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Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

PurposeThe appalling abuse healthcare workers have endured from patients is long documented in the popular press and social media. Less explored in the healthcare management literature is workplace abuse that professional nurses experience from their coworkers.Design/methodology/approachThe authors use text-based first-hand accounts from nurses posting on Reddit (N = 75) to better understand the types and context of abusive acts endured by their coworkers in the contemporary healthcare setting. Each account is content analyzed using two raters, and thematic analysis is utilized to summarize findings.FindingsFindings indicate that nurse workplace abuse frequently targets new entrants to a work unit (e.g. recent grads), typically is ongoing, takes verbal and nonverbal forms, mainly stems from coworkers (i.e. lateral mistreatment), and frequently takes place in front of other coworkers, mainly in hospital settings.Practical implicationsBy applying the lens of mindfulness, healthcare organizations can transform these harmful interactions within the nursing profession. The authors offer administrators and frontline workers practical implications for mitigating workplace abuse, including reshaping the culture, bystander interventions and explicit leadership support.Originality/valueFirst-hand accounts from nurses in the frontlines of healthcare provide a rich voice that reveals the reality of ongoing verbal and nonverbal peer abuse in hospitals and healthcare settings.

Flavonoid-nitroxide hybrids were prepared and displayed limited antioxidant protection, performing antagonistically compared to the individual components in a peroxyl radical scavenging assay.

Although the practice of forgiveness is encouraged, the healing properties of this virtue by health care professionals are often overlooked. Forgiveness is the voluntary, conscious decision to abandon negative feelings toward another who has caused hurt and replacing those feelings with unconditional love and compassion. It is not about forgetting the hurt or ignoring the pain; it is an actual transformation of the heart. The Enright Forgiveness Process Model and the Pyramid Model of Forgiveness are 2 models that facilitate the forgiveness process. By utilizing either of these pathways, the forgiver ultimately experiences peace of mind and a "release from emotional prison" that leads to holistic healing. As a result, the forgiver experiences lower levels of depression, anxiety, and aggression, which improves quality of life. In addition, physiological benefits such as decreased stress levels, lower blood pressure, and a lower heart rate have also been reported. Throughout the course of their careers, nurses encounter patients and families in acute or end-of-life care situations who want to forgive or be forgiven. As holistic health care providers, nurses should be able to facilitate and close this gap in patient care. This article attempts to raise awareness to the importance of forgiveness in health and well-being among nurses and other health care professionals.

Visceral adiposity has been established as a predictor of outcomes in various cancers. We aimed to determine the association of radiographic measurements of visceral fat with clinical outcomes in patients with endometrial cancer.A retrospective review of patients with stage III-IV endometrial cancer who underwent surgery between 2004 and 2014 was performed. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT;VAT+SAT) were assessed on preoperative computed tomography (CT) scans. Exploratory analysis was performed to establish the optimal cut-off values for VAT, SAT, and TAT to identify patients with poor prognostic body composition. Survival rates were analyzed using Kaplan-Meier analysis, log-rank tests, and cox-regression.Eighty-three patients were included. Forty-two (51%) patients had a low VAT/SAT ratio (0.45) and 41 (49.4%) had a high VAT/SAT ratio (0.45). There were no significant differences in demographics between the groups. The mean VAT, SAT, and TAT were 176.3 cmVisceral fat measurements are predictive of outcomes in patients with advanced stage endometrial cancer. Specifically, VAT to SAT ratios are predictive of overall survival. Future studies should be pursued to identify potential therapeutic targets and biological mechanisms that underlie obesity's relationship with endometrial cancer.

