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Disseminated cancer cells in the peritoneal fluid often colonize omental fat-associated lymphoid clusters but the mechanisms are unclear. Here, we identify that innate-like B cells accumulate in the omentum of mice and women with early-stage ovarian cancer concomitantly with the extrusion of chromatin fibers by neutrophils called neutrophil extracellular traps (NETs). Studies using genetically modified NET-deficient mice, pharmacologic inhibition of NETs, and adoptive B cell transfer show that NETs induce expression of the chemoattractant CXCL13 in the pre-metastatic omentum, stimulating recruitment of peritoneal innate-like B cells that in turn promote expansion of regulatory T cells and omental metastasis through producing interleukin (IL)-10. Ex vivo studies show that NETs elicit IL-10 production in innate-like B cells by inactivating SHP-1, a phosphatase that inhibits B cell activation pathways, and by generating reactive oxygen species. These findings reveal that NETs alter immune cell dynamics in the pre-metastatic omentum, rendering this niche conducive for colonization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The fallopian tube undergoes extensive molecular changes during the menstrual cycle and menopause. We use single-cell RNA and ATAC sequencing to construct a comprehensive cell atlas of healthy human fallopian tubes during the menstrual cycle and menopause. Our scRNA-seq comparison of 85,107 pre- and 46,111 post-menopausal fallopian tube cells reveals substantial shifts in cell type frequencies, gene expression, transcription factor activity, and cell-to-cell communications during menopause and menstrual cycle. Menstrual cycle dependent hormonal changes regulate distinct molecular states in fallopian tube secretory epithelial cells. Postmenopausal fallopian tubes show high chromatin accessibility in transcription factors associated with aging such as Jun, Fos, and BACH1/2, while hormone receptors were generally downregulated, a small proportion of secretory epithelial cells had high expression of ESR2, IGF1R, and LEPR. While a pre-menopausal secretory epithelial gene cluster is enriched in the immunoreactive molecular subtype, a subset of genes expressed in post-menopausal secretory epithelial cells show enrichment in the mesenchymal molecular type of high-grade serous ovarian cancer., Competing Interests: Competing interests: E.L. receives research funding to study ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. All other authors declare no competing interest., (© 2025. The Author(s).)

Objective: To describe postpartum visit attendance and postpartum blood pressure control among patients enrolled in a remote patient monitoring program and compare these outcomes by race., Study Design: A prospective cohort study of postpartum patients with a diagnosis of hypertensive disorders of pregnancy at the University of Chicago between October 2021 and April 2022. All patients received remote patient monitoring as routine care but consented separately for the use of their data. Data were obtained from the electronic medical record for up to six weeks postpartum., Main Outcome Measures: The primary outcome was attendance at the first postpartum blood pressure check visit. Secondary outcomes included postpartum blood pressure control, readmissions, and remote patient monitoring response rates. Outcomes were compared by patient-reported race., Results: 545 patients were enrolled in the remote patient monitoring program, of which 306 consented to data collection. 64.7% of patients identified as Black/African American. Attendance for first postpartum blood pressure check was high (overall 84.0%, Black 81.3% and non-Black 88.9%, p = 0.08). The rate of Stage 2 hypertension at six weeks was higher among Black patients than non-Black patients (22.4% vs 2.2%, p < 0.0001). Engagement with remote patient monitoring decreased over the 6-week period, with more attrition among Black patients., Conclusion: There was a high follow-up rate across all patients regardless of race and a decrease in hypertension over the six-week period. However, rates of hypertension were higher, and engagement with the program lower in Black patients, suggesting further work is needed to address this gap., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. Rana reports serving as a consultant to Roche Diagnostics and ThermoFisher Scientific and has received funding from Roche Diagnostics and Siemens for studies related to the use of angiogenic factors in pregnancy which is unrelated to work for this manuscript. All other authors report no conflict of interest]., (Copyright © 2024 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Black women face the highest mortality-to-incidence ratio from high grade serous ovarian cancer (HGSOC). This study investigated biological differences in HGSOC tumors from Black vs. White women. HGSOC from 35 Black and 31 White patients were analyzed by Infinium Methyation-EPIC array and RNA sequencing. 191 CpG sites were differentially methylated (FDR < 0.05, β value change> 10%) and 277 genes were differentially expressed (FDR < 0.05). Gene Ontology identified enriched pathways related to DNA damage response, p53/apoptosis signaling, and cholesterol/lipid metabolism directly connected with genes like INSR, FOXA1 and FOXB1. INSR and FOXA1 knockdown enhanced cisplatin sensitivity and inhibited cell proliferation and colony formation. Tumors from Black patients were infiltrated by fewer CD4+ naïve and regulatory T-cells. Overall, differences in DNA methylation, transcriptomic profiles and immune cell infiltration were detected in tumors from Black vs. White patients. Further investigation is warranted into how these differences may affect treatment response and outcomes in Black women., Competing Interests: Competing interests: The authors declare no potential conflicts of interest., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway ( KRAS , BRAF , and NRAS ), and in genes related to the MAPK pathway ( NF1/2 , EIF1AX, and ERBB2 ). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of CDKN2A mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include USP9X , ARID1A, and PIK3CA, but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research., Competing Interests: Competing interests: LS is a current employee of OmicVision Biosciences ApS. EL receives research funding to study the biology of ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. The remaining authors declare no conflicts of interest., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: Segmentation of ovarian/adnexal masses from surrounding tissue on ultrasound images is a challenging task. The separation of masses into different components may also be important for radiomic feature extraction. Our study aimed to develop an artificial intelligence-based automatic segmentation method for transvaginal ultrasound images that (1) outlines the exterior boundary of adnexal masses and (2) separates internal components., Approach: A retrospective ultrasound imaging database of adnexal masses was reviewed for exclusion criteria at the patient, mass, and image levels, with one image per mass. The resulting 54 adnexal masses (36 benign/18 malignant) from 53 patients were separated by patient into training (26 benign/12 malignant) and independent test (10 benign/6 malignant) sets. U-net segmentation performance on test images compared to expert detailed outlines was measured using the Dice similarity coefficient (DSC) and the ratio of the Hausdorff distance to the effective diameter of the outline ( R HD - D ) for each mass. Subsequently, in discovery mode, a two-level fuzzy c-means (FCM) unsupervised clustering approach was used to separate the pixels within masses belonging to hypoechoic or hyperechoic components., Results: The DSC (median [95% confidence interval]) was 0.91 [0.78, 0.96], and R HD - D was 0.04 [0.01, 0.12], indicating strong agreement with expert outlines. Clinical review of the internal separation of masses into echogenic components demonstrated a strong association with mass characteristics., Conclusion: A combined U-net and FCM algorithm for automatic segmentation of adnexal masses and their internal components achieved excellent results compared with expert outlines and review, supporting future radiomic feature-based classification of the masses by components., (© 2024 The Authors.)

