Assessing Sarcopenia in Advanced-Stage Ovarian Cancer Patients Undergoing Neoadjuvant Chemotherapy: A Case Series.

OBJECTIVES: In ovarian and other cancers, low muscle mass and density are associated with poorer clinical outcomes. However, screening for cancer-related sarcopenia (typically defined as low muscle mass) is not routinely conducted. The European Working Group on Sarcopenia in Older People (EWGSOP) recommends an algorithm for sarcopenia screening and diagnosis in clinical settings, with sarcopenia based on muscle strength and mass, and severity on physical performance. We explored the application of the EWGSOP2 algorithm to assess sarcopenia in six ovarian cancer patients receiving neoadjuvant chemotherapy. METHODS: We assessed sarcopenia risk with the SARC-F screening questionnaire (at risk ≥4 points), muscle strength with a handgrip strength test (cut point <16 kg) and five times sit-to-stand test (cut point >15 s), muscle mass by skeletal muscle index (SMI in cm2/m2 from a single computed tomography [CT] image; cut point <38.5 cm2/m2), and physical performance with a 4-m gait speed test (cut point ≤0.8 m/s). RESULTS: Of six participants, none were identified as "at risk" for sarcopenia based on SARC-F scores. Two participants were severely sarcopenic based on EWGSOP2 criteria (had low muscle strength, mass, and physical performance), and five participants were sarcopenic based on muscle mass only. DISCUSSION: Ovarian cancer patients with low muscle mass during neoadjuvant chemotherapy may not be identified as sarcopenic based on the EWGSOP2 diagnostic algorithm. While lacking a universally accepted definition for cancer-related sarcopenia and cancer-specific recommendations for the screening, diagnosis, and treatment of sarcopenia, ovarian cancer clinicians should focus on the diagnosis and treatment of low muscle mass and density.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Improved Risk Prediction in Human Papillomavirus-Associated Endocervical Adenocarcinoma Through Assessment of Binary Silva Pattern-based Classification: An International Multicenter Retrospective Observational Study Led by the International Society of Gynecological Pathologists (ISGyP).

Endocervical adenocarcinomas (EACs) are a group of malignant neoplasms associated with diverse pathogenesis, morphology, and clinical behavior. As a component of the International Society of Gynecological Pathologists International Endocervical Adenocarcinoma Project, a large international retrospective cohort of EACs was generated in an effort to study potential clinicopathological features with prognostic significance that may guide treatment in these patients. In this study, we endeavored to develop a robust human papillomavirus (HPV)-associated EAC prognostic model for surgically treated International Federation of Gynecology and Obstetrics (FIGO) stage IA2 to IB3 adenocarcinomas incorporating patient age, lymphovascular space invasion (LVSI) status, FIGO stage, and pattern of invasion according to the Silva system (traditionally a 3-tier system). Recently, a 2-tier/binary Silva pattern of invasion system has been proposed whereby adenocarcinomas are classified into low-risk (pattern A/pattern B without LVSI) and high-risk (pattern B with LVSI/pattern C) categories. Our cohort comprised 792 patients with HPV-associated EAC. Multivariate analysis showed that a binary Silva pattern of invasion classification was associated with recurrence-free and disease-specific survival (P < 0.05) whereas FIGO 2018 stage I substages were not. Evaluation of the current 3-tiered system showed that disease-specific survival for those patients with pattern B tumors did not significantly differ from that for those patients with pattern C tumors, in contrast to that for those patients with pattern A tumors. These findings underscore the need for prospective studies to further investigate the prognostic significance of stage I HPV-associated EAC substaging and the inclusion of the binary Silva pattern of invasion classification (which includes LVSI status) as a component of treatment recommendations.

Incorporating patient-reported outcome measures (PROMs) into a clinical quality registry (CQR) for ovarian cancer: considerations and challenges.

As medical treatment increasingly focuses on improving health-related quality of life, patient-reported outcome measures (PROMs) are an essential component of clinical research. The National Gynae-Oncology Registry (NGOR) is an Australian clinical quality registry. A suitable PROM was required for the NGOR ovarian cancer module to complement clinical outcomes and provide insights into outcomes important to patients. Our narrative review aimed to identify existing ovarian cancer-specific PROMs and ascertain which tool would be most appropriate for implementation into the NGOR ovarian cancer module.A literature review of Cochrane Library, Embase, MEDLINE and PubMed databases was performed to identify existing ovarian cancer-specific PROM tools. A steering committee was convened to (1) determine the purpose of, and criteria for our required PROM; and (2) to review the available tools against the criteria and recommend the most appropriate one for implementation within the NGOR.The literature review yielded five tools: MOST, EORTC QLQ-OV28, FACIT-O, NFOSI-18 and QOL-OVCA. All were developed and validated for use in clinical trials, but none had been validated for use in clinical quality registry. Our expert steering committee pre-determined purpose of a PROM tool for use within the NGOR was to enable cross-service comparison and benchmarking to drive quality improvements. They identified that while there was no ideal, pre-existing, ovarian cancer-specific PROM tool for implementation into the NGOR, on the basis of its psychometric properties, its available translations, its length and its ability to be adapted, the EORTC tool is most fit-for-purpose for integration into the NGOR.This process enabled identification of the tool most appropriate to provide insights into how ovarian cancer treatments impact patients' quality of life and permit benchmarking across health services.