Patient characteristics of patient-derived ovarian cancer cells

RAD51 expression and platinum chemotherapy response in vitro and in patient tumors

Patient characteristics of patient-derived ovarian cancer organoids

Patient characteristics of FFPE discovery cohort

Summary of Antibodies

Purpose:To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples.Experimental Design:RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if >10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated.Results:RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P < 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P < 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P < 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P < 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P < 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status.Conclusions:RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

Patient characteristics of FFPE validation cohort

Supplementary Table S1. Comprehensive radiologic, surgical, and pathologic scoring system used to evaluate tumor response to neoadjuvant chemotherapy. Supplementary Table S2. Summary of antibodies used. Supplementary Table S3. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by chemoresponse. Supplementary Table S4. Disease characteristics of ovarian cancer patients receiving neoadjuvant chemotherapy and undergoing interval cytoreductive surgery stratified by high and low serum GAS6 expression prior to neoadjuvant chemotherapy. Supplementary Figure S1. RAD51 foci formation in irradiated ovarian cancer cells. Supplementary Figure S2. GAS6 and AXL expression in four ovarian cancer cell lines. Supplementary Figure S3. Mean combination indexes and dose response curves for paclitaxel and AVB-500 in three ovarian cancer cell lines. Supplementary Figure S4. GAS6/AXL inhibitor AVB-500 improves response to carboplatin and decreases tumor burden in PDX mouse model of ovarian cancer. Supplementary Figure S5. GAS6/AXL inhibitor AVB-500 decreases GAS6 and pAKT expression in mouse tumors. Supplementary Figure S6. Cleaved Caspase 3 levels in OVCAR8 ovarian cancer cells at 24 and 48 hours of treatment. Supplementary Figure S7. Treatment with AVB-500 increases DNA damage. Supplementary Figure S8. Treatment with AVB-500 decreases activation of AKT and does not affect protein expression of 53BP1, AXL, or RAD51. Supplementary Figure S9. Treatment with carboplatin plus AVB-500 decreases pATM and increases pCHK1. Supplementary Figure S10. Treatment with AVB-500 decreases RPA binding and does not affect the cell cycle. Supplementary Figure S11. Treatment with AVB-500 in addition to olaparib increases DNA damage and decreases homologous recombination. Supplementary Figure S12. Proposed mechanism of AVB-500 and carboplatin increasing DNA damage through replication fork perturbation.

Supplementary Figure from GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis

Supplementary Table from GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis

Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.Implications:GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.

Chemotherapy is often ineffective in advanced-stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared with tumors with a good response to chemotherapy. We showed that chemotherapy-resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared with paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling, which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong preclinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.

Purpose of study: The need for forgiveness education for nursing self-care and forgiveness facilitation has risen. Therefore, the present pilot study tested the efficacy of an 8-week forgiveness bibliotherapy with a small number of undergraduate nursing students. Design of study: Matched pairs of nursing students were randomly assigned to either the experimental group or no-contact control group. The experimental group, using 8 keys to forgiveness by R. Enright (2015) as the treatment manual, read one chapter a week for 8 weeks and provided weekly reflections. Forgiveness and forgiveness-related outcome measures were administered at pretest, posttest, and one-month follow-up. Findings: At the posttest, the experimental group had significantly greater improvement in forgiveness compared to the control group with a large effect size, which was maintained at one month follow-up. There was no other significant difference between the two groups. Within-group comparisons of the experimental group showed improvement in forgiveness, anxiety, depression, and fatigue from pre to post testing periods and forgiveness, anger, anxiety, depression, and fatigue from pre to follow-up testing periods. Conclusion: Use of bibliotherapy may be a cost-effective way to promote the virtue of forgiveness for students in nursing programs.

Background Falls are the most commonly reported incident in the Health Service Executive (HSE). Inappropriate medications and polypharmacy in the elderly can contribute to increased falls risk. Our aim was to assess whether a medication review was being completed at the time of the post-fall clinician review. Methods We completed a retrospective chart review using an audit tool of consecutive inpatient falls, resulting in serious injury, from March–December 2019. Standards measured against were: HSE Guideline—Service User Falls: A Practical Guide for Review, Medicines and Falls in Hospital: British Society Guidelines, STOPP & START criteria and NICE Guidelines: Falls in Older People 2013. Results We identified 33 charts for review (n = 33)—54.55% (18) female and 45.45% (15) male. Average age was 81 ± 11.2 years. The immediate post-fall review was mainly completed by interns (48.49% (16)) and SHO’s (39.39% (13)). A medication review was carried out 9.09% (3) of the time. A total of n = 28 (84.85%) had poly pharmacy. When analysed for medications known to increase risk of falling, 51.52% (n = 17) were on anti-hypertensives, 45.45% (n = 15) on laxatives, 24.24% (n = 8) on sedative medications, 18.18% (n = 6) on hypnotics/anxiolytics, 15.15% (n = 5) on opioids and 15.15% (n = 5) on diuretics at the time of fall. The majority of these medications (77.42% (n = 24)) were commenced prior to admission. None of these medications were discontinued or the dose changed on review post fall. Conclusion Our audit demonstrates that in a cohort of patients who had an inpatient fall medication discontinuation and dose reductions were not performed. Yet, a high burden of polypharmacy and high-risk falls medication were found. This may result in missing a pertinent opportunity to prevent future falls. We advise a structured medication review is carried out for each patient who suffers an in-patient fall to efficiently modify such an easily identifiable risk factor.

