bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of multiple genomic-factors affecting the homologous recombination deficiency (HRD) in Chinese ovarian cancer.
Authors: Wang Min , Nguyen Thi Phuong Anh , Ding ShouTai , Ye Linxiong , Fei Liping , He Hongsheng , Luo Peng 
Published: August 2023

88 Background: A large proportion of (but not all) ovarian cancers with high homologous recombination deficiency (HRD) scores are sensitive to Poly (ADP-ribose) polymerase inhibitors (PARPi). This study aimed to identify multiple genomic factors that could increase HRD scores, helped us understand the potential causes for high HRD scores, and thus make therapy decisions. Methods: A total of 370 Chinese ovarian cancer patients were retrospectively obtained from ovarian patients for HRD status and HRR gene alterations from October, 2021 to January, 2023. Patient information including age, gender, pathology type was collected. All specimens were detected by OncoDrug-SeqTM603-gene panel assay through next-generation sequencing (NGS) using Illumina NovaSeq 6000. The interaction between genomic alternation and its overall instability was analyzed to look for multi-factors affecting HRD. Results: Of 370 patients, there were 296 (80.08%) patients with over 50 years, 225(76.01%) with positive HRD, and 48 (16.2%) patients with BRCA1/2 mutations. The top ten commonly mutated genes were TP53 (54.05%), BRCA1 (8.1%), BRCA2 (8.11%), KRAS (8.11%), PDE1C (8.11%), ARID1A (5.41%), BRAF (5.41%), CDK12 (5.41%), CHEK2 (5.41%), and MSH2 (5.41%).Among of them, there were 24.32% of patients with both HRR and TP53 mutations, and 13.51% of patients had both BRCA1/2 and TP53 mutations. Furthermore, in the trio negative of BRCA1/2, TP53, and HRD groups, KRAS mutations were found in 30 (50%)patients. The mutations in TP53, BRAC1/2, and other HRR genes had positive correlations with HRD scores. Importantly, BRCA1/2-negative patients with mutant TP53 other than wild type had a significantly high HRD score (p<0.05). Although it did not hold true for other HRR gene (excluding BRCA) negative patients (p>0.05), an increasing trend in HRD score was still observed. Conclusions: Alterations of multiple genes including TP53, BRAC1/2, and other HRR genes are correlated with higher HRD scores. In this Chinese cohort, a large number of BRCA1/2-negative patients with TP53 mutations tend to have higher HRD scores. Whether this specific subgroup of Chinese ovarian cancers can benefit from PARPi is in question, although they present high HRD scores.
The relationship between telomerase reverse transcriptase promoter rs2853669 allele C accompanied by C228T and the grade of thyroid malignancy.
Authors: Nakazato Yoko , Miya Toshimichi , Hirano Koichi , Kondo Haruhiko 
Published: August 2023

91 Background: Two-point mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) gene are considered molecular indicators of adverse thyroid tumor biology. The regulatory single nucleotide polymorphism rs2853669 (TrSNP) is located near these TERT promoter mutations and its association with the grade of various cancers has been recently reported. To clarify whether the TrSNP can be a clinically useful molecular marker, we analyzed the relationship of the TrSNP with tumor growth and malignant potential in papillary thyroid cancer and follicular tumors. Methods: DNA was extracted from blood and FFPE specimens of 218 patients with thyroid tumors (133 papillary and 85 follicular), and TrSNP, C228T, and C250T were analyzed. BRAFV600E and NRAS Q61R mutations were also analyzed. The association of these genotypes and mutations with clinicopathological parameters were investigated. Results: The C allele of TrSNP from blood and FFPE specimens were validated with 97.3% concordance, so the C allele of TrSNP from blood samples were used in this study. Univariate analysis of 133 papillary carcinomas for clinicopathologic features showed that the C allele of TrSNP significantly correlated with tumor size as did the C228T mutation (p<0.05, p<0.001). Co-expression of the TrSNP and C228T were significantly corelated with tumor size, extrathyroidal invasion and lymph nodal metastasis (p<0.01, p<0.05). Eighty-five follicular tumors (19 follicular carcinomas and 66 follicular adenomas) were examined. Univariate analysis showed no significant association between the C allele of TrSNP, C228T, or C250T and tumor size. Multivariate analysis demonstrated the C allele TrSNP and C228T were significantly frequent in follicular carcinoma (p<0.05, p<0.001) and therefore were considered a risk factor for malignancy. Conclusions: This study demonstrates that the C-allele of the TrSNP is an indicator of tumor growth of papillary carcinoma and co-expression of the TrSNP and C228T relate tumor progression and malignant grade. These genetic features are expected to be a useful molecular marker for differential diagnosis of benign and malignant tumors and for determining treatment strategies.
A novel pathological finding, "BABA", for a prognostic factor in oral tongue carcinoma.
Authors: Baba Daisuke , Sakashita Shingo , Adachi Masahiro , Sakamoto Naoya , Kojima Motohiro , Matsuura Kazuto , Nakatsura Tetsuya , Hayashi Ryuichi , Ishii Genichiro 
Published: August 2023

