bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical Stress Signaling in Pancreatic Cancer Cells Triggers p38 MAPK- and JNK-Dependent Cytoskeleton Remodeling and Promotes Cell Migration via Rac1/cdc42/Myosin II
Authors: Kalli Maria , Li Ruxuan , Mills Gordon B. , Stylianopoulos Triantafyllos , Zervantonakis Ioannis K. 
Published: November 2021

AbstractAdvanced or metastatic pancreatic cancer is highly resistant to existing therapies, and new treatments are urgently needed to improve patient outcomes. Current studies focus on alternative treatment approaches that target the abnormal microenvironment of pancreatic tumors and the resulting elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a proteomic assay to profile mechanical stress–induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and myosin II. In addition, mechanical stress upregulated transcription factors associated with epithelial-to-mesenchymal transition and stimulated the formation of stress fibers and filopodia. p38 MAPK and JNK inhibition resulted in lower cell proliferation and more effectively blocked cell migration under mechanical stress compared with control conditions. The enhanced tumor cell motility under mechanical stress was potently reduced by cdc42 and Rac1 silencing with no effects on proliferation. Our results highlight the importance of targeting aberrant signaling in cancer cells that have adapted to mechanical stress in the tumor microenvironment, as a novel approach to effectively limit pancreatic cancer cell migration.Implications:Our findings highlight that mechanical stress activated the p38 MAPK and JNK signaling axis and stimulated pancreatic cancer cell migration via upregulation of the actin cytoskeleton remodelers cdc42 and Rac1.
Chk1 Inhibition Potently Blocks STAT3 Tyrosine705 Phosphorylation, DNA-Binding Activity, and Activation of Downstream Targets in Human Multiple Myeloma Cells
Authors: Zhou Liang , Pei Xinyan , Zhang Yu , Ning Yanxia , Li Lin , Hu Xiaoyan , Chalasani Sri Lakshmi , Sharma Kanika , Nkwocha Jewel , Yu Jonathan , Bandyopadhyay Dipankar , Sebti Said M. , Grant Steven 
Published: November 2021

Abstract

The relationship between the checkpoint kinase Chk1 and the STAT3 pathway was examined in multiple myeloma cells. Gene expression profiling of U266 cells exposed to low (nmol/L) Chk1 inhibitor [PF-477736 (PF)] concentrations revealed STAT3 pathway-related gene downregulation (e.g., BCL-XL, MCL-1, c-Myc), findings confirmed by RT-PCR. This was associated with marked inhibition of STAT3 Tyr705 (but not Ser727) phosphorylation, dimerization, nuclear localization, DNA binding, STAT3 promoter activity by chromatin immunoprecipitation assay, and downregulation of STAT-3-dependent proteins. Similar findings were obtained in other multiple myeloma cells and with alternative Chk1 inhibitors (e.g., prexasertib, CEP3891). While PF did not reduce GP130 expression or modify SOCS or PRL-3 phosphorylation, the phosphatase inhibitor pervanadate antagonized PF-mediated Tyr705 dephosphorylation. Significantly, PF attenuated Chk1-mediated STAT3 phosphorylation in in vitro assays. Surface plasmon resonance analysis suggested Chk1/STAT3 interactions and PF reduced Chk1/STAT3 co-immunoprecipitation. Chk1 CRISPR knockout or short hairpin RNA knockdown cells also displayed STAT3 inactivation and STAT3-dependent protein downregulation. Constitutively active STAT3 diminished PF-mediated STAT3 inactivation and downregulate STAT3-dependent proteins while significantly reducing PF-induced DNA damage (γH2A.X formation) and apoptosis. Exposure of cells with low basal phospho-STAT3 expression to IL6 or human stromal cell conditioned medium activated STAT3, an event attenuated by Chk1 inhibitors. PF also inactivated STAT3 in primary human CD138+ multiple myeloma cells and tumors extracted from an NSG multiple myeloma xenograft model while inhibiting tumor growth.

