Search

Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX)., Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA ( NR3C1 ) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography., Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response., Conclusion: The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy., Competing Interests: JTV is currently an employee of GlaxoKlineSmith. GFF reports honorarium for talk from Curio Science, advisory board for GSK, uncompensated advisory board for TTC, and PI of industry-sponsored study for Corcept, Abbvie, Genentech/Roche, Tesaro/GSK, Syndax, 47 inc, Iovance, Syros, Astex, Merck, Sanofi, Sermonix, Compugen, INcyte, Hoffman LaRoche, Eisai. The authors acknowledge supply of Relacorilant from Corcept Therapeutics. SDC and The University of Chicago have been issued patents on methods of measuring GR expression in triple-negative breast cancer (TNBC) and using GR antagonists in TNBC and prostate cancer., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: As primary care populations age, timely identification of palliative care need is becoming increasingly relevant. Previous studies have targeted particular patient populations with life-limiting disease, but few have focused on patients in a primary care setting. Toward this end, we propose a stepped-wedge pragmatic randomized trial whereby a machine learning algorithm identifies patients empaneled to primary care units at Mayo Clinic (Rochester, Minnesota, United States) with high likelihood of palliative care need., Methods: 42 care team units in 9 clusters were randomized to 7 wedges, each lasting 42 days. For care teams in treatment wedges, palliative care specialists review identified patients, making recommendations to primary care providers when appropriate. Care teams in control wedges receive palliative care under the standard of care., Discussion: This pragmatic trial therefore integrates machine learning into clinical decision making, instead of simply reporting theoretical predictive performance. Such integration has the possibility to decrease time to palliative care, improving patient quality of life and symptom burden., Trial Registration: Clinicaltrials.gov NCT04604457 , restrospectively registered 10/26/2020., Protocol: v0.5, dated 9/23/2020., (© 2023. The Author(s).)

Objective: To estimate rates and identify factors associated with asymptomatic COVID-19 in the population of Olmsted County during the prevaccination era., Patients and Methods: We screened first responders (n=191) and Olmsted County employees (n=564) for antibodies to SARS-CoV-2 from November 1, 2020 to February 28, 2021 to estimate seroprevalence and asymptomatic infection. Second, we retrieved all polymerase chain reaction (PCR)-confirmed COVID-19 diagnoses in Olmsted County from March 2020 through January 2021, abstracted symptom information, estimated rates of asymptomatic infection and examined related factors., Results: Twenty (10.5%; 95% CI, 6.9%-15.6%) first responders and 38 (6.7%; 95% CI, 5.0%-9.1%) county employees had positive antibodies; an additional 5 (2.6%) and 10 (1.8%) had prior positive PCR tests per self-report or medical record, but no antibodies detected. Of persons with symptom information, 4 of 20 (20%; 95% CI, 3.0%-37.0%) first responders and 10 of 39 (26%; 95% CI, 12.6%-40.0%) county employees were asymptomatic. Of 6020 positive PCR tests in Olmsted County with symptom information between March 1, 2020, and January 31, 2021, 6% (n=385; 95% CI, 5.8%-7.1%) were asymptomatic. Factors associated with asymptomatic disease included age (0-18 years [odds ratio {OR}, 2.3; 95% CI, 1.7-3.1] and >65 years [OR, 1.40; 95% CI, 1.0-2.0] compared with ages 19-44 years), body mass index (overweight [OR, 0.58; 95% CI, 0.44-0.77] or obese [OR, 0.48; 95% CI, 0.57-0.62] compared with normal or underweight) and tests after November 20, 2020 ([OR, 1.35; 95% CI, 1.13-1.71] compared with prior dates)., Conclusion: Asymptomatic rates in Olmsted County before COVID-19 vaccine rollout ranged from 6% to 25%, and younger age, normal weight, and later tests dates were associated with asymptomatic infection., (© 2022 The Authors.)

Background: Formalin-fixed, paraffin-embedded (FFPE) tissues have many advantages for identification of risk biomarkers, including wide availability and potential for extended follow-up endpoints. However, RNA derived from archival FFPE samples has limited quality. Here we identified parameters that determine which FFPE samples have the potential for successful RNA extraction, library preparation, and generation of usable RNAseq data., Methods: We optimized library preparation protocols designed for use with FFPE samples using seven FFPE and Fresh Frozen replicate pairs, and tested optimized protocols using a study set of 130 FFPE biopsies from women with benign breast disease. Metrics from RNA extraction and preparation procedures were collected and compared with bioinformatics sequencing summary statistics. Finally, a decision tree model was built to learn the relationship between pre-sequencing lab metrics and qc pass/fail status as determined by bioinformatics metrics., Results: Samples that failed bioinformatics qc tended to have low median sample-wise correlation within the cohort (Spearman correlation < 0.75), low number of reads mapped to gene regions (< 25 million), or low number of detectable genes (11,400 # of detected genes with TPM > 4). The median RNA concentration and pre-capture library Qubit values for qc failed samples were 18.9 ng/ul and 2.08 ng/ul respectively, which were significantly lower than those of qc pass samples (40.8 ng/ul and 5.82 ng/ul). We built a decision tree model based on input RNA concentration, input library qubit values, and achieved an F score of 0.848 in predicting QC status (pass/fail) of FFPE samples., Conclusions: We provide a bioinformatics quality control recommendation for FFPE samples from breast tissue by evaluating bioinformatic and sample metrics. Our results suggest a minimum concentration of 25 ng/ul FFPE-extracted RNA for library preparation and 1.7 ng/ul pre-capture library output to achieve adequate RNA-seq data for downstream bioinformatics analysis., (© 2022. The Author(s).)