92 Background: Oral tongue carcinoma is one of the cancers with poor prognosis. The UICC staging classification is commonly used to predict outcomes and to select the treatments, although there are cases where cancer relapse early despite being at the same Stages, indicating a need for additional prognostic factors to predict patient outcomes accurately. Recent advances in RNA sequencing of tumor and immune cells, as well as elucidation of the tumor microenvironment, have enabled the identification of many genes associated with recurrence risk and immunosuppressive environment around the tumor, which essential for precision treatment of the patients with high risks of recurrence. However pathological findings remain the first step in selecting samples with a high risk of recurrence for further analysis of RNA sequencing or the tumor microenvironment. In this study, we identified a novel pathological feature named as “BABA” (Broadening Amoeboid Behavior of Advanced tumor cells) that appears around the invasive front of tumors. It describes the way in which cancer cells progress like amoeba between muscle fibers and affect the prognosis of oral tongue carcinoma, making it a potential factor for the future analysis of next-generation sequencing or tumor microenvironment. Methods: Patients with oral tongue squamous cell carcinoma who underwent surgery were recruited, excluding those who had received salvage treatment for recurrence, those with simultaneous occurrence of carcinoma, those who had undergone palliative therapy, postoperative therapy, or those who lacked any pathological findings. Survival analyses for existing pathological findings, such as pT (pathological primary stage), pN (pathological nodal stage), ENE (extra nodal extension) status, lymphatic invasion, venous invasion, perineural extension, margin status, WPOI (worst pattern of invasion) and BABA were conducted. Results: A total number of 211 patients were analyzed in this study. Patients with positive for BABA had a two-year overall survival rate and recurrence-free survival rate of 0.78(p=0.02) and 0.39 (p<0.001), respectively, according to Kaplan-Meier analysis. In the multivariate analysis for overall survival using Cox regression model, venous invasion and pN ≥1 were significant prognostic factors, with HR (95%CI) of 3.0 (1.5-6.3) and 2.4 (1.2-4.5), respectively. In the multivariate analysis for recurrence free survival using Cox regression model, positive for lymphatic invasion, venous invasion, BABA, pN ≥1 were significant factors, with HR (95%CI) of 2.1 (1.2-3.6), 2.0 (1.1-3.4), 2.2 (1.3-3.7) and 2.0 (1.2-3.6), respectively. Conclusions: BABA is the novel risk factor for recurrence in oral tongue carcinoma. Identifying BABA could help clinicians better predict recurrence and develop more personalized treatment strategies.
Clinical implications of drug-metabolizing genes CYP3A4 and GSTP1 single nucleotide polymorphisms in oral cancer patients undergoing induction chemotherapy.
Authors: Sahoo Pranab Kumar , Mistry Tanuma , GHOSH SUSHMITA , Mahata Sutapa , Sarkar Sinjini , Pal Ranita , Choudhury Trisha , Datta Sriparna , Mandal Syamsundar , Bhowmick Anup Kumar , MUKHERJEE KALYAN KUSUM , Nasare Vilas 
Published: August 2023

95 Background: Despite well-established induction chemotherapeutics for advanced-stage oral cavity cancer (OCC), there are no reliable markers to detect drug-induced toxicity and clinical efficacy. The presence of genetic polymorphisms can cause certain enzymes to behave differently in various populations, which can lead to varied outcomes. Thus, we analyzed the effect of metabolizing (CYP3A4) and detoxifying (GSTP1) genes involved in taxane/platinum/5-fluorouracil (TPF) or paclitaxel/carboplatin (PC) metabolism and their clinical outcomes in OCC patients. Methods: The current study included 121 OCC patients who received fixed dose of TPF or PC-based chemotherapy. PCR-RFLP was used to assess the polymorphism of the metabolising gene. SNPs were tested for toxicity and progression-free survival. Results: The grade ≥2 patients (47.9%) having higher fever (33.8%) and vomiting (34.7%) as a result of chemotherapy, showed significant association with the gene CYP3A4 (rs2687105) in both the PM and IM genotypes. For PM genotypes, the odd ratio (OR) of CYP3A4 for fever was 2.33E8 (95% CI: 4.702E7-1.154E9, p = 0.000), and for IM genotypes, it was 6.99E8 (95% CI: 1.89E8-2.581E9, p = 0.000). Meanwhile, the patients with grade ≥2 (58.6%) having anaemia (11.5%) and nausea (32.2%) also found to be significantly associated with GSTP1 (rs749174) in PM genotypes; the odds ratio was (OR: 8; 95%CI:1. 1001-63.963; p=0.05) and (OR: 2.667; 95%CI:1.043-6.815; p=0.04). Moreover, patients with these SNPs showing poor survival rate, however there was no significant association observed between the genotypes of each SNPs with progression-free survival (PFS). Conclusions: In conclusion, our data showed that the rs2687105 in CYP3A4 and the rs749174 in GSTP1 were associated with adverse events of TPF or PC chemotherapeutic regimens among the oral cancer patients. Therefore these genes might be used as predictive markers for minimising the adverse effects caused by chemotherapy and for optimization of drug dose in oral cancer patients.
Disparities in African-American patient enrollment in pivotal phase 3 immunotherapy trials that led to FDA drug approval in patients with non-small cell lung cancer.
Authors: Ubbaonu Chimezie , Ou Sai-Hong Ignatius 
Published: August 2023

99 Background: Blacks/African American have historically been underrepresented in enrollment into clinical trials. This leads to uncertainty regarding the efficacy and tolerability of treatments in this patient population following drug approval by the FDA. One of the approval criterion for the FDA is the patient population represents the diversity of patient population in the US as argued by the US FDA in the ORIENT-11 trial (NCT03607539). We abstracted the percentage of African-American into clinical enrolled into pivotal randomized phase 3 trials that led to approval of immunotherapy in advanced NSCLC. Methods: We abstracted the racial composition of randomized phase 3 trials that led to immunotherapy approval including neoadjuvant, adjuvant, consolidation/maintenance, first line and second line indication of immunotherapy in the U.S. Results: We identified a total of 20 randomized phase 3 trials that led to immunotherapy indication in NSCLC by the FDA including neoadjuvant (N = 1), adjuvant (N = 2), consolidation/maintenance (N = 1), first-line (N = 12), and second line (N = 4). We excluded 3 trials (ENPOWER-Lung01, -Lung03, and Checkmate-227) that did not report the racial composition of the patient participants. A total of 12490 subjects participated in the 17 trials analyzed. Of these, 66.3% were male and 33.7% were female. Distribution by race revealed 75.7% White (range 55.9% - 94.3%); 1.9% African-American (range 0.03% - 3.6%); 18.6% Asian (range 1.3% - 34.6%); and 3.8% (0.5% - 7.6%) were either mixed race, American Indian, Pacific Islander or unknown. Conclusions: African-Americans comprised an estimated 13.6% of the U.S. population respectively but our survey indicated only 1.9% of the trial population that led to immunotherapy approval in the US were African-Americans. The patient population in the clinical trials leading to immunotherapy regimen approval in the U.S. significantly under-represented African-Americans and here the true efficacy of and potential unknown adverse events of immunotherapy in African-Americans may over- or under-estimated. The U.S. FDA has the power to approve immunotherapy trials that are more representative of the US population.
ERK5 Cooperates With MEF2C to Regulate Nr4a1 Transcription in MA-10 and MLTC-1 Leydig Cells
Authors: de Mattos Karine , Dumas Félix-Olivier , Campolina-Silva Gabriel Henrique , Belleannée Clémence , Viger Robert S , Tremblay Jacques J 
Published: August 2023

