bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetylated HOXB13 Regulated Super Enhancer Genes Define Therapeutic Vulnerabilities of Castration-Resistant Prostate Cancer
Authors: Nguyen Duy T. , Yang Wei , Renganathan Arun , Weimholt Cody , Angappulige Duminduni H. , Nguyen Thanh , Sprung Robert W. , Andriole Gerald L. , Kim Eric H. , Mahajan Nupam P. , Mahajan Kiran 
Published: July 2022

AbstractPurpose:Androgen receptor (AR) antagonism is exacerbated by HOXB13 in castration-resistant prostate cancers (CRPC). However, it is unclear when and how HOXB13 primes CRPCs for AR antagonism. By mass-spectrometry analysis of CRPC extract, we uncovered a novel lysine 13 (K13) acetylation in HOXB13 mediated by CBP/p300. To determine whether acetylated K13-HOXB13 is a clinical biomarker of CRPC development, we characterized its role in prostate cancer biology.Experimental Design:We identified tumor-specific acK13-HOXB13 signal enriched super enhancer (SE)-regulated targets. We analyzed the effect of loss of HOXB13K13-acetylation on chromatin binding, SE proximal target gene expression, self-renewal, enzalutamide sensitivity, and CRPC tumor growth by employing isogenic parental and HOXB13K13A mutants. Finally, using primary human prostate organoids, we evaluated whether inhibiting an acK13-HOXB13 target, ACK1, with a selective inhibitor (R)-9b is superior to AR antagonists in inhibiting CRPC growth.Results:acK13-HOXB13 promotes increased expression of lineage (AR, HOXB13), prostate cancer diagnostic (FOLH1), CRPC-promoting (ACK1), and angiogenesis (VEGFA, Angiopoietins) genes early in prostate cancer development by establishing tumor-specific SEs. acK13-HOXB13 recruitment to key SE-regulated targets is insensitive to enzalutamide. ACK1 expression is significantly reduced in the loss of function HOXB13K13A mutant CRPCs. Consequently, HOXB13K13A mutants display reduced self-renewal, increased sensitivity to enzalutamide, and impaired xenograft tumor growth. Primary human prostate tumor organoids expressing HOXB13 are significantly resistant to AR antagonists but sensitive to (R)-9b.Conclusions:In summary, acetylated HOXB13 is a biomarker of clinically significant prostate cancer. Importantly, PSMA-targeting agents and (R)-9b could be new therapeutic modalities to target HOXB13–ACK1 axis regulated prostate cancers.
Microsatellite Instability–High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles
Authors: Manning-Geist Beryl L. , Liu Ying L. , Devereaux Kelly A. , Paula Arnaud Da Cruz , Zhou Qin C. , Ma Weining , Selenica Pier , Ceyhan-Birsoy Ozge , Moukarzel Lea A. , Hoang Timothy , Gordhandas Sushmita , Rubinstein Maria M. , Friedman Claire F. , Aghajanian Carol , Abu-Rustum Nadeem R. , Stadler Zsofia K. , Reis-Filho Jorge S. , Iasonos Alexia , Zamarin Dmitriy , Ellenson Lora H. , Lakhman Yulia , Mandelker Diana L. , Weigelt Britta 
Published: July 2022

Abstract

Purpose:
Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph).

Experimental Design:
Of &gt; 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses.

Results:
Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P &lt; 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P &lt; 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively).

Conclusions:
MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.
Combined Performance of Fecal Immunochemical Tests and a Genetic Risk Score for Advanced Neoplasia Detection
Authors: Niedermaier Tobias , Guo Feng , Weigl Korbinian , Hoffmeister Michael , Brenner Hermann 
Published: July 2022

Abstract

Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer–screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in colorectal cancer screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared with using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with AN (colorectal cancer or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated on the basis of the number of risk alleles in 140 SNPs. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%–80%. Both FITs showed similar performance characteristics with pAUCs of 0.661 (95% confidence interval (CI), 0.625–0.698; Ridascreen Hemoglobin) and 0.682 (95% CI, 0.661–0.701; FOB Gold) for AN detection. PRS alone reached a pAUC of 0.524 (95% CI, 0.499–0.550) and 0.530 (95% CI, 0.516–0.545), respectively, and its addition to FIT did not improve pAUCs (0.659; 95% CI, 0.622–0.697) and 0.667 (95% CI, 0.650–0.687), respectively. This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90%, and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic colorectal cancer screening population from South-Western Germany.

