bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer
Authors: Blanc-Durand Félix , Tang Roseline , Pommier Margaux , Nashvi Marzieh , Cotteret Sophie , Genestie Catherine , Le Formal Audrey , Pautier Patricia , Michels Judith , Kfoury Maria , Hervé Robert , Mengue Sylvie , Wafo Estelle , Elies Antoine , Miailhe Gregoire , Uzan Jennifer , Rouleau Etienne , Leary Alexandra 
Published: April 2023

Abstract

Purpose:
Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance.

Experimental Design:
This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.

Results:
Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P &lt; 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.

Conclusions:
Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.
See related commentary by Garg and Oza, p. 2957
Preclinical Evaluation of ON203, A Novel Bioengineered mAb Targeting Oxidized Macrophage Migration Inhibitory Factor as an Anticancer Therapeutic
Authors: Rossmueller Gregor , Mirkina Irina , Maurer Barbara , Hoeld Verena , Mayer Julia , Thiele Michael , Kerschbaumer Randolf J. , Schinagl Alexander 
Published: April 2023

Abstract
High levels of macrophage migration inhibitory factor (MIF) in patients with cancer are associated with poor prognosis. Its redox-dependent conformational isoform, termed oxidized MIF (oxMIF), is a promising tumor target due to its selective occurrence in tumor lesions and at inflammatory sites. A first-generation anti-oxMIF mAb, imalumab, was investigated in clinical trials in patients with advanced solid tumors, where it was well tolerated and showed signs of efficacy. However, imalumab has a short half-life in humans, increased aggregation propensity, and an unfavorable pharmacokinetic profile. Here, we aimed to optimize imalumab by improving its physicochemical characteristics and boosting its effector functions. Point mutations introduced into the variable regions reduced hydrophobicity and the antibodies’ aggregation potential, and increased plasma half-life and tumor accumulation in vivo, while retaining affinity and specificity to oxMIF. The introduction of mutations into the Fc region known to increase antibody-dependent cellular cytotoxicity resulted in enhanced effector functions of the novel antibodies in vitro, whereas reduced cytokine release from human peripheral blood mononuclear cells in the absence of target antigen by the engineered anti-oxMIF mAb ON203 versus imalumab reveals a favorable in vitro safety profile. In vivo, ON203 mAb demonstrated superior efficacy over imalumab in both prophylactic and established prostate cancer (PC3) mouse xenograft models. In summary, our data highlight the potential of the second-generation anti-oxMIF mAb ON203 as a promising immunotherapy for patients with solid tumors, warranting clinical evaluation.
Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors
Authors: Khlebus Eleonora , Vuttaradhi Veena K. , Welte Thomas , Khurana Namrata , Celestino Joseph , Beird Hannah C. , Gumbs Curtis , Little Latasha , Legarreta Alejandra Flores , Fellman Bryan M. , Nguyen Tri , Lawson Barrett , Ferri-Borgogno Sammy , Mok Samuel C. , Broaddus Russell R. , Gershenson David M. , Futreal P. Andrew , Hillman R. Tyler 
Published: April 2023

Abstract

Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets.

Implications:
Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.
Stressful Life Events, Social Support, and Incident Breast Cancer by Estrogen Receptor Status
Authors: Lawrence Wayne R. , McDonald Jasmine A. , Williams Faustine , Shiels Meredith S. , Freedman Neal D. , Lin Ziqiang , Magnani Jared W. 
Published: April 2023

Abstract

Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. Using the Women's Health Initiative study, we included 76,951 postmenopausal women followed for events for a median of 16.7 years to investigate the association between baseline self-reported stressful life events and incident breast cancer by ER status and whether the association was modified by social support. We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate HRs and 95% confidence intervals (95%CI). The mean age was 63 (SD, 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared with women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs. Quartile 1; HR = 1.30; 95%CI, 1.01–1.68; Ptrend = 0.050). Moreover, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR = 2.39; 95%CI, 1.29–4.44; Pinteraction&lt;0.001). Association between stressful life events and ER-negative breast cancer was not modified by social support. In this cohort of postmenopausal women, higher experiences of prediagnostic stressful life events were associated with increased risk of ER-negative breast cancer.

