bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current status of cancer genome medicine for pancreatic ductal adenocarcinoma
Authors: Doi Toshifumi , Ishikawa Takeshi , Moriguchi Michihisa , Itoh Yoshito 
Published: February 2025

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden–high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.
Validation of five prognostic models treated with axitinib beyond first-line nivolumab plus ipilimumab therapy for metastatic renal cell carcinoma: a Japanese multicenter retrospective study
Authors: Kikuchi Hiroshi , Osawa Takahiro , Matsushita Yuto , Kojima Takahiro , Sazuka Tomokazu , Hatakeyama Shingo , Goto Keisuke , Numakura Kazuyuki , Yamana Kazutoshi , Kandori Shuya , Ueda Kosuke , Tanaka Hajime , Kurahashi Toshifumi , Bando Yukari , Kimura Takahiro , Nishiyama Naotaka , Kato Takuma , Hara Hiroaki , Ito Yoichi , Kitamura Hiroshi , Miyake Hideaki , Shinohara Nobuo 
Published: February 2025

Abstract

Objective
To validate multiple prognostic models in metastatic renal cell carcinoma patients who received second-line axitinib following first-line nivolumab plus ipilimumab therapy.

Methods
Five prognostic models (ACL, albumin, C-reactive protein, and lactate dehydrogenase; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC, Memorial Sloan Kettering Cancer Center; ATP, axitinib treatment prediction; JMRC, Japanese metastatic renal cancer) to predict overall survival (OS) were validated and compared using data from 86 metastatic renal cell carcinoma patients who received second-line axitinib therapy following first-line nivolumab plus ipilimumab therapy at 34 hospitals affiliated with the Japan Urologic Oncology Group.

Results
The Karnofsky performance status, time from initial diagnosis to first-line therapy, and hemoglobin, platelet, albumin, and C-reactive protein levels correlated with OS in univariate Cox regression analyses. Among these factors, only albumin had a significant impact on OS in the multivariate analysis. The integrated area under the curve (AUC) of the ACL, IMDC, MSKCC, ATP, and JMRC models were 0.78, 0.76, 0.76, 0.69, and 0.70, respectively. The ACL model showed a higher value than the others in the time-dependent AUC.

Conclusions
The accuracy of the five prognostic models (ACL, IMDC, MSKCC, ATP, and JMRC) created in the pre–immuno-oncology (IO) treatment cohort was maintained in the second-line axitinib group after nivolumab plus ipilimumab therapy. The ACL model demonstrated moderate accuracy in predicting OS with the fewest number of clinical variables.
Real-world clinical usage and efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer: a multi-institutional study in the CsJUC
Authors: Tohi Yoichiro , Kobayashi Keita , Daizumoto Kei , Sekino Yohei , Fukuhara Hideo , Niigawa Heima , Katayama Satoshi , Shimizu Ryutaro , Takamoto Atsushi , Nishimura Kenichi , Nagami Taichi , Hayashida Yushi , Hirama Hiromi , Shiraishi Koji , Tomida Ryotaro , Kobatake Kohei , Inoue Keiji , Miyaji Yoshiyuki , Bekku Kensuke , Morizane Shuichi , Miura Noriyoshi , Wada Koichiro , Sugimoto Mikio ,   Chu-shikoku Japan Urological Consortium, Inoue Keiji , Yamamoto Shinkuro , Shiraishi Koji , Miyaji Yoshiyuki , Hinata Nobuyuki , Furukawa Junya , Araki Motoo , Kawada Tatsushi , Takenaka Atsushi , Saika Takashi , Wada Koichiro , Tohi Yoichiro , Kato Takuma , Naito Hirohito , Fukuhara Hideo , Kobayashi Keita , Ohira Shin , Daizumoto Kei , Sasaki Yutaro , Tomida Ryotaro , Katayama Satoshi , Shimizu Ryutaro , Nishimura Kenichi , Watanabe Ryuta , Nagami Taichi , Takamoto Atsushi , Niigawa Heima , Sekino Yohei , Kobatake Kohei , Sugimoto Mikio 
Published: February 2025

Abstract

Objective
To evaluate the real-world clinical usage and effectiveness of apalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Methods
We retrospectively reviewed the data of 186 men who received apalutamide across 17 institutions. The primary outcomes were the clinical usage of apalutamide for nmCRPC: prior usage of other androgen receptor signaling inhibitors (ARSIs), prior radical treatment, and the distribution of the prostate-specific antigen (PSA) doubling time (PSA-DT) at the initial administration of apalutamide. The secondary outcomes were the efficacy of apalutamide: PSA response (50% or 90% decline), progression-free survival, and skin-adverse events (AEs).

