bluuebunny/crossref_metadata_2025_split huggingface dataset:
43 Epigenomic profiling of translocation renal cell carcinoma via liquid biopsy
Authors: Garinet Simon , Semaan Karl , Canniff John , Phillips Noa , Davidsohn Matthew , Berchuck Jacob , Li Jiao , Sadagopan Ananthan , Fortunato Brad , O’toole Jillian , Gwo-shu Mary , Horst Jack , Freeman Dory , Seo Ji-Heui , Freedman Matthew , Choueiri Toni , Baca Sylvan , Viswanathan Srinivas 
Published: August 2024

Abstract

Background
Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer usually driven by a fusion involving the TFE3 gene. Due to histologic overlap with other subtypes of RCC, tRCC is frequently misclassified. Methods for accurate diagnosis and detection of this molecularly distinct entity are therefore a pressing need.
Epigenomic profiling of ctDNA via plasma chromatin immunoprecipitation and sequencing (ChIP-seq) has recently emerged as a powerful tool to detect and molecularly subtype cancers and may offer a more sensitive and specific detection of molecular fusions. We aimed to detect tRCC in plasma and to discriminate tRCC from ccRCC based on epigenomic profiling of cfDNA.

Methods
We first identified differentially expressed gene, methylated regions (DMRs) and regulatory elements (REs) specific to tRCC vs. ccRCC via RNA-seq, methylated DNA immunoprecipitation sequencing (MeDIP-seq) and ChIP-Seq, of 4 tRCC and 5 ccRCC cell lines. We collected 16 plasma samples from metastatic patients with tRCC, 11 with ccRCC and 9 healthy patients (HP). Ultra low pass whole genome sequencing (ulpWGS) was performed to infer ctDNA fraction (TF), and cfMeDIP-seq, H3K4me3/H3K27ac cfChIP-seq for epigenomic profiling. Signal at tRCC-specific regions derived from cell lines profiling was aggregated for each mark and normalized to common active REs and DMRs, then compared between classes using a Wilcoxon rank-sum test. Classification performance was evaluated using the area under the receiver operating characteristic (AUROC) curve.

Results
Overall 8/16 tRCC and 5/12 ccRCC samples had &gt;3% TF by ulpWGS. H3K4me3 and H3K27ac cfChIP-seq signal was significantly higher in all tRCC samples compared to healthy patients (p&lt;10-6, AUROC =1), at tRCC-specific promoters and tRCC-specific REs respectively. Furthermore, H3K27ac signal in plasma was also significantly higher at tRCC-specific REs in tRCC samples compared to ccRCC (p&lt;10-4, AUROC=0.95). MeDIP-seq could not discriminate between tRCC and ccRCC.

Conclusions
Although a majority of tRCC plasma samples profiled had TF &lt; 3%, all could be distinguished from healthy samples on the basis of cfChIP. H3K27ac cfChIP-Seq was also discriminatory for tRCC vs. ccRCC. Epigenomic profiling of cfDNA appears as a powerful tool for both detection of tRCC and discrimination from ccRCC/healthy plasma, with potential implications for diagnosis and guiding therapy.
55 Influence of gender on immunosurveillance in a novel mouse model of clear cell renal cell carcinoma
Authors: Zheng Ms Doris 
Published: August 2024

Abstract

Background
Renal Cell Carcinoma (RCC) is a cancer that exhibits sex dimorphism. Males have twice the incidence rate of their female counterparts and more than twice the mortality rate. They frequently present with larger, higher-grade tumors, greater metastatic spread, and earlier diagnosis of disease. Many hormonal, genetic, and environmental reasons have been explored, however a considerable amount of uncertainty remains.

Methods
Here, we explored the immunologic differences using a novel syngeneic mouse model of ccRCC. Tumors were orthotopically implanted by sub-renal capsular injection in immunocompetent WT C57Bl/6 and immunodeficient mice NOD/Scid/Gamma (NSG) mice, and tumor growth was longitudinally monitored using ultrasound imaging. At necropsy, liver and lung metastases were quantified and immune populations in the tumor and peripheral blood were analyzed by flow cytometry.