Background: Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC., Methods: A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC, and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two types of burden tests and adjusted for clinical and technical covariates., Results: After filtering, the variant frequency of SNPs in our sample was highly consistent with population allele frequencies reported in 1 KG/ExAC (0.986, p < 1e-16). The top ten genes found to be nominally associated with later cancer status by four of 12 association methods(p < 0.05) were MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1, although these were not statistically significant in permutation testing. However, all 10 gene-level associations had OR < 1 with lower mutation burden in controls compared to cases, which was marginally statistically significant in permutation testing (p = 0.04). Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p < 0.001)., Conclusions: Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development., (© 2021. The Author(s).)

Predictive models have played a critical role in local, national, and international response to the COVID-19 pandemic. In the United States, health care systems and governmental agencies have relied on several models, such as the Institute for Health Metrics and Evaluation, Youyang Gu (YYG), Massachusetts Institute of Technology, and Centers for Disease Control and Prevention ensemble, to predict short- and long-term trends in disease activity. The Mayo Clinic Bayesian SIR model, recently made publicly available, has informed Mayo Clinic practice leadership at all sites across the United States and has been shared with Minnesota governmental leadership to help inform critical decisions during the past year. One key to the accuracy of the Mayo Clinic model is its ability to adapt to the constantly changing dynamics of the pandemic and uncertainties of human behavior, such as changes in the rate of contact among the population over time and by geographic location and now new virus variants. The Mayo Clinic model can also be used to forecast COVID-19 trends in different hypothetical worlds in which no vaccine is available, vaccinations are no longer being accepted from this point forward, and 75% of the population is already vaccinated. Surveys indicate that half of American adults are hesitant to receive a COVID-19 vaccine, and lack of understanding of the benefits of vaccination is an important barrier to use. The focus of this paper is to illustrate the stark contrast between these 3 scenarios and to demonstrate, mathematically, the benefit of high vaccine uptake on the future course of the pandemic., (Copyright © 2021. Published by Elsevier Inc.)

Repeated measures studies are frequently performed in patient-derived xenograft (PDX) models to evaluate drug activity or compare effectiveness of cancer treatment regimens. Linear mixed effects regression models were used to perform statistical modeling of tumor growth data. Biologically plausible structures for the covariation between repeated tumor burden measurements are explained. Graphical, tabular, and information criteria tools useful for choosing the mean model functional form and covariation structure are demonstrated in a Case Study of five PDX models comparing cancer treatments. Power calculations were performed via simulation. Linear mixed effects regression models applied to the natural log scale were shown to describe the observed data well. A straight growth function fit well for two PDX models. Three PDX models required quadratic or cubic polynomial (time squared or cubed) terms to describe delayed tumor regression or initial tumor growth followed by regression. Spatial(power), spatial(power) + RE, and RE covariance structures were found to be reasonable. Statistical power is shown as a function of sample size for different levels of variation. Linear mixed effects regression models provide a unified and flexible framework for analysis of PDX repeated measures data, use all available data, and allow estimation of tumor doubling time.

Purpose: Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention., Experimental Designs: APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens ( n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates ( n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages., Results: One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival ( P = 0.026) and moderately with overall survival ( P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues., Conclusions: These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types., (©2020 American Association for Cancer Research.)

BRCA1 plays a key role in homologous recombination (HR) DNA repair. Accordingly, changes that downregulate BRCA1, including BRCA1 mutations and reduced BRCA1 transcription, due to promoter hypermethylation or loss of the BRCA1 transcriptional regulator CDK12, disrupt HR in multiple cancers. In addition, BRCA1 has also been implicated in the regulation of metabolism. Here, we show that reducing BRCA1 expression, either by CDK12 or BRCA1 depletion, led to metabolic reprogramming of ovarian cancer cells, causing decreased mitochondrial respiration and reduced ATP levels. BRCA1 depletion drove this reprogramming by upregulating nicotinamide N-methyltransferase (NNMT). Notably, the metabolic alterations caused by BRCA1 depletion and NNMT upregulation sensitized ovarian cancer cells to agents that inhibit mitochondrial metabolism (VLX600 and tigecycline) and to agents that inhibit glucose import (WZB117). These observations suggest that inhibition of energy metabolism may be a potential strategy to selectively target BRCA1-deficient high-grade serous ovarian cancer, which is characterized by frequent BRCA1 loss and NNMT overexpression. SIGNIFICANCE: Loss of BRCA1 reprograms metabolism, creating a therapeutically targetable vulnerability in ovarian cancer., (©2019 American Association for Cancer Research.)

Objectives: Inhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models., Methods: PAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis., Results: The addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive., Conclusions: The addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic., Competing Interests: Dr. Cheryl A. Conover holds a patent(US 8,653,020) on the monoclonal antibody which can selective exosite inhibition of PAPP-A activity against IGFBP-4). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Reports highlighting the problems with the standard practice of using bar graphs to show continuous data have prompted many journals to adopt new visualization policies. These policies encourage authors to avoid bar graphs and use graphics that show the data distribution; however, they provide little guidance on how to effectively display data. We conducted a systematic review of studies published in top peripheral vascular disease journals to determine what types of figures are used, and to assess the prevalence of suboptimal data visualization practices. Among papers with data figures, 47.7% of papers used bar graphs to present continuous data. This primer provides a detailed overview of strategies for addressing this issue by (1) outlining strategies for selecting the correct type of figure depending on the study design, sample size, and the type of variable; (2) examining techniques for making effective dot plots, box plots, and violin plots; and (3) illustrating how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. We also present solutions to other common problems identified in the systematic review. Resources include a list of free tools and templates that authors can use to create more informative figures and an online simulator that illustrates why summary statistics are meaningful only when there are enough data to summarize. Last, we consider steps that investigators can take to improve figures in the scientific literature.

Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that BRCA1 is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote BRCA1 transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces BRCA1 promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors, ZC3H18 and E2F4 mRNA levels are positively correlated with BRCA1 mRNA levels, further supporting ZC3H18 role in regulating BRCA1. Given that ZC3H18 lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that ZC3H18 copy number losses could contribute to HR defects in HGSOC.

Background: Archived formalin fixed paraffin embedded (FFPE) samples are valuable clinical resources to examine clinically relevant morphology features and also to study genetic changes. However, DNA quality and quantity of FFPE samples are often sub-optimal, and resulting NGS-based genetics variant detections are prone to false positives. Evaluations of wet-lab and bioinformatics approaches are needed to optimize variant detection from FFPE samples., Results: As a pilot study, we designed within-subject triplicate samples of DNA derived from paired FFPE and fresh frozen breast tissues to highlight FFPE-specific artifacts. For FFPE samples, we tested two FFPE DNA extraction methods to determine impact of wet-lab procedures on variant calling: QIAGEN QIAamp DNA Mini Kit ("QA"), and QIAGEN GeneRead DNA FFPE Kit ("QGR"). We also used negative-control (NA12891) and positive control samples (Horizon Discovery Reference Standard FFPE). All DNA sample libraries were prepared for NGS according to the QIAseq Human Breast Cancer Targeted DNA Panel protocol and sequenced on the HiSeq 4000. Variant calling and filtering were performed using QIAGEN Gene Globe Data Portal. Detailed variant concordance comparisons and mutational signature analysis were performed to investigate effects of FFPE samples compared to paired fresh frozen samples, along with different DNA extraction methods. In this study, we found that five times or more variants were called with FFPE samples, compared to their paired fresh-frozen tissue samples even after applying molecular barcoding error-correction and default bioinformatics filtering recommended by the vendor. We also found that QGR as an optimized FFPE-DNA extraction approach leads to much fewer discordant variants between paired fresh frozen and FFPE samples. Approximately 92% of the uniquely called FFPE variants were of low allelic frequency range (< 5%), and collectively shared a "C > T|G > A" mutational signature known to be representative of FFPE artifacts resulting from cytosine deamination. Based on control samples and FFPE-frozen replicates, we derived an effective filtering strategy with associated empirical false-discovery estimates., Conclusions: Through this study, we demonstrated feasibility of calling and filtering genetic variants from FFPE tissue samples using a combined strategy with molecular barcodes, optimized DNA extraction, and bioinformatics methods incorporating genomics context such as mutational signature and variant allelic frequency.

Background: More than 1 million women per year in the United States with benign breast biopsies are known to be at elevated risk for breast cancer (BC), with risk stratified on histologic categories of epithelial proliferation. Here we assessed women who had serial benign biopsies over time and how changes in the histologic classification affected BC risk., Methods: In the Mayo Clinic Benign Breast Disease Cohort of 13 466 women, 1414 women had multiple metachronous benign biopsies (10.5%). Both initial and subsequent biopsies were assessed histologically. BC risk for clinical and prognostic factors was assessed using subdistribution models to account for competing risks, and logistic regression/Wilcoxon/chi-square tests to assess covariates. All statistical tests were two-sided., Results: Breast cancer risk for women with serial biopsies, stratified by histologic category in the later biopsies, was similar to women with a single biopsy. We found that changes in histological category between initial and subsequent biopsy statistically significantly impacted BC risk. Women with nonproliferative initial findings and subsequent proliferative findings had an increased risk (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.06 to 2.94, P = .03) compared with no change. Among women with proliferative disease without atypia at initial biopsy, risk decreased if later biopsy regressed to nonproliferative (HR = 0.49, 95% CI = 0.25 to 0.98) and increased if later biopsy showed progression to atypical hyperplasia (HR = 1.49, 95% CI = 0.73 to 3.05) compared with no change ( P = .04)., Conclusions: We found that breast cancer risk increases in women with progressive epithelial proliferation over time and decreases in women whose biopsies show less proliferation. This finding has important implications for effective clinical management of the 100 000 women per year who have multiple benign breast biopsies., (© The Author 2017. Published by Oxford University Press.)