Abstract
Leydig cells produce hormones required for the development and maintenance of sex characteristics and fertility in males. MEF2 transcription factors are important regulators of Leydig cell gene expression and steroidogenesis. ERK5 is an atypical member of the MAP kinase family that modulates transcription factor activity, either by direct phosphorylation or by acting as a transcriptional coactivator. While MEF2 and ERK5 are known to cooperate transcriptionally, the presence and role of ERK5 in Leydig cells remained unknown. Our goal was to determine whether ERK5 is present in Leydig cells and whether it cooperates with MEF2 to regulate gene expression. We found that ERK5 is present in Leydig cells in testicular tissue and immortalized cell lines. ERK5 knockdown in human chorionic gonadotrophin–treated MA-10 Leydig cells reduced steroidogenesis and decreased Star and Nr4a1 expression. Luciferase assays using a synthetic reporter plasmid containing 3 MEF2 elements revealed that ERK5 enhances MEF2-dependent promoter activation. Although ERK5 did not cooperate with MEF2 on the Star promoter in Leydig cell lines, we found that ERK5 and MEF2C do cooperate on the Nr4a1 promoter, which contains 2 adjacent MEF2 elements. Mutation of each MEF2 element in a short version of the Nr4a1 promoter significantly decreased the ERK5/MEF2C cooperation, indicating that both MEF2 elements need to be intact. The ERK5/MEF2C cooperation did not require phosphorylation of MEF2C on Ser387. Taken together, our data identify ERK5 as a new regulator of MEF2 activity in Leydig cells and provide potential new insights into mechanisms that regulate Leydig cell gene expression and function.
Astragalus polysaccharide promotes osteogenic differentiation of human bone marrow derived mesenchymal stem cells by facilitating ANKFY1 expression through miR-760 inhibition
Authors: Hu Xianfeng , Yang Liu , Du Yanhua , Meng Xiangping , Shi Yuanyuan , Zeng Juan 
Published: August 2023

AimsAstragalus polysaccharide (APS) participates in various processes, such as the enhancement of immunity and inhibition of tumours. APS can affect osteoporosis (OP) by regulating the osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs). This study was designed to elucidate the mechanism of APS in hBMSC proliferation and osteoblast differentiation.MethodsReverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting were performed to determine the expression of microRNA (miR)-760 and ankyrin repeat and FYVE domain containing 1 (ANKFY1) in OP tissues and hBMSCs. Cell viability was measured using the Cell Counting Kit-8 assay. The expression of cyclin D1 and osteogenic marker genes (osteocalcin (OCN), alkaline phosphatase (ALP), and runt-related transcription factor 2 (RUNX2)) was evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mineral deposits were detected through Alizarin Red S staining. In addition, Western blotting was performed to detect the ANKFY1 protein levels following the regulation of miR-760. The relationship between miR-760 and ANKFY1 was determined using a luciferase reporter assay.ResultsThe expression of miR-760 was upregulated in OP tissues, whereas ANKFY1 expression was downregulated. APS stimulated the differentiation and proliferation of hBMSCs by: increasing their viability; upregulating the expression levels of cyclin D1, ALP, OCN, and RUNX2; and inducing osteoblast mineralization. Moreover, APS downregulated the expression of miR-760. Overexpression of miR-760 was found to inhibit the promotive effect of APS on hBMSC differentiation and proliferation, while knockdown of miR-760 had the opposite effect. ANKFY1 was found to be the direct target of miR-760. Additionally, ANKFY1 participated in the APS-mediated regulation of miR-760 function in hBMSCs.ConclusionAPS promotes the osteogenic differentiation and proliferation of hBMSCs. Moreover, APS alleviates the effects of OP by downregulating miR-760 and upregulating ANKFY1 expression.Cite this article: Bone Joint Res 2023;12(8):476–485.
Impact of severe mental illnesses on health-related quality of life among patients attending the Institute of Psychiatry, Rawalpindi from 2019 to 2021: A cross-sectional study
Authors: Umar Zarnain , Tahir Zona , Nizami Asad 
Published: August 2023

