bluuebunny/crossref_metadata_2025_split huggingface dataset:
YAP Regulates HER3 Signaling–Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers
Authors: Katayama Yuki , Yamada Tadaaki , Tanimura Keiko , Kawachi Hayato , Ishida Masaki , Matsui Yohei , Hirai Soichi , Nakamura Ryota , Morimoto Kenji , Furuya Naoki , Arai Sachiko , Goto Yasuhiro , Sakata Yoshihiko , Nishino Kazumi , Tsuchiya Michiko , Tamiya Akihiro , Saito Go , Muto Satoshi , Takeda Takayuki , Date Koji , Fujisaka Yasuhito , Watanabe Satoshi , Fujimoto Daichi , Uehara Hisanori , Horinaka Mano , Sakai Toshiyuki , Yano Seiji , Tokuda Shinsaku , Takayama Koichi 
Published: November 2024

Abstract

Purpose:
Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.

Experimental Design:
Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho–receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion–positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes.

Results:
In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion–positive lung cancer was associated with poor RET-TKI treatment outcomes.

Conclusions:
The YAP–HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.
Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability
Authors: Ma Nina , Wu Fangfang , Liu Jiayu , Wu Ziru , Wang Lu , Li Bochuan , Liu Yuming , Dong Xue , Hu Junhao , Fang Xi , Zhang Heng , Ai Ding , Zhou Jing , Wang Xiaohong 
Published: November 2024

BACKGROUND:
Atheroprotective shear stress preserves endothelial barrier function, while atheroprone shear stress enhances endothelial permeability. Yet, the underlying mechanisms through which distinct flow patterns regulate EC integrity remain to be clarified. This study aimed to investigate the involvement of Kindlin-2, a key component of focal adhesion and endothelial adherens junctions crucial for regulating endothelial cell (EC) integrity and vascular stability.

METHODS:

Mouse models of atherosclerosis in EC-specific
Kindlin-2
knockout mice (
Kindlin-2

iΔEC

) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (12±4 dynes/cm
2
) or oscillatory shear (0.5±4 dynes/cm
2
) were applied to culture ECs. Live-cell imaging, fluorescence recovery after photobleaching assay, and OptoDroplet assay were used to study the liquid-liquid phase separation (LLPS) of Kindlin-2. Co-immunoprecipitation, mutagenesis, proximity ligation assay, and transendothelial electrical resistance assay were used to explore the underlying mechanism of flow-regulated Kindlin-2 function.

RESULTS:

We found that Kindlin-2 localization is altered under different flow patterns.
Kindlin-2

iΔEC

mice showed heightened vascular permeability.
Kindlin-2

iΔEC

were bred onto
ApoE

−/−

mice to generate
Kindlin-2

iΔEC

;
ApoE

−

/−

mice, which displayed a significant increase in atherosclerosis lesions. In vitro data showed that in ECs, Kindlin-2 underwent LLPS, a critical process for proper focal adhesion assembly, maturation, and junction formation. Mass spectrometry analysis revealed that oscillatory shear increased arginine methylation of Kindlin-2, catalyzed by PRMT5 (protein arginine methyltransferase 5). Functionally, arginine hypermethylation inhibits Kindlin-2 LLPS, impairing focal adhesion assembly and junction maturation. Notably, we identified R290 of Kindlin-2 as a crucial residue for LLPS and a key site for arginine methylation. Finally, pharmacologically inhibiting arginine methylation reduces EC activation and plaque formation.

CONCLUSIONS:
Collectively, our study elucidates that mechanical force induces arginine methylation of Kindlin-2, thereby regulating vascular stability through its impact on Kindlin-2 LLPS. Targeting Kindlin-2 arginine methylation emerges as a promising hemodynamic-based strategy for treating vascular disorders and atherosclerosis.
Novel Adiposity Indices Are Associated With Poor Prognosis in Heart Failure With Preserved Ejection Fraction Without the Obesity Paradox
Authors: Zhang Shuai , Xu Panpan , Wei Tianhao , Wei Changjiang , Zhang Yanling , Lu Huixia , Zhang Cheng 
Published: November 2024

Background
There is limited study that illuminates the relationship between obesity indices and prognosis in patients with heart failure with preserved ejection fraction, nor has it been examined whether the obesity paradox persists when using these metrics.