Implications:
These findings identify a heretofore unrecognized link between the Chk1 and STAT3 pathways and suggest that Chk1 pathway inhibitors warrant attention as novel and potent candidate STAT3 antagonists in myeloma.
Bemcentinib and Gilteritinib Inhibit Cell Growth and Impair the Endo-Lysosomal and Autophagy Systems in an AXL-Independent Manner
Authors: Zdżalik-Bielecka Daria , Kozik Kamila , Poświata Agata , Jastrzębski Kamil , Jakubik Marta , Miączyńska Marta 
Published: November 2021

Abstract

AXL, a receptor tyrosine kinase from the TAM (TYRO3 AXL and MER) subfamily, and its ligand growth arrest-specific 6 (GAS6) are implicated in pathogenesis of a wide array of cancers, acquisition of resistance to diverse anticancer therapies and cellular entry of viruses. The continuous development of AXL inhibitors for treatment of patients with cancer and COVID-19 underscores the need to better characterize the cellular effects of AXL targeting.

In the present study, we compared the cellular phenotypes of CRISPR–Cas9-induced depletion of AXL and its pharmacological inhibition with bemcentinib, LDC1267 and gilteritinib. Specifically, we evaluated GAS6–AXL signaling, cell viability and invasion, the endo-lysosomal system and autophagy in glioblastoma cells. We showed that depletion of AXL but not of TYRO3 inhibited GAS6-induced phosphorylation of downstream signaling effectors, AKT and ERK1/2, indicating that AXL is a primary receptor for GAS6. AXL was also specifically required for GAS6-dependent increase in cell viability but was dispensable for viability of cells grown without exogenous addition of GAS6. Furthermore, we revealed that LDC1267 is the most potent and specific inhibitor of AXL activation among the tested compounds. Finally, we found that, in contrast to AXL depletion and its inhibition with LDC1267, cell treatment with bemcentinib and gilteritinib impaired the endo-lysosomal and autophagy systems in an AXL-independent manner.

Implications:
Altogether, our findings are of high clinical importance as we discovered that two clinically advanced AXL inhibitors, bemcentinib and gilteritinib, may display AXL-independent cellular effects and toxicity.
Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study
Authors: Uson Junior Pedro LS , Kunze Katie L. , Golafshar Michael A. , Riegert-Johnson Douglas , Boardman Lisa , Borad Mitesh J. , Ahn Daniel , Sonbol Mohamad B. , Faigel Douglas O. , Fukami Norio , Pannala Rahul , Barrus Kathleen , Mountjoy Luke , Esplin Edward D. , Nussbaum Robert L. , Stewart A. Keith , Bekaii-Saab Tanios , Samadder N. Jewel 
Published: November 2021

Abstract

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a &gt;80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers.

Prevention Relevance:
Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.
Sex Differences in Cumulative Exposure to Metabolic Risk Factors Before Hypertension Onset: The Cohort of the Tehran Lipid and Glucose Study
Authors: Ramezankhani Azra , Azizi Fereidoun , Momenan Amir Abbas , Hadaegh Farzad 
Published: November 2021

Background
Previous studies have shown a sex difference in the association between hypertension and cardiovascular disease; however, the precise mechanism remains unclear. Because there are strong associations between metabolic risk factors (MRFs) and hypertension, a sex‐specific analysis of MRFs before hypertension onset could offer new insights and expand our understanding of sex differences in cardiovascular disease. We evaluated cumulative exposure to major MRFs and rate of change of those factors, including body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, triglycerides, and high‐density lipoprotein cholesterol among individuals who did and did not develop hypertension at follow‐up.

