bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a widespread reduction in treatment duration for group A streptococcal pharyngitis on outcomes and household transmission
Authors: Bloomfield Max , Reed Hamish , Todd Sue , van der Werff Koen , Balm Michelle , Blackmore Tim 
Published: October 2024

AbstractBackgroundthe optimal treatment duration for group A streptococcal pharyngitis (GAS-P) is debated. Shorter courses appear inferior for pharyngeal GAS eradication, however the effect of this on household transmission is uncertain. In 2022 a laboratory reporting change drove reduced treatment durations for GAS-P in our region. This study sought to assess the effect of this on outcomes.Methodspositive throat swab cultures (TSC) for GAS from two years pre-change until 21 months post-change were matched to antibiotic dispensing data. Logistic models were fitted to examine associations between treatment duration and 30-day repeat antibiotic treatment, repeat GAS-positive TSC, and hospitalisation with complications; 90-day incidence of rheumatic fever; 30-day incident household GAS-P cases.Results865 patients pre-change and 1604 post-change were included. Pre-change 32.8% received ≤7 days treatment, versus 60.0% post-change (p<0.01). There were no significant differences across any outcome measure at a population level between periods. When the post-change period was examined specifically, no significant differences occurred for any outcome measure for patients receiving five- or seven-days of antibiotics versus ten-days. Patients receiving no antibiotics also had similar outcomes, except for significantly higher odds of 30-day household cases (aOR 2.93, 95%-CI 1.44-5.96, p<0.01).Conclusionsshorter treatment durations driven by a change in laboratory reporting resulted in no detectable change in GAS-P outcomes, except for more common household transmission in those receiving no treatment.
Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma
Authors: Sun Nai-Yun , Kumar Suresh , Kim Yoo Sun , Varghese Diana , Mendoza Arnulfo , Nguyen Rosa , Okada Reona , Reilly Karlyne , Widemann Brigitte , Pommier Yves , Elloumi Fathi , Dhall Anjali , Patel Mayank , Aber Etan , Contreras-Burrola Cristie , Kaplan Rosie , Martinez Dan , Pogoriler Jennifer , Hamilton Amber K. , Diskin Sharon J. , Maris John M. , Robey Robert W. , Gottesman Michael M. , Del Rivero Jaydira , Roper Nitin 
Published: October 2024

AbstractImmunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potentin vitroactivity among established cell lines and a new cohort of patient-derived organoids as well as robustin vivoanti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1+ACC and SCLCin vivomodels with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial (NCT06041516).
Evidence of opportunistic blood feeding in the parasitic nematodeHeligmosomoides bakeri
Authors: Szabo Edina K. , Wasmuth James D. , Leon-Coria Aralia , Rich Kaylee D. , Liu Holly , Finney Constance A. M. 
Published: October 2024

ABSTRACTHaem, which binds iron and oxygen, is essential for parasitic nematode growth. Nematodes lack endogenous haem synthesis pathways and acquire haem from their environment or intracellular symbionts. Genes involved in haem degradation and detoxification have been identified in parasitic nematodes who are either specialised blood feeders (haematophages) or reside in the blood stream. Targeting these genes, so limiting parasite growth and promoting parasite death, provides a new therapeutic avenue against blood feeding parasitic nematodes.Heligmosomoides bakeri, a model intestinal parasitic nematode, has not been considered a blood feeder. Adults live in the intestinal lumen and graze on host tissue. However, the earlier larval stages enter the intestinal tissue, where they grow and moult multiple times, an oxygen demanding process. We have shown that,in vivo, likely through nematode-induced damage, many tissue-dwellingH. bakeriare in close vicinity of red blood cells. During this time, infection induces host anemia. Further, tissue-dwellingH. bakerithat have fed on blood have an increased expression of collagen genes compared to those parasites that had not fed on blood.In vitro, this translates to a growth advantage.Our findings suggest blood feeding is more widespread among nematodes than currently described. We argue that biochemical adaptations previously considered to be limited to blood-feeders are found in other nematodes. Moreover,H. bakerican serve as a model for studying blood-feeding mechanisms and developing anthelminthic strategies to them.
Protein Kinases in Phagocytosis: Promising Genetic Biomarkers for Cancer
Authors: Arumilli Sadhika , Liu Hengrui 
Published: October 2024