Methods and Results

This study is a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. A total of 3114 individuals were included in our final analysis, and a total of 481 (15.4%) all‐cause deaths, and 389 (12.5%) heart failure hospitalizations were recorded. In a multivariable Cox regression model, compared with patients with a body mass index (BMI) <24.9 kg/m
2
, those with a BMI of 25.0–29.9, 30.0–34.9, and 35–39.9 kg/m
2
were associated with a decreased risk of all‐cause death, with hazard ratio (95% CI) of 0.59 (0.45–0.78), 0.61 (0.46–0.82), and 0.66 (0.47–0.92), respectively. Conversely, patients with a BMI ≥40 kg/m
2
showed an increased risk of heart failure hospitalization, compared with BMI <24.9 kg/m
2
. Furthermore, patients in the highest quintile of obesity indices exhibited a significantly elevated hazard ratio for both all‐cause death and heart failure hospitalization, compared with the lowest quintile.

Conclusions
An elevated BMI over a certain range was associated with a reduced risk of all‐cause death in heart failure with preserved ejection fraction, displaying a U‐shaped relationship, with no mortality reduction observed in cases of extreme obesity. In contrast, higher values of novel obesity indices were positively correlated with all‐cause death and heart failure hospitalization without the obesity paradox.
From Petersburg to Shipka via Mount Athos: Slavic Saints on the Shipka Iconostasis
Authors: Gergova Ivanka 
Published: November 2024

From Petersburg to Shipka via Mount Athos: Slavic Saints on the Shipka Iconostasis
The article explores the images of Slavic saints on the iconostasis of the Russian Memorial Church in the town of Shipka in Bulgaria, which were completed in 1899–1901 at the Russian Saint Panteleimon Monastery on Mount Athos. Its main objective is to analyze the iconostasis’s conceptual framework, the meanings behind the selection of the saints, as well as the main iconographical models utilized. The Committee for the Construction of the Memorial Church and its chairperson Count Nikolay Ignatyev conceived of one tier of images of saints depicting the heroes of the Russo-Turkish War of 1877–1878, while a number small icons would feature local Bulgarian and Slavic saints that were to be selected by the monks themselves. The icon painting monks mainly relied on Archbishop Philaret of Chernigov’s book The Saints of the Southern Slavs with engravings by academician Fedor Solntsev as the main source and model for their depictions of saints.

Z Petersburga do Szipki przez Górę Athos. Słowiańscy święci na ikonostasie w Szipce
Przedmiotem uwagi są wizerunki słowiańskich świętych na ikonostasie w Cerkwi pw. Narodzenia Pańskiego w Szipce w Bułgarii, które powstały w latach 1899–1901 w rosyjskim klasztorze św. Pantelejmona na Górze Athos. Celem artykułu jest analiza ram koncepcyjnych ikonostasu, znaczeń stojących za wyborem świętych, a także głównych wykorzystanych modeli ikonograficznych. Członkowie Komitetu ds. budowy świątyni upamiętniającej wydarzenia na przełęczy Szipka, wraz z przewodniczącym, hrabią Nikołajem Ignatjewem na czele, wymyślili rząd wizerunków świętych przedstawiających bohaterów wojny rosyjsko-tureckiej z lat 1877–1878. Kilka mniejszych ikon miało przedstawiać lokalnych bułgarskich i słowiańskich świętych, wybranych przez mnichów. Głównym źródłem i wzorcem dla tych przedstawień było dzieło arcybiskupa Filareta (Gumilewskiego) Święci południowosłowiańscy, zawierające ryciny Fiodora Sołncewa.
What Does One Need to Build a Bridge in Slovenia? Research on Slovenian Folk Tales, Games, Dances and Rituals Related to Bridge Construction and the Building Process
Authors: Olszewski Maciej Bolesław 
Published: November 2024

What Does One Need to Build a Bridge in Slovenia? Research on Slovenian Folk Tales, Games, Dances and Rituals Related to Bridge Construction and the Building Process
Human sacrifices and supernatural beings are the two most common motifs in folklore material related to bridge-building projects. This article is an attempt to deal with Slovenian folklore material that refers to the act of bridge building and to show which of these motifs seem to be closer to the Slovenian tradition. To achieve this goal, I present examples of Slovenian folktales, dances, games and other folk culture texts. I also highlight the root causes that potentially resulted in the prevalence of one of these motifs.