Methods and Results
We included 5374 participants (2191 men) initially without hypertension with age range of 20–50 years at baseline who participated in the Tehran Lipid and Glucose Study, and had been examined at least 3 times during the study period (1999–2018). In both sexes, the cumulative exposure to all MRFs (except for fasting plasma glucose and high‐density lipoprotein cholesterol in men) were higher in those who developed hypertension, compared with those who did not develop hypertension. However, women experienced greater cumulative exposure to major MRFs, compared with their male counterparts. Also, they experienced a faster increase in waist circumference, systolic blood pressure, diastolic blood pressure, and high‐density lipoprotein cholesterol than men. Furthermore, rapid increase in systolic blood pressure began earlier in women than men, at the age of 30 years. We also found that those men who developed hypertension experienced unfavorable change in major MRFs during young adulthood (<50 years of age).

Conclusions
Women exhibited more metabolic disturbances than men before onset of hypertension, which may explain the stronger impact of hypertension for major types of cardiovascular disease in women, compared with men.
Atrial Fibrillation in Patients With Cardiomyopathy: Prevalence and Clinical Outcomes From Real‐World Data
Authors: Buckley Benjamin J. R. , Harrison Stephanie L. , Gupta Dhiraj , Fazio‐Eynullayeva Elnara , Underhill Paula , Lip Gregory Y. H. 
Published: November 2021

Background
Cardiomyopathy is a common cause of atrial fibrillation (AF) and may also present as a complication of AF. However, there is a scarcity of evidence of clinical outcomes for people with cardiomyopathy and concomittant AF. The aim of the present study was therefore to characterize the prevalence of AF in major subtypes of cardiomyopathy and investigate the impact on important clinical outcomes.

Methods and Results
A retrospective cohort study was conducted using electronic medical records from a global federated health research network, with data primarily from the United States. The TriNetX network was searched on January 17, 2021, including records from 2002 to 2020, which included at least 1 year of follow‐up data. Patients were included based on a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy and concomitant AF. Patients with cardiomyopathy and AF were propensity‐score matched for age, sex, race, and comorbidities with patients who had a cardiomyopathy only. The outcomes were 1‐year mortality, hospitalization, incident heart failure, and incident stroke. Of 634 885 patients with cardiomyopathy, there were 14 675 (2.3%) patients with hypertrophic, 90 117 (7.0%) with restrictive, and 37 685 (5.9%) with dilated cardiomyopathy with concomitant AF. AF was associated with significantly higher odds of all‐cause mortality (odds ratio [95% CI]) for patients with hypertrophic (1.26 [1.13–1.40]) and dilated (1.36 [1.27–1.46]), but not restrictive (0.98 [0.94–1.02]), cardiomyopathy. Odds of hospitalization, incident heart failure, and incident stroke were significantly higher in all cardiomyopathy subtypes with concomitant AF. Among patients with AF, catheter ablation was associated with significantly lower odds of all‐cause mortality at 12 months across all cardiomyopathy subtypes.

Conclusions
Findings of the present study suggest AF may be highly prevalent in patients with cardiomyopathy and associated with worsened prognosis. Subsequent research is needed to determine the usefulness of screening and multisdisciplinary treatment of AF in this population.
Metabolic Factors Mediate the Association Between Serum Uric Acid to Serum Creatinine Ratio and Cardiovascular Disease
Authors: Wang Anxin , Tian Xue , Wu Shouling , Zuo Yingting , Chen Shuohua , Mo Dapeng , Luo Yanxia , Wang Yongjun 
Published: November 2021

Background
The serum uric acid/serum creatinine ratio (SUA/SCr), which represents renal function‐normalized SUA, is associated with diverse adverse outcomes. The aim of this study was to investigate the association between SUA/SCr and cardiovascular disease (CVD), and determine whether and to what extent this association is mediated by cardiometabolic factors.

