bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sexual and gender diversity in cancer care and survivorship
Authors: Schulz-Quach Christian , Kennedy Margo , Lyver Brendan 
Published: January 2023

Purpose of the review
Sexual and gender diverse (SGD) cancer patients possess unique identities and needs that must be considered during their cancer care. This narrative review explores the current literature on sexual and gender diversity in cancer care and survivorship, in addition to providing recommendations encouraged by the current literature.

Recent findings
We performed a literature search for articles published in English between January 2021 and June 2022 in Medline ALL and Embase. Fifty-two studies were included in this review. The many identities encapsulated in 2SLGBTQIA+ (2 Spirited, Lesbian, Gay, Bisexual, Transgender, Queer, Intersexual, Asexual, Agender, Aromantic and all gender identities and sexual orientations that are not listed) communities each have their own unique backgrounds, needs and disparities in cancer care and survivorship. However, we also identified specific protective factors in the cancer experience of SGD patients such as reports of higher resiliency and stronger support networks. Much of the recent research features recommendations on improving cancer care by creating inclusive patient questionnaires, improving in-person and online resources, and educating healthcare providers and patient-facing staff on inclusive care.

Summary
SGD patients have their own specific challenges during and following their cancer care. As the research continues to grow, we gain a better understanding of the needs of these patients and future steps to take to improve SGD patients’ cancer experience.
Morphological profiling by Cell Painting in human neural progenitor cells classifies hit compounds in a pilot drug screen for Alzheimer’s disease
Authors: McDiarmid Amina H. , Gospodinova Katerina O. , Elliott Richard J.R. , Dawson John C. , Hughes Rebecca E. , Anderson Susan M. , Glen Sophie C. , Glerup Simon , Carragher Neil O. , Evans Kathryn L. 
Published: January 2023

1AbstractAlzheimer’s disease (AD) accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to AD drug discovery. We chose to develop a cell phenotype-based drug screen centred on the AD-risk gene,SORL1, which encodes the protein SORLA. Increased AD risk has been repeatedly linked to variants inSORL1, particularly those that confer loss of, or decreased, SORLA. This is consistent with the lowerSORL1levels observed in post-mortem brain samples from individuals with AD. Consistent with its role in the endolysosomal pathway, deletion ofSORL1is associated with enlarged endosomes in neural progenitor cells (NPCs) and neurons. We, therefore, hypothesised that multiparametric, image-based phenotyping would identify features characteristic ofSORL1deletion. An automated morphological profiling assay (known as Cell Painting) was adapted to wild-type andSORL1-/-NPCs. This methodology was used to determine the phenotypic response ofSORL1-/-NPCs to treatment with compounds from a small FDA/internationally-approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures forSORL1-/-NPCs compared to isogenic wild-type controls. Furthermore, we identified 16 approved drugs that reversed the mutant morphological signatures in NPCs derived from 3SORL1-/-subclonal iPSC lines. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis confirmed targeting to gene sets associated with these annotated targets, and to pathways/biological processes associated with DNA synthesis/damage/repair, Proteases/proteasome and metabolism._Prediction of novel targets for some compounds revealed enrichment in pathways associated with neural cell function and AD. The findings suggest that image-based phenotyping by morphological profiling distinguishesSORL1-/-NPCs from isogenic wild-type lines, and predicts treatment responses that rescueSORL1-/--associated cellular signatures that are relevant to both SORLA function and AD. Overall, this work suggests that i) a quantitative phenotypic metric can distinguish iPSC-derived SORL1-/-NPCs from isogenic wild-type control and ii) phenotypic screening combined with multiparametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer’s disease.
A Network-based Transcriptomic Landscape of HepG2 cells to Uncover Causal Gene Cytotoxicity Interactions Underlying Drug-Induced Liver Injury
Authors: Wijaya Lukas S. , Gabor Attila , Pot Iris E. , van de Have Luca , Saez-Rodriguez Julio , Stevens James L. , Le Dévédec Sylvia E. , Callegaro Giulia , van de Water Bob 
Published: January 2023