Czego potrzeba, by zbudować most w Słowenii? Badania nad słoweńskimi tekstami ludowymi, grami, tańcami i rytuałami związanymi z budowaniem mostów i procesem budowy
Ofiary zakładzinowe i istoty nadprzyrodzone to dwa motywy najczęściej pojawiające się w tekstach kultury ludowej dotyczących budowania mostów. Artykuł stanowi próbę omówienia słoweńskiego materiału folklorystycznego związanego z budową mostów i pokazania, który z tych motywów wydaje się bliższy słoweńskiej tradycji. W tym celu przedstawiam przykłady zaczerpnięte z zachowanych podań ludowych, gier, tańców i innych tekstów kultury ludowej. Zwracam również uwagę na przyczyny mogące powodować przewagę w częstotliwości występowania jednego z motywów.
Benzodiazepine use and incident risk of sudden cardiac arrest in patients with cardiovascular diseases
Authors: Mo Chunbao , Wang Shuang , Li Xia , Li Furong , Jin Cheng , Bai Bo , Pei Haolong , Zheng Jing , Liang Fengchao 
Published: November 2024

Background Benzodiazepines (BZDs) are commonly prescribed as adjunctive drugs for patients with cardiovascular diseases (CVDs), particularly those who experience anxiety or insomnia. However, the relationship between the use of BZDs and incident risk of sudden cardiac arrest (SCA) has not been well investigated. In this study, we aimed to examine the association between the use of BZDs and the incident risk of SCA among patients with CVD. Method In this retrospective cohort study, a total of 74,715 eligible patients with new-onset CVD as a primary cause of hospitalization between July 2016 and August 2022 were included from the health information platform in Shenzhen, China. Among them, 61,761 BZD non-initiators were identified and matched to 12,954 BZD initiators by propensity score at a maximum ratio of 5:1. Propensity score-matched Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results Over a 12-month follow-up period, 29 (2.24 per 1000 person-years) and 137 (2.22 per 1000 person-years) SCA cases occurred among propensity score-matched BZD initiators and non-initiators, respectively. Patients who initiated BZD treatment were associated with a 101% increased risk of SCA incidence compared with patients without BZD treatment (adjusted HR: 2.01, 95% CI: 1.42, 2.83). Furthermore, compared with the non-use (0 defined daily dose, DDD), the adjusted HR was 1.43 (95% CI: 1.32, 1.56) for the BZD consumption of ≤1 DDD and 2.58 (95% CI: 2.37, 2.81) for the BZD consumption of >1 DDD ( P for trend < 0.001) within a 12-month follow-up period. Conclusion This study provides evidence that BZD initiation may be associated with an increased incident risk of SCA in patients with CVD. Our finding highlights the importance of cautious prescribing BZDs in the health management of patients with CVD.
The safety of cell saver washing all shed mediastinal blood before re-transfusing it to the patient
Authors: Scicluna Sara , Dencker Magnus , Bjursten Henrik 
Published: November 2024