Results
We identified 75 patients with nmCRPC. A total of 31 (41.3%) patients received prior treatment with other ARSIs. A total of 42 men (56%) did not receive any prior radical treatment. The PSA-DT was &lt;3.0, 3.0–5.9, 6.0–10, and &gt; 10 months in 34.7%, 40%, 14.7%, and 10.6% of the patients, respectively. Patients receiving prior treatment with other ARSIs showed a significantly lower PSA response (PSA 50% decline, 88.4% vs. 18.8%; PSA 90% decline, 60.5% vs. 6.2%, P &lt; .001, respectively) and significantly shorter progression-free survival (median: 37 months vs. 4 months; log-rank P &lt; .001) than those without prior ARSI treatment, although cancer status did not differ between the groups. Skin-AEs were observed in 42.7%.

Conclusions
This real-world study revealed that apalutamide was used for the treatment after other ARSIs in &gt;40% of patients with nmCRPC and showed limited efficacy in this context, although the effectiveness of apalutamide without prior other ARSI treatment was comparable with that reported in clinical trial results.
Celebrating World Neglected Tropical Diseases Day: A Global Call to Unite, Act, and Eliminate Neglected Tropical Diseases
Authors: Wilder-Smith Annika B , Fuller L C , Parajuli Niraj 
Published: February 2025

Abstract
World Neglected Tropical Diseases (NTD) Day on January 30th, with the theme ‘Unite. Act. Eliminate.’, emphasizes the global fight against NTDs, underlining efforts to address the inequalities that perpetuate NTDs. This article explores the milestones and calls for sustained collaboration to achieve a healthier, more equitable future for vulnerable populations.
The single-berry metabolomic clock paradigm reveals new stages and metabolic switches during grapevine berry development
Authors: Tavernier Flora , Savoi Stefania , Torregrosa Laurent , Hugueney Philippe , Baltenweck Raymonde , Segura Vincent , Romieu Charles 
Published: February 2025

Abstract
Asynchronicity causes metabolic chimerism in usual grapevine phenological stages, calling for a revisit of berry development at the individual fruit scale. To reveal the dynamics of metabolite composition in grapevine berries without phenological a priori, a dataset of 9,256 ions was obtained on 125 fruits at different stages by non-targeted ultra-performance liquid chromatography coupled to high-resolution mass spectrometry. This large metabolomic dataset was submitted to an analysis workflow combining classification and dimension reduction tools. This led to the clustering of metabolites into 12 specific kinetic patterns and a metabolome-based definition of the pericarp intrinsic clock outperforming expert timing procedures. Such increased temporal resolution enabled the identification of metabolite clusters that are annunciative of the onset of ripening, noticeably characterized by transient lipidic changes and the start of ABA accumulation. We also highlighted a cluster of stilbenes that accumulate during terminal fruit shriveling, after the arrest of phloem unloading. This non-targeted approach enables a more precise characterization of grapevine berry development through the concept of metabolomic clock. The discovery of new metabolic milestones of berry development paves the way toward a better assessment of the impact of environmental changes on the metabolism of non-climacteric fruit, in different genotypes.
Red deer resequencing reveals the importance of sex chromosomes for reconstructing Late Quaternary events
Authors: de Jong Menno J , Anaya Gabriel , Niamir Aidin , Pérez-González Javier , Broggini Camilla , Membrillo del Pozo Alberto , Nebenfuehr Marcel , de la Peña Eva , Ruiz-Olmo Jordi , Seoane Jose Manuel , Vedel Giovanni , Barboiron Aurelie , Bartoš Luděk , Buzan Elena , Carden Ruth F , Darchiashvili Giorgi , Dragan Gačić , Frantz Alain C , Gérard Adrien , Gort-Esteve Araceli , Guillaumat Etienne , Hantschmann Anja , Hemami Mahmoud-Reza , Höglund Jacob , de Jong Joost F , Kerdikoshvili Niko , Kern Christian , Konjevic Dean , Koubek Petr , Karaiskou Nikoleta , Pellerin Maryline , Krojerová-Prokešová Jarmila , McDevitt Allan D , Merker Stefan , Pfenninger Markus , Røed Knut H , Saint-Andrieux Christine , Sarigol Fatih , Sykut Maciej , Triantafyllidis Alexandros , Pemberton Josephine , Saarma Urmas , Iacolina Laura , Niedziałkowska Magdalena , Zachos Frank E , Carranza Juan , Janke Axel 
Published: February 2025

Abstract
Sex chromosomes differ in their inheritance properties from autosomes, and hence may encode complementary information about past demographic events. We compiled and analysed a range-wide resequencing dataset of the red deer (Cervus elaphus), one of the few Eurasian herbivores of the Late Pleistocene megafauna still found throughout much of its historic range. Our analyses of 144 whole genomes reveal striking discrepancies between the population clusters suggested by autosomal and X-chromosomal data. We postulate that the genetic legacy of Late Glacial population structure is better captured and preserved by the X chromosome than by autosomes, for two reasons. First, X chromosomes have a lower Ne and hence lose genetic variation faster during isolation in glacial refugia, causing increased population differentiation. Second, following postglacial recolonisation and secondary contact, immigrant males pass on their X chromosomes to female offspring only, which effectively halves the migration rate when gene flow is male-mediated. Our study illustrates how a comparison between autosomal and sex chromosomal phylogeographic signals unravels past demographic processes which otherwise would remain hidden.
Are women with disabilities more at risk of intimate partner violence?
Authors: Hervé Justine , Theiss Katherine , Mitra Sophie 
Published: February 2025

Abstract
Women with disabilities may face heightened risks of intimate partner violence (IPV) given the discrimination and barriers they face in society. While some country-specific studies explore the link between disability and IPV, cross-country research remains limited. Using internationally comparable data for women aged 15–49 from eleven countries (Cambodia, Haiti, Kenya, Mali, Mauritania, Pakistan, Rwanda, Senegal, South Africa, Timor-Leste, and Uganda), we assess whether women with disabilities consistently face higher IPV risks. Controlling for socioeconomic and demographic factors, women with disabilities have a 6-percentage-point higher risk of IPV compared to those without (P &lt; .05) in the pooled sample. At the country level, this association is significant in five countries. The link between disability and IPV also varies by type, with stronger associations for severe physical IPV (seven countries) and weaker associations for sexual IPV (two countries). Logit decomposition analysis in the five countries where the disability gap in exposure to IPV is significant shows that observed differences in characteristics account for part of the gap. However, unobserved factors, such as stigma, also play a significant role in driving the disparity. Additionally, our results suggest that the lack of consistent findings across countries may result from data limitations, such as small sample sizes, measurement errors, and reporting biases. This underscores the importance of developing evidence-based approaches to better measure disability and IPV in household surveys.
Layover start timing predicts layover sleep quantity and timing on Long-Range and Ultra-Long-Range trips
Authors: Rempe Michael J , Rasmussen Ian , Gregory Kevin , Johnson Cheyenne , Hsin Matthew , Flynn-Evans Erin , Hilditch Cassie J , Lamp Amanda 
Published: February 2025

Abstract

Study Objectives
Airline pilot sleep during layover is an important factor for alertness on subsequent flights. Assessing pilots’ sleep on layover is an important first step in helping them obtain the most recuperative sleep possible on layover. Here we investigate the quantity and timing of sleep during layovers and determine predictors for layover sleep.

Methods
Sleep was assessed in 256 pilots flying a total of 473 long-range (LR; flight time 12-16h) or ultra-long-range (ULR; flight time &gt; 16h) trips. Sleep was assessed using actigraphy. We employed linear mixed-effects models with layover sleep characteristics as the outcomes. The predictor variables included operational factors and sleep history.

Results
Overall, pilots averaged 7.2 hours of sleep per 24 hours of layover, which was significantly less than their daily sleep before or after the trip. Layover start time (relative to home base time) was the most salient predictor of sleep timing and quantity during both shorter (∼24-h) and the first 24h of longer (∼48-h) layovers. During the last 24h of longer layovers, crew type predicted sleep quantity.

Conclusions
Although average sleep quantity during layovers was within the margins of recommended sleep duration, it was still less than pre- and post-trip sleep duration, suggesting modest sleep loss on layovers. Layover start timing was the strongest predictor of layover sleep quantity and timing and, thus, may be a modifiable factor to protect circadian-aligned sleep opportunities during layover.
Local urothelial cell-driven detrusor contractions
Authors: Alom Firoj , Ratcliff Kyle Joseph , Mickle Aaron D 
Published: February 2025

AbstractSignaling molecules released from the urothelium by mechanical stretch are known to play a sensory role in bladder contractions via neuronal signaling. It is also theorized that these molecules released from the urothelium could act locally to induce urothelial cell-mediated local bladder contractions. In this study, we specifically stimulated the urothelial cells using optogenetics to investigate how the urothelial released signaling molecules can influence bladder contractions locally. Using anex-vivowhole bladder preparation, we stimulated the urothelial cells by activating channelrhodopsin-2 (ChR2) with blue light and initiated the urothelial cell-mediated local bladder contractions. The P2X receptor antagonist, PPADS, nearly abolished the contractions. The muscarinic receptor antagonist, atropine, significantly inhibited the contractions. Nifedipine, which blocks extracellular Ca2+entry, abolished the contractions. G protein-coupled receptor inhibitor YM-254890 significantly inhibited the contractions. Hemichannel inhibitor carbenoxolone disodium and the exocytotic pathway of transmitter release inhibitor brefeldin A also showed significant inhibition of the contractions. In conclusion, we validated the previous hypothesis that urothelial release factors can influence bladder contractions locally without the need for signaling from the central nervous system. Further studies are needed to determine the relevance of this signaling pathway in normal bladder physiology and pathophysiologic conditions.
B cell subsets have different capacities for phagocytosis and subsequent presentation of antigen to cognate T cells
Authors: Morelli Daniel M , Langille Morgan , Zhang Richard , Craig Heather C , Shooshtari Parisa , Heit Bryan , Kerfoot Steven M 
Published: February 2025

AbstractB cells have been shown to be phagocytic under some circumstances. However, the phagocytic capacity of different B cell subsets and how this is linked to Antigen (Ag) presentation or other functions has not been characterized. To address this, we developed 2 µm phagocytic Ag conjugated bead targets that target phagocytic pathways including the BCR, scavenger, Fc, and complement receptors to study potential pathways by which B cells phagocytose both cognate and non-cognate Ags. We found that while follicular B2 (Fo B), marginal zone, and B1 B cells are highly phagocytic of BCR-engaging targets through their BCR, only peritoneal cavity B1 cells could uptake non-cognate Ag-coated beads or bacteria. Despite this, B1 cells were not effective at presenting Ag to activate cognate T cells or at killing phagocytosed bacteria. Finally, analysis of scRNA-seq data revealed that these differences in phagocytic capacity could not be explained by differential expression of relevant phagocytic receptors, implying that there is likely some form of regulation in place preventing non-cognate Ag uptake by Fo B cells. Our work will help contribute to a better understanding of non-classical Ag uptake mechanisms employed by B cells and their relevance to inflammation.
ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis
Authors: Kennedy Benjamin B. , Raza Mohsin , Mirza Sameer , Rajan Asher Rajkumar , Oruji Farshid , Storck Matthew M. , Lele Subodh M. , Reznicek Timothy E. , Li Lusheng , Rowley M. Jordan , Wan Shibiao , Mohapatra Bhopal C. , Band Hamid , Band Vimla 
Published: February 2025

ABSTRACTThe ecdysoneless (ECD) mRNA and protein are overexpressed in breast cancer (BC), and its overexpression correlates with poor prognosis and short patient survival, particularly in ERBB2/HER2-positive BC. This study investigates the co-operative oncogenic mechanism of ECD and ERBB2 by deriving transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under MMTV promoter, as well as human mammary immortal epithelial cell lines (hMECs) overexpressing ECD and/or ERBB2. WhilehuHER2Tg mice developed more homogenous solid nodular carcinomas, double transgenic mice (ECD;huHER2Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, likeECDTg tumors, resembling more to patient tumors. Importantly, transcriptomic profile ofECD;huHER2Tg tumors revealed upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis. Similarly, hMECs expressing both ECD and ERBB2 as compared to single gene expressing cells showed increase in oncogenic traits, and RNA-seq analysis showed a significant upregulation of glycolysis and UPR pathways. ECD is an RNA binding protein, and directly associates with three key glycolytic enzymes (LDHA,PKM2andHK2) and mRNA of a major UPR regulated gene GRP78, that results in increased mRNA stability. Lastly, we show an increase in glucose uptake and enhanced glycolytic rate in ECD+ERBB2-overexpressing cells as compared to ECD− or ERBB2-overexpressing hMECs. Taken together, our findings support a co-operative role of ECD and ERBB2 in oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis.SignificanceThis study provides mechanistic insights that overexpression of ECD in ERBB2+ breast cancer patients correlates with shorter patient survival, by identifying direct ECD binding to mRNAs for UPR and glycolysis pathways.
Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2
Authors: Makrides Neoklis , Sun Emily , Mir Hilal , Jiang Ziyuan , Wu Yihua , Serra Carlos , Cardoso Wellington V , Shah Neel H. , Zhang Xin 
Published: February 2025

AbstractSHP2, a protein tyrosine phosphatase (PTP) crucial in Ras-MAPK signaling, is associated with various human congenital diseases and cancers. Here, we show that the catalytically inactiveShp2C459Smutation results in communicating hydrocephalus, similar to the catalytically activatingShp2E76KandMek1DDmutants. Unlike previous mutants, however,Shp2C459S/+mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed thatSHP2C459S, SHP2E76KandSHP2C459S/E76Kmutations all induce an open SHP2 conformation, but onlySHP2C459Sleads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues ofShp2C459S/+mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype inShp2C459Smice can be mitigated by allosteric inhibition of Shp2. These findings suggest thatShp2-associated hydrocephalus is driven by conformational changes rather than altered catalytic activity. Our results underscore the therapeutic potential of conformation-specific allosteric inhibitors in targeting both catalytically active and inactiveSHP2mutants.
A small lipidated peptide targeting NaV1.8 channels attenuates osteoarthritic pain behavior and prevents bone erosion
Authors: Rodriguez Raider , Kuechle Joseph B. , Bhattacharjee Arin 
Published: February 2025

AbstractChronic pain is a major concern for patients with osteoarthritis (OA). Current treatments for OA-related pain often fail and may worsen the disease. The sodium channel subtype NaV1.8 has emerged as a potential target for treating pain, leading to the development of NaV1.8 inhibitors in clinical trials. We previously identified Magi-1, a WW domain-containing scaffold protein, as a regulator of NaV1.8 at the plasma membrane of nociceptive neurons. Disrupting the interaction between NaV1.8 and Magi-1 facilitated channel degradation in neurons, reducing pain behavior in multiple animal models. In this study, we investigated the impact of disrupting NaV1.8 scaffolding on an animal model of OA pain using genetic and pharmacological approaches. Genetic Magi-1 knockdown effectively attenuated established OA pain in mice. Pharmacological targeting of the NaV1.8-Magi-1 interaction in rats with a lipidated NaV1.8 WW binding domain decoy peptide inhibited pain behavior for multiple weeks. MicroCT imaging revealed minimal alterations in subchondral bone remodeling in animals injected with the lipidated decoy peptide compared to those receiving scrambled peptide-control animals. This suggested that the NaV1.8 peptidomimetic not only alleviated OA pain but also delayed joint degeneration. Our preclinical studies indicate that intraarticular injection of lipidated peptides capable of disrupting ion channel scaffolding in neurons can provide effective and sustained analgesia for several weeks after a single administration.