Methods and Results
This prospective study enrolled 96 378 participants from the Kailuan study without stroke and myocardial infarction at baseline (2006). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses were conducted to separately explore the mediating effects of cardiometabolic factors on the association between SUA/SCr and CVD. During median follow up of 11.01 years, 6315 (6.55%) individuals developed incident CVD. After adjustment for potential confounders, the highest quartile of SUA/SCr was associated with the highest risk of CVD (HR, 1.15; 95% CI, 1.07–1.23), stroke (HR, 1.16; 95% CI, 1.07–1.26), ischemic stroke (HR, 1.12; 95% CI, 1.02–1.22), and hemorrhagic stroke (HR, 1.36; 95% CI, 1.11–1.65), but not with myocardial infarction (HR, 1.07; 95% CI, 0.92–1.25). The association was consistent across different degrees of kidney function and glucose tolerance statuses. Additionally, the association between high SUA/SCr and CVD was partially mediated by triglycerides (30.74%), body mass index (BMI) (19.52%), total cholesterol (15.06%), hs‐CRP (high‐sensitivity C‐reactive protein) (13.06%), diastolic blood pressure (11.75%), and blood glucose (−16.38%).

Conclusions
SUA/SCr and CVD were positively associated. Furthermore, this association was partially mediated through blood lipids, BMI, blood pressure, hs‐CRP, and blood glucose.
Lectotypification of names of three species of Poa (Poaceae) and their morphological affinities
Authors: BHADRA RUMA , PRASANNA P. V. , NASKAR SAIKAT 
Published: November 2021

Poa aitchisonii, P. falconeri and P. wardiana are lectotypified with nomenclatural notes. In absence of proper icons with analysis, worked out plant parts of two species from voucher specimens are provided as photoplates. Due to high degree of variability and in absence of concrete morphological features to distinguish species, morphological affinities of the three species with that of other close species are provided.
Desert Climate Regionalization for Joshua Tree National Park and Surrounding Areas Using New Climate Network Observations
Authors: Heintzman Ryan , Balling Robert C. , Cerveny Randall S. 
Published: November 2021

Abstract
A new amalgamation of weather stations in and around Joshua Tree National Park in southeastern California has allowed for objective climate analysis regionalization at a much finer scale than past studies. First, it sets a baseline for many regions within the park’s boundaries that were not subject to direct observations. Second, these new observations are key to understanding shifting microclimate regimes in a desert ecosystem prone to the effects of climate change. Principal component analysis was used to regionalize the climate network based on monthly temperature and precipitation climate observations and standardized anomalies. Both the observation values and standardized climate anomalies identified regional boundaries. In general, these boundaries align with traditional ideas and past studies of the Mojave and Sonoran Deserts based on elevation (specifically the 1000-m contour) for the National Park Service. Standardized anomaly values identified a boundary based on seasonal precipitation, whereas observation values identified a boundary based on elevation. The boundary line within the park is similar for both data approaches, with the boundary running along the higher western one-third of the park. Conversely, the two methods differ significantly in the Coachella Valley, where low elevations and low precipitation meet winter-dominated seasonal precipitation. This study highlights the importance and opportunity of field observations to create climatological and ecological regionalization, and it also constructs a baseline to monitor and manage shifting desert regions in the future.

Significance Statement
This study identifies a high-resolution climate boundary zone in Joshua Tree National Park between the Sonoran and Mojave Deserts. The new transition zone presents the seasonal and elevational temperature and precipitation components of the two deserts, connecting with the unique ecology of the deserts. This finding highlights just one study opportunity of new field observation networks in arid or topographically diverse regions. It also provides a baseline for climate change as a resource for environmental management groups to better understand and preserve our natural spaces.
Trauma Computed Tomography in the Modern Era: Not Always Quick and Safe
Authors: Ghafil Cameron , Matsushima Kazuhide , Chiba Hiroto , Wu Renqing , Shin Heeseop , Menchine Michael , Inaba Kenji 
Published: November 2021

