bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
Authors: Alonso-Nocelo Marta , Ruiz-Cañas Laura , Sancho Patricia , Görgülü Kıvanç , Alcalá Sonia , Pedrero Coral , Vallespinos Mireia , López-Gil Juan Carlos , Ochando Marina , García-García Elena , David Trabulo Sara Maria , Martinelli Paola , Sánchez-Tomero Patricia , Sánchez-Palomo Carmen , Gonzalez-Santamaría Patricia , Yuste Lourdes , Wörmann Sonja Maria , Kabacaoğlu Derya , Earl Julie , Martin Alberto , Salvador Fernando , Valle Sandra , Martin-Hijano Laura , Carrato Alfredo , Erkan Mert , García-Bermejo Laura , Hermann Patrick C , Algül Hana , Moreno-Bueno Gema , Heeschen Christopher , Portillo Francisco , Cano Amparo , Sainz Bruno 
Published: April 2022

ObjectiveThe lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.DesignTowards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies,K-Ras+/LSL-G12D;Trp53LSL-R172H;Pdx1-Cremice (KPC) and theK-Ras+/LSL-G12D;Pdx1-Cremice (KC) were crossed withLoxl2allele floxed mice (Loxl2Exon2fl/fl) or conditionalLoxl2overexpressing mice (R26Loxl2KI/KI) to generate KPCL2KOor KCL2KOand KPCL2KIor KCL2KImice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.ResultsUsing these PDAC mouse models, we show that whileLoxl2ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling.Loxl2overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affectsOsmandLoxl2expression and collagen fibre alignment.ConclusionTaken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.
Diversity in clinical research: public health and social justice imperatives
Authors: Varma Tanvee , Jones Camara P , Oladele Carol , Miller Jennifer 
Published: April 2022

It is well established that demographic representation in clinical research is important for understanding the safety and effectiveness of novel therapeutics and vaccines in diverse patient populations. In recent years, the National Institutes of Health and Food and Drug Administration have issued guidelines and recommendations for the inclusion of women, older adults, and racial and ethnic minorities in research. However, these guidelines fail to provide an adequate explanation of why racial and ethnic representation in clinical research is important. This article aims to both provide the missing arguments for why adequate representation of racial and ethnic minorities in clinical research is essential and to articulate a number of recommendations for improving diversity going forward.Appropriate racial and ethnic representation and fair inclusion help (1) increase the generalisability of clinical trial results, (2) equitably distribute any benefits of clinical research and (3) enable trust in the research enterprise.
Poor clinical outcome despite successful basilar occlusion recanalization in the early time window: incidence and predictors
Authors: Pop Raoul , Finitsis Stephanos Nikolaos , Arquizan Caroline , Elhorany Mahmoud , Naggara Olivier , Darcourt Jean , Clarençon Frédéric , Richard Sébastien , Marnat Gaultier , Bourcier Romain , Sibon Igor , Dargazanli Cyril , Blanc Raphaël , Lapergue Bertrand , Consoli Arturo , Eugene Francois , Vannier Stephane , Caroff Jildaz , Denier Christian , Boulanger Marion , Gauberti Maxime , Rouchaud Aymeric , Macian Francisco , Rosso Charlotte , Turc Guillaume , Ozkul-Wermester Ozlem , Albucher Jean François , Le Bras Anthony , Evain Sarah , Wolff Valerie , Timsit Serge , Gentric Jean-Christophe , Bourdain Frédéric , Veunac Louis , Papagiannaki Chrysanthi , Gory Benjamin 
Published: April 2022