In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we leverage a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. We discovered that the pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/cancer stem cells crosstalk, contributing to the identification of tumor vulnerabilities., (© 2024. The Author(s).)

The temporal and spatial variations of 16 Polycyclic Aromatic Hydrocarbons (PAHs) were examined at multiple sites around Lake Balaton from February 2023 to January 2024. The results indicated that the concentrations of PAHs in sediment were high during the winter months, 448.35 to 619.77 ng/g dry weight, and low during the summer months, 257.21 to 465.49 ng/g dry weight. The concentration of high molecular weight PAHs (HMWPAHs), consisting of 5-6 rings, was greater than that of low molecular weight PAHs (LMWPAHs), which had 2-3 rings. The total incremental lifetime cancer risk (ILCR) for both dermal and ingestion pathways was high for both adults and children during the four seasons, with the highest records as the following: winter > spring > summer > autumn. The ecological effects of the 16 PAHs were negligible except for acenaphthylene (Acy) and fluorene (Fl), which displayed slightly higher concentrations during the autumn and spring, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study examined the use of modified multiwall carbon nanotubes (M-MWCNTs) with immobilized laccase (L@M-MWCNTs) for removing ciprofloxacin (Cip), carbamazepine (Cbz), diclofenac (Dcf), benzo[a]pyrene (Bap), and anthracene (Ant) from different water samples. The synthesized materials were characterized using an array of advanced analytical techniques. The physical immobilization of laccase onto M-MWCNTs was confirmed through Scanning electron microscope (SEM)-dispersive X-ray spectroscopy (EDS) analysis and Brunner-Emmet-Teller (BET) surface area measurements. The specific surface area of M-MWCNTs decreased by 65% upon laccase immobilization. There was also an increase in nitrogen content seen by EDS analysis asserting successful immobilization. The results of Boehm titration and Fourier transform infrared (FTIR) exhibited an increase in acidic functional groups after laccase immobilization. L@M-MWCNTs storage for two months maintained 77.8%, 61.6%, and 57.6% of its initial activity for 4 °C, 25 °C, and 35 °C, respectively. In contrast, the free laccase exhibited 55.3%, 37.5%, and 23.5% of its initial activity at 4 °C, 25 °C, and 35 °C, respectively. MWCNTs improved storability and widened the working temperature range of laccase. The optimum removal conditions of studied pollutants were pH 5, 25 °C, and 1.6 g/L of M-MWCNTs. These parameters led to >90% removal of the targeted pollutants for four treatment cycles of both synthetic water and spiked lake water. L@M-MWCNTs demonstrated consistent removal of >90% for up to five cycles even with spiked wastewater. The adsorption was endothermic and followed Langmuir isotherm. Oxidation, dehydrogenation, hydroxylation, and ring cleavage seem to be the dominant degradation mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The environmental load by isoxaflutole and its formulated herbicide products has increasingly become apparent because, after the ban of atrazine, isoxaflutole has become its replacement active ingredient (a.i.). Obtaining information regarding the fate of this a.i. in environmental matrices and its ecotoxicological effects on aquatic organisms is essential for the risk assessment of the herbicide. In this study, the effects of Merlin Flexx- and Merlin WG75 formulated isoxaflutole-based herbicide products and two selected additives (cyprosulfamide safener and 1,2-benzisothiazol-3(2H)-one antimicrobial agent) were investigated on Raphidocelis subcapitata in growth inhibition assays. In ecotoxicological tests, two conventional (optical density and chlorophyll-a content) and two induced fluorescence-based (Fv*/Fp: efficiency of the photosystem PSII and Rfd* changes in the observed ratio of fluorescence decrease) endpoints were determined by UV-spectrophotometer and by our FluoroMeter Module, respectively. Furthermore, dissipation of isoxaflutole alone and in its formulated products was examined by an HPLC-UV method. In ecotoxicological assays, the fluorescence-based Rfd* was observed as the most sensitive endpoint. In this study, the effects of the safener cyprosulfamide and the antimicrobial agent 1,2-benzisothiazol-3(2H)-one on R. subcapitata is firstly reported. The results indicated that the isoxaflutole-equivalent toxicity of the mixture of the isoxaflutole-safener-antimicrobial agent triggered lower toxicity (EC 50 = 2.81 ± 0.22 mg/L) compared to the individual effect of the a.i. (EC 50 = 0.02 ± 0.00 mg/L). The Merlin Flexx formulation (EC 50 = 27.04 ± 1.41 mg/L) was found to be approximately 50-fold less toxic than Merlin WG75, which can be explained by the different chemical characteristics and quantity of additives in them. The additives influenced the dissipation of the a.i. in Z8 medium, as the DT 50 value decreased by approximately 1.2- and 3.5-fold under light and dark conditions, respectively.