AbstractDrug-induced liver injury (DILI) remains the main reason of drug development attritions largely due to poor mechanistic understanding. Toxicogenomics to interrogate the mechanism of DILI has been broadly performed. Gene network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improving mechanistic interpretation of toxicogenomics data. In this current study, we performed an extensive concentration time course response-toxicogenomics study in the HepG2 cell line exposed to various DILI compounds, reference compounds for stress response pathways, cytokine receptors, and growth factor receptors. We established > 500 conditions subjected to whole transcriptome targeted RNA sequences and applied weighted gene co-regulated network analysis (WGCNA) to the transcriptomics data followed by identification of gene networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress responses gene networks. We correlated gene network with cell death as the progressive cellular outcomes. Causality of the target genes of these modules was evaluated using RNA interference validation experiments. We identified thatGTPBP2, HSPA1B, IRF1, SIRT1andTSC22D3exhibited strong causality towards cell death. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI.
Developmental diet alters the fecundity-longevity relationship and age-related gene expression inDrosophila melanogaster
Authors: Collins David H. , Prince David C. , Donelan Jenny L. , Chapman Tracey , Bourke Andrew F. G. 
Published: January 2023

ABSTRACTThe standard evolutionary theory of ageing predicts a negative relationship (trade-off) between fecundity and longevity. However, this relationship can become positive: (i) under the influence of longevity-enhancing mutations; (ii) when individuals have unequal resources; and (iii) in eusocial insects, in which reproductive queens outlive less- or non-reproductive workers. Developmental diet is likely to be central to determining trade-offs as it affects key fitness traits such as adult body size, but its exact role remains uncertain. For example, inDrosophila melanogasterfruit flies, changes in adult diet can affect fecundity, longevity, and gene expression throughout life, but it is unknown how changes in developmental (larval) diet affect fecundity-longevity relationships or gene expression in adults. UsingD. melanogaster, we therefore tested the hypothesis that variation in developmental diet alters the directionality of fecundity-longevity relationships in adults, and characterised associated gene expression changes. We rearedD. melanogasterlarvae on low (20%), medium (100%), and high (120%) SYA (Sugar Yeast Agar) diets, and transferred adult females developing from these larvae to a common (110% SYA) adult diet. We measured life-time fertility (realised fecundity) and longevity of individual adult females and, using mRNA-seq, profiled gene expression changes across two time-points. Adult females raised on the different larval diets exhibited fecundity-longevity relationships that were significantly different in directionality, i.e., varied from positive to negative, despite minimal differences in mean life-time fertility or longevity. Treatments also differed in age-related gene expression, including expression of genes known to be associated with ageing. Hence, this study shows that the sign of fecundity-longevity relationships in adult insects can be altered and even reversed by variation in larval diet quality. Furthermore, larval diet quality may be a key mechanistic factor underpinning positive fecundity-longevity relationships observed in species such as eusocial insects.
Oncogenic GNAS uses PKA-dependent and independent mechanisms to induce cell proliferation in human pancreatic ductal and acinar organoids
Authors: Desai Ridhdhi , Muthuswamy Senthil 
Published: January 2023

AbstractDuctal and acinar pancreatic organoids generated from human pluripotent stem cells (hPSCs) are promising models to study pancreatic diseases, including precursor lesions of pancreatic cancer. Genome sequencing studies have revealed that mutations in a G-protein (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMNs), one of the most common cystic pancreatic precancerous lesions. GNASR201Ccooperates with oncogenic KRASG12V/Dto produce IPMN lesions in mice; however, the biological mechanisms by which oncogenic GNAS affects the ductal and acinar exocrine pancreas are not understood. In this study, we use pancreatic ductal and acinar organoids generated from human embryonic stem cells to investigate mechanisms by which GNASR201Cfunctions. As expected, GNASR201C-induced cell proliferation in acinar organoids was PKA-dependent. Surprisingly, GNASR201C-induced cell proliferation independent of the canonical PKA signaling in short-term and stable, long-term cultures of GNAS-expressing ductal organoids and in an immortalized ductal epithelial cell line, demonstrating that GNASR201Cuses PKA-dependent and independent mechanisms to induce cell proliferation in the exocrine pancreas. Co-expression of oncogenic KRASG12V and GNASR201Cinduced cell proliferation in ductal and acini organoids in a PKA-independent and dependent manner, respectively. Thus, we identify cell lineage-specific roles for PKA signaling driving pre-cancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-induced IPMNs.
Self-supervised vision transformers accurately decode cellular state heterogeneity
Authors: Pfaendler Ramon , Hanimann Jacob , Lee Sohyon , Snijder Berend 
Published: January 2023

AbstractCharacterising cellular phenotypic heterogeneity is essential to understand the relationship between the molecular and morphological determinants of cellular state. Here we report that publicly available self-supervised vision transformers (ss-ViTs) accurately elucidate phenotypic stem cell heterogeneity out-of-the-box. Moreover, we introduce scDINO, an adapted ss-ViT trained on five-channel automated microscopy data, attaining excellent performance in delineating peripheral blood immune cell identity. Thus, ss-ViTs represent a leap forward in the unsupervised analysis of phenotypic heterogeneity.
PacBio Hi-Fi genome assembly of the Iberian dolphin freshwater musselUnio delphinusSpengler, 1793
Authors: André Gomes-dos-Santos , Manuel Lopes-Lima , André Machado M. , Amílcar Teixeira , Filipe C. Castro L. , Elsa Froufe 
Published: January 2023