OBJECTIVE To evaluate the efficacy of ethylene oxide (EtOH) sterilization of 4 different waterproof camera cases and the ability of those sterilized cases to maintain a sterile barrier for intraoperative camera use. SAMPLE 3 action cameras, 1 smartphone, and associated waterproof cases. PROCEDURES Cases were inoculated by immersion in medium containing Staphylococcus pseudintermedius, Escherichia coli, and Pseudomonas aeruginosa and then manually cleaned and subjected to EtOH sterilization. Cameras were disinfected, loaded into sterile cases, and sterilely operated for 2 hours. Samples were collected from cases after inoculation, EtOH sterilization, camera loading, and 1 and 2 hours of operation and from all cameras after 2 hours of operation. Procedures were repeated twice, followed by an additional challenge round wherein cameras were purposefully contaminated prior to loading. All samples underwent bacterial culture. RESULTS All cases were successfully sterilized, and loading of nonsterile cameras into sterile cases caused no contamination when cameras had been disinfected beforehand. Nonpathogenic environmental contaminants were recovered from 6 of 64 culture samples and 2 of 4 room samples. During the challenge round, only the postload sample for 1 case yielded E coli, suggesting sterile glove contamination; however, postload, 1-hour, and 2-hour samples for the GoPro case yielded E coli and S pseudintermedius, suggesting major contamination. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the evaluated cases can be safely sterilized with EtOH and used for image acquisition by aseptically prepared surgeons when cameras are disinfected prior to loading. Except for the GoPro camera, camera use did not jeopardize sterile integrity.

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease.OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure.METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States.RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001).CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Background Standard treatment for placental site trophoblastic tumor is hysterectomy. This may be unacceptable to women desiring fertility. Cells aberrant in placental site trophoblastic tumor display an ability to invade normal tissue while evading the immune system. Case We present a case of a 23-year-old woman with stage I placental site trophoblastic tumor who declined hysterectomy. Tumor assay for program cell death-ligand 1 staining was performed and suggestive of an immune-responsive tumor. The patient initiated intravenous pembrolizumab 200 mg every 2 weeks, and by cycle 3 her β-hCG level fell to undetectable. She subsequently conceived and went on to have an uncomplicated term vaginal birth after cesarean. At 6 weeks postpartum, she remained without evidence of disease. Conclusion Immunotherapy can eliminate early program cell death-ligand 1-positive placental site trophoblastic tumor with subsequent normal pregnancy.

OBJECTIVE. To determine the association between scores from a 25-item patient-reported Rockwood Accumulation of Deficits Frailty Index (DAFI) and survival outcomes in gynecologic cancer patients. METHODS. A frailty index was constructed from the SEER-MHOS database. The DAFI was applied to women age ≥ 65 diagnosed with all types of gynecologic cancers between 1998 and 2015. The impact of frailty status at cancer diagnosis on overall survival (OS) was analyzed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS. In this cohort (n = 1336) the median age at diagnosis was 74 (range 65–97). Nine hundred sixty-two (72%) women were Caucasian and 132 (10%) were African-American. Overall, 651(49%) of patients were considered frail. On multivariate analysis, frail patients had a 48% increased risk for death (aHR 1.48; 95% CI 1.29–1.69; P < 0.0001). Each 10% increase in frailty index was associated with a 16% increased risk of death (aHR, 1.16; 95% CI, 1.11 to 1.21; P < 0.0001). In subgroup analyses of the varying cancer types, the association of frailty status with prognosis was fairly consistent (aHR 1.15–2.24). The DAFI was more prognostic in endometrial (aHR 1.76; 95% CI 1.41–2.18, P < 0.0001) and vaginal/vulvar (aHR 1.94; 95% CI 1.34–2.81, P = 0.0005) cancers as well as patients with loco-regional disease (aHR 1.94; 95% CI 1.62–2.33, P < 0.0001). CONCLUSIONS. Frailty appears to be a significant predictor of mortality in gynecologic cancer patients regardless of chronological age. This measure of functional age may be of particular utility in women with loco-regional disease only who otherwise would have a favorable prognosis.