Prevention Relevance:
Epidemiologic studies on the association between psychosocial stress and breast cancer risk remain inconsistent, while investigation of whether the association differs by ER status is limited. In this prospective cohort of postmenopausal women, high experiences of stressful life events were positively associated with ER-negative disease but not ER-positive.
Converging on a Cure: The Roads to Predictive Immunotherapy
Authors: Stein-O'Brien Genevieve L. , Le Dung T. , Jaffee Elizabeth M. , Fertig Elana J. , Zaidi Neeha 
Published: April 2023

Summary:
Convergence science teams integrating clinical, biological, engineering, and computational expertise are inventing new forecast systems to monitor and predict evolutionary changes in tumor and immune interactions during early cancer progression and therapeutic response. The resulting methods should inform a new predictive medicine paradigm to select adaptive immunotherapeutic regimens personalized to patients’ tumors at a given time during their cancer progression for durable patient response.
Data from METTL3-Mediated m<sup>6</sup>A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
Authors: Wu Yiming , Jin Meiling , Fernandez Mike , Hart Kevyn L. , Liao Aijun , Ge Xinzhou , Fernandes Stacey M. , McDonald Tinisha , Chen Zhenhua , Röth Daniel , Ghoda Lucy Y. , Marcucci Guido , Kalkum Markus , Pillai Raju K. , Danilov Alexey V. , Li Jingyi Jessica , Chen Jianjun , Brown Jennifer R. , Rosen Steven T. , Siddiqi Tanya , Wang Lili 
Published: April 2023

<div>Abstract<p>RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) on mRNA. <i>METTL3</i> is essential for cell growth <i>in vitro</i> and <i>in vivo</i> and controls splicing factor protein expression in a methyltransferase-dependent manner through m<sup>6</sup>A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m<sup>6</sup>A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.</p>Significance:<p>METTL3 controls widespread splicing factor abundance via translational control of m<sup>6</sup>A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL.</p><p><i><a href="https://aacrjournals.org/bloodcancerdiscov/article/doi/10.1158/2643-3230.BCD-23-0035" target="_blank">See related commentary by Janin and Esteller.</a></i></p></div>
RAB27B Drives a Cancer Stem Cell Phenotype in NSCLC Cells Through Enhanced Extracellular Vesicle Secretion
Authors: Meneses Kayleah M. , Pandya Prita , Lindemann Jennifer A. , Al-Qasrawi Dania S. , Argo Ryan A. , Weems Celeste M. , Beetler Danielle J. , Vijay Geraldine V. , Yan Irene K. , Wolfram Joy , Patel Tushar , Justilien Verline 
Published: April 2023

Cancer stem cells (CSC) within non–small cell lung carcinoma (NSCLC) tumors drive NSCLC progression, metastasis, relapse, and intrinsic chemoresistance. Understanding the mechanisms that support the malignant phenotypes of NSCLC CSCs may provide insights for improved NSCLC therapeutic interventions. Here, we report that expression of RAB27B, a small GTPase, is significantly upregulated in NSCLC CSCs when compared with bulk cancer cells (BCC). Short hairpin RNA–mediated knockdown of RAB27B leads to a loss of stem cell marker gene expression and reduced NSCLC spheroid growth, clonal expansion, transformed growth, invasion, and tumorigenicity. We find that NSCLC CSCs secrete significantly more extracellular vesicles (EV) than BCCs, and that this is RAB27B-dependent. Furthermore, CSC-derived EVs, but not BCC-derived EVs, induce spheroid growth, clonal expansion, and invasion in BCCs. Finally, RAB27B is required for CSC-derived EV-induced stemness in BCCs. Taken together, our results indicate that RAB27B is required for maintenance of a highly tumorigenic, cancer-initiating, invasive stem-like cell population in NSCLC and RAB27B is involved in propagating EV-mediated communication from NSCLC CSCs to BCCs. Our findings further suggest that inhibition of RAB27B-dependent EV secretion may be a potential therapeutic strategy for NSCLC.Significance:Expression of RAB27B in CSCs leads to elevated levels of EVs that mediate communication between CSCs and BCCs that maintains a stem-like phenotype in NSCLC cells.
MOLECULAR DOCKING ANALYSIS OF SELECTED CURCUMA XANTHORRHIZA CONSTITUENTS AS POTENTIAL ANTICANCER DRUG
Authors: Endang Zainal Hasan Akhmad , Artika I Made , Suryani  , Luthfi Ramadhani Dhani 
Published: April 2023