AbstractCancer is a complex disease characterized by genetic and molecular diversity, often involving dysregulation of critical cellular pathways. Recent advances in pan-cancer research have highlighted the importance of shared oncogenic mechanisms across different cancer types, providing new avenues for therapeutic exploration. Protein kinases, particularly those involved in phagocytosis, play pivotal roles in cellular homeostasis and immune response. This study systematically examines the genetic alterations and expression profiles of protein kinases associated with phagocytosis across various cancer types, using data from The Cancer Genome Atlas (TCGA) and other publicly available resources. We analyzed single nucleotide variations (SNVs), copy number variations (CNVs), methylation patterns, and mRNA expression to identify recurring alterations and their associations with survival outcomes. Our findings reveal that MET and MERTK are the most frequently mutated genes, with missense mutations dominating across cancers. CNV analysis shows significant correlations with survival in cancers like UCEC, KIRP, and KIRC, while methylation analysis indicates cancer-specific regulatory patterns affecting gene expression. Differential expression analysis highlights distinct cancer-type-specific expression profiles, with genes like MET and BTK displaying significant variation. Crosstalk pathway analysis further reveals the involvement of these kinases in key cancer-related pathways, such as epithelial-mesenchymal transition (EMT) and apoptosis. Drug sensitivity analysis identifies potential therapeutic targets, with gene expression correlating significantly with cancer cell line responsiveness to specific compounds. These findings underscore the importance of the phagocytotic kinome in cancer biology and suggest potential therapeutic strategies targeting protein kinases to enhance immune response and improve treatment outcomes.
Biosynthetic characterization and combinatorial biocatalysis of the cysteine protease inhibitor E-64
Authors: Liu Mengting , Zang Xin , Vlahakis Niko W. , Rodriguez Jose A. , Ohashi Masao , Tang Yi 
Published: October 2024

AbstractE-64 is an irreversible and selective cysteine protease inhibitor prominently used in chemical biology and drug discovery. In this work, we uncovered and characterized the NRPS-independent pathway responsible for biosynthesis of E-64, which is widely conserved in fungi. Heterologous reconstitution and biochemical assays show the pathway starts with epoxidation of fumaric acid to the warhead (2S,3S)-trans-epoxysuccinic acid with an α-ketoglutarate (αKG)/Fe(II)-dependent oxygenase, followed by successive condensation with anl-amino acid by an ATP-grasp enzyme, and with an amine by the first characterized amide bond synthetase from fungi. Both amide bond-forming enzymes displayed significant biocatalytic potential, including scalability, stereoselectivity towards the warhead and broader substrate scopes in forming the amide bonds. Combinatorial biocatalysis with the two amide-bond forming enzymes generated a library of cysteine protease inhibitors and led to more potent analogs towards cathepsin B. In addition, preparative synthesis of clinically relevant cysteine protease inhibitors was accomplished from a single reaction mixture. Our work highlights the importance of biosynthetic investigation for enzyme discovery and the potential of amide bond-forming enzymes as biocatalysts for a library synthesis of small molecules.
Body Fatness Increases Risk of Monoclonal Gammopathy of Undetermined Significance in the U.S. Population
Authors: Ji Mengmeng , Huber John , Wang Mei , Shih Yi-Hsuan , Lan Tuo , Wang Shi-Yi , Chang Su-Hsin 
Published: October 2024