Objective: The genome-wide profiling of 5-hydroxymethylcytosines (5hmC) on circulating cell-free DNA (cfDNA) has revealed promising biomarkers for various diseases. The purpose of this study was to investigate 5hmC signals in serum cfDNA and identify novel predictive biomarkers for the development of chemoresistance in high-grade serous ovarian cancer (HGSOC). We hypothesized that 5hmC profiles in cfDNA reflect the development of chemoresistance and elucidate pathways that may drive chemoresistance in HGSOC. Moreover, we sought to identify predictors that would better stratify outcomes for women with intermediate-sensitive HGSOC., Methods: Women diagnosed with HGSOC and known platinum sensitivity status were selected for this study. Nano-hmC-Seal was performed on cfDNA isolated from archived serum samples, and differential 5hmC features were identified using DESeq2 to establish a model predictive of chemoresistance., Results: A multivariate model consisting of three features (preoperative CA-125, largest residual implant after surgery, 5hmC level of OSGEPL), stratified samples from intermediate sensitive, chemo-naive women diagnosed with HGSOC into chemotherapy-resistant- and sensitive-like strata with a significant difference in overall survival (OS). Independent analysis of The Cancer Genome Atlas data further confirmed that high OSGEPL1 expression is a favorable prognostic factor for HGSOC., Conclusions: We have developed a novel multivariate model based on clinico-pathologic data and a cfDNA-derived 5hmC modified gene, OSGEPL1, that predicted response to platinum-based chemotherapy in intermediate-sensitive HGSOC. Our multivariate model applies to chemo-naïve samples regardless if the patint was treated with adjuvant or neoadjuvant chemotherapy. These results merit further investigation of the predictive capability of our model in larger cohorts., Competing Interests: Declaration of competing interest Ernst Lengyel reported receiving research funding to perform experimental pre-clinical research on ovarian cancer from Arsenal Bioscience, AbbVie, outside the submitted work. Chuan He is a scientific founder, a member of the scientific advisory board and equity holder of Aferna Bio, Inc., and AccuraDX Inc., a scientific cofounder and equity holder of Accent Therapeutics, Inc., and a member of the scientific advisory board of Rona Therapeutics. Wei Zhang is a consultant for the biomarker discovery program of Tempus Labs, Inc. All other authors declare no relationships that may present a conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Climate change threatens surface waters worldwide, especially shallow lakes where one of the expected consequences is a sharp increase in their water temperatures. Phytobenthos is an essential, but still less studied component of aquatic ecosystems, and it would be important to learn more about how global warming will affect this community in shallow lakes. In this research, the effects of different climate change scenarios (SSP2-4.5 and SSP5-8.5, as intermediate and high emission scenarios) on the structure and function of the entire phytobenthos community using species- and trait-based approaches were experimentally investigated in an outdoor mesocosm system. Our results show that the forecasted 3 °C increase in temperature will already exert significant impacts on the benthic algal community by (1) altering its species and (2) trait composition (smaller cell size, lower abundance of colonial and higher of filamentous forms); (3) decreasing Shannon diversity; and (4) enhancing the variability of the community. Higher increase in the temperature (+5 °C) will imply more drastic alterations in freshwater phytobenthos by (1) inducing very high variability in species composition and compositional changes even in phylum level (towards higher abundance of Cyanobacteria and Chlorophyta at the expense of Bacillariophyta); (2) continuing shift in trait composition (benefits for smaller cell volume, filamentous life-forms, non-motile and weakly attached taxa); (3) further reducing the functional diversity; (4) increasing biofilm thickness (1.4 μm/°C) and (5) decreasing maximum quantum yield of photosystem II. In conclusion, already the intermediate emission scenario will predictably induce high risk in biodiversity issues, the high emission scenario will imply drastic impacts on the benthic algae endangering even the function of the ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes., Graphical Summary: Graphical summary of results. During the proliferative phase (estrogen high ) of the menstrual cycle, SE2 cells (OVGP1 + ) dominate the fallopian tube (FT) epithelium, while SE1 cells (OVGP1 - ) dominate the epithelium during the secretory phase. Though estrogen levels decrease during menopause, SE post-cells (OVGP1 + , CXCL2 + ) make up most of the FT epithelium.

Serous borderline tumors (SBT) are epithelial neoplastic lesions of the ovaries that commonly have a good prognosis. In 10-15% of cases, however, SBT will recur as low-grade serous cancer (LGSC), which is deeply invasive and responds poorly to current standard chemotherapy 1,2,3 . While genetic alterations suggest a common origin, the transition from SBT to LGSC remains poorly understood 4 . Here, we integrate spatial proteomics 5 with spatial transcriptomics to elucidate the evolution from SBT to LGSC and its corresponding metastasis at the molecular level in both the stroma and the tumor. We show that the transition of SBT to LGSC occurs in the epithelial compartment through an intermediary stage with micropapillary features (SBT-MP), which involves a gradual increase in MAPK signaling. A distinct subset of proteins and transcripts was associated with the transition to invasive tumor growth, including the neuronal splicing factor NOVA2, which was limited to expression in LGSC and its corresponding metastasis. An integrative pathway analysis exposed aberrant molecular signaling of tumor cells supported by alterations in angiogenesis and inflammation in the tumor microenvironment. Integration of spatial transcriptomics and proteomics followed by knockdown of the most altered genes or pharmaceutical inhibition of the most relevant targets confirmed their functional significance in regulating key features of invasiveness. Combining cell-type resolved spatial proteomics and transcriptomics allowed us to elucidate the sequence of tumorigenesis from SBT to LGSC. The approach presented here is a blueprint to systematically elucidate mechanisms of tumorigenesis and find novel treatment strategies., Competing Interests: Competing interests E.L. receives research funding to study ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. The authors declare no competing interests in the context of this manuscript.