OBJECTIVE To compare the rate of postoperative dehiscence on the basis of intraoperative anastomotic leak test results (ie, positive or negative for leakage or testing not performed) between dogs that underwent hand-sewn anastomosis (HSA) or functional end-to-end stapled anastomosis (FEESA) of the small intestine. ANIMALS 131 client-owned dogs that underwent 144 small intestinal anastomoses (94 FEESA and 50 HSA). PROCEDURES Medical records were searched to identify dogs that had undergone a small intestinal anastomosis (HSA or FEESA) from January 2008 through October 2019. Data were collected regarding signalment, indication for surgery, location of the anastomosis, surgical technique, the presence of preoperative septic peritonitis, performance of intraoperative leak testing, development of postoperative dehiscence, and duration of follow-up. RESULTS Intraoperative leak testing was performed during 62 of 144 (43.1%) small intestinal anastomoses, which included 26 of 94 (27.7%) FEESAs and 36 of 50 (72.0%) HSAs. Thirteen of 144 (9.0%) anastomoses underwent dehiscence after surgery (median, 4 days; range, 2 to 17 days), with subsequent septic peritonitis, including 10 of 94 (10.6%) FEESAs and 3 of 50 (6.0%) HSAs. The incidence of postoperative dehiscence was not significantly different between FEESAs and HSAs; between anastomoses that underwent intraoperative leak testing and those that did not, regardless of anastomotic technique; or between anastomoses with positive and negative leak test results. Hand-sewn anastomoses were significantly more likely to undergo leak testing than FEESAs. Preoperative septic peritonitis, use of omental or serosal reinforcement, preoperative serum albumin concentration, and surgical indication were not significantly different between anastomotic techniques. CONCLUSIONS AND CLINICAL RELEVANCE Performance of intraoperative anastomotic leak testing, regardless of the anastomotic technique, was not associated with a reduction in the incidence of postoperative anastomotic dehiscence.

Background– Since publication of the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain, there have been growing concerns that providers, including those in primary care, are tapering opioids too quickly and without concomitant use of non-opioid strategies for pain, leading to inadequate pain management. As a result, in November 2022 the CDC published Clinical Practice Guidelines for Prescribing Opioids for Pain, emphasizing the importance of creating comprehensive care plans for pain management and developing a consensual plan between provider and patient when tapering opioids. Objective–Determine the impact of a pharmacist-assisted approach aimed at helping primary care providers minimize opioid use while improving management of chronic, non-malignant pain (CNMP). Methods – This quality improvement project focused on one primary care provider partnering with a pharmacist to reassess the management of patients on long-term opioid therapy (LTOT) for CNMP. The intervention included a letter informing patients of the provider’s intent, pharmacist outreach to intervention patients, and pharmacist development of a patient registry, updated regularly with clinical data, recommendations, and outcomes for the provider to reference throughout the project. The intervention group was compared to patients prescribed opioids for CNMP by the remaining providers at the clinic who did not engage in the quality initiative. Results – The intervention group had a mean effective daily morphine milligram equivalent (MME) reduction of 73.7% (17.2% control) after 18 months and 60% of patients discontinued opioids (14.3% control). In a subset of patients with functional assessment scores, 93.3% were either improved or unchanged, despite a 62.5% decrease in their mean effective daily MME. In both groups, one patient transferred care to a new provider. Conclusions – With targeted recommendations and assistance from a pharmacist, a primary care provider can make significant progress in improving management of CNMP while reducing opioid prescribing.

