bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irinotecan hydrochloride liposome HR070803 in combination with 5-fluorouracil and leucovorin in locally advanced or metastatic pancreatic ductal adenocarcinoma following prior gemcitabine-based therapy (PAN-HEROIC-1): a phase 3 trial
Authors: Cui Jiujie , Qin Shukui , Zhou Yuhong , Zhang Shuang , Sun Xiaofeng , Zhang Mingjun , Cui Jiuwei , Fang Weijia , Gu Kangsheng , Li Zhihua , Wang Jufeng , Chen Xiaobing , Yao Jun , Zhou Jun , Wang Gang , Bai Yuxian , Xiao Juxiang , Qiu Wensheng , Wang Bangmao , Xia Tao , Wang Chunyue , Kong Li , Yin Jiajun , Zhang Tao , Shen Xionghu , Fu Deliang , Gao Chuntao , Wang Huan , Wang Quanren , Wang Liwei 
Published: September 2024

AbstractLiposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1–8.4] versus 5.0 months [95% CI 4.3–6.0]; HR 0.63 [95% CI 0.48–0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.
The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma
Authors: Shan Qiaonan , Yin Lu , Zhan Qifan , Yu Jiongjie , Pan Sheng , Zhuo Jianyong , Zhou Wei , Bao Jiaqi , Zhang Lincheng , Hong Jiachen , Xiang Jianan , Que Qingyang , Chen Kangchen , Xu Shengjun , Wang Jingrui , Zhu Yangbo , He Bin , Wu Jingbang , Xie Haiyang , Zheng Shusen , Feng Tingting , Ling Sunbin , Xu Xiao 
Published: September 2024

AbstractLenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.
Current topic of vascular function in hypertension in 2023–2024
Authors: Maruhashi Tatsuya , Higashi Yukihito 
Published: September 2024

AbstractNoninvasive tests of vascular function are useful for assessing the severity of atherosclerosis and risk of cardiovascular events, understanding the pathophysiology of cardiometabolic disorders, and investigating the effects of therapeutic interventions on cardiovascular morbidity and mortality, all of which can provide additional information for the management of patients with cardiovascular risk factors or a history of cardiovascular disease. In 2023–2024, many excellent articles on vascular function were published in Hypertension Research and other major cardiovascular and hypertension journals, and we summarize the emerging evidence on vascular function in this review. We hope that this review will be helpful for the management of patients with cardiovascular risk factors in clinical practice and for future basic and clinical research on vascular function.
A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination
Authors: Bai Qing , Shao Enhua , Ma Denglei , Jiao Binxuan , Scheetz Seth D. , Hartnett-Scott Karen A. , Ilin Vladimir A. , Aizenman Elias , Kofler Julia , Burton Edward A. 
Published: September 2024

AbstractProgressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/− mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.
Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children
Authors: Patel Harsita , Carter Michael J. , Jackson Heather , Powell Oliver , Fish Matthew , Terranova-Barberio Manuela , Spada Filomena , Petrov Nedyalko , Wellman Paul , Darnell Sarah , Mustafa Sobia , Todd Katrina , Bishop Cynthia , Cohen Jonathan M. , Kenny Julia , van den Berg Sarah , Sun Thomas , Davis Francesca , Jennings Aislinn , Timms Emma , Thomas Jessica , Nyirendra Maggie , Nichols Samuel , Estamiana Elorieta Leire , D’Souza Giselle , Wright Victoria , De Tisham , Habgood-Coote Dominic , Ramnarayan Padmanabhan , Tissières Pierre , Whittaker Elizabeth , Herberg Jethro , Cunnington Aubrey , Kaforou Myrsini , Ellis Richard , Malim Michael H. , Tibby Shane M. , Shankar-Hari Manu , Levin Michael ,   On behalf of the DIAMONDS Consortium, van den Berg Sarah , Estamiana Elorieta Leire 
Published: September 2024