Purpose: Here we assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC). Experimental Design: Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define molecular subtypes of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information. Results: Five molecular subtypes of HGSOC were identified. In the pooled dataset, three subtypes were largely concordant with prior studies describing proliferative, mesenchymal, and immunoreactive tumors (concordance > 70%), and the group of tumors previously described as differentiated type was segregated into two new types, one of which (anti-mesenchymal) had downregulation of genes that were typically upregulated in the mesenchymal subtype. Molecular subtypes were significantly associated with overall survival ( P < 0.001) and with rate of optimal surgical debulking (≤1 cm, P = 1.9E-4) in the pooled dataset. Among stage III-C or IV Mayo Clinic patients, molecular subtypes were also significantly associated with overall survival ( P = 0.001), as well as rate of complete surgical debulking (no residual disease; 16% in mesenchymal tumors compared with >28% in other subtypes; P = 0.02). Conclusions: HGSOC tumors may be categorized into five molecular subtypes that associate with overall survival and the extent of residual disease following debulking surgery. Because mesenchymal tumors may have features that were associated with less favorable surgical outcome, molecular subtyping may have future utility in guiding neoadjuvant treatment decisions for women with HGSOC. Clin Cancer Res; 23(15); 4077-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Atypical hyperplasia (AH) and mammographic breast density (MBD) are established risk factors for breast cancer (BC), but their joint contributions are not well understood. We examine associations of MBD and BC by histologic impression, including AH, in a subcohort of women from the Mayo Clinic Benign Breast Disease Cohort., Methods: Women with a diagnosis of BBD and mammogram between 1985 and 2001 were eligible. Histologic impression was assessed via pathology review and coded as non-proliferative disease (NP), proliferative disease without atypia (PDWA) and AH. MBD was assessed clinically using parenchymal pattern (PP) or BI-RADS criteria and categorized as low, moderate or high. Percent density (PD) was also available for a subset of women. BC and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from date of benign biopsy to BC, death or last contact. Standardized incidence ratios (SIRs) compared the observed number of BCs to expected counts. Cox regression estimated multivariate-adjusted MBD hazard ratios., Results: Of the 6271 women included in the study, 1132 (18.0%) had low MBD, 2921 (46.6%) had moderate MBD, and 2218 (35.4%) had high MBD. A total of 3532 women (56.3%) had NP, 2269 (36.2%) had PDWA and 470 (7.5%) had AH. Over a median follow-up of 14.3 years, 528 BCs were observed. The association of MBD and BC risk differed by histologic impression (p-interaction = 0.03), such that there was a strong MBD and BC association among NP (p < 0.001) but non-significant associations for PDWA (p = 0.27) and AH (p = 0.96). MBD and BC associations for AH women were not significant within subsets defined by type of MBD measure (PP vs. BI-RADS), age at biopsy, number of foci of AH, type of AH (lobular vs. ductal) and body mass index, and after adjustment for potential confounding variables. Women with atypia who also had high PD (>50%) demonstrated marginal evidence of increased BC risk (SIR 4.98), but results were not statistically significant., Conclusion: We found no evidence of an association between MBD and subsequent BC risk in women with AH.

Within ovarian cancer research, patient-derived xenograft (PDX) models recapitulate histologic features and genomic aberrations found in original tumors. However, conflicting data from published studies have demonstrated significant transcriptional differences between PDXs and original tumors, challenging the fidelity of these models. We employed a quantitative mass spectrometry-based proteomic approach coupled with generation of patient-specific databases using RNA-seq data to investigate the proteogenomic landscape of serially-passaged PDX models established from two patients with distinct subtypes of ovarian cancer. We demonstrate that the utilization of patient-specific databases guided by transcriptional profiles increases the depth of human protein identification in PDX models. Our data show that human proteomes of serially passaged PDXs differ significantly from their patient-derived tumor of origin. Analysis of differentially abundant proteins revealed enrichment of distinct biological pathways with major downregulated processes including extracellular matrix organization and the immune system. Finally, we investigated the relative abundances of ovarian cancer-related proteins identified from the Cancer Gene Census across serially passaged PDXs, and found their protein levels to be unstable across PDX models. Our findings highlight features of distinct and dynamic proteomes of serially-passaged PDX models of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI. [ABSTRACT FROM AUTHOR]

Objective: To report the effect of fibrosis on yield of Deoxyribonucleic Acid extraction from Formalin-Fixed Paraffin-Embedded tissue. Study Design: Cross sectional study. Place and Duration of Study: Department of Molecular Pathology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, Jul to Dec 2021. Methodology: Fifty-four Formalin-Fixed Paraffin-Embedded tissues having size <2cm containing fibrosis (Mild, Moderate, Severe) were included in the study. Formalin-Fixed Paraffin-Embedded tissues having tissue size > 2cm were excluded. Deoxyribonucleic Acid was extracted and quantified from Formalin-Fixed Paraffin-Embedded blocks. Results: Nine (17%) Formalin-Fixed Paraffin-Embedded tissues had no fibrosis, 28(51%) had Mild fibrosis, 9(17%) and 8(15%) had Moderate and Severe fibrosis. Measurement scale in 5 different stages for evaluation of our quantified results were used. For specimens with no fibrosis the DNA quantity fel on scale 1, 0(0%); on scale 2, 1(11%); on scale 3, 0(0%); on scale 4, 1(11%); and on scale 5, 7(78%). Deoxyribonucleic Acid yield in moderate fibrosis specimens fel on scale 1, 0(0%)' on scale 2, 7(78%); on scale 3, 0(0%); on scale 4, 1(11%); and on scale 5, 1(11%). Among severe fibrosis the Deoxyribonucleic Acid quantity fal on scale 1, 5(62%); on scale 2, 3(38%); on scale 3, 0(0%); on scale 4, 0(0%); and on scale 5, 0(0%). Conclusion: Formalin-Fixed Paraffin-Embedded tissues having severe fibrosis resulted in significantly lower Deoxyribonucleic Acid yield as compared to Formalin-Fixed Paraffin-Embedded tissues having no fibrosis. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) treatment has reached a milestone with the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors (PARPi) induce breaks in single-stranded and/or double-stranded DNA, resulting in synthetic lethality in cancer cells lacking functional homologous recombination genes. Around 20% to 25% of patients with metastatic castrationresistant prostate cancer harbor mutations in DNA damage repair genes, either somatic or germline. The success of PARPi in these patients has prompted studies exploring its potential in tumors classified as "BRCAness," which refers to tumors without germline BRCA1 or BRCA2 mutations. Additionally, there is a proposed connection between androgen receptor signaling and synthetic lethality of PARPi. The inclusion of genetic mutation tests in the treatment algorithm for PC is a significant step towards precision and personalized medicine, marking a first in the field. The objectives of this review encompass understanding the mechanism of action of PARPi in both monotherapy and combination therapy, exploring patient selection criteria, discussing pivotal studies that led to its approval, and offering future prospects. However, numerous unanswered questions remain, including the identification of the patient population that could benefit most from PARPi, determining whether to use PARPi as monotherapy or in combination, and finding the optimal timing of PARPi administration in advanced or localized disease. To address these questions, several ongoing clinical trials are being conducted. [ABSTRACT FROM AUTHOR]