The use of Poly ADP ribose polymerase inhibitors (PARPi) has revolutionized the treatment of homologous recombination (HR) deficient ovarian cancer tumors. A subset of these tumors exhibit genetic and acquired resistance to PARPi treatment. We have previously shown histone deacetylase inhibitors (HDACi) resensitizes ovarian cancer cells to PARPi. The objective of this study is to examine the effectiveness of combination HDACi and PARPi treatment in two in vitro models of mouse ovarian cancer cells. To investigate these effects, we used the following three ID8 murine ovarian cancer epithelial cell lines: TP53− / − (HR deficient), TP53− / −/BRCA2− / − (HR proficient), and an olaparib resistant line TP53− / −/BRCA2− / −-OR (ID8_OR). We also created ovarian cancer organoids from these three lines. In short, 8-week old female C57BL/6 mice were injected with 7 million untreated cells in PBS. Following the formation of ascites, mice were sacrificed and organoids were derived from both ascites and tumors. For viability assays, cells were pretreated with entinostat (Ent, 0.25uM) for 24h, followed by 72h (2D cells) or 7 days (organoids) of Ent (0-2uM), olaparib (Ola, 0-40uM), or in combination. Cell proliferation and viability was assessed using MTS and ATP-based assays. For immunofluorescence and western blotting analysis, cells were treated with 0.5uM Ent, 10uM Ola or the combination.TP53 adherent cells and organoids treated with 0.5uM Ent + 10uM of Ola significantly reduced cell proliferation when compared to Ola alone (p= 0.0028, 0.0021 Two-Way ANOVA). When compared to Ola and Ent alone, TP53/BRCA2 adherent cells treated with 0.125uM of Ent + 2.5uM of Ola also reduced cell proliferation (p=0.0011 and p=0.0072, 0.0845). Lastly, ID8_OR adherent cells and organoids treated with 0.125uM of Ent + 2.5μM of Ola significantly reduced cell proliferation when compared to Ola alone (p=0.0018, 0.0264).Immunofluorescences analysis revealed, when treated with Ola and Ent combination, adherent TP53 (p= 0.002, n.s), TP53/BRCA2 (p=0.0033, 0.0315), and ID8_OR (n.s) cells displayed increased expression of DNA damage marker gH2AX when compared to Control and Ola alone. We also observed decreased expression of RAD51 in cells treated with combination when compared to control and Ola alone, TP53 (p= Citation Format: Bisiayo E. Fashemi, Lilian N. van Biljon1, Tyler Woodard, Vijayalaxmi Gupta, Mary M. Mullen, Benjamin Bitler, Dineo Khabele. Entinostat restores sensitivity to olaparib in two in vitro models of PARPi resistant ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB164.

Controlled and complete assembly of supramolecular systems on solid supports is a challenge that would elevate the function of interlocked architectures. Building on the success of other dynamic covalent synthetic methods, we present hydrazone exchange as a strategy to improve the formation of rotaxanes in solution and on solid surfaces. Solution-state analogues containing naphthalenediimide (NDI) or bipyridinium motifs and 1,5-dinaphtho[38]crown-10 were initially prepared to establish ideal conditions for maintaining thermal equilibrium throughout the exchange reaction. Solid-state rotaxanes were synthesised on hydrazide-functionalised TentaGel™ polymer resins and analysed with HR MAS 1H NMR spectroscopy. Surface rotaxane functionalisation of 80% was achieved for the NDI rotaxane, which is significantly higher than previously reported with either dynamic covalent or traditional irreversible synthetic strategies.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in women with gynecologic malignancies. This practice statement provides clinical data and overall quality of evidence regarding the use of direct oral anticoagulants (DOACs) in this patient population. Specifically, it reviews patient selection, safety measures, and nuances of perioperative use of these medications. The scope of this document is limited to DOAC use in gynecologic oncology rather than a broad discussion of VTE prophylaxis and management in general. The following recommendations and examination of extant data are based on DOAC trials conducted primarily in mixed populations with different cancer subtypes. Many of these trials include few, or no, women with gynecologic cancer. However, because there is very limited data in gynecologic cancer-specific populations, the results of these studies represent the best available evidence to support treatment recommendations in our patients. The members of the Society of Gynecologic Oncology (SGO) Clinical Practice Committee believe that the results of these studies may be extrapolated, with caution, to VTE treatment and prophylaxis for patients with gynecologic cancer.