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

BACKGROUND: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. METHODS: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. RESULTS: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. CONCLUSION: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. FUNDING: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Metabolic flux regulates growth transitions and antibiotic tolerance in uropathogenic Escherichia coli.

Reducing growth and limiting metabolism are strategies that allow bacteria to survive exposure to environmental stress and antibiotics. During infection, uropathogenic Escherichia coli (UPEC) may enter a quiescent state that enables them to reemerge after the completion of successful antibiotic treatment. Many clinical isolates, including the well-characterized UPEC strain CFT073, also enter a metabolite-dependent, quiescent state in vitro that is reversible with cues, including peptidoglycan-derived peptides and amino acids. Here, we show that quiescent UPEC is antibiotic tolerant and demonstrate that metabolic flux in the tricarboxylic acid (TCA) cycle regulates the UPEC quiescent state via succinyl-CoA. We also demonstrate that the transcriptional regulator complex integration host factor and the FtsZ-interacting protein ZapE, which is important for E. coli division during stress, are essential for UPEC to enter the quiescent state. Notably, in addition to engaging FtsZ and late-stage cell division proteins, ZapE also interacts directly with TCA cycle enzymes in bacterial two-hybrid assays. We report direct interactions between the succinate dehydrogenase complex subunit SdhC, the late-stage cell division protein FtsN, and ZapE. These interactions may enable communication between oxidative metabolism and the cell division machinery in UPEC. Moreover, these interactions are conserved in an E. coli K-12 strain. This work suggests that there is coordination among the two fundamental and essential pathways that regulate overall growth, quiescence, and antibiotic susceptibility. IMPORTANCE: Uropathogenic Escherichia coli (UPEC) are the leading cause of urinary tract infections (UTIs). Upon invasion into bladder epithelial cells, UPEC establish quiescent intracellular reservoirs that may lead to antibiotic tolerance and recurrent UTIs. Here, we demonstrate using an in vitro system that quiescent UPEC cells are tolerant to ampicillin and have decreased metabolism characterized by succinyl-CoA limitation. We identify the global regulator integration host factor complex and the cell division protein ZapE as critical modifiers of quiescence and antibiotic tolerance. Finally, we show that ZapE interacts with components of both the cell division machinery and the tricarboxylic acid cycle, and this interaction is conserved in non-pathogenic E. coli, establishing a novel link between cell division and metabolism.

Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones.

High-grade serous ovarian carcinoma (HGSOC) is genetically unstable and characterised by the presence of subclones with distinct genotypes. Intratumoural heterogeneity is linked to recurrence, chemotherapy resistance, and poor prognosis. Here, we use spatial transcriptomics to identify HGSOC subclones and study their association with infiltrating cell populations. Visium spatial transcriptomics reveals multiple tumour subclones with different copy number alterations present within individual tumour sections. These subclones differentially express various ligands and receptors and are predicted to differentially associate with different stromal and immune cell populations. In one sample, CosMx single molecule imaging reveals subclones differentially associating with immune cell populations, fibroblasts, and endothelial cells. Cell-to-cell communication analysis identifies subclone-specific signalling to stromal and immune cells and multiple subclone-specific autocrine loops. Our study highlights the high degree of subclonal heterogeneity in HGSOC and suggests that subclone-specific ligand and receptor expression patterns likely modulate how HGSOC cells interact with their local microenvironment.

Medicolegal, infrastructural, and financial aspects in gynecologic cancer surgery and their implications in decision making processes: Quo Vadis?

Surgical decision making is complex and involves a combination of analytic, intuitive, and cognitive processes. Medicolegal, infrastructural, and financial factors may influence these processes depending on the context and setting, but to what extent can they influence surgical decision making in gynecologic oncology? This scoping review evaluates existing literature related to medicolegal, infrastructural, and financial aspects of gynecologic cancer surgery and their implications in surgical decision making. Our objective was to summarize the findings and limitations of published research, identify gaps in the literature, and make recommendations for future research to inform policy.