Results
In the immune-competent model, female mice had lower tumor penetrance as well as delayed tumor growth compared to male mice. In contrast, in the immune-deficient model female mice had similar tumor penetrance and growth rates as males suggesting that the female immune system may be protective against tumor development. No metastases were seen in either sex in the immune-competent model, whereas both lung and liver masses were found in the immune-deficient model suggesting the immune system is critical for restricting metastatic development. Interestingly, increased lung metastases were observed in females compared with male counterparts in NSG mice, suggesting that perhaps hormonal or other non-adaptive immunity-mediated mechanisms can promote metastatic seeding into the lungs.
Flow cytometry characterization revealed higher peripheral B- and T-cells in females, with a higher CD8/CD4 T-cell ratio. Tumors from females had more activated and cytotoxic CD8 T cells and were more frequently metastatic to the lung compared to male mice.

Conclusions
Our findings suggest sex-related immunologic differences in immunosurveillance and metastatic tropism that warrants further interrogation.
DOD CDMRP Funding: yes
74 Unraveling the Complexities of Obesity in Clear Cell Renal Cell Carcinoma Carcinogenesis
Authors: Rodriguez Olivia , Wride Joseph , Tufts Mathew , Peterson Connor , Quinteros Badí , McRae Elisa , Khanderao Gayatri , Tan Aik Choon , Firpo Matthew , Sanchez Alejandro 
Published: August 2024

Abstract

Background
Obesity has been identified as an established risk factor in the development of clear cell renal cell carcinoma (ccRCC). ccRCC arises from the proximal convoluted tubule (PCT) of the kidney which is also the site of obesity-associated chronic kidney disease. Obesity can lead to chronic cellular insults which may lead to DNA injury and whether these mechanisms are critical to cancer initiation in the kidney is unclear. One potential way that obesity can lead to cancer is by altering lipid metabolism, including increasing circulating saturated fatty acids. In particular, palmitic acid is known to be lipotoxic to proximal tubules of the kidney. Understanding how free fatty acids initiate cancer is critical to understanding the role of obesity in cancer initiation and development. We hypothesize that chronic injury and repair due to excess FFA exposure could lead to ccRCC carcinogenesis and aim to define the metabolic phenotype of obesity associated ccRCC.

Methods
Using publicly available data from The KIRC Cancer Genome Atlas Program (TCGA) and clinicopathologic data, we compared the RNAseq profiles of obese (BMI &gt;= 30) to normal weight (BMI =&lt; 25) sample origins. Of the 337, a total of 333 had BMI available for analysis. We evaluated differences in Hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Using DESeq, we adjusted for age and sex. In vitro, HK PCT cells were cultured in DMEM+10%FBS treated with bovine serum albumin (BSA)-palmitic acid complex for 48 hrs. We measured cell viability using Alamar Blue. Results were normalized to controls with BSA only. We extracted protein and performed western blots to identify DNA damage (pATM, H2AX) and endoplasmic reticulum stress (ATF4, eFI2alpha).

Results
Most of the patients in our clinical data cohort are male (64.4%), while 45.4% of patients are categorized by BMI as obese and 33.2% are categorized as normal. We utilized 333 individuals from the Kyoto Encyclopedia of Genes and Genomes (KEGG) to link genomic information to pathways associated with fatty acid metabolism as well as other cancer-associated hallmark metabolic pathways. We confirmed that excess free fatty acid supplementation leads to decreased cell viability in renal proximal tubule cells and renal embryonal cells and aim to assess differences in gene expression and metabolomic variation with fatty acid supplementation.