AbstractSevere febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.
Intergenerational effects of a casino-funded family transfer program on educational outcomes in an American Indian community
Authors: Bruckner Tim A. , Bustos Brenda , Dodge Kenneth A. , Lansford Jennifer E. , Odgers Candice L. , Copeland William E. 
Published: September 2024

AbstractCash transfer policies have been widely discussed as mechanisms to curb intergenerational transmission of socioeconomic disadvantage. In this paper, we take advantage of a large casino-funded family transfer program introduced in a Southeastern American Indian Tribe to generate difference-in-difference estimates of the link between children’s cash transfer exposure and third grade math and reading test scores of their offspring. Here we show greater math (0.25 standard deviation [SD], p =.0148, 95% Confidence Interval [CI]: 0.05, 0.45) and reading (0.28 SD, p = .0066, 95% CI: 0.08, 0.49) scores among American Indian students whose mother was exposed ten years longer than other American Indian students to the cash transfer during her childhood (or relative to the non-American Indian student referent group). Exploratory analyses find that a mother’s decision to pursue higher education and delay fertility appears to explain some, but not all, of the relation between cash transfers and children’s test scores. In this rural population, large cash transfers have the potential to reduce intergenerational cycles of poverty-related educational outcomes.
Claustrum and dorsal endopiriform cortex complex cell-identity is determined by Nurr1 and regulates hallucinogenic-like states in mice
Authors: Mantas Ioannis , Flais Ivana , Masarapu Yuvarani , Ionescu Tudor , Frapard Solène , Jung Felix , Le Merre Pierre , Saarinen Marcus , Tiklova Katarina , Salmani Behzad Yaghmaeian , Gillberg Linda , Zhang Xiaoqun , Chergui Karima , Carlén Marie , Giacomello Stefania , Hengerer Bastian , Perlmann Thomas , Svenningsson Per 
Published: September 2024

AbstractThe Claustrum/dorsal endopiriform cortex complex (CLA) is an enigmatic brain region with extensive glutamatergic projections to multiple cortical areas. The transcription factor Nurr1 is highly expressed in the CLA, but its role in this region is not understood. By using conditional gene-targeted mice, we show that Nurr1 is a crucial regulator of CLA neuron identity. Although CLA neurons remain intact in the absence of Nurr1, the distinctive gene expression pattern in the CLA is abolished. CLA has been hypothesized to control hallucinations, but little is known of how the CLA responds to hallucinogens. After the deletion of Nurr1 in the CLA, both hallucinogen receptor expression and signaling are lost. Furthermore, functional ultrasound and Neuropixel electrophysiological recordings revealed that the hallucinogenic-receptor agonists’ effects on functional connectivity between prefrontal and sensorimotor cortices are altered in Nurr1-ablated mice. Our findings suggest that Nurr1-targeted strategies provide additional avenues for functional studies of the CLA.
High radiative forcing climate scenario relevance analyzed with a ten-million-member ensemble
Authors: Sarofim Marcus C. , Smith Christopher J. , Malek Parker , McDuffie Erin E. , Hartin Corinne A. , Lay Claire R. , McGrath Sarah 
Published: September 2024

AbstractDeveloping future climate projections begins with choosing future emissions scenarios. While scenarios are often based on storylines, here instead we produce a probabilistic multi-million-member ensemble of radiative forcing trajectories to assess the relevance of future forcing thresholds. We coupled a probabilistic database of future greenhouse gas emission scenarios with a probabilistically calibrated reduced complexity climate model. In 2100, we project median forcings of 5.1 watt per square meters (5th to 95th percentiles of 3.3 to 7.1), with roughly 0.5% probability of exceeding 8.5 watt per square meters, and a 1% probability of being lower than 2.6 watt per square meters. Although the probability of 8.5 watt per square meters scenarios is low, our results support their continued utility for calibrating damage functions, characterizing climate in the 22nd century (the probability of exceeding 8.5 watt per square meters increases to about 7% by 2150), and assessing low-probability/high-impact futures.
Mosquito salivary apyrase regulates blood meal hemostasis and facilitates malaria parasite transmission
Authors: Pala Zarna Rajeshkumar , Alves e Silva Thiago Luiz , Minai Mahnaz , Crews Benjamin , Patino-Martinez Eduardo , Carmona-Rivera Carmelo , Valenzuela Leon Paola Carolina , Martin-Martin Ines , Flores-Garcia Yevel , Cachau Raul E. , Muslinkina Liya , Gittis Apostolos G. , Srivastava Naman , Garboczi David N. , Alves Derron A. , Kaplan Mariana J. , Fischer Elizabeth , Calvo Eric , Vega-Rodriguez Joel 
Published: September 2024