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In this study, pomegranate peels (PPs) as an abundant fruit processing waste was used to produce cost-effective, eco-friendly, and high-quality activated carbon. The produced carbon (fossil free activated carbon) was used for immobilizing laccase to remove a range of emerging pollutants namely diclofenac, amoxicillin, carbamazepine, and ciprofloxacin from water and wastewater. The loaded activated carbon by laccase (LMPPs) and the unloaded one (MPPs) were characterized using advanced surface chemistry analysis techniques. MPPs was found to have a porous structure with a large surface area and an abundance of acidic functional groups. Laccase immobilization reduced surface area but added active degradation sites. The optimal immobilization parameters were determined as pH 4, 35 °C, and a laccase concentration of 2.5 mg/mL resulting in a 69.8% immobilization yield. The adsorption of the emerging pollutant onto MPPs is best characterized as a spontaneous endothermic process that adheres to the Langmuir isotherm and first-order kinetics. Using synergistic adsorption and enzymatic degradation, the target pollutants (50 mg/L) were eliminated in 2 h. In both water types, LMPPs outperformed MPPs. This study shows that pomegranate peels can effectively be harnessed as an enzyme carrier and adsorbent for the removal of emerging pollutants even from a complex sample matrix. The removal of contaminants from wastewater lasted five cycles, whereas it continued up to six cycles for water., (© 2023. The Author(s).)

Importance: Ultrasonography-based risk models can help nonexpert clinicians evaluate adnexal lesions and reduce surgical interventions for benign tumors. Yet, these models have limited uptake in the US, and studies comparing their diagnostic accuracy are lacking., Objective: To evaluate, in a US cohort, the diagnostic performance of 3 ultrasonography-based risk models for differentiating between benign and malignant adnexal lesions: International Ovarian Tumor Analysis (IOTA) Simple Rules with inconclusive cases reclassified as malignant or reevaluated by an expert, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX), and Ovarian-Adnexal Reporting and Data System (O-RADS)., Design, Setting, and Participants: This retrospective diagnostic study was conducted at a single US academic medical center and included consecutive patients aged 18 to 89 years with adnexal masses that were managed surgically or conservatively between January 2017 and October 2022., Exposure: Evaluation of adnexal lesions using the Simple Rules, ADNEX, and O-RADS., Main Outcomes and Measures: The main outcome was diagnostic performance, including area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. Surgery or follow-up were reference standards. Secondary analyses evaluated the models' performances stratified by menopause status and race., Results: The cohort included 511 female patients with a 15.9% malignant tumor prevalence (81 patients). Mean (SD) ages of patients with benign and malignant adnexal lesions were 44.1 (14.4) and 52.5 (15.2) years, respectively, and 200 (39.1%) were postmenopausal. In the ROC analysis, the AUCs for discriminative performance of the ADNEX and O-RADS models were 0.96 (95% CI, 0.93-0.98) and 0.92 (95% CI, 0.90-0.95), respectively. After converting the ADNEX continuous individualized risk into the discrete ordinal categories of O-RADS, the ADNEX performance was reduced to an AUC of 0.93 (95% CI, 0.90-0.96), which was similar to that for O-RADS. The Simple Rules combined with expert reevaluation had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 91.9% specificity (95% CI, 88.9%-94.3%), and the Simple Rules combined with malignant classification had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 88.1% specificity (95% CI, 84.7%-91.0%). At a 10% risk threshold, ADNEX had 91.4% sensitivity (95% CI, 83.0%-96.5%) and 86.3% specificity (95% CI, 82.7%-89.4%) and O-RADS had 98.8% sensitivity (95% CI, 93.3%-100%) and 74.4% specificity (95% CI, 70.0%-78.5%). The specificities of all models were significantly lower in the postmenopausal group. Subgroup analysis revealed high performances independent of race., Conclusions and Relevance: In this diagnostic study of a US cohort, the Simple Rules, ADNEX, and O-RADS models performed well in differentiating between benign and malignant adnexal lesions; this outcome has been previously reported primarily in European populations. Risk stratification models can lead to more accurate and consistent evaluations of adnexal masses, especially when used by nonexpert clinicians, and may reduce unnecessary surgeries.

The objective of the study is to evaluate whether rates of selected labor and delivery interventions and severe maternal morbidity (SMM) differ between Black and White pregnant patients. This retrospective observational cohort study included all Black or White pregnant patients who delivered at the University of Chicago Medical Center between January 2015 and December 2019. Data queried included demographic information, antepartum complications, preterm interventions, labor and delivery events, and neonatal outcomes. SMM was a composite outcome, including intensive care unit admission, blood transfusion, hysterectomy, eclampsia, cardiac arrest, or death. In total, 10,885 parturients (9001 Black and 1884 White) and 11,211 neonates (9254 born to Black and 1957 to White patients) were included in the study. Black patients were more likely to have preterm labor (3.51% vs. 1.86%, p = 0.0002) and no prenatal care (17.83% vs. 4.05%, p < 0.0001). There was no significant difference in the administration of magnesium sulfate for fetal neuroprotection (Black 44.78% vs. White 49.32%, p = 0.48) or antenatal corticosteroids (Black 67.83% vs. White 71.98%, p = 0.28) among those with preterm delivery. There was no significant difference in SMM (Black 2.24% vs. White 2.44%, p = 0.60), and SMM rates decreased over time (OR 0.79 per year, 95% CI: 0.72-0.87, p < 0.0001) for all patients. Black patients had more pregnancy complications, but their complications were addressed with similar rates of obstetrical interventions. In a high-resource setting, there was no difference in rates of SMM when compared to White patients., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