Background
Severe mental illnesses have huge impact on health-related quality of life. They contribute to significant morbidity in terms of number of number of years of life lost in form DALYS (disability adjusted life years) and shorter life expectancy and early mortality. There is limited evidence on their burden in low- and middle-income countries like Pakistan.

Objective
To determine the health-related quality of life in patients suffering from severe mental illness (schizophrenia, depression, and bipolar affective disorder) and demographic factors associated with poor health related quality of life in these patients.

Methodology
This was descriptive cross sectional, using retrospective record view of data. Study was done under IMPACT (Improving Mental And Physical health Together) Program, which conducted a multi-morbidity survey conducted at institute of psychiatry, Benazir Bhutto hospital, Rawalpindi, using EQ 5d 5l (EURO QOL 5D5L) questionnaire having both subjective (EQVAS) and objective domains.

Results
The study included 922 SMI patients, of whom 555 participants (60.2%) were males and 367(39.69%) were females. The participants suffered from major depressive disorder (422;45.8%), followed by bipolar affective disorder (392; 42.51%) and schizophrenia (108;11.7%). Most participants were in a younger age group with (80%) of population being below 50 years old and had education level below secondary education (57.4%). In the analysis of association between EQ-VAS (subjective quality of life scale) and demographic factors, a significant association was found for marital status(p<0.001), gender (p< 0.001) and education (p< 0.001). Women had lower EQ-VAS scores (M = 49.43±SD = 27.72) as compared to males (M = 58.81±SD = 27.1) and individuals with lower educational status also had lower mean scores. Additionally, participants who were single, divorced or widowed also had lower mean EQVAS scores. When health related quality of life was analyzed across SMI, it was lower in all SMI, but was significantly lower for depression in both subjective and objective domains of health related of quality-of-life instrument.

Conclusion
Health related quality of life is an important outcome measure and regular assessment of both subjective and objective aspects should be incorporated in management plans of patients suffering from severe mental illnesses.
Involvement of service user representatives on a healthcare organizational level at Norwegian Healthy Life Centres: A qualitative study exploring health professionals’ experiences
Authors: Sagsveen Espen , Rise Marit By , Westerlund Heidi , Grønning Kjersti , Bratås Ola 
Published: August 2023

Background
The involvement of service user representatives in planning, delivering, and evaluating health care services is regarded as essential in Healthy Life Centres (HLCs) to ensure high-quality services. However, information on how HLC-professionals involve service user representatives at a healthcare organizational level at HLCs remains sparse.

Objective
To explore HLC professionals’ experiences involving service user representatives in planning, delivering, and evaluating the HLC services.

Methods
Five qualitative semi-structured focus group interviews with 27 health professionals from 27 Norwegian HLCs were conducted. Data were analysed using systematic text condensation.

Results
The involvement of service user representatives at the HLCs varied from well-integrated and systematized to the opposite. The professionals’ primary rationale for involving service user representatives was to include the representatives’ unique experiential knowledge to ensure the quality of the service. Experiential knowledge was seen as a ‘different’ competence, which came in addition to professional competence. The professionals’ choice of service user representatives depended on the purpose behind the involvement initiative. The HLC professionals often hand-picked former service users according to their health problems, motivation, and the HLC’s need. The professionals said they were responsible for initiating the facilitation to accomplish genuine involvement. Support from their leaders to prioritize these tasks was essential.

Conclusion
To meet the demand for adequate service user representatives, the HLCs need access to different service user representatives, representing both diagnose-based and generic service user organisations and the public. To achieve genuine involvement, the rationale behind the involvement and the representatives’ role must be clarified, both for the HLC professionals and service user representatives. This will require resources for continuous organizational preparation and facilitation.