Background: Mitophagy, a prominent cellular homeostasis process, has been implicated in modulating endothelial cell function. Emerging evidence suggests that extracellular vesicles (EVs) participate in intercellular communication, which could modulate tumor angiogenesis, a hallmark of ovarian cancer (OC) progression. However, the underlying mechanisms through how EVs regulate endothelial mitophagy associated with tumor angiogenesis during OC development remain obscure. Methods: The effect of cancer cell-derived EVs on endothelial mitophagy and its correlation with tumor angiogenesis and OC development were explored by in vitro and in vivo experiments. Multi-omics integration analysis was employed to identify potential regulatory mechanisms of cancer cell-derived EVs on endothelial mitophagy, which is involved in tumor angiogenesis associated with OC development. These insights were then further corroborated through additional experiments. An orthotopic OC mouse model was constructed to assess the antiangiogenic and therapeutic potential of the Indoleamine 2,3 dioxygenase-1 (IDO1) inhibitor. Results: Cancer cell-derived EVs promoted tumor angiogenesis via the activation of endothelial mitophagy, contributing to the growth and metastasis of OC. The aberrantly high expression of IDO1 mediated abnormal tryptophan metabolism in cancer cells and promoted the secretion of l-kynurenine (L-kyn)-enriched EVs, with associated high levels of L-kyn in EVs isolated from both the tumor tissues and patient plasma in OC. EVs derived from IDO1high ovarian cancer cells elevated nicotinamide adenine dinucleotide (NAD +) levels in endothelial cells via delivering L-kyn. Besides, IDO1high ovarian cancer cell-derived EVs upregulated sirt3 expression in endothelial cells by increasing acetylation modification. These findings are crucial for promoting endothelial mitophagy correlated with tumor angiogenesis. Notably, both endothelial mitophagy and tumor angiogenesis could be suppressed by the IDO1 inhibitor in the orthotopic OC mouse model. Conclusions: Together, our findings unveil a mechanism of mitophagy in OC angiogenesis and indicate the clinical relevance of EV enriched L-kyn as a potential biomarker for tumorigenesis and progression. Additionally, IDO1 inhibitors might become an alternative option for OC adjuvant therapy. [ABSTRACT FROM AUTHOR]

Objective: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group. Methods: A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, MLH1 promoter hypermethylation analysis, and germline sequencing to identify pathogenic variants. All patients who were excluded during MSP received germline sequencing for MMR genes to simulate IGS for the detection of LS. Results: Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional MLH1 promoter hypermethylation, bringing the total LS cases to ten (32.3%). Intriguingly, we observed no significant differences in clinical characteristics or overall survival between patients with and without LS in our cohort. Conclusion: Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria. [ABSTRACT FROM AUTHOR]

RNA-Seq analysis of Formalin-Fixed and Paraffin-Embedded (FFPE) samples has emerged as a highly effective approach and is increasingly being used in clinical research and drug development. However, the processing and storage of FFPE samples are known to cause extensive degradation of RNAs, which limits the discovery of gene expression or gene fusion-based biomarkers using RNA sequencing, particularly methods reliant on Poly(A) enrichment. Recently, researchers have developed an exome targeted RNA-Seq methodology that utilizes biotinylated oligonucleotide probes to enrich RNA transcripts of interest, which could overcome these limitations. Nevertheless, the standardization of this experimental framework, including probe designs, sample multiplexing, sequencing read length, and bioinformatic pipelines, remains an essential requirement. In this study, we conducted a comprehensive comparison of three main commercially available exome capture kits and evaluated key experimental parameters, to provide the overview of the advantages and limitations associated with the selection of library preparation protocols and sequencing platforms. The results provide valuable insights into the best practices for obtaining high-quality data from FFPE samples. [ABSTRACT FROM AUTHOR]

In this note, we present an innovative approach called "homologous hypothesis tests" that focuses on cross-sectional comparisons of average tumor volumes at different time-points. By leveraging the correlation structure between time-points, our method enables highly efficient per time-point comparisons, providing inferences that are highly efficient as compared to those obtained from a standard two-sample t test. The key advantage of this approach lies in its user-friendliness and accessibility, as it can be easily employed by the broader scientific community through standard statistical software packages. [ABSTRACT FROM AUTHOR]

Objective: To analyze the clinical and ultrasonic characteristics of breast sclerosing adenosis (SA) and invasive ductal carcinoma (IDC), and construct a predictive nomogram for SA. Materials and methods: A total of 865 patients were recruited at the Second Hospital of Shandong University from January 2016 to November 2022. All patients underwent routine breast ultrasound examinations before surgery, and the diagnosis was confirmed by histopathological examination following the operation. Ultrasonic features were recorded using the Breast Imaging Data and Reporting System (BI-RADS). Of the 865 patients, 203 (252 nodules) were diagnosed as SA and 662 (731 nodules) as IDC. They were randomly divided into a training set and a validation set at a ratio of 6:4. Lastly, the difference in clinical characteristics and ultrasonic features were comparatively analyzed. Result: There was a statistically significant difference in multiple clinical and ultrasonic features between SA and IDC (P<0.05). As age and lesion size increased, the probability of SA significantly decreased, with a cut-off value of 36 years old and 10 mm, respectively. In the logistic regression analysis of the training set, age, nodule size, menopausal status, clinical symptoms, palpability of lesions, margins, internal echo, color Doppler flow imaging (CDFI) grading, and resistance index (RI) were statistically significant (P<0.05). These indicators were included in the static and dynamic nomogram model, which showed high predictive performance, calibration and clinical value in both the training and validation sets. Conclusion: SA should be suspected in asymptomatic young women, especially those younger than 36 years of age, who present with small-size lesions (especially less than 10 mm) with distinct margins, homogeneous internal echo, and lack of blood supply. The nomogram model can provide a more convenient tool for clinicians. [ABSTRACT FROM AUTHOR]