AbstractObjectiveCurrent evidence on whether obesity is associated with MGUS remains inconsistent. This study aims to evaluate the association between objectively measured obesity markers and the risk of developing MGUS, using nationally representative data from the U.S. population.MethodData came from the third National Health and Nutrition Examination Survey III (1988-1994) and continuous NHANES (1999-2004). Multivariable-adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for the association between the risk of developing MGUS and seven obesity markers—including baseline body mass index (BMI), maximum lifetime BMI, waist circumference (WC), waist-hip ratio (WHR), total body fat, fat-free mass, and body percentage fat—were estimated using logistic regression.ResultsIn the study cohort, a total of 364 participants tested positive for MGUS, compared to 12,043 participants without MGUS. Multivariate logistic regression analysis indicates that each 1% increase in body fat percentage is associated with a 4% (aOR: 1.04, 95% CI [1.01, 1.07]) higher risk of MGUS. Each 1% increase in body fat percentage is also associated with a 6% (aOR: 1.06, 95% CI [1.02, 1.10]) higher risk of non-IgM MGUS. No statistically significant association was found between MGUS and other obesity markers, including baseline BMI, maximum lifetime BMI, WC, WHR, and fat-free mass.ConclusionOur findings show that obesity is associated with an increase in the risk of MGUS. However, many obesity markers, including the commonly used BMI, fail to capture this association.
Characteristics and care trajectories of older patients in temporary stays in Denmark
Authors: Harbi Hanin , Lundby Carina , Jensen Peter Bjødstrup , Larsen Søren Post , Rørbæk Linda Grouleff , Ravn-Nielsen Lene Vestergaard , Ryg Jesper , Reilev Mette , Edwards Kasper , Pottegård Anton 
Published: October 2024

AbstractBackgroundTemporary stays for patients requiring short-term care outside the home, often following hospital discharge, has gained increasing importance. This study aimed to describe the characteristics and care trajectories of older patients in Danish temporary stays to improve care delivery and patient safety.MethodsWe conducted a descriptive study on a cohort of patients in temporary stays across 14 Danish municipalities from 2016 to 2023, using data from national health registries.ResultsWe identified 11,424 patients with a median age of 81 years (interquartile range [IQR] 73-87 years); 54% were women. Patients exhibited a high level of comorbidity, with a median Charlson Comorbidity Index of 1 (IQR 0-2), and a median of 3 hospital admissions (IQR 2-6) in the year preceding their move into temporary care. The majority (70%) transitioned to temporary stays following hospital discharge, while 30% were admitted directly from their homes. The median duration of temporary stays was 24 days (IQR 11-49 days), with 9.1% staying ≥ 90 days. Additionally, 8.2% of patients were hospitalised directly from the temporary stay facility, with a median time to hospital admission of 13 days (IQR 5-28 days). Median survival after admission to a temporary stay was 23 months (IQR 3.6-57 months). Predictors of mortality included male sex, older age, higher comorbidity burden, and increased number of hospital admissions prior to temporary stay.ConclusionPatients in temporary stays are generally older individuals with multimorbidity and limited life expectancy. Most patients are admitted following hospital discharge, and their stays are often prolonged.
The association between outdoor ambient temperature and depression and mania: an ecological momentary assessment study
Authors: Clery P , Hayes JF , Launders N , Thompson R , Kandola A , Osborn DPJ , Lawrance EL , Jeffery A , Dykxhoorn J 
Published: October 2024

