Omicron variants using models trained on previous variants. We found that approximately 5% of the data in the model needed to be from the new variant in order to learn its Ct values. Finally, to understand how the model is working, we evaluated the top features and found that the model is using a multitude of k-mers from across the genome to make the predictions. However, when we looked at the top k-mers that occurred most frequently across the set of genomes, we observed a clustering of k-mers that span spike protein regions corresponding with key variations that are hallmarks of the VOCs including G339, K417, L452, N501, and P681, indicating that these sites are informative in the model and may impact the Ct values that are observed in clinical samples.
FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases
Authors: Breeze Charles E. , Haugen Eric , Gutierrez-Arcelus María , Yao Xiaozheng , Teschendorff Andrew , Beck Stephan , Dunham Ian , Stamatoyannopoulos John , Franceschini Nora , Machiela Mitchell J. , Berndt Sonja I. 
Published: November 2022

AbstractThe majority of disease-associated variants identified through genome-wide association studies (GWAS) are located outside of protein-coding regions and are overrepresented in sequences that regulate gene expression. Prioritizing candidate regulatory variants and potential biological mechanisms for further functional experiments, such as genome editing, can be challenging, especially in regions with a high number of variants in strong linkage disequilibrium or multiple proximal gene targets. Improved annotation of the regulatory genome can help identify promising variants and target genes for functional genomics experiments. To advance this area, we developed FORGEdb (https://forge2.altiusinstitute.org/files/forgedb.html), a web-based tool that can rapidly integrate data for individual genetic variants, providing information on associated regulatory elements, transcription factor (TF) binding sites and target genes for over 37 million variants. FORGEdb uses annotations derived from data across a wide range of biological samples to delineate the regulatory context for each variant at the cell type level. Multiple data types, such as Combined Annotation Dependent Depletion (CADD) scores, expression quantitative trait loci (eQTLs), activity-by-contact (ABC) interactions, Contextual Analysis of TF Occupancy (CATO) scores, transcription factor (TF) motifs, DNase I hotspots, histone mark ChIP-seq peaks and chromatin states, are included in FORGEdb and these annotations are integrated into a FORGEdb score to guide assessment of functional importance. In summary, FORGEdb provides an expansive and unique resource of genomic annotations and an integrated score that can be used to accelerate the translation of identified genetic loci into biological insight.
AhR-mediated activation of innate lymphocytes restrains tissue-resident memory-like CD8+ T cell responses during contact hypersensitivity
Authors: Romero-Suárez S. , Correia M.P. , Jeong M. , Ast V. , Platten M. , Sexl V. , Mogler C. , Cerwenka A. , Stojanovic A. 
Published: November 2022

AbstractAllergic contact dermatitis (ACD) and the mouse model of hapten-induced contact hypersensitivity (CHS) are inflammatory skin responses triggered by the repeated exposure to exogenous allergens and haptens. ACD and CHS effector responses have been extensively studied, but the regulatory mechanisms that control inflammation and determine the kinetics of its resolution are still incompletely understood. In addition, although CHS can be mediated by both innate and adaptive effector cells in a non-redundant manner, leading to distinct skin pathologies, their interplay during the course of inflammation remains so far unaddressed. Here, we show that NKp46+innate lymphoid cells (ILCs) limit the extent of CHS inflammation by modulating the CD8+TRMimmune compartment. This regulatory effect of ILCs depends on the expression of the ligand-induced transcription factor aryl-hydrocarbon receptor (AhR). AhR-deficiency in NKp46+ILCs did not affect the memory response to hapten, but led to spatial propagation and amplification of inflammatory response in the skin. This phenotype correlated with increased numbers ofIfng-producing CD8+TRM-like cells and neutrophilic infiltration in the skin. Our study thereby demonstrates a novel AhR-driven innate-adaptive immune interplay in regulating skin inflammation.
Two-Photon Targeted, Quad Whole-Cell Patch-Clamping Robot
Authors: Vera Gonzalez Gema I , Kgwarae Phatsimo O , Schultz Simon R 
Published: November 2022