Copyright of Ginecología y Obstetricia de México is the property of Federacion Mexicana de Ginecologia y Obstetricia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Cancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility. Methods: A cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Results: Meta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (PASSET< 5x10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (Padj<0.05, PFDR<0.05). Furthermore, GO pathway analysis identified significant enrichment of synaptic transmission and neuron development pathways shared by all three cancer types. Conclusion: Rare variants and the corresponding genes potentially contribute to shared susceptibility in different GI cancer types. The discovery of these novel variants and genes offers new insights for the carcinogenic mechanisms and missing heritability of GI cancers. [ABSTRACT FROM AUTHOR]

Motivation The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging. Results We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way. When used to analyze tumor growth kinetics over time in 1599 patient-derived xenograft growth curves from ovarian and colorectal cancers, CONNECTOR allowed the aggregation of time-series data through an unsupervised approach in informative clusters. We give a new perspective of mechanism interpretation, specifically, we define novel model aggregations and we identify unanticipated molecular associations with response to clinically approved therapies. Availability and implementation CONNECTOR is freely available under GNU GPL license at https://qbioturin.github.io/connector and https://doi.org/10.17504/protocols.io.8epv56e74g1b/v1. [ABSTRACT FROM AUTHOR]

Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials. [ABSTRACT FROM AUTHOR]

Formalin-fixed paraffin-embedded (FFPE) tissue samples are routinely used in prospective and retrospective studies. It is crucial to obtain high-quality nucleic acid (NA) from FFPE samples for downstream molecular analysis, such as quantitative polymerase chain reaction (PCR), Sanger sequencing, next-generation sequencing, and microarray, in both clinical diagnosis and basic research. The current NA extraction methods from FFPE samples using chemical solvent are tedious, environmentally unfriendly, and unamenable to automation or field deployment. We present a tool for NA extraction from FFPE samples using a high-intensity focused ultrasound (HIFU) technology. A cartridge strip containing reagents for FFPE sample deparaffinization and NA extraction and purification is operated by an automation tool consisting of a HIFU module, a liquid handling robot unit, and accessories including a thermal block and magnets. The HIFU module is a single concaved piezoelectric ceramic plate driven by a current-mode class-D power amplifier. Based on the ultrasonic cavitation effects, the HIFU module provides highly concentrated energy introducing paraffin emulsification and disintegration. The high quantity and quality of NA extracted using the reported system are evaluated by PCR and compared with the quantity and quality of NA extracted using the current standard methods. [ABSTRACT FROM AUTHOR]

Introduction: To examine the reduction of transverse rectal diameter and its effect on bladder dynamics in children with spinal dysraphism.Methods: We prospectively evaluated 61 consecutive children with spinal dysraphism, 25 (41%) boys and 36 (59%) girls, aged 4 to 16 years; mean age 9.3 ± 3.8 years, who received bowel management. All children underwent echosonographic measurement of transverse rectal diameter before and after starting bowel management. Also, all the patients had undergone urodynamic studies before and after starting bowel management, with no changes in their urological treatment.Results: Bowel management caused an decrease in transverse rectal diameter by 56 ± 7.2% (p < 0.001). In addition, a decrease was observed for maximal detrusor pressure by 27.8 ± 7.8% (p < 0.001), leak point pressure by 37.2 ± 4.4% (p < 0.001), and PVR by 36.7 ± 8.0 (p < 0.001). Maximum bladder capacity was significantly increased after bowel management in both non-adjusted (36.4 ± 14.8%; p < 0.001) and adjusted analysis for age (39.4 ± 14.3%, p < 0.001). Detrusor compliance was also increased by 89.2 ± 24.8% (p < 0.001). Female gender and % change of maximal detrusor pressure were significant predictors of transversal rectal diameter change in univariate as well as in multivariate analysis (OR = 10.548, 95% CI 2.309-48.180; p = 0.002 and OR = 1.121, 95% CI 1.009-1.245; p = 0.034).Conclusions: Decrease in transverse rectal diameter may be useful for bladder function and urodynamic findings in children with spinal dysraphism. Therefore, decrease in transverse rectal diameter should be a supplement to standard urotherapy. [ABSTRACT FROM AUTHOR]

Purpose: High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer due to metastasis. CircRNAs are recently identified to be modified by N6-methyladenosine (m6A) in many cells. However, the significance of m6A-modified circular RNAs (circRNAs) has not been elucidated in HGSOC peritoneal metastasis. Here, we aimed to investigate the participation and potential functions of m6A-modified circRNAs in HGSCO peritoneal metastasis. Methods: Cancerous tissues were collected from the in situ and the peritoneal metastasis lesions of HGSCO patients. M6A-tagged circRNAs were identified by m6A-modified RNA immunoprecipitation sequencing (m6A-RIP-seq). Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the potential functions of the m6A-modified circRNAs. Results: For the m6A-modified circRNAs, 259 were upregulated and 227 were downregulated in the peritoneal metastasis than in the situ lesions of HGSCO patients. For the m6A peaks, 1541 were upregulated and 1293 were downregulated in the peritoneal metastasis than in the in situ lesions of HGSCO patients. For the differential expressed circRNAs, 1911(19.6%) were upregulated and 2883(29.6%) were downregulated in the peritoneal metastasis than in the in situ lesions of HGSCO patients. The upregulated m6A-modified circRNAs were associated with the HIF-1 signaling. The downregulated m6Amodified circRNAs were associated with the MAPK signaling. Conclusions: This work firstly identified the transcriptome-wide map of m6Amodified circRNAs in peritoneal metastasis of HGSCO. Our findings provided novel evidences about the participation of m6A-modified circRNAs via HIF-1 and MAPK signaling and a new insight in molecular target of HGSCO peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Translational biomedical research relies on animal experiments and provides the underlying proof of practice for clinical trials, which places an increased duty of care on translational researchers to derive the maximum possible output from every experiment performed. The implementation of open science practices has the potential to initiate a change in research culture that could improve the transparency and quality of translational research in general, as well as increasing the audience and scientific reach of published research. However, open science has become a buzzword in the scientific community that can often miss mark when it comes to practical implementation. In this Essay, we provide a guide to open science practices that can be applied throughout the research process, from study design, through data collection and analysis, to publication and dissemination, to help scientists improve the transparency and quality of their work. As open science practices continue to evolve, we also provide an online toolbox of resources that we will update continually. Open science has become a buzzword in the scientific community that too often misses the practical application for individual researchers. This Essay, provides a guide to choosing the most appropriate tools to make animal research more transparent. [ABSTRACT FROM AUTHOR]