Conclusions
Through the investigation of these questions, we hope to improve understanding of obesity associated ccRCC and ultimately impact oncological outcomes for patients with this cancer. Understanding changes in lipid metabolism around ccRCC initiation will help identify novel pathways for pharmacologic intervention at earlier stages of the disease.
DOD CDMRP Funding: yes
Conflicting identities: cosmopolitan or anxious? Appreciating concerns of host country population improves attitudes towards immigrants
Authors: Heidland Tobias , Wichardt Philipp C 
Published: August 2024

Abstract
This paper connects insights from the literature on cosmopolitan worldviews and the effects of perspective-taking in political science, (intergroup) anxiety in social psychology, and identity economics in a vignette-style experiment. In particular, we asked German respondents about their attitudes towards a Syrian refugee, randomizing components of his description (N = 662). The main treatment describes the refugee as being aware of and empathetic towards potential worries in the German population about cultural change, costs, and violence associated with refugee inflows. This perspective-taking by the refugee increases the reported ability to empathize with the refugee and, especially for risk-averse people, reported sympathy and trust. We argue that acknowledging the potential concerns of the host population relieves the tension between an anxious and a cosmopolitan/open part of people’s identities. Moreover, relieved tension renders people less defensive; i.e. when one aspect of identity is already acknowledged (expressing anxieties), it has less influence on actual behavior (expressing sympathy). In addition, previous contact with foreigners and a higher willingness to take risks are important factors in determining an individual’s willingness to interact with refugees.
G protein coupled receptor in apoptosis and apoptotic cell clearance
Authors: Li Xinyan , Li Chao , Kang Yang , Zhang Rui , Li Peiyao , Zheng Qian , Wang Hui , Xiao Hui , Yuan Lei 
Published: August 2024

AbstractApoptosis is a genetically programmed form of cell death that is substantially conserved across the evolutionary tree. Apoptotic cell elimination includes recognition, phagocytosis, and degradation. Failure to clear apoptotic cells can ultimately cause a series of human diseases, such as systemic lupus erythematosus, Alzheimer's disease, atherosclerosis, and cancer. Consequently, the timely and effective removal of apoptotic cells is crucial to maintaining the body's homeostasis. GPCRs belong to the largest membrane receptor family. Its intracellular domain exerts an effect on the trimer G protein. By combining with a variety of ligands, the extracellular domain of G protein initiates the dissociation of G protein trimers and progressively transmits signals downstream. Presently, numerous G protein‐coupled receptors (GPCRs) have been identified as participants in the apoptosis signal transduction pathway and the apoptotic cell clearance pathway. Therefore, studies on the mechanism of GPCRs in the clearance of apoptotic cells is important for the development of GPCRs therapeutics.
The Influence of Adolescent Health-related Behaviors on Degenerative Low Back Pain Hospitalizations and Surgeries in Adulthood
Authors: Vaajala Matias , Teuho Alisa , Liukkonen Rasmus , Ponkilainen Ville , Rimpelä Arja , Koivusilta Leena K. , Mattila Ville M. 
Published: August 2024

Study Design.
Retrospective longitudinal study.

Objective.
This study aims to investigate the influence of adolescent health-related behaviors (physical activity, high BMI, drunkenness, smoking), self-reported chronic disease, and low socioeconomic status (SES) on the development of low back pain requiring hospitalization or surgery.

Background.
The baseline data were surveys gathered biennially in 1981–1997 (the Adolescent Health and Lifestyle Survey) and individually linked with outcome data, degenerative low back pain hospitalizations, and spine surgeries retrieved from the Care Register for Health Care. A total of 47,724 participants were included. Explanatory variables included physical activity, high BMI, smoking, monthly drunkenness, chronic diseases, and family SES.

Materials and Methods.
A logistic regression model was used to analyze the influence of adolescent health-related behaviors (physical activity, high BMI, drunkenness, smoking), self-reported chronic disease, and low SES on degenerative low back pain hospitalization, lumbar disc herniation (LDH) hospitalization, and/or spine surgery. Covariates were selected using directed acyclic graphs (DAGs).

Results.
A total of 5538 participants had degenerative low back pain hospitalizations, 2104 had LDH hospitalizations, and 913 had spinal surgery over an average of 27-year follow-up. High BMI [adjusted odds ratio (aOR): 1.25, CI: 1.12–1.38], smoking (aOR: 1.53, CI: 1.43–1.62), monthly drunkenness (aOR: 1.17, CI: 1.10–1.26), and chronic diseases (aOR: 1.47, CI: 1.35–1.61) in adolescence increased the odds of hospitalizations during follow-up. In addition, high BMI (aOR: 1.37, CI: 1.09–1.72), smoking (aOR: 1.40, CI: 1.21–1.61), and monthly drunkenness (aOR: 1.19, CI: 1.01–1.39) increased the odds of spine surgeries.