The omentum contains immune cell structures called milky spots that are niches for transcoelomic metastasis. It is difficult to remove the omentum completely, and there are no effective strategies to minimize the risk of colonization of preserved omental tissues by cancer cells that circulate in the peritoneal fluid. Normal saline is commonly administered into the peritoneal cavity for diagnostic and intraoperative lavage. Here we show that normal saline, when administered into the peritoneal cavity of mice, is prominently absorbed by the omentum, exfoliates its mesothelium, and induces expression of CX3CL1, the ligand for CX3CR1, within and surrounding the omental vasculature. Studies using CX3CR1-competent and CX3CR1-deficient mice showed that the predominant response in the omentum following saline administration is an accumulation of CX3CR1+ monocytes/macrophages that expand milky spots and promote neoangiogenesis within these niches. Moreover, saline administration promoted the implantation of cancer cells of ovarian and colorectal origin onto the omentum. By contrast, these deleterious effects were not observed following i.p. administration of lactated Ringer's solution. Our findings suggest that normal saline stimulates the receptivity of the omentum for cancer cells and that the risk of colonization can be minimized by using a biocompatible crystalloid for lavage procedures.

The genetic changes during high-grade serous ovarian cancer metastasis have largely remained a mystery. Lahtinen et al. show that ovarian cancer metastasizes along three different evolutionary states that have distinct mutations and signaling pathways, potentially allowing the identification of targeted treatments., Competing Interests: Declaration of interests E.L. receives funds for his laboratory research from Abbvie and Arsenal bioscience., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell-derived EVs and subpopulations of biomarker-containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin + EVs in their biogenesis. Notably, we identified that CD147 + EVs have substantially higher microRNA (miRNA) content than tetraspanin + EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147 + EVs predominantly derive from cancer cells, whereas the majority of tetraspanin + EVs are not of cancer cell origin. Circulating CD147 + EVs, but not tetraspanin + EVs, were significantly increased in prevalence in patients with ovarian and renal cancers as compared to healthy individuals and patients with benign conditions. Furthermore, we found that isolating miRNAs from body fluids by CD147 immunocapture increases the sensitivity of detecting cancer cell-specific miRNAs, and that circulating miRNAs isolated by CD147 immunocapture more closely reflect the tumor miRNA signature than circulating miRNAs isolated by conventional methods. Collectively, our findings reveal that CD147 defines miRNA-enriched, cancer cell-derived EVs, and that CD147 immunocapture could be an effective approach to isolate cancer-derived miRNAs for liquid biopsy., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Adnexal lesions are a common finding in women and pose a clinical challenge since ovarian cancer is a highly lethal disease. However, most adnexal masses are benign, benefiting from a more conservative approach. In preoperative assessment, transvaginal ultrasound plays a key role in evaluating morphologic features that correlate with the risk of malignancy. The acoustic shadow is the loss of echo behind sound-absorbing components, such as calcifications or fibrous tissues, which are predominantly found in benign lesions. However, recognizing the acoustic shadow is a difficult skill to master, and its usefulness may be underappreciated., (© 2022 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell-lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin-mediated ablation in Msln-Cre mice significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietin-like 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell-induced monocyte migration, endothelial cell vessel formation, and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell-induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with Abs reduced the ex vivo colonization of 3 different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8p53-/-Brca2-/- cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis and that the crosstalk between mesothelial cells and the tumor microenvironment promotes OvCa metastasis through the secretion of ANGPTL4.

The current study deals with the biological response variations on some biochemical properties of the freshwater green algae Chlorella vulgaris by exposure to different Mg 2+ concentrations (5, 10, and 15) mg/L. Physiological and biochemical parameters, including growth curve, doubling time, photosynthesis pigments, total protein and carbohydrates were investigated. Moreover, enzymatic parameters such as catalase (CAT), superoxide dismutase (SOD), and reactive oxygen species (ROS) were also examined. The maximum growth rate was 0.482/day during the 9th day with 5 mg/L Mg 2+ , while the minimum was 0.019/day during the 13th and 14th days with 10 mg/L Mg 2+ . Furthermore, doubling time ranged between 15.501 during the 13th day with 10 mg/L Mg 2+ , and 0.624 during the 9th day with 5 mg/L. The maximum value of chlorophyll-a was 0.157 μg/mL during the 1st day with 10 mg/L Mg 2+ , while the minimum was 0.062 μg/mL during the 14th day with 15 mg/L Mg 2+ . The carotenoid ranged between 0.029 μg/mL during the 7th day with 15 mg/L Mg 2+ and 0.002 μg/mL during the 14th day. The maximum protein value was 9.620 μg/L during the 1st day with 15 mg/L Mg 2+ , while the minimum was 1.772 μg/L during the 14th day with 15 mg/L Mg 2+ . The carbohydrate showed a maximum value of 0.824 μg/mL during the 1st day with 10 mg/L Mg 2+ , while the minimum was 0.293 μg/mL during the 14th day with 15 mg/L. Moreover, SOD ranged between 0.884 unit/L during the 1st day with 15 mg/L Mg 2+ , and 0.073 unit/L as the minimum value during the 14th day with 15 mg/L Mg 2+ . The maximum value of ROS was 3.627 mM/mL during the 1st day with 5 and 15 mg/L Mg 2+ , while the minimum was 1.674 mM/mL during the 14th day with 10 mg/L. The results show that values of CAT ranged between 0.200 unit/mL during the 7th day with 10 mg/L Mg 2+ , and 0.010 unit/mL during the 14th day with 15 mg/L. Overall, 5 mg/L for biomass production and 15 mg/L for protein and carbohydrate production were optimum doses., Competing Interests: The authors declare no conflict of interest., (© 2023 Published by Elsevier Ltd.)