Stress conditions will trigger the histone hyperacetylation process due to histone acetyltransferase p300/CBP (HAT PCAF) constantly transfers acetyl groups from acetyl-CoA to conserved lysine residues on histone proteins to form ε-N-acetyllysine. This can be a cause of cancer. The purpose of this study was to investigate the potential mechanisms and inhibition of PCAF HAT by chemical components of C. xanthorrhiza namely, curcumin, demethoxycurcumin, bisdemethoxycurcumin, and xanthorrizhol using in silico, the molecular docking method. Results showed that the components of C. xanthorrhiza as ligands have the capability to inhibit the binding of acetyl-CoA to histone. These results can be used to predict the inhibitory mechanisms exhibited by C. xanthorrhiza components, as competitive and noncompetitive substances. We hypothesize that C. xanthorrhiza components resemble a substrate, leading to prevention of the natural substrate (histone) to bind to the enzyme, and hence block the product formation. The smallest free Gibs energy was exhibited by curcumin on chain B and by bismethoxycurcumin on chain A, with values of -8.8 and -8.4 Kcal/mol, respectively.
Clinical Outcome After Left Ventricular Thrombus Resolution: Who Needs Long‐Term or Lifetime Use of Anticoagulants?
Authors: Zhou Xiao‐Dong , Chen Qin‐Fen , Katsouras Christos S. , Nijjar Prabhjot S. , Zheng Kenneth I. , Zhu Haihui , Gong Mengge , Lin Qingcheng , Jin Youkai , Huang Weijian , Shan Peiren 
Published: April 2023

Background
Patients with left ventricular thrombus (LVT) resolution can have LVT recurrence and risk for thromboembolism. However, these outcomes after LVT resolution are not well known. We aimed to assess the prevalence, risk factors, and clinical outcomes for LVT recurrence in patients with LVT resolution to inform follow‐up and treatment.

Methods and Results

Patients with LVT resolution were identified retrospectively from a large echocardiography database between January 2009 and May 2022. Participants had echocardiograms at 3 time points, including baseline at LVT diagnosis, at LVT resolution, and a follow‐up for identification of LVT recurrence. The cumulative LVT recurrence rate was estimated by the Kaplan–Meier method, and predictors of LVT recurrence were evaluated using Cox regression analysis. Among 115 patients with LVT resolution, 28 (24.3%) had LVT recurrence at a median follow‐up of 1.2 (0.5–2.8) years. LV aneurysm (hazard ratio [HR], 2.59 [95% CI, 1.20–5.58],
P
=0.015) and anticoagulant use (HR, 0.12 [95% CI, 0.04–0.41],
P
=0.001) were predictors of LVT recurrence on multivariable analysis. Patients with an LV aneurysm who did not receive any anticoagulation demonstrated an LVT recurrence rate of 69.5%, whereas those without an LV aneurysm who received anticoagulation had a recurrence rate of 0%. Patients with LVT recurrence had a higher incidence of an embolic event (10.7% versus 1.1%,
P
=0.016).

Conclusions
LVT recurrence after LVT resolution is common, especially in those with an LV aneurysm, and is associated with a higher embolic risk. Continued anticoagulation is protective against LVT recurrence, although bleeding risk needs to be considered. These findings can inform follow‐up and treatment of patients with documented LVT resolution.
Tomographic 3D ultrasound for grading stenosis of superficial femoral artery
Authors: Alzahrani Adel , Sultan Salahaden R , Aslam Mohammed 
Published: April 2023

Introduction Treatment decision of lower extremity peripheral arterial disease (PAD) is governed by the severity of stenosis. Tomographic 3D ultrasound (t3DUS) is a reliable imaging technique for measuring vessel stenosis. In this study we attempted to provide a precise measurement of superficial femoral artery (SFA) stenosis using t3DUS in patients with PAD. Methods t3DUS was used to measure maximum stenosis percentage in SFA from 50 patients with lower extremity PAD. The maximum stenosed segment in SFA was defined using Duplex 2DUS aliasing was noted. The peak systolic velocity (PSV) was measured at the maximum stenotic site and proximal to aliasing for calculating the velocity ratio. The association between blood flow velocity ratio and the degree of stenosis measured using Duplex 2DUS and t3DUS, respectively, was assessed using Spearman rank correlation. Results There was a strong positive correlation between velocity ratio and degree of stenosis in SFA measured using t3DUS (correlation value (r) = 0.99, p < 0.001). The correlation between Stenosis percentage and velocity ratio in SFA are as followed: <50:<2; 50–54:2–2.4; 55–59:2.5–2.9; 60–64:3–3.4; 65–69:3.5–3.9; 70–74:4–4.4; 75–79:4.5–4.9; >80:>5. t3DUS can be used to provide precise measurement of the severity of SFA stenosis in patients with lower extremities arterial disease. The established criteria for grading SFA stenosis in this study can be applied to the current practice alongside Duplex 2DUS as it showed a strong positive correlation with velocity ratio. Further studies investigating the sensitivity and specificity of t3DUS in the assessment of stenosis in lower limbs arteries are required.
The Relationship Between the Joint Space and Outcomes After Hip Arthroscopic Surgery for Femoroacetabular Impingement: Reevaluating the 2-mm Rule
Authors: Ruzbarsky Joseph J. , Comfort Spencer M. , Lee Simon , Pierpoint Lauren A. , Philippon Marc J. 
Published: April 2023