Conclusions.
We found that smoking, high BMI, monthly drunkenness, chronic diseases, and low family SES in adolescence increased the likelihood of degenerative low back pain hospitalizations in adulthood. In addition, high BMI, smoking, and monthly drunkenness in adolescence increased the odds of spinal surgeries.
Simultaneous Determination of Ripretinib and Its Desmethyl Metabolite in Human Plasma Using LC-MS/MS
Authors: Qian Zhou-Yi , Wang Ping , Wang Zi-Yi , Zhao Yang , Du Tian-Tian , Xu Hao , Wang Yong-Qing , Sun Lu-Ning 
Published: August 2024

Background:
Ripretinib, a recently developed tyrosine kinase inhibitor with switch-control abilities, can inhibit both primary and secondary activation of KIT (KIT proto-oncogene receptor tyrosine kinase) and platelet-derived growth factor receptor alpha (PDGFRA) mutants, which contribute to gastrointestinal stromal tumor progression.

Methods:
In this study, a high-performance liquid chromatography–tandem mass spectrometry method to measure the concentrations of ripretinib and its active desmethyl metabolite DP-5439 in human plasma was developed and validated. Plasma samples were extracted and recovered by precipitation with acetonitrile containing the internal standard and diluted with acetonitrile before analysis. Ripretinib and DP-5439 were separated using chromatography on a Waters ACQUITY UPLC HSS T3 column (2.1 mm × 50 mm, 1.8 μm) with gradient elution using 0.1% formic acid and 5 mM ammonium formate in water as mobile phase A and acetonitrile as mobile phase B. The mobile phase was set to a flow rate of 0.5 mL/min.

Results:
The calibration curves were linear across the following concentration range: 7.5 to 3000 ng/mL for ripretinib and 10 to 4000 ng/mL for DP-5439. The intraday and interday precisions were approximately 15% for all analytes in the quality control samples. The relative matrix effects in extracted plasma samples (90.3%–108.8% at different levels) were considered acceptable.

Conclusions:
This method will be a useful tool in oncology to facilitate the further clinical development of ripretinib.
Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients
Authors: Takahashi Ren , Itohara Kotaro , Nakagawa Shunsaku , Katada Yoshiki , Sugimoto Mitsuhiro , Umemura Keisuke , Matsumura Katsuyuki , Hira Daiki , Tsuda Masahiro , Katsube Yurie , Tanaka Satona , Ohsumi Akihiro , Nakajima Daisuke , Nagao Miki , Date Hiroshi , Terada Tomohiro 
Published: August 2024

Background:
Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients.

Methods:
This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed.

Results:
A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug–drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation.

Conclusions:
This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.
Menopause in adult women with human papillomavirus: health-related quality of life and determinants
Authors: Calvo-Torres Javier , Rejas Javier , Ramírez-Mena Mar , González-Granados Carmen , Bradbury Melissa , del Pino Marta , Procas Beatriz , Rubio-Arroyo Mar , Presa-Lorite Jesús , Gippini Isabel , Fasero María , Fiol Gabriel , Romero Pablo , Cohen Aaron , Coronado Pluvio J. ,   on behalf of the HPV-QoL Study group
Published: August 2024

Abstract

Objective
Human papillomavirus (HPV) infection and menopause entail a considerable impairment in health-related quality of life (HRQoL). The objective of the present study was to analyze the impact of the menopause status on HRQoL in women with HPV infection.

Methods
A cross-sectional, nationwide, multicenter sample of women with HPV infection was conducted throughout clinics of gynecology representative of the Spanish population with regard to age, geographic density, and autonomous regions. Demographic and clinical characteristics and the specific HPV-QoL questionnaire score with its domains were compared according to reproductive status: premenopausal and peri-/postmenopausal. Correlation with other validated patient-reported outcomes measurements was also tested, including General Health Questionnaire-12 (GHQ-12), Female Sexual Function Index (FSFI), and Hospital Anxiety and Depression Scale (HADS).