AbstractWe present an automated quad-channel patch-clamp technology platform forex vivobrain slice electrophysiology, capable of both blind and two-photon targeted robotically automated patching. The robot scales up the patch-clamp singlecell recording technique to four simultaneous channels, with seal success rates for two-photon targeted and blind modes of 54% and 68% respectively. In 50% of targeted trials (where specific cells were required), at least 2 simultaneous recordings were obtained. For blind mode, most trials yielded dual or triple recordings. This robot, a milestone on the path to a truein vivorobotic multi-patching technology platform, will allow numerous studies into the function and connectivity patterns of both primary and secondary cell types.
Balance-directed protein engineering ofIsPETase enhances both PET hydrolysis activity and thermostability
Authors: Lee Seul Hoo , Seo Hogyun , Hong Hwaseok , Park Jiyoung , Ki Dongwoo , Kim Mijeong , Kim Hyung-Joon , Kim Kyung-Jin 
Published: November 2022

AbstractA mesophilic PETase fromIdeonella sakaiensis(IsPETase) has been shown to exhibit high PET hydrolysis activity, but its low thermostability limits its industrial applications. We herein developed an engineering strategy forIsPETase to enhance PET hydrolysis activity, thermostability, and protein folding of the enzyme. Balance-directed Z1-PETase variant outperforms the stability-directed Z2-PETase variant under both mesophilic and thermophilic conditions, although Z2-PETase exhibits higher thermostability than Z1-PETase. The Z1-PETase is also superior to Fast-PETase, Dura-PETase, and LC-CICCGin terms of depolymerization rate regardless of temperature conditions we tested. Thus, maintaining a balance between PET hydrolysis activity and thermostability is essential for the development of high-performance PET hydrolases. In a pH-stat bioreactor, Z1-PETase depolymerized >90% of both transparent and colored post-consumer PET powders within 24 and 8 hours at 40°C and 55°C, respectively, demonstrating that the balance-directedIsPETase variant produced herein may be applicable in the bio-recycling of PET.
Anti-oxidant Response of Lipidom Modulates Lipid Metabolism inCaenorhabditis elegansand in OxLDL-Induced Human Macrophages by Tuning Inflammatory Mediators
Authors: Balkrishna Acharya , Gohel Vivek , Pathak Nishit , Singh Rani , Tomer Meenu , Rawat Malini , Dev Rishabh , Varshney Anurag 
Published: November 2022

AbstractAtherosclerosis is the main pathological process of most cardiovascular diseases. It can begin early in life and may remain latent and asymptomatic for an extended period before its clinical manifestation. Lipidom, an ayurvedic prescription medicine, contains five herbal constituents with reported anti-inflammatory, anti-oxidant and lipid lowering properties. The present study is aimed to characterize the pharmacological potentials of Lipidom. The phytochemical analysis of Lipidom was performed on high performance liquid chromatography (HPLC) platform. Lipidom was evaluated for cytosafety, NF-κB activity, IL-1β and MCP-1 levels, modulation of NLRP3 pathway, ROS generation, lipid accumulation and gene expression in oxidized LDL stimulated THP1 macrophages. Furthermore, assessment of Lipidom was also done in the in-vivoCaenorhabditis elegansmodel. Analysis of brood size, % adult, lipid accumulation, triglyceride levels, MDA formation, SOD-3 levels and gene expression was performed inC. elegans. Lipidom treatment significantly reduced the inflammatory markers, lipid accumulation, oxidative stress and normalized genes involved in atherosclerosis development in THP1 macrophages. Lipidom treatedC. elegansshowed a significant decline in the lipid accumulation and oxidative stress. Lipidom showed a multifaceted approach in modulating the mediators responsible for development and progression of atherosclerosis.