The promoting physical activity in regional and remote cancer survivors (PPARCS) trial: Physical activity maintenance.

INTRODUCTION: The study examined whether increased physical activity (PA) in nonmetropolitan cancer survivors was maintained 12 weeks following the PPARCS intervention. METHODS: PA outcomes were assessed using an accelerometer at baseline, end of the intervention, and at 24 weeks. Linear mixed models were used to examine between-group changes in PA outcomes. RESULTS: The increased moderate-to-vigorous PA (MVPA) following intervention was maintained with significantly higher MVPA in the intervention group at 24 weeks (vs. controls) compared to baseline nett change of 52.5 min/week (95% CI 11.0-94.0.4). CONCLUSIONS: Distance-based interventions using wearables and health coaching may produce MVPA maintenance amongst nonmetropolitan cancer survivors.

Nutrition of Escherichia coli within the intestinal microbiome.

In this chapter, we update our 2004 review of "The Life of Commensal Escherichia coli in the Mammalian Intestine" (https://doi.org/10.1128/ecosalplus.8.3.1.2), with a change of title that reflects the current focus on "Nutrition of E. coli within the Intestinal Microbiome." The earlier part of the previous two decades saw incremental improvements in understanding the carbon and energy sources that E. coli and Salmonella use to support intestinal colonization. Along with these investigations of electron donors came a better understanding of the electron acceptors that support the respiration of these facultative anaerobes in the gastrointestinal tract. Hundreds of recent papers add to what was known about the nutrition of commensal and pathogenic enteric bacteria. The fact that each biotype or pathotype grows on a different subset of the available nutrients suggested a mechanism for succession of commensal colonizers and invasion by enteric pathogens. Competition for nutrients in the intestine has also come to be recognized as one basis for colonization resistance, in which colonized strain(s) prevent colonization by a challenger. In the past decade, detailed investigations of fiber- and mucin-degrading anaerobes added greatly to our understanding of how complex polysaccharides support the hundreds of intestinal microbiome species. It is now clear that facultative anaerobes, which usually cannot degrade complex polysaccharides, live in symbiosis with the anaerobic degraders. This concept led to the "restaurant hypothesis," which emphasizes that facultative bacteria, such as E. coli, colonize the intestine as members of mixed biofilms and obtain the sugars they need for growth locally through cross-feeding from polysaccharide-degrading anaerobes. Each restaurant represents an intestinal niche. Competition for those niches determines whether or not invaders are able to overcome colonization resistance and become established. Topics centered on the nutritional basis of intestinal colonization and gastrointestinal health are explored here in detail.

A randomized controlled trial of Promoting Physical Activity in Regional and Remote Cancer Survivors (PPARCS).

BACKGROUND: Physical activity (PA) is important for cancer survivors. Trials of remotely delivered interventions are needed to assist in reaching under-served non-metropolitan cancer survivors. The objective of this study was to ascertain whether wearable technology, coupled with health coaching was effective in increasing PA in breast and colorectal cancer survivors living in regional and remote areas in Australia. METHODS: Cancer survivors from 5 states were randomized to intervention and control arms. Intervention participants were given a Fitbit Charge 2TM and received up to 6 telephone health coaching sessions. Control participants received PA print materials. Accelerometer assessments at baseline and 12 weeks measured moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior. RESULTS: Eighty-seven participants were recruited (age = 63 ± 11 years; 74 (85%) female). There was a significant net improvement in MVPA of 49.8 min/week, favoring the intervention group (95% confidence interval (95%CI): 13.6-86.1, p = 0.007). There was also a net increase in MVPA bouts of 39.5 min/week (95%CI: 11.9-67.1, p = 0.005), favoring the intervention group. Both groups improved light PA and sedentary behavior, but there were no between-group differences. CONCLUSION: This is the first study to demonstrate that, when compared to standard practice (i.e., PA education), a wearable technology intervention coupled with distance-based health coaching, improves MVPA in non-metropolitan cancer survivors. The results display promise for the use of scalable interventions using smart wearable technology in conjunction with phone-based health coaching to foster increased PA in geographically disadvantaged cancer survivors.

Perceptions of Controversies and Unresolved Issues in the 2014 FIGO Staging System for Endometrial Cancer: Survey Results From Members of the International Society of Gynecological Pathologists and International Gynecologic Cancer Society.