AbstractBackgroundEnvironmental heat exposure can negatively impact mental health. Evidence for its effect on mood disorder symptoms is inconsistent. Current studies are limited by poor temporal and geographical resolution.MethodsWe used ecological momentary assessment (EMA) data from the smartphone appjulito investigate the association between real-time mean and maximum ambient temperature collected from smartphone geolocation, and depressive and manic symptom scales, every two weeks, in adults with depression and bipolar disorder. We used negative binomial mixed-effects regression models, controlled for demographic and weather variables, and stratified by season.ResultsWe analysed data from 4,000 participants with depressive symptom scores and 2,132 with manic symptom scores, between 2021 and 2023. We found that each 1°C increase in mean daily temperature in the preceding two weeks was associated with a 0.2% reduction in depressive symptom scores (coeff 0.998, 95%CI 0.997-0.999) and a 0.4% increase in manic symptom scores (coeff 1.004, 95%CI 1.001-1.007). Associations between maximum temperature and symptom scores followed a similar pattern.LimitationsWe were unable to capture several socio-demographic covariates, had limited geographical information due to privacy regulations, and included a non-random sample.ConclusionsWe found evidence that higher temperatures were associated with increased manic symptoms and decreased depressive symptoms, indicating an important relationship between temperature and the mood disorder continuum. With global heating, there is a need to understand the impact of temperature on mood symptoms, to provide targeted clinical prevention and support. This study demonstrates potential for EMA methods to inform our understanding of these links.
Estimating the generation time for SARS-CoV-2 transmission using household data in the United States, December 2021 – May 2023
Authors: Chan Louis Yat Hin , Morris Sinead E. , Stockwell Melissa S. , Bowman Natalie M. , Asturias Edwin , Rao Suchitra , Lutrick Karen , Ellingson Katherine D. , Nguyen Huong Q. , Maldonado Yvonne , McLaren Son H. , Sano Ellen , Biddle Jessica E. , Smith-Jeffcoat Sarah E. , Biggerstaff Matthew , Rolfes Melissa A. , Talbot H. Keipp , Grijalva Carlos G. , Borchering Rebecca K. , Mellis Alexandra M. ,   RVTN-Sentinel Study Group
Published: October 2024

AbstractBackgroundGeneration time, representing the interval between infection events in primary and secondary cases, is important for understanding disease transmission dynamics including predicting the effective reproduction number (Rt), which informs public health decisions. While previous estimates of SARS-CoV-2 generation times have been reported for early Omicron variants, there is a lack of data for subsequent sub-variants, such as XBB.MethodsWe estimated SARS-CoV-2 generation times using data from the Respiratory Virus Transmission Network – Sentinel (RVTN-S) household transmission study conducted across seven U.S. sites from December 2021 to May 2023. The study spanned three Omicron sub-periods dominated by the sub-variants BA.1/2, BA.4/5, and XBB. We employed a Susceptible-Exposed-Infectious-Recovered (SEIR) model with a Bayesian data augmentation method that imputes unobserved infection times of cases to estimate the generation time.FindingsThe estimated mean generation time for the overall Omicron period was 3.5 days (95% credible interval, CrI: 3.3-3.7). During the sub-periods, the estimated mean generation times were 3.8 days (95% CrI: 3.4-4.2) for BA.1/2, 3.5 days (95% CrI: 3.3-3.8) for BA.4/5, and 3.5 days (95% CrI: 3.1-3.9) for XBB.InterpretationOur study provides estimates of generation times for the Omicron variant, including the sub-variants BA.1/2, BA.4/5, and XBB. These up-to-date estimates specifically address the gap in knowledge regarding these sub-variants and are consistent with earlier studies. They enhance our understanding of SARS-CoV-2 transmission dynamics by aiding in the prediction of Rt, offering insights for improving COVID-19 modeling and public health strategies.FundingCenters for Disease Control and Prevention, and National Center for Advancing Translational Sciences.
De novo rates of aTrypanosoma-resistant mutation in two human populations
Authors: Melamed Daniel , Shemer Revital , Bolotin Evgeni , Yakass Michael B. , Fink-Barkai Dorit , Hiadzi Edem K. , Skorecki Karl L. , Livnat Adi 
Published: October 2024