Results
A sample of 1,016 noninstitutionalized women, aged 18‐80 y, was recorded, 191 (18.8%) peri-/postmenopausal and 825 (81.2%) premenopausal. Total HPV-QoL scoring was significantly lower in peri-/postmenopausal (38.8, 95% CI [35.2-42.4]) compared to premenopausal (46.4, 95% CI [45.0‐47.8]) women, and also in every domain of the scale (P < 0.05), except in social well-being and health domains, with a small effect size of 0.39. In women with sexual dysfunction according to FSFI, adjusted total scoring and domains sexuality, general well-being, and psychological well-being scored significantly higher in premenopause women (P < 0.01), although the magnitude of differences were of small to moderate size.

Conclusions
HRQoL was impaired during menopause in women with HPV infection according to HPV-QoL questionnaire. The sexuality domain was the most differentiating dimension between these populations.
The effects of motivational interviewing on sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction
Authors: Kamalak Hülya , Aksoy Derya Yeşim 
Published: August 2024

Abstract

Objective
This study was conducted to determine the effects of motivational interviewing on sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction.

Methods
This randomized controlled study was conducted with 164 postmenopausal women with sexual dysfunction who presented to the gynecology outpatient clinic of a university hospital in Kahramanmaras, Türkiye (82 experimental, 82 control). The data were collected using a personal information form, the Arizona Sexual Experiences Scale–Female Version Questionnaire, the Sexual Quality of Life–Female Questionnaire, and the Sexual Self-Efficacy Scale. Four motivational interview sessions were conducted with the postmenopausal women in the experimental group at 1-week intervals, and those in the control group did not receive any intervention. The data were analyzed using descriptive statistics, Pearson's chi-squared test, and independent samples and paired samples t tests.

Results
Both the sexual quality of life and sexual self-efficacy levels of the participants in the experimental and control groups were similar in the pretest stage (P > 0.05). After the motivational interviews with those in the experimental group, the rate of sexual dysfunction was determined as 82.9% in the experimental group and 98.8% in the control group. Additionally, after the motivational interviews, the sexual dysfunction scores of the participants in the experimental group decreased significantly, and their sexual quality of life and sexual self-efficacy levels increased significantly compared to those in the control group (P < 0.001).

Conclusions
The results of this study revealed that motivational interviewing decreased sexual dysfunction and increased sexual quality of life and sexual self-efficacy in postmenopausal women with sexual dysfunction.
Simulating the Morphological Changes of Facial Deformities after Using 3D-printed Polyether Ether Ketone Facial Implants
Authors: Ahmad Ahmad Fayez , Yacoub Hekmat , Khalil Ali 
Published: August 2024

Background:
Patient-specific implants (PSIs) have been presented as an effective solution for diseases that require reconstruction. PSIs are designed to precisely fit anatomical defects or deformities in terms of shape and size. In addition to the possibility of predicting the results of surgery regarding soft tissue changes.

Methods:
A research sample consisting of 10 patients with facial deformities underwent maxillofacial reconstructive surgery between 2020 and 2021 in the Tishreen University Hospital, Syria. All patients underwent computed tomography scans; then, the design of the required facial implant was carried out, and the three-dimensional soft tissues were reconstructed using the ExoCad 3.0 program based on the computed tomography. The final form of the facial implant was printed from polyether ether ketone, and then surgical work was performed. The patients were followed up after 6 months. Then, a comparison was made between the virtual design and the real result.

Results:
The absolute difference between the expected soft tissue changes result and the actual result did not exceed three-tenths for all patients, and only two of 10 patients had measurements higher than 20%.

Conclusions:
This technique can be relied upon with the placement of implants to predict the outcome of the surgical procedure in terms of morphological changes in the facial soft tissues covering PSI polyether ether ketone. Therefore, it is possible to make a virtual design based on the cosmetic requirements of the patient.