BackgroundEndovascular treatment (EVT) for basilar artery occlusions (BAO) is associated with a higher rate of futile recanalization compared with anterior circulation procedures. We aimed to identify the incidence and predictors of poor clinical outcome despite successful reperfusion in current clinical practice.MethodsWe used data from the ETIS (Endovascular Treatment in Ischemic Stroke) registry, a prospective multicenter observational registry of stroke treated with EVT in France. Patients undergoing EVT for acute BAO from January 2014 to May 2019 successfully treated within 8 hours from onset were included. Predictors of 90-day poor outcome (modified Rankin Scale (mRS) 4–6) were researched within patients with successful (modified Thrombolysis In Cerebral Infarction (mTICI 2b-3)) and excellent (mTICI 2c-3) reperfusion.ResultsAmong 242 patients treated within 8 hours, successful reperfusion was achieved in 195 (80.5%) and excellent reperfusion in 120 (49.5%). Poor outcome was observed in 107 (54.8%) and 60 (50%) patients, respectively. In patients with successful early reperfusion, age, higher initial National Institutes of Health Stroke Scale (NIHSS) score, lower posterior circulation Alberta Stroke Programme Early CT Score (pc-ASPECTS), and absence of prior intravenous thrombolysis were independent predictors of poor outcome. The only treatment factor with an independent predictive value was first-pass mTICI 2b-3 reperfusion (adjusted OR 0.13, 95% CI 0.05 to 0.37, p<0.001). In patients with excellent early reperfusion, independent predictors were age, initial NIHSS score, first-pass mTICI 2c-3 reperfusion, and hemorrhagic transformation on post-interventional imaging.ConclusionsEarly successful reperfusion with EVT occurred in 80.5% of patients, and the only treatment-related factor predictive of clinical outcome was first pass mTICI 2b-3 reperfusion. Further research is warranted to identify the optimal techniques and devices associated with first pass reperfusion in the posterior circulation.
Determinants of cerebral aneurysm occlusion after embolization with the WEB device: a single-institution series of 215 cases with angiographic follow-up
Authors: Cortese Jonathan , Caroff Jildaz , Chalumeau Vanessa , Gallas Sophie , Ikka Léon , Moret Jacques , Sabuzi Federico , Popescu Septimiu Daniel , Ozanne Augustin , Grimaldi Lamiae , Mihalea Cristian , Spelle Laurent 
Published: April 2022

BackgroundWoven EndoBridge (WEB) devices are becoming a reliable option for the treatment of wide-neck bifurcation aneurysms, but clear predictive factors are still missing to understand the one in five aneurysm remnant rate.ObjectiveTo evaluate occlusion outcomes after WEB treatment to identify potential determinants of aneurysm occlusion.MethodsA single-center database with consecutive aneurysms treated with WEB between July 2012 and October 2021 was reviewed for potential determinants of aneurysm adequate occlusion (defined as a Bicêtre Occlusion Scale Score (BOSS) of 0, 0’, 1 or 2), through univariate and multivariable analysis. Patients without angiographic follow-up were excluded.Results215 of 247 individual aneurysms were included in the final analysis, of which 59 (27%) were ruptured. Mean age of patients was 56 years (range 23–90 years) and 65% were female. Mean angiographic follow-up was at 18 months (range 3–97 months). Adequate and complete occlusion were achieved in 171/215 (79.5%) and 135/215 (62.8%) of cases, respectively. Aneurysm irregular shape (aOR=0.42, 95% CI 0.20 to 0.88; p=0.02), aneurysm height (aOR=0.79, 95% CI 0.66 to 0.94; p<0.01), and WEB shape modification (aOR=0.98, 95% CI 0.97 to 1.00; p=0.02) were all independent predictors of aneurysm recurrence, whereas the WEB oversizing ratio (WEB width/aneurysm mean width) (aOR=16.4, 95% CI 1.4 to 266.7; p=0.04) was an independent predictor of adequate occlusion.ConclusionIn this study we demonstrated that a width oversizing strategy of the WEB device was an independent predictor of aneurysm angiographic occlusion. Conversely, aneurysm height, irregular aneurysm, and WEB shape modification were all independent determinants of angiographic aneurysm remnant. These results may help to select aneurysms suitable for the WEB device and WEB sizing.
Pneumomediastinum in patients with COVID-19 undergoing CT pulmonary angiography: a retrospective cohort study
Authors: Baslas Rohit , Condurache Dorina-Gabriela , Jayal Ambikesh , Colquhoun Matthew , de Wolff Jacob Frederik 
Published: April 2022

Abstract

Background
Various complications have been reported in patients with COVID-19 including pneumomediastinum.

Methods
The primary objective of the study was to determine the incidence of pneumomediastinum in COVID-19 positive patients who underwent CT pulmonary angiography (CTPA). The secondary objectives were to analyse if the incidence of pneumomediastinum changed between March and May 2020 (peak of the first wave in the UK) and January 2021 (peak of the second wave in the UK) and to determine the mortality rate in patients with pneumomediastinum. We undertook an observational, retrospective, single-centre, cohort study of patients with COVID-19 admitted to Northwick Park Hospital.

Results
74 patients in the first wave and 220 patients in the second wave met the study criteria. Two patients during the first wave and eleven patients during the second wave developed pneumomediastinum.