AbstractUntil recently, mutation rates have only been measured as averages across many genomic positions. Recently, a method to measure mutation rates at the single-mutation resolution was applied to a narrow region in the human hemoglobin subunit beta (HBB) gene containing the site of the hemoglobin S (HbS) mutation as well as to a paralogous hemoglobin subunit delta (HBD) region, in sperm samples from sub-Saharan African and northern European donors. The HbS mutation, which protects against malaria while causing sickle-cell anemia in homozygotes originated de novo significantly more frequently in theHBBgene in Africans compared to the other three test cases combined (the EuropeanHBBgene and the European and AfricanHBDgene). Here, we apply this approach to the human apolipopro-tein L1 (APOL1) gene containing the site of the G1 1024A→G mutation, which protects against African sleeping sickness caused byTrypanosoma brucei gambiensewhile causing a substantially increased risk of chronic kidney disease (CKD) in homozygotes. We find that the 1024A→G mutation is the mutation of highest de novo origination rate and deviates most from the genome-wide average rate for its type (A→G) compared to all other observable mutations in the region, and that it originates de novo significantly more frequently in Africans than in Europeans—i.e., in the population where it is of adaptive significance. The results are inconsistent with the notion that the probability of a specific mutational event is independent of its value to the organism and underscore the importance of studying mutation rates at the single-mutation resolution.
Loss of PKCθ-GADD45a axis drives triple-negative breast cancer cells into p53-independent senescence
Authors: Nicolle Amandine , Zhang Ye , Choesmel-Cadamuro Valérie , Wang Xiaobo , Belguise Karine 
Published: October 2024

BackgroundPKCθ is a serine/threonine kinase that is well known for its role in the immune system. However, increasing evidence implicates PKCθ in the pathology of breast cancer. PKCθ is highly expressed in triple negative breast cancer (TNBC) cells in which it controls cell migration and invasion, while its implication in cell proliferation remains poorly understood.MethodsTo determine the function of PKCθ in cell proliferation, siRNAs were used to modulate the expression of PKCθ in TNBC cells (MDA-MB-231, MDA-MB-436, HCC1937) and cell growth was examined by clonogenic and EdU assays. β-galactosidase assay, RT-qPCR and western blot were used to characterize the senescence features. PCR microarrays and rescue experiments were conducted to investigate the underlying mechanism.ResultsWe show that PKCθ inhibition leads to a growth arrest in TNBC cells harboring a p53 loss-of-function mutation. This p53-independent growth arrest is accompanied by an increased activity of senescence-associated β-galactosidase, the presence of a senescence-associated secretory phenotype, and the striking expression change of various genes implicated in cell proliferation and senescence. Thus, our data show that PKCθ silencing drives TNBC cells into a senescence-like phenotype. Mechanistically, we demonstrate that p27 is the main CDK inhibitor controlling the PKCθ loss-induced senescence. The accumulation of p27 is due to a surprising strong reduction in GADD45a expression. Indeed, similar to PKCθ silencing phenotype, GADD45a knockdown drives TNBC cells into a senescence-like phenotype.ConclusionsAltogether, our study highlights that the loss of PKCθ-GADD45a axis triggers a p27-dependent senescence response in TNBC cells and further supports strategies targeting PKCθ as treatment for this type of aggressive breast cancer.
Structural Insights into Selective and Dual Antagonism of EP2 and EP4 Prostaglandin Receptors
Authors: Wu Yanli , Zhang Heng , Xu Jiuyin , Wu Kai , Hu Wen , Wu Canrong , Xu H. Eric 
Published: October 2024

AbstractProstaglandin E2 (PGE2) signaling through EP2 and EP4 receptors plays a crucial role in inflammation, pain, and cancer progression. Selective and dual antagonists of these receptors have shown promising therapeutic potential. However, the structural basis for their binding modes and selectivity remained unclear. Here, we present cryo-EM structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, respectively, as well as the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that govern antagonist selectivity and efficacy. Combining the structural data and functional studies, we uncover the key residues and structural features that differentiate EP2 and EP4 binding sites, including a unique π-π stacking interaction in EP2 and variations in pocket shape and charge distribution. The dual antagonist TG6-129 exhibited a novel binding mode, interacting deeply with EP2 but only shallowly with EP4 in a two-warhead manner. These findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors.