bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy
Authors: Saigusa Natsuki , Hirai Hideaki , Tada Yuichiro , Kawakita Daisuke , Nakaguro Masato , Tsukahara Kiyoaki , Kano Satoshi , Ozawa Hiroyuki , Kondo Takahito , Okami Kenji , Togashi Takafumi , Sato Yukiko , Urano Makoto , Kajiwara Manami , Shimura Tomotaka , Fushimi Chihiro , Shimizu Akira , Okamoto Isaku , Okada Takuro , Suzuki Takayoshi , Imanishi Yorihisa , Watanabe Yoshihiro , Sakai Akihiro , Ebisumoto Koji , Sato Yuichiro , Honma Yoshitaka , Yamazaki Keisuke , Ueki Yushi , Hanazawa Toyoyuki , Saito Yuki , Takahashi Hideaki , Ando Mizuo , Kohsaka Shinji , Matsuki Takashi , Nagao Toshitaka 
Published: February 2022

ObjectiveSalivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy.Materials and MethodsThe EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases).ResultsEZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups.ConclusionsA high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.
Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics
Authors: Yao Qianlan , Liu Yanhui , Zhang Lihua , Dong Lin , Bao Longlong , Bai Qianming , Cui Qian , Xu Jie , Li Min , Liu Jing , Chuai Shannon , Ying Jianming , Zhang Zhihong , Zhou Xiaoyan 
Published: February 2022

ObjectiveThe status of homologous recombination repair (HRR) gene mutations and their impact on the survival of patients with Chinese epithelial ovarian cancer (EOC) are still unclear. In this study, we retrospectively analyzed the mutations of HRR genes in tumor tissues and evaluated their values for predicting the survival of Chinese EOC patients.MethodsA total of 273 primary EOC patients from five different hospitals between 2015 and 2016 were recruited. All patients received staging surgeries or debulking surgeries combined with systemic platinum-based chemotherapy. DNA was extracted from formalin-fixed, paraffin-embedded sections and analyzed for mutations using a 21-gene panel (including 13 well-known HRR genes) by next-generation sequencing.ResultsHigh-grade serous carcinoma (HGSOC) accounted for 76.2% of the cohort. A total of 34.1% (93/273) cases had 99 deleterious mutations in 9 HRR genes, namely, BRCA1 (56/273, 20.5%), BRCA2 (20/273, 7.3%), ATM (5/273, 1.8%), RAD51C (5/273, 1.8%), RAD51D (5/273, 1.8%), BRIP1 (2/273, 1.8%), CHEK2 (2/273, 0.7%), FANCI (2/273, 0.7%), and RAD54L (1/273, 0.4%). There is a strong mutual exclusion between HRR genes. The mutation landscape revealed several unappreciated deleterious variants in BRCA1/2 and other HRR genes reported previously. Estimated according to the mutation allele frequency, about 4.8% of the patients had potential somatic HRR gene mutations, which might be underestimated. Moreover, HRR mutations mainly exist in HGSOC (83/208, 39.9%), clear cell (2/30, 6.7%), and endometroid subtypes (8/20, 40%), but not seen in other rare subtypes. BRCA1 mutations tend to be present in younger patients with family history or multiple primary foci. Patients with BRCA1/2 mutations tend to have a longer progression-free survival and overall survival, while other HRR mutation carriers tend to have a shorter progression-free survival, but no significant difference in overall survival.ConclusionThis study revealed the distribution of HRR gene mutations in Chinese EOC tissues. BRCA1/2 account for the majority of HRR gene mutations and predict long prognosis in HGSOC. Non-BRCA HRR mutations also account for a very important proportion and might be associated with poor prognosis in HGSOC. It is suggested that HRR gene mutations need to be detected in EOC tissues and germline status be further clarified in clinical algorithm for potential targeted therapy, genetic screening, and prognosis prediction.
Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis
Authors: Ma Jiao , Li Lanying , Liao Taiping , Gong Weidong , Zhang Chunyin 
Published: February 2022

ObjectiveTo conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence.MethodsSearch for retrospective studies about 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer from establishment to July 2021 in PubMed and EMBASE. The primary endpoint was 225Ac-PSMA-617 biochemical response evaluation criteria after treatment [any prostate specific antigen (PSA) decrease and PSA decrease &gt;50% from baseline] to evaluate the treatment effect. Secondary endpoints included assessment of overall survival (OS), progression-free survival (PFS), molecular response, and toxicity for all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Use stata16.0 software for analysis, fixed-effects model for data merging and forest plots for display.ResultsA total of 6 retrospective studies, namely, 201 patients, were included in the final analysis. The pooled proportions of patients with decreased PSA and PSA decreased by more than 50% were 87.0% (95% confidence interval, 0.820 to 0.920) and 66.1% (95% confidence interval, 0.596 to 0.726), respectively. The pooled proportions of OS and PFS were 12.5 months (95%CI: 6.2–18.8 months) and 9.1 months (95%CI: 2.6–15.7 months). The patients showing molecular responses were 54% (95% confidence interval: 25–84%). In all studies, the most common side effect of 225Ac-PSMA-617 TAT was xerostomia, with any degree of xerostomia occurring in 77.1% (155 out of 201), and grade III only accounted for 3.0%. The second was 30.3% (61 out of 201) anemia of any degree, and grade III accounts for 7.5% (15 out of 201). Grade III leukopenia and thrombocytopenia were 4.5% (9 out of 201) and 5.5% (11 out of 201), respectively. Only 6 (3.0%) of 201 patients had Grade III nephrotoxicity.Conclusion225Ac-PSMA-617 is an effective and safe treatment option for mCRPC patients, and the toxicity caused by it is relatively low. However, future randomized controlled trials and prospective trials are required in the future to judge the therapeutic effects and survival benefits compared with existing clinical treatments.Systematic Review RegistrationPROSPERO: CRD42021281967.
Congenitally Corrected Transposition of the Great Arteries: Mid-term Outcomes of Different Surgical Strategies
Authors: He Xiaomin , Shi Bozhong , Song Zhiying , Pan Yanjun , Luo Kai , Sun Qi , Zhu Zhongqun , Xu Zhiwei , Zheng Jinghao , Zhang Zhifang 
Published: February 2022

BackgroundOptimal management for congenitally corrected transposition of the great arteries (ccTGA) is controversial. We applied different surgical strategies based on individual variations in our single-centered practice over 10 years, aming to describe the mid-term results.MethodsFrom January 2008 to June 2021, 90 patients with ccTGA were reviewed and grouped by three different surgical strategies: 41 cases with biventricular correction as biventricular group, 11 cases with 1.5 ventricular correction as 1.5 ventricular group, and 38 cases with Fontan palliation as univentricular group. The mean age at primary surgery was 41.4 ± 22.7 months. Patients were followed for mortality, complications, reoperation, cardiac function, and valve status.ResultsThe median follow-up period was 5.1 years (range, 1.5–12.5 years). The overall 10-year survival and freedom from reoperation rate was 86.7 and 82.4%, respectively. There were 3 early deaths and 3 mid-term deaths in the biventricular group, while 2 early deaths and 1 mid-term deaths were reported in the univentricular group. Although 1.5 ventricular group presented no death and the fewest complications, we still found similar mortality (p = 0.340) and morbidity (p = 0.670) among the three groups. The bypass time, aortic-clamp time, and ICU stay length were the longest in the biventricular group, followed by the 1.5 ventricular group (p &lt; 0.001). However, in mid-term follow-up, biventricular and 1.5 ventricular groups both showed excellent cardiac function and obvious improvement of tricuspid regurgitation (p = 0.008 and p = 0.051, respectively). Fontan palliation provided acceptable mid-term outcomes as well, despite a lower ejection fraction.ConclusionSatisfactory mid-term outcomes could be achieved for highly selected ccTGA patients using the whole spectrum of surgical techniques. Moreover, 1.5 ventricular correction, as a new emerging technique in recent years, might hold great promise in future practice.
Different Reaction Patterns of Caregivers of Children With Imperforate Anus: A Latent Profile Analysis
Authors: Wang Dan , Xu Hongzhen , Liu Kexian , Tou Jinfa , Jia Yushuang , Gao Wei , Chen Xiaofei , Luo Feixiang 
Published: February 2022

AimThis study aimed to explore how different dimensions of caregivers' reaction shape their caring experience, and the factors associated with different reaction patterns.DesignA second analysis of a multisite cross-sectional study were conducted. Caregivers of children with imperforate anus (IA) were enrolled in three tertiary children's hospitals in Eastern China between November 2018 and February 2019.MethodsThe caregiver's experience, stigma feeling, social support level and perception of uncertainty were assessed by Caregiver Reaction Assessment, Parent Stigma Scale, Social Support Scale and Parent's Perception of Uncertainty Scale accordingly. The demographic information of caregivers as well as the children's clinical data were collected. Latent profile analysis was conducted to determine different patterns of caregiver's reaction, and logistics analysis was used to explore the associated factors of the reaction pattern.FindingsA total number of 229 caregivers (median age = 30, quartiles: 28, 36) were included. Three distinguishable caregiving reaction types were identified (Class 1: low burden and high benefit, 4.8%; Class 2: moderate burden and benefit, 48.9%; Class 3: high burden and low benefit, 46.3%). In logistics analysis, the Class 1 and Class 2 were combined as one group due to the low population in Class 1. The marital status of caregiver (OR = 0.067, 95% CI: 0.006, 0.700, P = 0.024), IA type (OR = 1.745, 95% CI: 1.198, 2.541, P = 0.004), children aged &gt; 2 years (OR = 3.219, 95% CI: 1.364, 7.597, P = 0.008), social support (OR = 0.907, 95% CI: 0.865, 0.951, P &lt; 0.001) and perception of uncertainty (OR = 1.054, 95% CI: 1.026, 1.083, P &lt; 0.001) were associated with different caregiver reaction patterns.ConclusionNearly half of the caregivers of children with IA experience reaction of high burden and low benefit, but considerable proportion of caregivers could benefit from the caregiving rather than burden from. Married caregivers may have more negative reaction, especially when children &gt; 2 years and diagnosed with intermediate or high type of IA. However, increasing caregiver's social support and reducing perception of uncertainty may have the potential to modify their reaction pattern.
Berberine Facilitates Extinction and Prevents the Return of Fear
Authors: Huang Shihao , Zhou Yu , Wu Feilong , Shi Cuijie , Yan He , Chen Liangpei , Yang Chang , Luo Yixiao 
Published: February 2022

Exposure to a catastrophic event or intense stimulation can trigger fear memories, and the threatening memories persist even over a lifetime. Exposure therapy is based on extinction learning and is widely used to treat fear-related disorders, but its effect on remote fear memory is modest. Berberine, an isoquinoline alkaloid derived from Coptis chinensis or Berberis spp., has been recently reported to exert a diversity of pharmacological effects on the central nervous system, such as facilitating extinction of drug memory. Here, we explored the effect of berberine on extinction of fear memory using a classical contextual fear conditioning (CFC) paradigm, which is Pavlovian conditioning, can rapidly create fear memories related to contexts. Twenty-four hours or 30 days after CFC training, mice were subjected to context extinction (10 days) to extinguish their behaviors and treated with 12.5 or 25 mg/kg berberine intragastrically 1 or 6 h after each extinction session, followed by reinstatement and spontaneous recovery tests. The results showed that intragastric administration of 25 mg/kg berberine 1 h after extinction significantly promoted the extinction of recent and remote fear memories and prevented reinstatement and spontaneous recovery of extinguished fear in mice. These findings indicate that berberine combined with extinction training could serve as a promising novel avenue for the treatment of fear-related disorders.
Effects of the Full Coverage Policy of Essential Medicines on Inequality in Medication Adherence: A Longitudinal Study in Taizhou, China
Authors: Guo Zhigang , Zheng Liguang , Fu Mengyuan , Li Huangqianyu , Bai Lin , Guan Xiaodong , Shi Luwen 
Published: February 2022

The full coverage policy for essential medicines (FCPEMs) was proposed and implemented in Taizhou city of Zhejiang Province, China, to promote equal access and adherence to medicines. This study aimed to examine the effects of FCPEMs on the income-related inequality in medication adherence among local patients with hypertension or diabetes. We collected electronic health records of patients with hypertension or diabetes of three districts of Taizhou from 2011 to 2016. As the implementation schedule of the FCPEMs varied across districts, we applied a retrospective longitudinal study design and assigned records from 1 year before to 3 years following the implementation of FCPEMs as baseline and follow-up data. We thus generated a dataset with 4-year longitudinal data. The concentration index (CI) and its decomposition method were employed to measure factors contributing to inequality in medication adherence and the role played by FCPEMs. The sample size rose from 264,836 at the baseline to 315,677, 340,512, and 355,676 by each follow-up year, and the proportion of patients taking free medicines rose from 17.6 to 25.0 and 29.8% after FCPEMs implementation. The proportion of patients with high adherence increased from 39.9% at baseline to 51.6, 57.2, and 60.5%, while CI decreased from 0.073 to −0.011, −0.029, and −0.035. The contribution of FCPEMs ranked at 2nd/13, 7th/13, and 2nd/13 after the implementation of FCPEMs. Changes in CI of medication adherence for every 2 years were −0.084, −0.018, and −0.006, and the contribution of FCPEMs was −0.006, 0.006, and 0.007, ranking at 2nd/13, 2nd/13, and 1st/13, respectively. Most changes in CI of medication adherence can be attributed to FCPEMs. The medication adherence of patients with hypertension or diabetes improved after the implementation FCPEMs in Taizhou, although inequality did not improve consistently. In general, FCPEMs could be a protective factor against income-related inequalities in access and adherence to medicines. Future research is needed to investigate the change mechanism and the optimal design of similar interventions.
Pharmacodynamics and Pharmacokinetics of HSK3486, a Novel 2,6-Disubstituted Phenol Derivative as a General Anesthetic
Authors: Liao Juan , Li Meiting , Huang Chaoli , Yu Yan , Chen Yashu , Gan Jiaqi , Xiao Jie , Xiang Guilin , Ding Xizhi , Jiang Rong , Li Peng , Yang Mengchang 
Published: February 2022

Background: The purpose of this study was to characterize the novel sedative/hypnotic agent HSK3486, a 2,6-disubstituted alkylphenol analogue.Methods: The mechanism of action of HSK3486 was studied in competitive binding assays and whole-cell patch clamp assays. HSK3486 was administered by bolus intravenous injection to dogs and rats, and the loss of righting reflex as well as effects on the cardiovascular and respiratory systems were assessed. The in vitro metabolism of HSK3486 was analyzed by CYP450 genotyping and enzyme inhibition.Results: HSK3486 competed with t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) for binding to the gamma-aminobutyric acid type A (GABAA) receptor. HSK3486 potentiated GABA-evoked chloride currents at lower concentrations while activating GABAA receptor at higher concentrations. HSK3486 induced hypnosis in rats and dogs, and had a higher therapeutic index than propofol in rats. The hypnotic potency of HSK3486 was approximately 4-5 fold higher than that of propofol. HSK3486 exerted minimal effects on the cardiovascular system.Conclusions: HSK3486 is a positive allosteric regulator and direct agonist of GABAA receptor. It has a promising sedative/hypnotic effect and good in vivo pharmacokinetic properties, which justify further studies towards its clinical application.
The Protective Effect of Trichilia catigua A. Juss. on DEHP-Induced Reproductive System Damage in Male Mice
Authors: Chang Xinyue , Dong Mingran , Mi Xiao , Hu Meigeng , Lu Juan , Chen Xi 
Published: February 2022

The present study aimed to explore the protective effect and molecular mechanisms ofTrichilia catiguaA. Juss. extract (TCE) against di (2-ethylhexyl) phthalate (DEHP)-induced damage to the reproductive system of mice. Acute toxicity tests revealed that the maximum tolerated dose (MTD) in mice was up to 2.7 g kg−1. After induction with DEHP, TCE (L-TCE, M-TCE, H-TCE) was orally administered to mice for 28 days. Differences in indicators among groups showed that TCE significantly improved the anogenital distance and the organ indexes of the epididymides and testes. It also significantly reduced varicocele and interstitial cell lesions compared to the model group. H-TCE reduced the sperm abnormality rate, increased the levels of sex hormones, Na+K+and Mg2+, Ca2+-ATPase enzyme activity, antioxidant enzyme vitality, coupled with a significant decrease in LH and MDA contents. The levels of testicular marker enzymes ACP and LDH were significantly augmented by both M-TCE and H-TCE. Further studies claimed that DEHP induction reduced the mRNA expression levels ofNrf2, SOD2, SOD3, CDC25C CDK1,CYP11A1, 3β-HSD, 5ɑ-R, AR, SF1,andCYP17A1,increased the level ofKeap1, while TCE reversed the expression levels of these genes. Meanwhile, IHC results demonstrated a significant change in the expression activity of the relevant proteins compared to the control group. The results suggest that M-TCE and H-TCE enabled the recovery of DEHP-induced reproductive system damage in male mice by improving testicular histopathology, repairing testicular function, and reducing oxidative stress damage. The oxidation-related Keap1-Nrf2 pathway, SODs enzyme, the cell cycle control-related CDC25C-CDK1 pathway, and the steroidogenic-related pathway may contribute to this protective effects of TCE.
Differential Influence of Physical Activity on Cardiopulmonary Performance and Stroke Volume Assessed at Cardiopulmonary Exercise Test in Pectus Excavatum: A Pilot Study
Authors: Casatori Lorenzo , Pellegrino Alessio , Messineo Antonio , Ghionzoli Marco , Facchini Flavio , Modesti Alessandra , Modesti Pietro Amedeo 
Published: February 2022

BackgroundExercise training increases muscle VO2 by increasing O2 transport and O2 uptake while cardiac output increase might be limited by the conformation of the chest in subjects with pectus excavatum (PE).AimsThe aim of the present study was to investigate the influence of physical activity (PA) on functional parameters of cardiopulmonary performance and stroke volume obtained at Cardiopulmonary Exercise Test (CPET) in PE.Methods and ProceduresA cohort of adolescents (15 with PE and 15 age- and sex-matched healthy controls, HC) underwent Cardiopulmonary Exercise Test (CPET) and administration of the International Physical Activity Questionnaire – Short Form (IPAQ-SF) with estimation of weekly PA (METs h–1⋅week–1). Determinants of CPET parameters were investigated with multivariable linear regression analysis.ResultsAs expected, when compared to HC, PE had lower VO2 max (37.2 ± 6.6 vs. 45.4 ± 6.4 mL⋅kg–1⋅min–1, p &lt; 0.05), and VO2/HR max (O2 pulse, 12.1 ± 2.4 vs. 16.2 ± 3.6 mL⋅min–1⋅bpm–1, p &lt; 0.05). Importantly, physical activity level was a predictor of VO2 max (adjusted for sex, body mass index, FEV1%, and presence of PE, β = 0.085; 95% Cl 0.010 to 0.160, p = 0.029) whereas O2 pulse was independent from PA level (β = 0.035; 95% Cl −0.004 to 0.074).ConclusionPhysical activity is a determinant of VO2 max (cardiopulmonary performance), whereas it appears not to affect O2 pulse (a measure of stroke volume at peak exercise) related to constrained diastolic filling in PE.