Conclusions
The incidence of pneumomediastinum changed from 2.7% during the first wave to 5% during the second wave and this change was not statistically significant (p value 0.4057). The difference in mortality rates of patients with pneumomediastinum in both waves of COVID-19 (69.23%) versus patients without pneumomediastinum in both waves of COVID-19 (25.62%) was statistically significant (p value 0.0005). Many patients with pneumomediastinum were ventilated, which could be a confounding factor. When controlling for ventilation, there was no statistically significant difference in the mortality rates of ventilated patients with pneumomediastinum (81.81%) versus ventilated patients without pneumomediastinum (59.30%) (p value 0.14).
A multi-institutional prospective observational study to evaluate fascia iliaca compartment block (FICB) for preventing delirium in adults with hip fracture
Authors: Salottolo Kristin , Meinig Richard , Fine Landon , Kelly Michael , Madayag Robert , Ekengren Francie , Tanner Allen , Roman Phillip , Bar-Or David 
Published: April 2022

ObjectivesUntil recently, systemic opioids have been standard care for acute pain management of geriatric hip fracture; however, opioids increase risk for delirium. Fascia Iliaca compartment blocks (FICB) may be favored to systemic analgesia for reducing delirium, but this has not been well demonstrated. We evaluated the efficacy of adjunctive FICB versus systemic analgesia on delirium incidence, opioid consumption, and pain scores.MethodsThis prospective, observational cohort study was performed in patients (55–90 years) with traumatic hip fracture admitted to five trauma centers within 12 hours of injury, enrolled between January 2019 and November 2020. The primary end point was development of delirium, defined by the Confusion Assessment Method tool, from arrival through 48 hours postoperatively, and analyzed with multivariate Firth logistic regression. Secondary end points were analyzed with analysis of covariance models and included preoperative and postoperative oral morphine equivalents and pain numeric rating scale scores.ResultsThere were 517 patients enrolled, 381 (74%) received FICB and 136 (26%) did not. Delirium incidence was 5.4% (n=28) and was similar for patients receiving FICB versus no FICB (FICB, 5.8% and no FICB, 4.4%; adjusted OR: 1.2 (95% CI 0.5 to 3.0), p=0.65). Opioid requirements were similar for patients receiving FICB and no FICB, preoperatively (p=0.75) and postoperatively (p=0.51). Pain scores were significantly lower with FICB than no FICB, preoperatively (4.2 vs 5.1, p=0.002) and postoperatively (2.9 vs 3.5, p=0.04).ConclusionsFICB demonstrated significant benefit on self-reported pain but without a concomitant reduction in opioid consumption. Regarding delirium incidence, these findings suggest clinical equipoise and the need for a randomized trial.Level of evidenceII—prospective, therapeutic.
Superionic Lithium Argyrodite Electrolytes by Bromine-Doping for All-Solid-State Lithium Batteries
Authors: Zhang Zhichao , Tian Yongtao , Liu Gaozhan , Wu Ming , He Hao , Yao Xiayin 
Published: April 2022

High energy density all-solid-state rechargeable batteries with excellent safety are considered as reliable alternative to the current lithium-ion battery. The major challenge of all-solid-state rechargeable batteries is to develop new electrolyte material with high conductivity and good stability against lithium. In this work, the argyrodite electrolytes Li5.4PS4.4Cl1.6−x
Br
x
(0 ≤ x ≤ 0.8) are synthesized through wet-milling method. Benefit from higher concentration of Br and the lattice softening of crystal structure, Li5.4PS4.4Cl1.2Br0.4 electrolyte with the highest lithium ion conductivity of 8.17 mS cm−1 is realized. The Li/Li5.4PS4.4Cl1.2Br0.4/Li symmetric battery can stable cycle for 2500 h at 0.1 mA cm−2, showing favorable stability against lithium. The assembled LiCoO2/Li5.4PS4.4Cl1.2Br0.4/Li battery delivers an initial reversible capacity of 122.4 mAh g−1 with a capacity retention of 82.8% after 100 cycles. These results demonstrate a promising argyrodite electrolyte Li5.4PS4.4Cl1.2Br0.4 with high ionic conductivity and favorable electrochemical stability for all-solid-state lithium battery.
Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation
Authors: Sekar Divya , Dillmann Christina , Sirait-Fischer Evelyn , Fink Annika F. , Zivkovic Aleksandra , Baum Natalie , Strack Elisabeth , Klatt Stephan , Zukunft Sven , Wallner Stefan , Descot Arnaud , Olesch Catherine , da Silva Priscila , von Knethen Andreas , Schmid Tobias , Grösch Sabine , Savai Rajkumar , Ferreirós Nerea , Fleming Ingrid , Ghosh Sourav , Rothlin Carla V. , Stark Holger , Medyouf Hind , Brüne Bernhard , Weigert Andreas 
Published: April 2022

Abstract

An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylserine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk−/− mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk−/− TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation.