Cancers with deficiencies in homologous recombination-mediated DNA repair (HRR) demonstrate improved clinical outcomes and increased survival. Approximately 50% of high-grade serous ovarian cancers (HGSOC) exhibit homologous recombination deficiency (HRD). HRD can be caused by germline or somatic mutations of genes involved in the HR pathway. Given platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPis) are used in HGSOC, double-strand breaks (DSBs) are common. Unrepaired DSBs are toxic to cells as genomic instability ensues and cells eventually die. Thus, tumor cells with DSBs utilize the high-fidelity HRR as one of the central pathways for repair. In tumors that have HRD, an alternate pathway such as non-homologous end-joining (NHEJ) is used and leads to error-prone repair. To date, methods for clinical detection of homologous recombination deficiency (HRD) are limited to genomic changes of HRR genes and genomic mutation patterns resulting from HRD genes involved in HR-mediated DNA repair. However, these tests detect genomic scars that might not always correlate well with PARP inhibitor or platinum sensitivity in the current state. Therefore, a functional HRD assay should be able to more accurately predict tumor response in real-time. RAD51 foci formation has been used as a functional assay to define HRD and closely correlates with chemotherapy and PARPi sensitivity. The inability to form RAD51 foci is a common feature of HRD. DNA damage can also cause transient slowing or stalling of replication forks defined as replication stress. Replication fork stalling can lead to fork degradation and decreased cell viability if forks do not resume DNA synthesis. Fork degradation has been found to lead to chemosensitivity in BRCA-deficient tumors. To determine this fork degradation phenotype, replication fork/DNA fiber assays are utilized. This review will highlight functional assays for HRD in the context of translating these to real-time clinical assays.

Granular cell tumors (GCTs) can be diagnostically challenging due to their rarity, diverse anatomic locations, and clinical and radiologic similarities to other more common entities. GCTs involving the breast are rare and are most commonly encountered in premenopausal cisgender women. We report an unusual case of a breast GCT in a young transgender man.A 20-year-old transgender man who was on testosterone therapy for about 1 year presented with a painless, palpable mass in the right breast which radiologically resembled a lymph node. A fine needle aspiration showed morphology and immunohistochemistry consistent with a GCT. The tumor was excised by a mastectomy for therapeutic and gender-affirming purposes which confirmed the diagnosis of a breast GCT.Breast GCTs are most commonly found in cisgender women, however the mechanisms behind this relationship and whether transgender persons have an altered risk profile are not well understood. Breast GCTs are typically benign lesions with a low chance of recurrence following excision.GCTs are rare and poorly understood entities which have not been previously documented in transgender patients and can resemble other benign or malignant lesions.

OBJECTIVE To determine the feasibility of sidestream dark field (SDF) video microscopy for the evaluation of the jejunal microvasculature of healthy dogs. ANIMALS 30 healthy sexually intact female shelter dogs anesthetized for ovariohysterectomy. PROCEDURES Preoperative physical and clinicopathologic assessments were performed to confirm health status. Then healthy dogs were anesthetized, and the abdomen was incised at the ventral midline for ovariohysterectomy and jejunal microvasculature evaluation. An SDF video microscope imaged the microvasculature of 2 sites of a portion of the jejunum, and recorded videos were analyzed with software capable of quantitating parameters of microvascular health. Macrovascular parameters (heart rate, respiratory rate, and hemoglobin oxygen saturation) were also recorded during anesthesia. RESULTS Quantified jejunal microvascular parameters included valid microvascular density (mean ± SD, 251.72 ± 97.10 μm/mm), RBC-filling percentage (66.96 ± 8.00%), RBC column width (7.11 ± 0.72 μm), and perfused boundary region (2.17 ± 0.42 μm). The perfused boundary region and RBC-filling percentage had a significant negative correlation. Strong to weak positive correlations were noted among the perfused boundary regions of small-, medium-, and large-sized microvessels. No significant correlations were identified between microvascular parameters and age, body weight, preoperative clinicopathologic results, or macrovascular parameters. CONCLUSIONS AND CLINICAL RELEVANCE Interrogation of the jejunal microvasculature of healthy dogs with SDF video microscopy was feasible. Results of this study indicated that SDF video microscopy is worth additional investigation, including interrogation of diseased small intestine in dogs.