Background Computed tomography (CT) has emerged as the diagnostic modality of choice in trauma patients. Recent studies suggest its use in hemodynamically unstable patients is safe and potentially lifesaving; however, the incidence of adverse events (AE) during the trauma CT scanning process remains unknown. Study Design Over a 6-month period at a Level 1 trauma center, data on patients undergoing trauma CT (whole-body CT (WBCT) +/− additional CT studies) were prospectively collected. All patients requiring a trauma team activation (TTA) were included. Adverse events and specific time intervals were recorded from the time of TTA notification to the time of return to the resuscitation bay from the CT suite. Results Of the 94 consecutive patients included in the study, 47.9% experienced 1 or more AE. Median duration away from the resuscitation bay for all patients was 24 minutes. Patients with AE spent a significantly longer time away from the resuscitation bay and had longer scan times. Vasopressor support and ongoing transfusion requirement at the time of CT scanning were associated with AE. Conclusion Adverse events of varying clinical significance occur frequently in patients undergoing emergent trauma CT. A standard trauma CT protocol could improve the efficiency and safety of the scanning process.
Increased Risk of Postpartum Depression in Women With Allergic Rhinitis During Pregnancy: A Population-Based Case-Control Study
Authors: Yang Zhi-Chao , Wang Li-Xin , Yu Yang , Lin Huan-Yu , Shih Liang-Chun 
Published: November 2021

Objectives: Allergic rhinitis (AR) is associated with increased risk of major depression in the general population, however, no previous study has evaluated its role among pregnant women. We aimed to investigate the potential impact of AR during pregnancy on the development of postpartum depression (PPD). Methods: This is a population-based case-control study. Data were retrieved from the National Health Insurance Research Database (NHIRD). Medical records of a total of 199 470 deliveries during 2000 and 2010 were identified. Among which, 1416 women with PPD within 12 months after delivery were classified as the case group, while 198 054 women without PPD after delivery formed the control group. Univariate and multivariate regression analyses were conducted to determine the associations between AR during pregnancies and other study variables with PPD. Results: AR during pregnancy was found in 9.53% women who developed PPD and 5.44% in women without PPD. After adjusting for age at delivery, income level, various pregnancy and delivery-related conditions, asthma, atopic dermatitis and other medical comorbidities in the multivariate analysis, AR was significantly associated with increased odds of PPD (aOR: 1.498, 95% CI: 1.222-1.836). Conclusion: AR during pregnancy was independently and significantly associated with an approximately 50% increased risk of PPD among women giving birth. Closely monitoring of AR is warranted in the future in order to optimize mother and child outcomes after delivery.
Value of preoperative three-dimensional planning software (AI-HIP) in primary total hip arthroplasty: a retrospective study
Authors: Ding Xuzhuang , Zhang Bingshi , Li Wenao , Huo Jia , Liu Sikai , Wu Tao , Han Yongtai 
Published: November 2021

Objective We performed a retrospective study to compare the accuracy of preoperative planning using three-dimensional AI-HIP software and traditional two-dimensional manual templating to predict the size and position of prostheses. The purpose of this study was to evaluate the accuracy of AI-HIP in preoperative planning for primary total hip arthroplasty. Methods In total, 316 hips treated from April 2019 to June 2020 were retrospectively reviewed. A typical preoperative planning process for patients was implemented to compare the accuracy of the two preoperative planning methods with respect to prosthetic size and position. Intraclass correlation coefficients (ICCs) were used to evaluate the homogeneity between the actual prosthetic size and position and the preoperative planning method. Results When AI-HIP software and manual templating were used for preoperative planning, the stem agreement was 87.7% and 58.9%, respectively, and the cup agreement was 94.0% and 65.2%, respectively. The results showed that when AI-HIP software was used, an extremely high level of consistency (ICC > 0.95) was achieved for the femoral stem size, cup size, and femoral osteotomy level (ICC = 0.972, 0.962, and 0.961, respectively). Conclusion AI-HIP software showed excellent reliability for predicting the component size and implant position in primary total hip arthroplasty.