Long-standing controversial and unresolved issues in the current "International Federation of Gynecology and Obstetrics" staging system for endometrial cancer are well-recognized by pathologists and clinicians alike and exist primarily as a result of limitations to the existing literature. To guide the design of future outcome-based studies specifically aimed at resolving such gaps, the International Society of Gynecologic Pathologists developed a survey of the current perceptions of pathologists (n = 172) and clinicians (n= 135) from the International Society of Gynecological Pathologists and from the International Gynecologic Cancer Society on areas for potential refinement of the current International Federation of Gynecology and Obstetrics staging system. The highest priority issues for pathologists and clinicians alike were the need to determine whether stage IIIA patients (ovarian/fallopian tube involvement) can be reliably separated into favorable versus unfavorable outcome groups to avoid over-treatment of the former group and to determine whether stage IIIC patients (lymph node metastases) can be separated into favorable versus unfavorable outcome groups based on the size of lymph node metastases. The majority of pathologists and clinicians viewed lymphovascular space invasion as an independent prognostic variable and favored incorporating lymphovascular space invasion into staging, though the level of support did not meet the threshold of 75% in support that we used to define a formal consensus. While pathologists did agree on the prognostic value of reporting the extent of lymphovascular space invasion, there was no consensus on the diagnostic criteria to distinguish focal versus substantial involvement. The majority of pathologists and clinicians viewed that a universally accepted protocol for sentinel lymph node ultra-staging is lacking. Both survey groups conveyed a slight preference for incorporating tumor histotype and molecular classification into staging but the support was short of the 75% threshold for formal consensus. Collectively, this survey permits the International Society of Gynecological Pathologists to develop a pathologist and clinician-driven long-term strategy for prioritizing and designing outcome-based studies specifically targeted to resolving controversial and unresolved issues in the International Federation of Gynecology and Obstetrics staging of endometrial cancer.

Control of lipolysis by a population of oxytocinergic sympathetic neurons.

Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of ß-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

Metastatic well differentiated serotonin-producing pancreatic neuroendocrine tumor with carcinoid heart disease: a case report.

Background: Less than two percent of pancreatic neuroendocrine tumors (NETs) produce serotonin. Serotonin can cause carcinoid syndrome and less commonly carcinoid heart disease (CHD). CHD is associated with increased mortality and requires a more aggressive approach. Here we present a rare case of a serotonin-producing pancreatic NET complicated by CHD at presentation and discuss timing of systemic therapy, liver-directed therapy, and heart failure management. Case Description: A 36-year-old white man presented with diarrhea, lower extremity edema, and exertional dyspnea. He was found to have a well-differentiated serotonin-producing pancreatic NETs grade three with bilobar liver metastasis complicated by carcinoid syndrome and CHD. His symptoms and disease burden improved with somatostatin analog and liver-directed therapy with bland embolization to control carcinoid symptoms and obtain rapid hormonal control to prevent progression of CHD. He concurrently received diuretics to manage his heart failure and was considered for valvular replacement surgery, which was deferred for optimal hormonal control. Conclusions: Our case highlights the importance of multidisciplinary care for patients with pancreatic NETs and early identification and management of CHD. Although uncommon, serotonin-producing pancreatic NETs can present with CHD and require combination of somatostatin analogs, liver-directed therapy, and heart failure management.

The impact of an educational and information systems initiative on somatic BRCA testing rates in patients with high grade serous tubo-ovarian cancer in Western Australia.

Objective: Poly-ADP ribose polymerase inhibitors (PARPi) have expanded the management armamentarium against high grade serous tubo-ovarian cancer (HGSOC) in patients with germline and somatic BRCA pathogenic variants (PVs). Germline testing has been available in Western Australia (WA) since July 2015, whilst somatic BRCA testing was previously only available through interstate laboratories. We hypothesized that due to complexity of referral, testing rates for somatic BRCA would be low. We aimed to demonstrate that improving education and information systems would improve testing rates in our service. Methods: Retrospective data were collected for all patients with HGSOC reviewed between June - November 2021. BRCA testing for this period was discussed at multi-disciplinary tumor board. Patients eligible to commence PARPi that had not received somatic testing were referred. Changes were implemented to patient outcome reports, the results application was adjusted to flag clinicians, departmental guidelines were developed, and teaching sessions conducted. Testing rates from March - August 2022 were compared. Results: From June - November 2021, 98% of patients had germline BRCA testing performed. PVs in BRCA1/2 were detected in 18% of patients. Of those without germline PVs, further somatic BRCA testing was referred in 42% of patients. One somatic PV was detected. From March - August 2022, 99% of patients had germline BRCA testing and 17% had PVs detected. Further somatic BRCA testing was referred in 72% of patients. No somatic PVs were detected. Conclusion: Testing rates for germline BRCA variants in patients with HGSOC in WA are high. Focused education and information systems improved somatic BRCA testing rates.