Objective To compare leak pressures and construct completion time of six intestinal anastomoses and report normal canine gastrointestinal thickness. Study design Experimental study. Animals Grossly normal jejunal segments (n = 140) from 10 fresh canine cadavers. Methods Gastrointestinal thickness was recorded. Eight-centimeter cooled canine cadaveric jejunal segments were randomly assigned to a control group (20 segments) and six treatment groups (20 segments/group [10 constructs/group]): (1) handsewn anastomosis (HSA), (2) functional end-to-end stapled anastomosis (FEESA)-blue thoracoabdominal (TA; FEESA-TAB), (3) FEESA-green TA (FEESA-TAG), (4) FEESA TA-gastrointestinal anastomosis (GIA), (5) FEESA with suture oversew (FEESA-O), and (6) skin staples (SS). Construct assembly time, initial leak pressure (ILP), maximum intraluminal pressure (MIP), and leakage location were compared. Results Initial leak pressures (mean ± SD) for control (308.38 ± 115.91 mm Hg), HSA (41.96 ± 15.97), FEESA-TAB (31.71 ± 15.71), FEESA-TAG (27.24 ± 14.11), FEESA-GIA (25.62 ± 11.22), FEESA-O (31.01 ± 17.38), and SS (44.42 ± 28.88) groups were compared. No difference in ILP (P > .24) or MIP (P > .17) was detected between treatment groups. Sutured anastomoses took up to 10 times longer to complete (P = .0025). The stomach, duodenum, jejunum, and ileum mural thicknesses (mean ± SD) were 3.99 ± 0.44 mm, 2.34 ± 0.16, 2.49 ± 0.28, and 2.30 ± 0.31, respectively. Conclusion The ILP of all anastomoses exceeded maximum intraluminal peristaltic pressures. Stapled anastomoses were faster to complete. Clinical significance All anastomoses may be considered when performing an intestinal resection and anastomosis, with stapled anastomoses resulting in a shorter surgical time. Canine intestinal thickness may warrant use of a larger staple size.

We report on triethylene glycol-based orthoformate cryptands, which adapt their bridgehead configurations in response to metal templates and intramolecular hydrogen bonding in a complex manner. In contrast to smaller 1.1.1-orthoformate cryptands, the inversion from out,out-2.2.2 to in,in-2.2.2 occurs spontaneously by thermal homeomorphic isomerization, i. e., without bond breakage. The global thermodynamic minimum of the entire network, which includes an unprecedented third isomer (in,out-2.2.2), could only be reached under conditions that facilitate dynamic covalent exchange. Both inversion processes were studied in detail, including DFT calculations and MD simulations, which were particularly helpful for explaining differences between equilibrium compositions in solvents chloroform and acetonitrile. Unexpectedly, the system could be driven to the in,out-2.2.2 state by using a metal template with a size mismatch with respect to the out,out-2.2.2 cage.