Western blotting is a standard laboratory method used to detect proteins and assess their expression levels. Unfortunately, poor western blot image display practices and a lack of detailed methods reporting can limit a reader's ability to evaluate or reproduce western blot results. While several groups have studied the prevalence of image manipulation or provided recommendations for improving western blotting, data on the prevalence of common publication practices are scarce. We systematically examined 551 articles published in the top 25% of journals in neurosciences (n = 151) and cell biology (n = 400) that contained western blot images, focusing on practices that may omit important information. Our data show that most published western blots are cropped and blot source data are not made available to readers in the supplement. Publishing blots with visible molecular weight markers is rare, and many blots additionally lack molecular weight labels. Western blot methods sections often lack information on the amount of protein loaded on the gel, blocking steps, and antibody labeling protocol. Important antibody identifiers like company or supplier, catalog number, or RRID were omitted frequently for primary antibodies and regularly for secondary antibodies. We present detailed descriptions and visual examples to help scientists, peer reviewers, and editors to publish more informative western blot figures and methods. Additional resources include a toolbox to help scientists produce more reproducible western blot data, teaching slides in English and Spanish, and an antibody reporting template. A systematic assessment of more than 500 articles reveals that western blot figures and methods often omit essential details. The study also provides a collection of recommendations to help scientists avoid common problems, while making their western blot figures and methods more informative, transparent and reproducible. [ABSTRACT FROM AUTHOR]

Ovarian cancer is an aggressive tumor that remains to be the most lethal gynecological malignancy in women. Metabolic adaptation is an emerging hallmark of tumors. It is important to exploit metabolic vulnerabilities of tumors as promising strategies to develop more effective anti-tumor regimens. Tumor cells reprogram the metabolic pathways to meet the bioenergetic, biosynthetic, and mitigate oxidative stress required for tumor cell proliferation and survival. Oxidative phosphorylation has been found to be altered in ovarian cancer, and oxidative phosphorylation is proposed as a therapeutic target for management of ovarian cancer. Herein, we initially introduced the overview of oxidative phosphorylation in cancer. Furthermore, we discussed the role of oxidative phosphorylation and chemotherapeutic resistance of ovarian cancer. The role of oxidative phosphorylation in other components of tumor microenvironment of ovarian cancer has also been discussed. [ABSTRACT FROM AUTHOR]

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently being used for treating breast cancer patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic diseases. Despite durable responses, almost all patients receiving PARPis ultimately develop resistance and succumb to their illness, but the mechanism of PARPi resistance is not fully understood. To better understand the mechanism of PARPi resistance, we established two olaparib-resistant SUM159 and MDA468 cells by chronically exposing olaparib-sensitive SUM159 and MDA468 cells to olaparib. Olaparib-resistant SUM159 and MDA468 cells displayed 5-fold and 7-fold more resistance over their corresponding counterparts. Despite defects in PARPi-induced DNA damage, these olaparib-resistant cells are sensitive to cisplatin-induced cell death. Using an unbiased proteomic approach, we identified 6 447 proteins, of which 107 proteins were differentially expressed between olaparib-sensitive and -resistant cells. Ingenuity pathway analysis (IPA) revealed a number of pathways that are significantly altered, including mTOR and ubiquitin pathways. Among these differentially expressed proteins, p62/SQSTM1 (thereafter p62), a scaffold protein, plays a critical role in binding to and delivering the ubiquitinated proteins to the autophagosome membrane for autophagic degradation, was significantly downregulated in olaparib-resistant cells. We found that autophagy inducers rapamycin and everolimus synergistically sensitize olaparib-resistant cells to olaparib. Moreover, p62 protein expression was correlated with better overall survival in estrogen receptor-negative breast cancer. Thus, these findings suggest that PARPi-sensitive TNBC cells hyperactivate autophagy as they develop acquired resistance and that pharmacological stimulation of excessive autophagy could lead to cell death and thus overcome PARPi resistance. [ABSTRACT FROM AUTHOR]

Cancer cells typically exhibit a tightly regulated program of metabolic plasticity and epigenetic remodeling to meet the demand of uncontrolled cell proliferation. The metabolic–epigenetic axis has recently become an increasingly hot topic in carcinogenesis and offers new avenues for innovative and personalized cancer treatment strategies. Nicotinamide N -methyltransferase (NNMT) is a metabolic enzyme involved in controlling methylation potential, impacting DNA and histone epigenetic modification. NNMT overexpression has been described in various solid cancer tissues and even body fluids, including serum, urine, and saliva. Furthermore, accumulating evidence has shown that NNMT knockdown significantly decreases tumorigenesis and chemoresistance capacity. Most importantly, the natural NNMT inhibitor yuanhuadine can reverse epidermal growth factor receptor tyrosine kinase inhibitor resistance in lung cancer cells. In this review, we evaluate the possibility of NNMT as a diagnostic biomarker and molecular target for effective anticancer treatment. We also reveal the exact mechanisms of how NNMT affects epigenetics and the development of more potent and selective inhibitors. [ABSTRACT FROM AUTHOR]