As part of the Human Cell Atlas Initiative, our goal is to generate single-cell transcriptomics (single-cell RNA sequencing [scRNA-seq], 86,708 cells) and regulatory (single-cell assay on transposase accessible chromatin sequencing [scATAC-seq], 59,830 cells) profiles of the normal postmenopausal ovary and fallopian tube (FT). The FT contains 11 major cell types, and the ovary contains 6. The dominating cell type in the FT and ovary is the stromal cell, which expresses aging-associated genes. FT epithelial cells express multiple ovarian cancer risk-associated genes (CCDC170, RND3, TACC2, STK33, and ADGB) and show active communication between fimbrial epithelial cells and ovarian stromal cells. Integrated single-cell transcriptomics and chromatin accessibility data show that the regulatory landscape of the fimbriae is different from other anatomic regions. Cell types with similar gene expression in the FT display transcriptional profiles. These findings allow us to disentangle the cellular makeup of the postmenopausal FT and ovary, advancing our knowledge of gynecologic diseases in menopause., Competing Interests: Declaration of interests E.L. receives research funding to study ovarian cancer from Arsenal Bioscience and AbbVie through the University of Chicago unrelated to this work. A.B. is a consultant for Novartis IBRI., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gynecologic carcinosarcomas, specifically of endometrial and ovarian origin, are aggressive and rare tumors. Treatment data are limited and are often extrapolated from other histologies and smaller retrospective studies. While the optimal therapy approach remains contentious, treatment is often multimodal and may include surgery, chemotherapy, radiation, or a combination of multiple strategies. However, despite aggressive treatment, these tumors fare worse than carcinomas of the same anatomic sites irrespective of their stage. Recent studies have described in-depth molecular characterizations of gynecologic carcinosarcomas. Although many molecular features mirror those seen in other uterine and ovarian epithelial tumors, the high prevalence of epithelial-mesenchymal transition is more unique. Recently, molecular descriptions have expanded to begin to characterize the tumor immune microenvironment. While the importance of the immune microenvironment has been well-established for other tumor types, it has been less systematically explored in gynecologic carcinosarcomas. Furthermore, the use of immunotherapy in patients with gynecologic carcinosarcomas has not been extensively evaluated. In this review, we summarize the available data surrounding gynecologic carcinosarcomas, with a focus on the immune microenvironment. We end with a discussion of potential immunotherapy uses and future directions for the field.

Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples., (© 2022. The Author(s).)

Purpose: The COVID-19 pandemic has created new challenges for ovarian cancer survivors. This study aims to evaluate the psychologic morbidity and alterations in medical care caused by the pandemic., Methods: Advanced-stage ovarian cancer survivors at our institution were contacted for participation in a cross-sectional telephone-based quantitative survey study assessing pandemic-related psychologic morbidity. Psychologic domains using validated measures were explored: health-related quality of life (HRQOL; functional assessment of cancer therapy [FACT-G7]), anxiety (generalized anxiety disorder-7 [GAD7]), depression (Patient Health Questionnarie-2 [PHQ2]), global health Patient-Reported Outcomes Measurement Information System - Global Physical Health/Global Mental Health (PROMIS-GMH/GPH), resilience (brief resilience scale), and loneliness (English Longitudinal Study on Aging). Novel COVID-19 pandemic questions were drawn from a larger survey developed in our department., Results: Fifty-nine percent (61 of 104) of contacted patients completed the survey. One quarter of respondents had high resilience, with only 10% reporting low resilience. Only one patient screened positive for depression, and two for anxiety. Increased loneliness was reported by 43% of respondents. Patients' overall HRQOL was good (median = 21; range = 6-28). Few patients experienced treatment delays, with only four experiencing chemotherapy interruption and two reporting surgical delays. Multiple regression analyses revealed that high FACT-G7 HRQOL was predicted by age > 65 years, high self-reported mental health, high resilience, and being off chemotherapy. Lower COVID-19 concern was predicted by recurrent cancer and high resilience., Conclusion: Despite the far-reaching impact of the COVID-19 pandemic, ovarian cancer survivors' HRQOL has been maintained. Older age, high resilience, high mental health, and being off chemotherapy predicted better HRQOL. Ovarian cancer survivors remain resilient in the face of the pandemic, and the support of clinicians to preserve this invaluable personal resource is critical for well-being., Competing Interests: Fay J. HlubockyThis author is an Associate Editor for JCO Oncology Practice. Journal policy recused the author from having any role in the peer review of this manuscript. Katherine C. KurnitConsulting or Advisory Role: Leap TherapeuticsTravel, Accommodations, Expenses: Clovis Oncology Kathryn MillsConsulting or Advisory Role: Stryker Ernst LengyelStock and Other Ownership Interests: ExelixisResearch Funding: AbbVie, ArsenalBioNo other potential conflicts of interest were reported.

Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor expression in the sarcomatous versus carcinomatous components of ovarian and uterine carcinosarcomas. Eighteen patients diagnosed with Mullerian carcinosarcoma between May 2009 and August 2014 were included. Nuclear receptor expression was evaluated by immunohistochemistry using whole tissue specimens. Receptor expression was quantified using the H-score. Mean H-scores were compared between the sarcomatous and carcinomatous components of tumors using Wilcoxon signed-rank tests. We found that GR expression was significantly higher in the sarcomatous components than in the carcinomatous components of the cancers (mean H score 144.4 vs 38.9, p = 0.002). Conversely, ER (3.1 vs 63.1, p = 0.002) and PR (1.7 vs 47.2, p < 0.0001) expression were significantly decreased in the sarcomatous component compared to the carcinomatous component. Androgen receptor expression was low overall (0 versus 2.8, p = 0.04). We hypothesize that GR-high, ER/PR-low expression is associated with epithelial to mesenchymal transition in the sarcomatous cells and may serve as a potential therapeutic target., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