Introduction Cardiotomy suction blood is used in cardiopulmonary bypass (CPB) surgery to maintain blood volume in the CPB system, although it is known to contain micro emboli, cytokines and free plasma hemoglobin. Our aim was to investigate whether cell saver washing the cardiotomy suction blood before re-transfusing it is safe. Methods This is a retrospective study of 1671 elective coronary artery bypass patients, 209 of whom had their pericardial blood processed in a cell saver (Ce-S group). PS matching was performed with patients who had their pericardial blood returned back to the CPB-system by the cardiotomy suction (Ca-S group). Perioperative transfusion requirements, surgical outcome, postoperative lab data and mortality were then compared. Results There were no differences in baseline characteristics or EuroSCORE between the groups. The number of patients requiring transfusions did not differ, but the patients in the Ca-S group received more platelets (0.34 ± 1.0 vs 0.16 ± 0.7 units, p = .03) than in the Ce-S group. CRP (c-reactive protein) levels at day 2 and 4 were higher in the Ca-S group (174.8 ± 67.2 and 148.9 ± 74.3 mg/L vs 160.1 ± 64.6 and 125.9 ± 67.2 mg/L, p = .03, p = .002) and so were ASAT (aspartate aminotransferase) levels (0.97 ± 0.8 vs 0.81 ± 0.6 μkat/L, p = .03). Mortality, postoperative ventilation time, stroke, mediastinal infections and length of stay in the ICU were the same in both groups. Conclusions In this retrospective study of patients undergoing elective CABG surgery, washing the cardiotomy suction blood before re-transfusion was not associated with higher risk of allogenic blood transfusion, postoperative stroke, mediastinal infections, or 30- and 365-days mortality. Clinical registration number LU EPN 2016/4.
Risk factors for positive cervical cytology during early pregnancy screening and awareness of positive cytological results in Japan: a report from the Pregnant Women Health Initiative
Authors: Ushio Emiko , Mizushima Taichi , Sukegawa Akiko , Saigusa Yusuke , Kurasawa Kentaro , Iwata Akiko , Aoki Shigeru , Ueda Yutaka , Sekine Masayuki , Miyagi Etsuko 
Published: November 2024

Objective Cervical cancer screening rates are low in Japan. Therefore, when a woman is pregnant, this is a good opportunity to visit an obstetrics and gynecology clinic to have cervical cytology. This study aimed to clarify the association between cervical cancer screening and the management of pregnant women’s health. Methods We prospectively examined the relationships between cervical cytological results during prenatal checkups and the following factors: participant’s background, cytological sampling instruments, and awareness of cytological results. Results Of the 2725 participants, 71 showed abnormal results defined as atypical squamous cells of undetermined significance or higher grade (ASC-US+). ASC-US+ detection rates were higher in smokers, younger participants, those with a low education, those without cancer screening in the past 2 years, and those who received cytology using a spatula or brush. A multivariable logistic regression analysis identified smoking (adjusted odds ratio: 2.99 [95% confidence interval: 1.41–6.33]) and a spatula/brush (adjusted odds ratio: 2.46 [95% confidence interval: 1.09–5.53]) as independent variables associated with detecting ASC-US+. Among the participants, 39.4% (28/71) self-reported “no abnormalities,” despite obtaining an ASC-US+ result. Conclusions Pre-pregnancy smoking and cytological sampling tools may contribute to detecting ASC-US+. Patients with detected abnormalities need accurate information and reliable follow-up.
Low Lesion Clearance Rates in Neurocysticercosis: Is It Time to Review Guidelines?
Authors: Barman Prabal , Sankhyan Naveen , Suthar Renu , Vyas Sameer , Saini Lokesh , Saini Arushi , Sahu Jitendra K 
Published: November 2024

Background The standard treatment guidelines of neurocysticercosis have been described as per computed tomography (CT)–based studies. We aimed to prospectively study if posttreatment magnetic resonance imaging (MRI) clearance rates of neurocysticercosis were like those reported in literature using CT. Methods A prospective observational study in newly diagnosed children with neurocysticercosis was undertaken. Children were treated with antihelminthics and steroids and followed up after 6 months. The primary objective was to study the proportion of children with single-lesion neurocysticercosis who were in radiologic resolution at 6 months and clinical remission (seizure-free for the preceding 3 months). Results Eighty of 128 consecutive children screened were included (single lesion, 65; multiple lesions, 15). Seventy-two children were evaluated at 6 months. Seizure recurrence was seen in 5 (6.2%). Brain MRI showed an overall clearance of lesions in 10 (14%) children. In the children with single-lesion neurocysticercosis (65), 59 were followed up at 6 months, and lesions resolved in 9 (15.3%, 95% confidence interval of 6.1-24.4). Conclusions In children with single-lesion neurocysticercosis treated with antihelminthics and corticosteroids, the lesion resolution rate is only 15% at 6 months. Thus, there is a need to review old recommendations and use MRI as a standard outcome measure.
A 14-Year Analysis of Breast Cancer Risk Factors and Its Determinants of Mortality in Rural Southwestern Nigeria
Authors: Ibrahim Azeez Oyemomi , Omonijo Adetunji , Agbesanwa Tosin Anthony , Alabi Ayodele Kamal , Elegbede Olayide Toyin , Olusuyi Kolawole Michael , Yusuf Musah , Afolabi-Obe Eniola Ayoyemi , Erinomo Olagoke , Babalola Olakunle Fatai , Abiyere Henry , Orewole Olayinka Tesleem , Aremu Shuaib Kayode 
Published: November 2024