AbstractMussels of order Unionida are a group of strictly freshwater bivalves with nearly 1,000 described species widely dispersed across world freshwater ecosystems. They are highly threatened showing the highest record of extinction events within faunal taxa. Conservation is particularly concerning in species occurring in the Mediterranean biodiversity hotspot that are exposed to multiple anthropogenic threats, possibly acting in synergy. That is the case of the dolphin freshwater musselUnio delphinusSpengler, 1793, endemic to the western Iberian Peninsula with recently strong population declines. To date, only four genome assemblies are available for the order Unionida and only one European species. We present the first genome assembly ofUnio delphinus. We used the PacBio HiFi to generate a highly contiguous genome assembly. The assembly is 2.5 Gb long, possessing 1254 contigs with a contig N50 length of 10 Mbp. This is the most contiguous freshwater mussel genome assembly to date and is an essential resource for investigating the species’ biology and evolutionary history that ultimately will help to support conservation strategies.
HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds
Authors: Diprospero Thomas J. , Brown Lauren G. , Fachko Trevor D. , Lockett Matthew R. 
Published: January 2023

AbstractMonolayer cultures of hepatocytes lack many aspects of the liver sinusoid, including a tissue-level organization that results from extracellular matrix interactions and gradients of soluble molecules that span from the portal triad to the central vein. We measured the activity and transcript levels of drug-metabolizing enzymes in HepaRG cells maintained in three different culture configurations: as monolayers, seeded onto paper scaffolds that were pre-loaded with a collagen matrix, and when seeded directly into the paper scaffolds as a cell-laden gel. Drug metabolism was significantly decreased in the presence of the paper scaffolds compared to monolayer configurations when cells were exposed to standard culture conditions. Despite this decreased function, transcript levels suggest the cells undergo increased polarization and adopt a biliary-like character in the paper scaffolds, including the increased expression of transporter proteins (e.g.,ABCB11andSLOC1B1) and theKRT19cholangiocyte marker. When exposed to representative periportal or perivenous culture conditions, we observed in vivo zonal-like patterns, including increased cytochrome P450 (CYP) activity and transcript levels in the perivenous condition. This increased CYP activity is more pronounced in the laden configuration, supporting the need to include multiple aspects of the liver microenvironment to observe the post-differentiation processing of hepatocytes.TOC Figure
Composite Deep Network with Feature Weighting for Improved Delineation of COVID Infection in Lung CT
Authors: Dutta Pallabi , Mitra Sushmita 
Published: January 2023

AbstractAn early effective screening and grading of COVID-19 has become imperative towards optimizing the limited available resources of the medical facilities. An automated segmentation of the infected volumes in lung CT is expected to significantly aid in the diagnosis and care of patients. However, an accurate demarcation of lesions remains problematic due to their irregular structure and location(s) within the lung.A novel deep learning architecture, Composite Deep network with Feature Weighting(CDNetFW), is proposed for efficient delineation of infected regions from lung CT images. Initially a coarser-segmentation is performed directly at shallower levels, thereby facilitating discovery of robust and discriminatory characteristics in the hidden layers. The novel feature weighting module helps prioritise relevant feature maps to be probed, along with those regions containing crucial information within these maps. This is followed by estimating the severity of the disease.The deep networkCDNetFWhas been shown to outperform several state-of-the-art architectures in the COVID-19 lesion segmentation task, as measured by experimental results on CT slices from publicly available datasets, especially when it comes to defining structures involving complex geometries.
Prevalence of adequately iodized salt and its determinants in Gambela district, Southwest Ethiopia
Authors: Tesfaye Getamesay Aynalem , Gemechu Ebissa Negera , Umer Abdella Yasin , Chanie Fentaneh Teshome 
Published: January 2023