Significance:
This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine synthase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth.
PreclinicalIn VivoValidation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification
Authors: Pellegrino Benedetta , Herencia-Ropero Andrea , Llop-Guevara Alba , Pedretti Flaminia , Moles-Fernández Alejandro , Viaplana Cristina , Villacampa Guillermo , Guzmán Marta , Rodríguez Olga , Grueso Judit , Jiménez Jose , Arenas Enrique J. , Degasperi Andrea , Dias João M.L. , Forment Josep V. , O'Connor Mark J. , Déas Olivier , Cairo Stefano , Zhou Yinghui , Musolino Antonino , Caldas Carlos , Nik-Zainal Serena , Clarke Robert B. , Nuciforo Paolo , Díez Orland , Serres-Créixams Xavier , Peg Vicente , Espinosa-Bravo Martín , Macarulla Teresa , Oaknin Ana , Mateo Joaquin , Arribas Joaquín , Dienstmann Rodrigo , Bellet Meritxell , Oliveira Mafalda , Saura Cristina , Gutiérrez-Enríquez Sara , Balmaña Judith , Serra Violeta 
Published: April 2022

AbstractPARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies.Significance:This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin.
Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution
Authors: Wang Xiansong , Hu Wei , Li Xiangchun , Huang Dan , Li Qing , Chan Hung , Zeng Judeng , Xie Chuan , Chen Huarong , Liu Xiaodong , Gin Tony , Wang Maggie Haitian , Cheng Alfred Sze Lok , Kang Wei , To Ka-Fai , Plewczynski Dariusz , Zhang Qingpeng , Chen Xiaoting , Chan Danny Cheuk Wing , Ko Ho , Wong Sunny Hei , Yu Jun , Chan Matthew Tak Vai , Zhang Lin , Wu William Ka Kei 
Published: April 2022

Abstract

Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation.

Significance:
This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.
Understanding Drug Sensitivity and Tackling Resistance in Cancer
Authors: Tyner Jeffrey W. , Haderk Franziska , Kumaraswamy Anbarasu , Baughn Linda B. , Van Ness Brian , Liu Song , Marathe Himangi , Alumkal Joshi J. , Bivona Trever G. , Chan Keith Syson , Druker Brian J. , Hutson Alan D. , Nelson Peter S. , Sawyers Charles L. , Willey Christopher D. 
Published: April 2022

AbstractDecades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
Early Insights into Cancer Epigenetics: Gene Promoter Hypermethylation Emerges as a Potential Biomarker for Cancer Detection
Authors: Clark Susan J. , Molloy Peter L. 
Published: April 2022

Abstract
DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it plays an essential role in core biologic processes by assuring the proper regulation of gene expression and stable gene silencing. In cancer cells, genome-wide DNA methylation patterns are altered and often represent an early and fundamental step in neoplastic transformation. The landmark study from Esteller and colleagues, published in Cancer Research in 2001, was the first to reveal high frequency promoter methylation across multiple cancer types. They highlighted that widespread alterations in DNA methylation may be a key characteristic of oncogenesis and proposed aberrant DNA methylation of gene promoters could provide markers for sensitive detection of nearly all cancer types. The authors used a candidate gene approach to show promoter hypermethylation occurred across 12 cancer-associated genes in DNA from over 600 primary tumor samples, representing 15 major tumor types. The profile of promoter hypermethylation differed in every tumor type, suggesting that alterations in DNA methylation are pervasive, but the genes affected may be tumor-specific and impact multiple signaling pathways. Over the past 20 years since this publication, the cancer epigenetics field has exploded to generate thousands of normal and cancer methylome maps and developed sophisticated informatic tools for genome-wide methylome analyses. These methylomes are providing roadmaps for the study of cancer biology and discovery of DNA methylation biomarkers for early detection and monitoring of cancer.
See related article by Esteller and colleagues, Cancer Res 2001;61:3225–29.