Prevention Relevance:
In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.
Risk of device-related thrombosis following short-term oral anticoagulation with low-dose dabigatran versus warfarin after Watchman left atrial appendage occlusion
Authors: Ge Heng , Zhang Chi , Qiao Zhi-Qing , Hao Zi-Yong , Li Zheng , Gu Zhi-Chun , Jiang Li-Sheng , He Ben , Pu Jun 
Published: July 2022

Background: Percutaneous left atrial appendage occlusion (LAAO) provides an alternative for poor candidates for long-term oral anticoagulation (OAC). To prevent device-related thrombosis (DRT), OAC should be continued for the first 45 days to allow complete endothelialization post-LAAO implantation. Whereas, evidence is limited on the feasibility and safety of direct oral anticoagulants (DOACs) used after LAAO. Methods: This was a retrospective observational single-center study of AF patients undergoing LAAO with a Watchman device and receiving either low-dose dabigatran (110mg twice daily) or warfarin in the peri- and post-procedural period for 45 days. Transesophageal echocardiography was scheduled to perform at 6 weeks, 6 months, and 12 months after the procedure to assess the stability of the device and to detect DRT. Incidence of thromboembolic and bleeding events were also evaluated during the follow-up period. Results: There were a total of 84 patients who successfully underwent Watchman implantation, with 38 patients (45.2%) receiving low-dose dabigatran and 46 patients (54.8%) using warfarin post-LAAO. Peri-procedural complications occurred in 10 patients, with 3 patients in the dabigatran group and 7 patients in the warfarin group (7.9% vs. 15.2%, p = 0.30). During the 12-month follow-up, 1 patient experienced major bleeding and 16 patients suffered minor bleeding in the warfarin group, while 5 patients treated with dabigatran had minor bleeding (34.8% vs. 13.2%, p = 0.02). Besides, 6 DRT (15.8%) were detected in dabigatran groups, and the incidence was higher than in the warfarin group (15.8% vs. 2.2%, p = 0.03). No DRT-related ischemic events were found. Conclusions: This study suggested that short-term low-dose dabigatran (110 mg twice daily) could significantly decrease the risk of bleeding compared with warfarin at the expense of increased risk of DRT post-LAAO. Therefore, low-dose dabigatran should be used with caution for post-implant anticoagulation of LAAO. Further studies are urgently needed on the feasibility and safety of DOACs post-LAAO.
Management for lower limb malperfusion in acute type a aortic dissection patients
Authors: Qin Wei , Wang Jiankai , Huang Fuhua , Chen Xin 
Published: July 2022

Objective Acute type A aortic dissection (ATAAD) accompanied with lower limb malperfusion (LLM) is considered to be a catastrophic event, and remains a great challenge for cardiac surgeons. Here we introduce our experience in treating ATAAD patients accompanied with LLM. Methods 61 patients diagnosed with ATAAD accompanied by LLM enrolled in this study. All patients received aortic repair (Total-arch replacement or Hemi-arch replacement) as soon as possible on admission. Patients who still suffered LLM were performed extra-anatomic bypass using artificial vessels. All the discharged patients underwent the standard follow-up protocol. Results 38 patients (38/61, 62.3%) got satisfied reperfusion of the lower limbs after aortic repair while the others did not. Five patients had femorofemoral bypass, 16 received aortofemoral bypass, and two underwent aortofemoral bypass plus femorofemoral bypass. The ICU stay time was 5.4 ± 3.6 days. Fifty-five patients were discharged home successfully, while six patients died postoperatively with hospital mortality of 9.8%. Major postoperative complications included acute kidney injury requiring hemodialysis in seven patients, delayed wake-up (>3 days) in 5, prolonged ventilation (>4 days) in 8, and lower limb ischaemia in 1. Follow-up was successfully conducted in 50 patients with a mean follow-up time 4.9 ± 2.6 years. Five patients died during the follow-up. The estimated 5-year survival rate was 87.5 ± 6.1%. CTA images showed 100% patency of the extra-anatomic bypass. Conclusion Aortic repair plus concomitant extra-anatomic bypass grafting in one operative setting could be a simple, safe and effective treatment on ATAAD patients with LLM.
Causes of death in low-grade B-cell lymphomas in the rituximab era: a prospective cohort study
Authors: Tun Aung M. , Khurana Arushi , Mwangi Raphael , Link Brian K. , Wang Yucai , Feldman Andrew L. , Thompson Carrie A. , Novak Anne J. , Villasboas Jose C. , Thanarajasingam Gita , Farooq Umar , Syrbu Sergei , Nowakowski Grzegorz S. , Witzig Thomas E. , Ansell Stephen M. , Rimsza Lisa M. , Cerhan James R. , Habermann Thomas M. , Maurer Matthew J. 
Published: July 2022