AbstractThe evolution of hematophagy involves a series of adaptations that allow blood-feeding insects to access and consume blood efficiently while managing and circumventing the host’s hemostatic and immune responses. Mosquito, and other insects, utilize salivary proteins to regulate these responses at the bite site during and after blood feeding. We investigated the function of Anopheles gambiae salivary apyrase (AgApyrase) in regulating hemostasis in the mosquito blood meal and in Plasmodium transmission. Our results demonstrate that salivary apyrase, a known inhibitor of platelet aggregation, interacts with and activates tissue plasminogen activator, facilitating the conversion of plasminogen to plasmin, a human protease that degrades fibrin and facilitates Plasmodium transmission. We show that mosquitoes ingest a substantial amount of apyrase during blood feeding, which reduces coagulation in the blood meal by enhancing fibrin degradation and inhibiting platelet aggregation. AgApyrase significantly enhanced Plasmodium infection in the mosquito midgut, whereas AgApyrase immunization inhibited Plasmodium mosquito infection and sporozoite transmission. This study highlights a pivotal role for mosquito salivary apyrase for regulation of hemostasis in the mosquito blood meal and for Plasmodium transmission to mosquitoes and to the mammalian host, underscoring the potential for strategies to prevent malaria transmission.
Theoretical approaches for the description of plasmon generated hot carriers phenomena
Authors: Vanzan Mirko , Marsili Margherita 
Published: September 2024

AbstractPlasmonic-driven photocatalysis is one of the most vibrant and promising field in nanoscience. Out of the various mechanisms known to activate chemical reactions in molecules interacting with optically excited nanostructures, the one involving production and transfer of Hot Carriers (HCs) is among the most relevant. Over the past decade, along with stunning advances on HCs control and manipulation, a variety of theoretical and computational strategies have been developed to model this phenomenon and explore its underlying physics. These techniques have provided comprehensive understandings of HCs life stages and dynamics, and allowed valuable insights on their role in photocatalysis. However, to date it is hard to extricate within the plethora of methods developed and the growing number of applications they found. The purpose of this review is to survey the approaches employed so far to model HCs photophysics, rationalizing and classifying the different studies in terms of modelization, theoretical approaches, and approximations.
MEPO-ML: a robust graph attention network model for rapid generation of partial atomic charges in metal-organic frameworks
Authors: Luo Jun , Said Omar Ben , Xie Peigen , Gibaldi Marco , Burner Jake , Pereira Cécile , Woo Tom K. 
Published: September 2024

AbstractAccurate computation of the gas adsorption properties of MOFs is usually bottlenecked by the DFT calculations required to generate partial atomic charges. Therefore, large virtual screenings of MOFs often use the QEq method which is rapid, but of limited accuracy. Recently, machine learning (ML) models have been trained to generate charges in much better agreement with DFT-derived charges compared to the QEq models. Previous ML charge models for MOFs have all used training sets with less than 3000 MOFs obtained from the CoRE MOF database, which has recently been shown to have high structural error rates. In this work, we developed a graph attention network model for predicting DFT-derived charges in MOFs where the model was developed with the ARC-MOF database that contains 279,632 MOFs and over 40 million charges. This model, which we call MEPO-ML, predicts charges with a mean absolute error of 0.025e on our test set of over 27 K MOFs. Other ML models reported in the literature were also trained using the same dataset and descriptors, and MEPO-ML was shown to give the lowest errors. The gas adsorption properties evaluated using MEPO-ML charges are found to be in significantly better agreement with the reference DFT-derived charges compared to the empirical charges, for both polar and non-polar gases. Using only a single CPU core on our benchmark computer, MEPO-ML charges can be generated in less than two seconds on average (including all computations required to apply the model) for MOFs in the test set of 27 K MOFs.
Recent advances and challenges in single cell protein (SCP) technologies for food and feed production
Authors: Li Yu Pin , Ahmadi Fatemeh , Kariman Khalil , Lackner Maximilian 
Published: September 2024