Objectives There are limited methods to identify which obese patients will experience wound complications after undergoing gynecologic surgery. We sought to determine the association between frailty and postoperative wound complications and to develop a prediction model for wound complications in this patient population. Methods We reviewed prospectively collected data of obese patients undergoing laparotomy though midline vertical incisions from 7/2013-3/2016. Modified frailty index (mFI) was calculated using 11 comorbidities previously validated. The primary outcome was the composite rate of postoperative wound complication. Data was analyzed using Fisher exact test or Chi-square and t-tests or Kruskal-Wallis tests. Poisson regression models were used to generate relative risks. Prediction models were created with receiver-operator characteristic curve analysis. Results Of 163 patients included, 56 (34%) were considered frail. Wound complications occurred in 52 patients (31.9%): 28 (50%) frail and 24 (22.4%) non-frail patients (RR 2.23, 95%CI 1.29-3.85). Frail patients had significantly greater frequencies of wound breakdown (37.5% vs 15%, RR 2.51, 95%CI 1.31-4.81). After controlling for BMI, tobacco use, and maximum postoperative glucose, frailty remained an independent predictor of wound complication (aRR 1.88, 95%CI 1.04-3.40). The area under the curve for the predictive model incorporating frailty was 0.73 for wound complications. Conclusion Frailty is associated with wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision and is a useful tool in identifying the most high risk patients. Further prospective research is necessary to incorporate mFI into preoperative planning and counseling.

Here we describe the use of a dynamic covalent synthetic approach to improve the attachement of interlocked architectures to solid supports. Although, dynamic covalent chemistry, and even more specifically disulfide exchange reactions have proved to be a successful synthetic strategy for the synthesis of catenanes and knots, comparatively few examples of its use for the synthesis of rotaxanes have been reported. Our work demonstrates that disulfide exchange can be used to synthesise neutral naphthalene diimide containing rotaxanes. Detailed HPLC analysis enabled deconvolution of a complex equilibrium between 6 disulfide species in solution. Analogous experiments investigating dynamic covalent attachment of rotaxanes to TentaGel™ polymer resins using disulfide chemistry resulted in significantly increased attachment of interlocked architectures attached to the solid supports (65% rotaxane) as compared to traditional (kinetically controlled) synthetic approaches.

We present the first application of electrochemical reduction in an ion trap mass spectrometer as a dual-function tool to synthesise and probe the reactivity of interlocked viologen-based complexes. Compared with non-complexed archetypes, electron-donating macrocyclic porphyrin ethers retard electron transfer reaction rates and stabilise intact structures in low oxidation states.

The objective of this study was to investigate the use of potassium chloride (KCl) and tapioca starch (TS) to reduce salt levels below 1.5% in sausages manufactured using previously high pressure (HP) processed pork (150 MPa). A 3 × 2 × 1 factorial design was used to formulate breakfast sausages with three salt levels (0.5%, 1.0%, and 1.5%), two ingredient levels (no added ingredient or added as a combination of KCl\TS), and one pressure level (150 MPa). Partial replacement of NaCl with KCl and addition of TS had beneficial effects on the water binding abilities of sausage batters by decreasing (p < 0.05) total expressible fluid (%) and increasing water holding capacity (%). Overall, results indicated that the use of KCl\TS imparted some beneficial effects to salt-reduced low fat breakfast sausages and has the potential to reduce salt levels in the breakfast sausages to 1.0% while still maintaining the organoleptic and functional properties traditionally associated with these meat products.

Introduction: Food insecurity (FI), defined as “limited or uncertain availability of nutritionally adequate and safe foods, or limited or uncertain ability to acquire acceptable foods in socially acceptable ways,” affects over 12% of US households. Embarrassment persists for patients with FI, and due to the potential consequences of FI, including increased utilization of the health care system, it is important to find causes and potential interventions for FI. The purpose of this project was to better understand FI from the patient perspective, including contributing factors, perceived health effects, and helpful interventions. Methods: Interviews (N=21) were conducted with suburban community residency clinic patients who screened positive for FI in the last 12 months. Six open-ended questions and a ranking question examined contributors to FI, effects of FI, perceptions of clinic intervention helpfulness, and ideas for novel interventions. Results: Patients identified lack of income (85.7%) as the primary issue they faced. Secondary identified issues were lack of transportation (38.1%), too much debt (33.3%), and food assistance programs not providing for all needs (33.3%). FI effects on patients’ health included difficulty adhering to specialized diets and the need to modify eating patterns due to lack of food. Surprisingly, 28.6% perceived no FI related-health effects. Patients felt that the most valuable clinic intervention was provision of urgent need food boxes, followed by FI screening and referrals to community food resources. Conclusions: Frequent FI screening is in itself useful to patients. Screening paired with community food resource referrals and urgent-need food boxes are the most helpful interventions according to patients.