The goal of performance analysis is to capture the multitude of factors that affect sports strategy, and present them in an informative, interpretable, and accessible format. The aim of this study was to outline a performance analysis process in field hockey that captures, analyses and visualises strategy in layers of detail culminating in the creation of an RStudio Shiny application. Computerised notational analysis systems were developed to capture in-game events and ball tracking data of 74 matches from the Women's Pro League 2019. Game styles were developed using k-means cluster analysis to reduce detailed in-game events into practical profiles to identify the attack types, game actions and tempo of a team's strategy. Ball movement profiles were developed to identify the predictability (entropy) and direction (progression rates) of ball movements, and consequent distribution of possession in different attacking zones. The Shiny application, an interactive web-platform, links the information from simple game profiles with detailed game variables to understand each teams' holistic game plan, how they are different, and how to exploit these differences. The process outlined can be applied to any team invasion sport to understand, develop and communicate successful strategies under different match situations. [ABSTRACT FROM AUTHOR]

The breast and ovarian cancer susceptibility gene (BRCA1) is a tumor suppressor whose mutation has been associated with the development of breast, ovarian and, probably, other malignancies at young ages. The BRCA1 gene product participates in multiple biological pathways including the DNA damage response, transcriptional control, cell growth and apoptosis. Inactivating germline mutations of the BRCA1 gene can be detected in a substantial portion of families with inherited breast and/or ovarian cancer. While the genomic and cancer-related actions of BRCA1 have been extensively investigated, not much information exists regarding the cellular and circulating factors involved in regulation of BRCA1 expression and action. The present review article dissects the emerging role of BRCA1 as an important regulator of various endocrine and metabolic axes. Experimental and clinical evidence links BRCA1 with a number of peptide and steroid hormones. Furthermore, comprehensive analyses identified complex interactions between the insulin/insulin-like growth factor-1 (IGF1) signaling axis and BRCA1. The correlation between metabolic disorders, including diabetes and the metabolic syndrome, and BRCA1 mutations, are discussed in this article. [ABSTRACT FROM AUTHOR]

Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Nuclear receptor subfamily 1 group D member 1 (NR1D1), a nuclear receptor associated with a variety of physiological processes, has a low level in ovarian cancer tissues compared with adjacent normal tissues. However, its role in ovarian cancer remains unclear. Methods: The level of NR1D1 in ovarian cancer cells was determined by quantitative real-time PCR. Its role in ovarian cancer was explored through gain-of-function and lose-of-function. Cell growth was evaluated by CCK8 assay, immunofluorescence and flow cytometry. Western blot was conducted to assess the activation of JAK/STAT3 signaling pathway. A xenograft model of ovarian cancer was established to explore the role of NR1D1 in vivo. Results: Up-regulation of NR1D1 repressed the ovarian cancer cell proliferation and induced cell cycle arrest and apoptosis, while silencing NR1D1 promoted their proliferation and G1/S transition. In addition, the JAK/STAT3 signaling pathway, an intracellular signal transduction closely associated with cancer progression, was inhibited by NR1D1. Consistently, xenografts with NR1D1 over-expression grew more slowly in vivo than the controls. Furthermore, NR1D1 up-regulated the expression of suppressor of cytokine signaling 3 (SOCS3), an inhibitor of the JAK/STAT3 signaling pathway. Whereas, SOCS3 silencing abolished the function of NR1D1 over-expression on ovarian cancer growth and JAK/STAT3 signaling pathway. Conclusions: NR1D1 up-regulated the expression of SOCS3, resulting in suppression of the JAK/STAT3 signaling pathway, thus retarding the growth of ovarian cancer cells. This study highlights a profound role of NR1D1 in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background and Aim: Cancer and in particular Breast cancer are among the diseases that have the highest mortality rate in Iran after heart disease. The accurate prognosis for Breast cancer is important, and the presence of various symptoms and features of this disease makes it difficult for doctors to diagnose. This study aimed to identify the factors affecting Breast cancer, modeling and ultimately diagnosing the risk of Breast cancer. Materials and Methods: In the present study, first, by content analysis and library studies, the effective factors in Breast cancer were identified, then with the help of a team of experts consisting of physicians and subspecialists in Breast oncology and Breast surgery; With the help of the Delphi method, the factors were adjusted and 26 final factors that were numerically correct and string based on local and climatic conditions were approved. Then, according to the final factors and based on the medical records of 5208 patients in the Cancer Research Center of Shahid Beheshti University of medical sciences, to diagnose cancer, Decision Tree, Random Forest, and Support Vector Machine methods were used as machine learning methods. Results: In the first step, by content analysis method, 29 effective factors in Breast cancer were identified. Then, taking into account the indigenous and climatic conditions and using the Delphi method and also using the opinions of 18 Experts during three years, 26 factors were finalized. In the final step, using the medical records of the patients and the results obtained from the three methods mentioned, random forest, had the highest accuracy of 94.75% and precision of 97.26% in diagnosing Breast cancer. It has been noted that, compared to other similar studies, indigenous databases have been exploited, the accuracy obtained has been very close to previous studies, and in many cases much better. Conclusion: Using the random forest method and taking advantage of the factors affecting Breast cancer, the ability to diagnose cancer has been provided with greatest accuracy. [ABSTRACT FROM AUTHOR]