Background: A limited joint space (<2 mm) is associated with poorer outcomes and conversion to total hip arthroplasty (THA) after hip arthroscopic surgery. As indications for hip arthroscopic surgery expand, it is important to reevaluate established risk factors among large patient populations. Purpose: To reevaluate the relationship between the radiographic joint space and outcomes after hip arthroscopic surgery and to assess the validity of a joint space of 2 mm as the accepted cutoff for successful hip arthroscopic surgery. Study Design: Cohort study; Level of evidence, 3. Methods: Patients aged 18 to 50 years who underwent hip arthroscopic surgery for femoroacetabular impingement between January 2008 and December 2016 and had a minimum 2-year follow-up were included. Patients with previous ipsilateral hip surgery, a history of hip fractures, dysplasia (lateral center-edge angle <20°), or osteoarthritis (Tonnis grade >2) were excluded. The joint space was categorized as diminished (≤2 mm), borderline (>2 to ≤3 mm), or preserved (>3 mm). Minimum 2-year patient-reported outcomes (modified Harris Hip Score [mHHS], Hip Outcome Score–Activities of Daily Living [HOS-ADL], Hip Outcome Score–Sports-Specific Subscale [HOS-SSS]), revision rates, and rates of conversion to THA were compared between groups. Results: A total of 699 patients (782 hips) with a mean age of 33.8 ± 10.1 years met 2-year inclusion criteria. The mean follow-up time was 4.2 ± 2.1 years. Overall, 51 hips (6.5%) had a diminished joint space, 297 (38.0%) had a borderline joint space, and 434 (55.5%) had a preserved joint space. Patients with a diminished joint space had larger femoral and acetabular defects compared with those with larger joint spaces. All groups had improved patient-reported outcome scores compared with baseline ( P < .001 for all), and there were no differences between the groups in the percentage of patients who reached the minimal clinically important difference or patient acceptable symptom state. There were also no differences between the groups in revision rates ( P = .95). A greater number of hips with a diminished joint space converted to THA (n = 8 [15.7%]) compared with those with a borderline (n = 9 [3.0%]) or preserved (n = 9 [2.1%]) joint space ( P < .001). Considering joint space as a continuous variable, adjusted logistic regression showed that for every millimeter decrease in the joint space, the odds of conversion to THA increased by a factor of 2.5 (odds ratio, 2.5 [95% CI, 1.6-3.8]). Conclusion: This study demonstrated that patients with a diminished joint space were at a higher risk of conversion to THA. Although 2 mm should not serve as a strict cutoff, patients should be counseled based on their preoperative radiographic findings accordingly.
Factors affecting intradialytic hepatic oxygenation: Associations between ultrafiltration rate and changes in systemic blood pressure
Authors: Ookawara Susumu , Ito Kiyonori , Ueda Yuichiro , Minato Saori , Kaneko Shohei , Hirata Momoko , Kitano Taisuke , Miyazawa Haruhisa , Hirai Keiji , Morishita Yoshiyuki 
Published: April 2023

Introduction: Hepato-splanchnic circulation influences the oxygenation of abdominal organs and is important in preventing a reduction in intradialytic blood volume. However, the association between changes in intradialytic hepato-splanchnic circulation and clinical factors remain unknown. Methods: We enrolled 91 hemodialysis (HD) patients (20 with intradialytic hypotension (IDH) and 71 without IDH). During HD, hepatic regional oxygen saturation (rSO2), a marker of hepatic oxygenation reflecting hepato-splanchnic circulation and oxygenation, was monitored. Changes in hepatic rSO2 at the lowest systolic blood pressure (BP) during HD were analyzed to identify associations with clinical factors. Results: Hepatic rSO2 levels were 55.8 ± 15.3% before HD and 53.8 ± 14.9% at the lowest systolic BP; therefore, % changes in hepatic rSO2 were −2.7 ± 11.3%. These values were significantly lower in patients with IDH than in those without IDH (−13.8 ± 9.3% vs 0.4 ± 9.8%, p < 0.001). Multivariable regression analysis showed that % changes in hepatic rSO2 were independently associated with % changes in systolic BP (standardized coefficient: 0.416) and ultrafiltration rate (−0.206). Furthermore, % changes in mean BP (0.304) were identified as affecting % changes in hepatic rSO2 instead of those in systolic BP. Conclusions: Changes in intradialytic hepatic oxygenation is associated with ultrafiltration rate and changes in systemic BP. Further studies are required to clarify the directionality of the association between changes in hepatic oxygenation and changes in systemic BP during HD.