The role of resilience in mediating the negative effects of the COVID-19 pandemic on the mental health of US women is poorly understood. We examined socioeconomic factors associated with low resilience in women, the relationship of low resilience with psychiatric morbidity, and the mediating role of resilience in the relationship between pandemic-related stress and other coincident psychiatric morbidities. Using a quota-based sample from a national panel, we conducted a web-based survey of 3200 US women in April 2020. Weighted, multivariate logistic regression was used to model the odds of pandemic-related stress, and coincident depression and anxiety symptoms among those with and without low resilience. Structural equation modeling was used to evaluate resilience as a mediator of the relationship between pandemic-related stress and other coincident psychiatric morbidities. Risk factors for low resilience included younger age, lower household income, lower education, unemployment, East/Southeast Asian race, unmarried/unpartnered status, and higher number of medical comorbidities. Low resilience was significantly associated with greater odds of depression symptoms (OR = 3.78, 95% CI [3.10-4.60]), anxiety symptoms (OR = 4.17, 95% CI [3.40-5.11]), and pandemic-related stress (OR = 2.86, 95% CI [2.26-3.26]). Resilience acted as a partial mediator in the association between pandemic-related stress and anxiety symptoms (proportion mediated = 0.23) and depression symptoms (proportion mediated = 0.28). In the early days of the COVID-19 pandemic, low resilience mediated the association between pandemic-related stress and psychiatric morbidity. Strategies proven to enhance resilience, such as cognitive behavioral therapy, mindfulness-based stress reduction, and addressing socioeconomic factors, may help mitigate mental health outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes ( FOS , FOSB , FRA-1 ) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2 . In vitro , combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. SIGNIFICANCE: Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy., (©2021 American Association for Cancer Research.)

Three species of Stachys genus ( S. byzantina , S. officinalis , S. sylvatica ) were investigated in the present study in terms of aromatic profile and total polyphenol content, as well as antibacterial activity and antioxidant capacity. Gas chromatography coupled with flame ionization detection (GC/FID) was used for exploration of the herbal alcoholic extracts. Using statistical analysis, volatile organic compounds (VOCs) and total phenolic chemical fingerprints were compared in order to describe differences and identify putative signature traits of the three Stachys species. The results showed that the analyzed Stachys extracts have a total polyphenol content being between 197 ± 0.27 mg GAE/g for S. sylvatica and 232 ± 43 mg GAE/g for S. officinalis. The antioxidant activity was between 444 ± 58 mM Trolox/g ( S. sylvatica ) and 602 ± 75 mM Trolox/g ( S. officinalis ). The volatile compounds identified were mostly sesquiterpenes, followed by monoterpenes and secondary compounds. The most abundant in all three species was germacrene D (21.9% 28-25.2%). The multivariate analysis demonstrated the potential of using plant tissue VOC profiles to discriminate between different Stachy species, with a total of 31 VOCs being identified from all three species. Although there were strong similarities among the three species' VOC profiles, distinctions can be made using chemometric analysis. The microbiological results showed an antimicrobial capacity of all three extracts, especially on Gram-positive bacteria. In addition to increasing consumers' understanding regarding the health benefits of these Stachy species, this investigation contributes to defining and preserving a precious genetic and cultural-historical biodiversity.

Objective: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions., Methods: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes., Results: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant., Conclusions: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Inc.)

The high mortality of OvCa is caused by the wide dissemination of cancer within the abdominal cavity. OvCa cells metastasize to the peritoneum, which is covered by mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices (ECM) and stromal cells. In a study using a three-dimensional quantitative high-throughput screening platform (3D-qHTS), we found that β-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion/invasion. Here, we determine whether β-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of β-escin and horse chestnut seed extract inhibited OvCa cell adhesion/invasion, both in vitro and in vivo. From a collection of 160 structurally similar compounds to β-escin, we found that cardiac glycosides inhibited OvCa cell adhesion/invasion and proliferation in vitro, and inhibited adhesion/invasion and metastasis in vivo. Mechanistically, β-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of β-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, β-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1α-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by β-escin. This study reveals that the natural compound β-escin has a therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment.

Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2-7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3' untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. SIGNIFICANCE: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.

Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. ELANE attenuates primary tumor growth and produces a CD8 + T cell-mediated abscopal effect to attack distant metastases. Porcine pancreatic elastase (ELANE homolog) resists tumor-derived protease inhibitors and exhibits markedly improved therapeutic efficacy. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy., Competing Interests: Declaration of interests L.B. and C.C. are inventors on the following patent applications: UC provisional applications 62/610,711 and 62/520,325, PCT/US18/37800 and associated national filings; and US provisional application 62/782,690 and PCT/US19/67890; each filed by the University of Chicago. L.B. is an inventor on provisional patent application 63/067,059, filed by Onchilles Pharma. L.B. is a co-founder of Onchilles Pharma, a company seeking to develop ELANE/PPE-based cancer therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: During a pandemic, women may be especially vulnerable to secondary health problems driven by its social and economic effects. We examined the relationship between changes in health-related socioeconomic risks (HRSRs) and mental health. Materials and Methods: A cross-sectional survey of 3,200 women aged 18-90 years was conducted in April 2020 using a quota-based sample from a national panel (88% cooperation rate). Patterns of change in HRSRs (food insecurity, housing instability, interpersonal violence, and difficulties with utilities and transportation) were described. Weighted, multivariate logistic regression was used to model the odds of depression, anxiety, and traumatic stress symptoms among those with and without incident or worsening HRSRs. Results: More than 40% of women had one or more prepandemic HRSRs. In the early pandemic phase, 49% of all women, including 29% with no prepandemic HRSRs, had experienced incident or worsening HRSRs. By April 2020, the rates of depression and anxiety were twice that of prepandemic benchmarks (29%); 17% of women had symptoms of traumatic stress. The odds of depression, anxiety, and posttraumatic stress symptoms were two to three times higher among women who reported at least one incident or worsening HRSR; this finding was similar for women with and without prepandemic HRSRs. Conclusions: Increased health-related socioeconomic vulnerability among U.S. women early in the coronavirus disease 2019 (COVID-19) pandemic was prevalent and associated with alarmingly high rates of mental health problems. Pandemic-related mental health needs are likely to be much greater than currently available resources, especially for vulnerable women.