Abstract
Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non–lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P &lt; .001), whereas the rates for non–lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.
Skin/muscle incision and retraction regulates the persistent postoperative pain in rats by the Epac1/PKC-βII pathway
Authors: Qian Jiashu , Lin Xuezheng , Zhou Zhili 
Published: July 2022

AbstractPersistent postoperative pain causes influence the life quality of many patients. The Epac/PKC pathway has been indicated to regulate mechanical hyperalgesia. The present study used skin/muscle incision and retraction (SMIR) to induce postoperative pain in rats and evaluated the Epac/PKC pathway in postoperative pain. Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. The levels of Epac, PKC, proinflammatory cytokines, and blood-nerve barrier-related proteins were assessed using Western blotting. We found that SMIR induced the activation of the Epac/PKC pathway, mechanical allodynia, and upregulation of Glut1, VEGF, and PGP9.5 proteins in dorsal root ganglia. Under the influence of agonists of Epac/PKC, normal rats showed mechanical allodynia and increased Glut1, VEGF, and PGP9.5 proteins. After inhibition of Epac1 in rats with SMIR, mechanical allodynia was alleviated, and proinflammatory cytokines and Glut1, VEGF, and PGP9.5 proteins were decreased. Moreover, dorsal root ganglia neurons showed abnormal proliferation under the activation of the Epac/PKC pathway. Using Captopril to protect vascular endothelial cells after SMIR had a positive effect on postoperative pain. In conclusion, SMIR regulates the persistent postoperative pain in rats by the Epac/PKC pathway.
Capillary refill time for the management of acute circulatory failure: a survey among pediatric and adult intensivists
Authors: Jacquet-Lagrèze Matthias , Wiart Cléo , Schweizer Rémi , Didier Léa , Ruste Martin , Coutrot Maxime , Legrand Matthieu , Baudin Florent , Javouhey Etienne , Dépret François , Fellahi Jean-Luc 
Published: July 2022

Abstract
Introduction
Recent studies have shown the prognostic value of capillary refill time (CRT) and suggested that resuscitation management guided by CRT may reduce morbidity and mortality in patients with septic shock. However, little is known about the current use of CRT in routine clinical practice. This study aimed to assess the modalities of CRT use among French adult and pediatric intensivists.

Methods
A cross-sectional survey exploring CRT practices in acute circulatory failure was performed. The targeted population was French adult and pediatric intensivists (SFAR and GFRUP networks). An individual invitation letter including a survey of 32 questions was emailed twice. Descriptive and analytical statistics were performed.

Results
Among the 6071 physicians who received the letter, 418 (7%) completed the survey. Among all respondents, 82% reported using CRT in routine clinical practice, mainly to diagnose acute circulatory failure, but 45% did not think CRT had any prognostic value. Perfusion goal-directed therapy based on CRT was viewed as likely to improve patient outcome by 37% of respondents. The measurement of CRT was not standardized as the use of a chronometer was rare (3%) and the average of multiple measurements rarely performed (46%). Compared to adult intensivists, pediatric intensivists used CRT more frequently (99% versus 76%) and were more confident in its diagnostic value and its ability to guide treatment.

Conclusion
CRT measurement is widely used by intensivists in patients with acute circulatory failure but most often in a non-standardized way. This may lead to a misunderstanding of CRT reliability and clinical usefulness.
Patient-reported continuity of care and the association with patient experience of cardiovascular prevention: an observational study in Germany
Authors: Arnold Christine , Hennrich Patrick , Wensing Michel 
Published: July 2022

Abstract
Background
Cardiovascular diseases are often accompanied by comorbidities, which require good coordination of care. Especially in fragmented healthcare systems, it is important to apply strategies such as case management to achieve high continuity of care. The aim of this study was to document continuity of care from the patients’ perspective in ambulatory cardiovascular care in Germany and to explore the associations with patient-reported experience of cardiovascular prevention.

Methods
This cross-sectional observational study was performed in primary care practices in Germany. The study included patients with three recorded chronic diseases, including coronary heart disease. Continuity of care was measured with the Nijmegen Continuity Questionnaire, which addresses personal/relational and team/cross-boundary continuity. From aspects of medical care and health-related lifestyle counselling a patient-reported experience of cardiovascular prevention index was formed with a range of 0–7. The association between continuity of care within the family practice and patient-reported experience of cardiovascular prevention was examined, using a linear multilevel regression model that adjusted for sociodemographics, structured care programme and numbers of contacts with the family practice.

Results
Four hundred thirty-five patients from 26 family practices participated. In a comparison between general practitioners (GPs) and cardiologists, higher values for relational continuity of care were given for GPs. Team/cross-boundary continuity for ‘within the family practice’ had a mean of 4.0 (standard deviation 0.7) and continuity between GPs and cardiologists a mean of 3.8 (standard deviation 0.7). Higher personal continuity of care for GPs was positively associated with patient-reported experience (b = 0.75, 95% CI 0.45–1.05, P < 0.001).

Conclusions
Overall, there was high patient-reported continuity, which positively influenced the experience of cardiovascular prevention. Nevertheless, there is potential for improvement of personal continuity of the cardiologists and team/cross-boundary continuity between GPs and cardiologists. Structured care programs may be able to support this.

Trial registration
We registered the study prospectively on 7 November 2019 at the German Clinical Trials Register (DRKS) under ID no. DRKS00019219.
Including formal and informal caregivers in the development of Play Intervention for Dementia: a qualitative study
Authors: Li Bingyu , Ho Rainbow Tin Hung , Leung Wing Yeung Vivian , Tsang Ka Tat 
Published: July 2022

Abstract
Background
Play Intervention for Dementia is a practice initiative using play to help people living with dementia (PWD) experience engagements, autonomy, and cognitive stimulation. This program was developed under a participatory paradigm, with extensive contribution from formal and informal caregivers. This article describes how caregivers contributed to the practice principles, materials, and assessment during the development phase of Play Intervention for Dementia through community-based participatory research (CBPR).

Methods
Three service supervisors, 16 formal caregivers and 14 informal caregivers from the community participated in this study. Based on CBPR, the study progressed in a reflexive, iterative and collaborative way. Data were collected from diverse sources, including practice journals, observation notes and reflexive focus group interviews. Two trained qualitative researchers conducted thematic analysis on the data collected, with focus on practical skills, outcomes, and caregivers’ general experience during the intervention.

Results
The therapeutic and liberating power of play was thoroughly discussed by the caregivers. They considered play as an innovative way to understand, engage, and connect with the PWD. Also, improvement in energy level, motivation and communicative capacity was observed among the PWD. The researcher and caregivers collaboratively refined and designed the protocol of Play Intervention for Dementia, adding localized principles and games to the original design.

Conclusion
Caregivers found play to be a meaningful way to engage with PWD, as it provided an equal platform for them. The intervention also enabled them to reflect upon ageing and disease at a deeper level. Caregivers have contributed significantly to the refinement and contextualisation of the intervention. The efficiency of the refined program should be further tested on a larger scale.