Variation in prescribing for the prevention of postoperative nausea, vomiting, and pain following abdominal surgery: A retrospective study.

Background and Aims: Adequate postoperative analgesia and prevention of post-op nausea and vomiting (PONV) are core components of modern day anaesthesia and peri-operative care. As well as contributing to overall morbidity, postoperative pain and PONV are frequently cited as one of the most unpleasant and distressing aspects of surgery for patients. Variation in healthcare delivery is known to exist but has often been poorly described. A first step to understanding the consequences of variation is to describe the extent of variation. We aimed to assess variation in pharmacological strategies to prevent postoperative pain, nausea and vomiting in patients undergoing elective major abdominal surgery at a tertiary hospital in Perth, Western Australia, over a three-month period. Methods: Retrospective cross-sectional study. Results: We observed considerable variation in prescribing of postoperative analgesia and PONV prophylaxis and suggest that despite adequate evidence based guidelines, they are often overlooked in practice. Conclusion: Measurement of the consequences of variation requires randomised clinical trials that evaluate differences in outcome and cost, associated with the strategies that exist within the spectrum of variation.

Metabolic flux regulates growth transitions and antibiotic tolerance in uropathogenic Escherichia coli.

Reducing growth and limiting metabolism are strategies that allow bacteria to survive exposure to environmental stress and antibiotics. During infection, uropathogenic Escherichia coli (UPEC) may enter a quiescent state that enables them to reemerge after completion of successful antibiotic treatment. Many clinical isolates, including the well characterized UPEC strain CFT073, also enter a metabolite-dependent, quiescent state in vitro that is reversible with cues, including peptidoglycan-derived peptides and amino acids. Here, we show that quiescent UPEC is antibiotic tolerant and demonstrate that metabolic flux in the tricarboxylic acid (TCA) cycle regulates the UPEC quiescent state via succinyl-CoA. We also demonstrate that the transcriptional regulator complex IHF and the FtsZ-interacting protein ZapE, which is important for E. coli division during stress, are essential for UPEC to enter the quiescent state. Notably, in addition to engaging FtsZ and late-stage cell division proteins, ZapE also interacts directly with TCA cycle enzymes in bacterial two hybrid assays. We report direct interactions between succinate dehydrogenase complex subunit SdhC, the late-stage cell division protein FtsN, and ZapE. These interactions likely enable communication between oxidative metabolism and the cell division machinery in UPEC. Moreover, these interactions are conserved in an E. coli K-12 strain. This work suggests that there is coordination among the two fundamental and essential pathways that regulate overall growth, quiescence, and antibiotic susceptibility.

Skeletal muscle morphology in patients receiving primary versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer.

OBJECTIVE: Our primary aim was to compare muscle morphology (skeletal muscle mass and density) between patients who underwent primary cytoreductive surgery versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer. Secondarily, we explored the associations of muscle morphology with survival outcomes. METHODS: We retrospectively analysed computed tomography (CT) images for 88 ovarian cancer patients (aged 38-89 years) to calculate skeletal muscle index (cm2/m2) and skeletal muscle density (Hounsfield units (HU)). A skeletal muscle index of <38.5 cm2/m2 and skeletal muscle density of <33.7 HU were classified as low. Analyses included repeated measures analysis of covariance and multivariable Cox proportional hazards regression. RESULTS: At baseline, 44.3% of patients had low skeletal muscle index and 50.6% had low skeletal muscle density, with interval surgery patients having significantly lower mean skeletal muscle density than primary surgery patients (32.2±8.9 vs 37.3±8.6 HU, p=0.014). Although both groups had similar reductions in skeletal muscle index following treatment (p=0.49), primary surgery patients had a greater reduction in skeletal muscle density compared with interval surgery patients (-2.4 HU, 95% CI -4.3 to -0.5, p=0.016). Patients who experienced skeletal muscle density loss >2% during treatment (HR 5.16, 95% CI 1.33 to 20.02) and had low skeletal muscle density post-treatment (HR 58.87, 95% CI 3.70 to 935.68) had significantly worse overall survival. CONCLUSION: Low skeletal muscle index and skeletal muscle density were prevalent at ovarian cancer diagnosis. While both groups experienced muscle mass loss, greater reductions in skeletal muscle density occurred in patients undergoing primary surgery. In addition, skeletal muscle density loss during treatment and low skeletal muscle density post-treatment were associated with poorer overall survival. Supportive care involving resistance exercise targeting muscle hypertrophic drive, and nutrition counseling during and after ovarian cancer treatment may help preserve/enhance muscle mass and density.