AbstractBackgroundIodine deficiency disorders (IDDs) are among the major public health problems for populations all over the world. Even though the recommended strategy for IDD control is universal salt iodization, little was known about availability of adequately iodized salt in Gambela region.ObjectiveThis study was conducted to determine availability of adequately iodized salt and associated factors in Gambela district, Southwest Ethiopia.MethodsA community-based cross-sectional study was conducted in July 2019 in Gambela district. Multistage sampling method was employed to select 422 households. A structured questionnaire and rapid test kits were data collection instruments. Multivariate logistic regression was used to identify association.ResultsAbout 52.8% (95% CI: 0.47, 0.57) of households had adequately iodized salt. College diploma and above educational status (AOR=4.27, 95% CI: 1.47, 12.44), favorable attitude (AOR=5.69, 95% CI: 2.83, 11.42), walking less than 30 minutes to get iodized salt (AOR=4.69, 95% CI: 2.56, 8.60), using packed salt (AOR=2.75, 95% CI: 1.54, 4.93) and using covered salt container (AOR=3.93, 95% CI: 2.21, 6.98) were factors positively associated with availability of adequately iodized salt.ConclusionsThe availability of adequately iodized salt in Gambela district is very low. Enhancing community awareness about the benefit and good practice of iodized salt should be emphasized besides improving accessibility.
Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 153,122 U.S. patients
Authors: Liu Ruishan , Wang Lisa , Rizzo Shemra , Garmhausen Marius Rene , Pal Navdeep , Waliany Sarah , McGough Sarah , Lin Yvonne G. , Huang Zhi , Neal Joel , Copping Ryan , Zou James 
Published: January 2023

AbstractPatients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline) for multiple reasons including a lack of effective approved treatments. Here we present a systematic characterization of the patterns of off-label and off-guideline usage in 153,122 U.S. patients with 14 common cancer types using a large electronic health record (EHR)-derived de-identified database. We find that 18.3% and 3.9% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Out of the 14 malignancies investigated, advanced bladder cancer has the highest proportion with 8.1% of patients receiving off-guideline treatments, most of which are recommended for non-small cell lung cancer. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. Underrepresented minority patients are less likely to receive off-guideline treatments in several cancer types. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analysis of large real-world cohorts can identify interesting candidates for potential label expansion by identifying off-label treatments that demonstrate effectiveness in the real world setting. For example, we find that hormonal agents approved for breast cancer are used off-label in patients with ovarian cancer. Moreover, these hormonal agents show promising effectiveness in ovarian cancer with adjusted hazard ratio 0.53 (0.44, 0.65) compared to standard-of-care. This work demonstrates the power of large-scale computational analysis of real-world data for investigating non-standard cancer treatment usages.
N-terminal proteoforms may engage in different protein complexes
Authors: Bogaert Annelies , Fijalkowska Daria , Staes An , Van de Steene Tessa , Vuylsteke Marnik , Stadler Charlotte , Eyckerman Sven , Spirohn Kerstin , Hao Tong , Calderwood Michael A. , Gevaert Kris 
Published: January 2023

AbstractAlternative translation initiation and alternative splicing may give rise to N-terminal proteoforms, proteins that differ at their N-terminus compared to their canonical counterparts. Such proteoforms can have altered localizations, stabilities and functions. While proteoforms generated from splice variants can be engaged in different protein complexes, it remained to be studied to what extent this applies to N-terminal proteoforms. To address this, we mapped the interactomes of several pairs of N-terminal proteoforms and their canonical counterparts. First, we generated a catalogue of N-terminal proteoforms found in the HEK293T cellular cytosol from which 22 pairs were selected for interactome profiling. Additionally, we provide evidence for the expression of several N-terminal proteoforms, identified in our catalogue, across different human tissues as well as tissue-specific expression, highlighting their biological relevance. Protein-protein interaction profiling revealed that the overlap of the interactomes for both proteoforms is generally high, showing their functional relation. We also showed that N-terminal proteoforms can be engaged in new interactions and/or lose several interactions compared to their canonical counterpart, thus further expanding the functional diversity of proteomes.
Probing the sub-cellular mechanisms of LCA5-Leber Congenital Amaurosis and associated gene therapy with expansion microscopy
Authors: Faber Siebren , Mercey Olivier , Junger Katrin , Garanto Alejandro , Ueffing Marius , Collin Rob W.J. , Boldt Karsten , Guichard Paul , Hamel Virginie , Roepman Ronald 
Published: January 2023

AbstractLeber Congenital Amaurosis (LCA) is a group of Inherited Retinal Diseases (IRDs) characterized by the early onset and rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with Ultrastructure Expansion Microscopy (U-ExM), we revealed the structural and molecular defects underlying LCA type 5 (LCA5) with unprecedented resolution. We showed thatLCA5-encoded lebercilin, together with Retinitis Pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localize at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrated that mutant mice deficient for lebercilin exhibit early axonemal defects at the bulge region and the distal OS, accompanied by reduced level of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, we probed theLCA5gene augmentation therapy strategy using U-ExM by monitoring its subcellular outcome. We found that, expression ofLCA5partially restores the bulge region, preserves OS axoneme structure and membrane disc formation, as well as photoreceptor survival.