Background: Research on breast cancer risk factors and mortality is gaining recognition and attention globally; there is need to add more information on its determinants among patients admitted in hospital. Some studies on risk factors and mortality of breast cancer in Nigeria hospitals conducted in the urban and suburban areas have been documented. Therefore, an addition of a study conducted in the setting of a rural health institution is necessary. This study assessed the risk factors and determinants of mortality among patients admitted for breast cancer in rural Southwestern Nigeria. Methods: A retrospective observational study was conducted on 260 patients who were admitted for breast cancer between January 2010 and December 2023 using a data form and a standardized information form. The data were analyzed using SPSS version 22.0. The risk factors and the determinants of mortality of patients with breast cancer were identified using multivariate regression model. Results: The breast cancer risk factors were old age, family history, tobacco smoking, combined oral contraceptives, and hormonal therapy use. The case fatality rate was 38.1%, and its determinants of mortality were patients who were older (adjusted odds ratio [AOR], 1.956; 95% confidence interval [CI]:1.341-4.333), obese (AOR, 2.635; 95% CI: 1.485-6.778), stage IV (AOR, 1.895; 95% CI: 1.146-8.9742), mastectomy (AOR, 2.512; 95% CI: 1.003-6.569), discontinued adjuvant chemotherapy (AOR, 1.785; 95% CI: 1.092-4.6311), and yet to commence adjuvant chemotherapy (AOR, 2.568; 95% CI: 1.367-5.002). Conclusion: The study revealed that patients with breast cancer were associated with high mortality. Sustained health education to promote early diagnosis, managed co-morbidities, and access to treatment may contribute to reduction in breast cancer mortality in rural Nigeria.
Intra-Articular Injection of Human Umbilical Cord-Derived Mesenchymal Stromal Cells Reduces Radiographic Osteoarthritis in an Ovine Model
Authors: Perry Jade , Mennan Claire , Cool Paul , McCarthy Helen S. , Newell Karin , Hopkins Timothy , Hulme Charlotte , Wright Karina T. , Henson Frances M.D. , Roberts Sally 
Published: November 2024

Objective To determine if mesenchymal stromal cells (MSCs) derived from human umbilical cords (hUC) could reduce degeneration developing when injected into the knee of a large animal model of osteoarthritis (OA). Design Ten million culture-expanded UC-MSCs (pooled from 3 human donors) were injected in 50 μL of tissue culture medium into the left stifle joints of 7 sheep whose medial meniscus was transected 4 weeks previously. Seven other sheep had only 50 μL of medium injected as the no treatment “control” group. After 8 weeks the sheep underwent euthanasia, the joints were excised and examined macroscopically, via x-ray and magnetic resonance imaging (MRI), both via histology for degenerative and inflammatory changes and immunohistochemically to identify any human cells within the joint tissues. Activity monitoring both before meniscus transection and euthanasia was also undertaken. Results There was a significant reduction in the Kellgren–Lawrence x-ray score for joints injected with hUC-MSCs compared with the control joints. Likewise, macroscopic, MRI, synovitis and OARSI histology scores were all lower (better) in the joints injected with hUC-MSCs than in the control arm, but not significantly. Activity levels and synovitis scores were similar in both groups of animals. Conclusions hUC-MSCs appear to modify and reduce the development of osteoarthritic changes in the ovine stifle joint after meniscal destabilization, an injury which commonly leads to OA in humans. These results are encouraging for the potential benefit of culture expanded UC-MSCs as an allogeneic cell therapy in patients who may have early OA following a meniscal injury of the knee.