The medical and surgical treatment strategies for women with epithelial ovarian cancer continue to evolve. In the past several years, there has been significant progress backed by landmark clinical trials. Although primary epithelial ovarian cancer is still treated with a combination of surgery and systemic therapy, more complex surgical procedures and novel therapeutics have emerged as standard of care. Cytotoxic chemotherapy and maximal surgical effort remain mainstays, but targeted therapies are becoming more widespread and new data have called into question the role of surgery for women with recurrent disease. Poly ADP-ribose polymerase inhibitors have improved progression-free survival outcomes in both the frontline and recurrent settings, and their use has become increasingly widespread. The recent creation of treatment categories based on genetic changes reinforces the recommendation that all women with epithelial ovarian cancer have germline genetic testing, and new biomarker-driven drug approvals indicate that women may benefit from somatic molecular testing as well. To continue to identify novel strategies, however, enrollment on clinical trials remains of the utmost importance. With the evolving data on surgical approaches, targeted therapies such as antiangiogenics and poly ADP-ribose polymerase inhibitors, and the new therapeutic agents and combinations in development, we hope that advanced epithelial ovarian cancer will eventually transition from an almost universally fatal disease to one that can increasingly be cured., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2020 Vickman et al.)

Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Ernst LengyelStock and Other Ownership Interests: Exelixis Research Funding: AbbVieDaniel V. T. CatenacciHonoraria: Genentech, Eli Lilly, Amgen, Foundation Medicine, Taiho Pharmaceutical, Guardant Health, Merck, Bristol Myers Squibb, Gritstone Oncology, Five Prime Therapeutics, Astellas Pharma, Seattle Genetics, Tempus Consulting or Advisory Role: Genentech, Amgen, Merck, Eli Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Astellas Pharma, Seattle Genetics Speakers’ Bureau: Guardant Health, Foundation Medicine, Genentech, Eli Lilly, Merck, Tempus No other potential conflicts of interest were reported.

We present an instructive case of FIGO grade 1 endometrioid endometrial carcinoma with a biphasic morphology, corresponding to subclonal loss of mismatch repair proteins (MMRP) MLH1 and PMS2 by immunohistochemistry and subclonal microsatellite instability. A pulmonary metastasis represented only the tumor component with retention of MMRPs. This case illustrates the need for pathologists to recognize and report heterogenous expression of MMRPs in endometrial carcinoma, to consider tumor heterogeneity when selecting foci for molecular studies, and to re-evaluate MMRP expression in tumor metastases, when clinically indicated. These considerations are particularly important as the relevance of MMRP expression in endometrial cancer expands beyond Lynch syndrome screening, into a new role as a predictive marker for immunotherapy.

Formalin fixation and paraffin-embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis, and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)-based proteomics has so far proven challenging. Herein we describe a MS-based proteomic workflow for quantitative profiling of large FFPE tissue cohorts directly from histopathology glass slides. We demonstrate broad applicability of the workflow to clinical pathology specimens and variable sample amounts, including low-input cancer tissue isolated by laser microdissection. Using state-of-the-art data dependent acquisition (DDA) and data independent acquisition (DIA) MS workflows, we consistently quantify a large part of the proteome in 100 min single-run analyses. In an adenoma cohort comprising more than 100 samples, total workup took less than a day. We observed a moderate trend towards lower protein identification in long-term stored samples (>15 years), but clustering into distinct proteomic subtypes was independent of archival time. Our results underscore the great promise of FFPE tissues for patient phenotyping using unbiased proteomics and they prove the feasibility of analyzing large tissue cohorts in a robust, timely, and streamlined manner. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Adipocytes are critical for ovarian cancer cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells cocultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in ovarian cancer cells cocultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with ovarian cancer metastasis, and reduced clonogenic cancer cell survival. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated knockout of FABP4 in high-grade serous ovarian cancer cells reduced metastatic tumor burden in mice. Consequently, a small-molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells toward carboplatin both in vitro and in vivo . Taken together, these results show that targeting FABP4 in ovarian cancer cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of ovarian cancer metastasis. SIGNIFICANCE: Ovarian cancer metastatic progression can be restricted by targeting a critical regulator of lipid responses, FABP4., (©2020 American Association for Cancer Research.)

The Carpathian Basin is home to a number of astatic soda pans which are especially vulnerable to the climate change due to their high degree of hydrological sensitivity. The photosynthetic plasticity of the three most dominant benthic diatom species (Nitzschia aurariae, N. reskovii, N. supralitorea) in a number of soda pans was measured, along with sulphate and chloride ion content; conductivity and temperature gradients were also recorded. On the basis of the maximal photosynthetic activity (P s ), climate models were employed to observe and predict the effects of climate change on photosynthesis over three time-spans: past (1970-2000), recent past (2005-2015) and projected future (2041-2060). Comparing the periods, it becomes apparent that climate change has a significant effect on photosynthesis and the photosynthetically active period of the Nitzschia species, the dominant primary producers in soda pans, by enhancing their photosynthetic activity and extending their vegetation period by two months. Due to the breadth of their ecological niche, the competitive advantages of the diatom species studied in the course of this research as against others are expected to prevail under the conditions predicted by the climate scenario presented here., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)