AbstractThe global population is increasing, with a predicted demand for 1250 million tonnes of animal-derived protein by 2050, which will be difficult to meet. Single-cell protein (SCP) offers a sustainable solution. This review covers SCP production mechanisms, microbial and substrate choices, and advancements in metabolic engineering and CRISPR-Cas. It emphasizes second-generation substrates and fermentation for a circular economy. Despite challenges like high nucleic acid content, SCP promises to solve the global nutrition problem.
9,000 years of genetic continuity in southernmost Africa demonstrated at Oakhurst rockshelter
Authors: Gretzinger Joscha , Gibbon Victoria E. , Penske Sandra E. , Sealy Judith C. , Rohrlach Adam B. , Salazar-García Domingo C. , Krause Johannes , Schiffels Stephan 
Published: September 2024

AbstractSouthern Africa has one of the longest records of fossil hominins and harbours the largest human genetic diversity in the world. Yet, despite its relevance for human origins and spread around the globe, the formation and processes of its gene pool in the past are still largely unknown. Here, we present a time transect of genome-wide sequences from nine individuals recovered from a single site in South Africa, Oakhurst Rockshelter. Spanning the whole Holocene, the ancient DNA of these individuals allows us to reconstruct the demographic trajectories of the indigenous San population and their ancestors during the last 10,000 years. We show that, in contrast to most regions around the world, the population history of southernmost Africa was not characterized by several waves of migration, replacement and admixture but by long-lasting genetic continuity from the early Holocene to the end of the Later Stone Age. Although the advent of pastoralism and farming substantially transformed the gene pool in most parts of southern Africa after 1,300 bp, we demonstrate using allele-frequency and identity-by-descent segment-based methods that the ‡Khomani San and Karretjiemense from South Africa still show direct signs of relatedness to the Oakhurst hunter-gatherers, a pattern obscured by recent, extensive non-Southern African admixture. Yet, some southern San in South Africa still preserve this ancient, Pleistocene-derived genetic signature, extending the period of genetic continuity until today.
High-throughput drug screening identifies novel therapeutics for Low Grade Serous Ovarian Carcinoma
Authors: Pishas Kathleen I. , Cowley Karla J. , Llaurado-Fernandez Marta , Kim Hannah , Luu Jennii , Vary Robert , Bowden Nikola A. , Campbell Ian G. , Carey Mark S. , Simpson Kaylene J. , Cheasley Dane 
Published: September 2024

AbstractLow grade serous carcinoma (LGSOC) is a rare epithelial ovarian cancer with unique molecular characteristics compared to the more common tubo-ovarian high-grade serous ovarian carcinoma. Pivotal clinical trials guiding the management of epithelial ovarian cancer lack sufficient cases of LGSOC for meaningful subgroup analysis, hence overall findings cannot be extrapolated to rarer chemo-resistant subtypes such as LGSOC. Furthermore, there is a need for more effective therapies for the treatment of relapsed disease, as treatment options are limited. To address this, we conducted the largest quantitative high-throughput drug screening effort (n = 3436 compounds) in 12 patient-derived LGSOC cell lines and one normal ovary cell line to identify unexplored therapeutic avenues. Using a combination of high-throughput robotics, high-content imaging and novel data analysis pipelines, our data set identified 60 high and 19 moderate confidence hits which induced cancer cell specific cytotoxicity at the lowest compound dose assessed (0.1 µM). We also revealed a series of known (mTOR/PI3K/AKT) and novel (EGFR and MDM2-p53) drug classes in which LGSOC cell lines showed demonstrable susceptibility to.