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Contents Previous reports of the ability of melatonin to scavenge a variety of toxic oxygen and nitrogen-based reactants suggest that melatonin could be an effective antioxidant for protecting sperm. In this study, flow cytometry and laser tweezers Raman spectroscopy were used to evaluate the effect of melatonin on buffalo sperm quality to optimize sperm sex-sorting procedures. In fresh sperm incubated in the presence or absence of melatonin (10−4 m) for 1, 24, 48 h or 72 h at 27°C, the mitochondrial activity was significantly higher than in a non-melatonin control (p < 0.05). Also, during the flow-sorting process, sperm in melatonin-supplemented groups had higher (p < 0.05) mitochondrial activity than the control. The intensity of Raman spectra from sperm frozen in media supplemented with melatonin was significantly weaker than that for non-melatonin-treated groups, except for a band at 1302 per cm. Thus, melatonin helps to protect buffalo sperm from reactive oxygen species induced by staining, sorting and freezing and increases semen quality after the freezing-thawing processes. Furthermore, the results indicate the high potential of the laser tweezers Raman spectroscopy technique for rapid, effective and non-invasive assessment of the quality of sperm cells. [ABSTRACT FROM AUTHOR]

Although there have been many studies regarding physicians' knowledge of hereditary cancer syndromes, very little information exists regarding medical residents' knowledge of hereditary cancer syndromes. Obstetrics/gynecology residents completed a test which evaluated their knowledge of hereditary breast and ovarian cancer and Lynch syndrome. Areas of relative deficit were identified. Residents indicated a desire and need for more education regarding this topic. Cancer genetics education programs should place more emphasis on the areas in which residents' appeared to be deficient in order to aid future physicians in the identification of high-risk individuals. [ABSTRACT FROM AUTHOR]

Background: Constitutively activated nuclear factor kappa B (NFkappaB) contributes to the development of cancer by regulating the expression of genes involved in cell survival, metastasis, and angiogenesis. The authors have demonstrated that MEKK3 plays a critical role in cytokine-mediated NFkappaB activation, and that stable expression of MEKK3 in cultured cells leads to increased NFkappaB activity.Methods: MEKK3 expression in ovarian cancer cells or tumors was assessed by Western blotting and real-time polymerase chain reaction. NFkappaB activities were analyzed by electrophoretic mobility shift assay and luciferase reporter assays. Western blot analysis for the survival factors were also performed and correlated with MEKK3 and NFkappaB activities. Cell survival assays were used to determine the sensitivity of ovarian cancer cells to various chemotherapeutic agents.Results: The authors found that 63% of the ovarian cancers had higher MEKK3 expression than the normal ovarian epithelial cells. Ovarian cancers with high MEKK3 showed correspondingly high IkappaB kinase and NFkappaB activity. Moreover, MEKK3 coimmunoprecipitated with Akt and cooperated with Akt to synergistically activate NFkappaB. Consistent with increased MEKK3 and NFkappaB activity in ovarian cancers, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis levels were increased, which correlated with increased resistance to chemotherapeutic agents. Knockdown of MEKK3 with small interfering RNA significantly increased cancer cell sensitivity to paclitaxel.Conclusions: MEKK3 may be aberrantly expressed in ovarian cancers and plays an important role in tumors with constitutively activated NFkappaB. [ABSTRACT FROM AUTHOR]

Context: About 2% of all colorectal cancer occurs in the context of the autosomal dominantly inherited Lynch syndrome, which is due to mutations in mismatch repair genes. Potential risk-reducing interventions are recommended for individuals known to have these mutations.Objectives: To review cancer risks and data on screening efficacy in the context of Lynch syndrome (hereditary nonpolyposis colorectal cancer) and to provide recommendations for clinical management for affected families, based on available evidence and expert opinion.Data Sources and Study Selection: A systematic literature search using PubMed and the Cochrane Database of Systematic Reviews, reference list review of retrieved articles, manual searches of relevant articles, and direct communication with other researchers in the field. Search terms included hereditary non-polyposis colon cancer, Lynch syndrome, microsatellite instability, mismatch repair genes, and terms related to the biology of Lynch syndrome. Only peer-reviewed, full-text, English-language articles concerning human subjects published between January 1, 1996, and February 2006 were included. The US Preventive Services Task Force's 2-tier system was adapted to describe the quality of evidence and to assign strength to the recommendations for each guideline.Evidence Synthesis: The evidence supports colonoscopic surveillance for individuals with Lynch syndrome, although the optimal age at initiation and frequency of examinations is unresolved. Colonoscopy is recommended every 1 to 2 years starting at ages 20 to 25 years (age 30 years for those with MSH6 mutations), or 10 years younger than the youngest age of the person diagnosed in the family. While fully acknowledging absence of demonstrated efficacy, the following are also recommended annually: endometrial sampling and transvaginal ultrasound of the uterus and ovaries (ages 30-35 years); urinalysis with cytology (ages 25-35 years); history, examination, review of systems, education and genetic counseling regarding Lynch syndrome (age 21 years). Regular colonoscopy was favored for at-risk persons without colorectal neoplasia. For individuals who will undergo surgical resection of a colon cancer, subtotal colectomy is favored. Evidence supports the efficacy of prophylactic hysterectomy and oophorectomy.Conclusions: The past 10 years have seen major advances in the understanding of Lynch syndrome. Current recommendations regarding cancer screening and prevention require careful consultation between clinicians, clinical cancer genetic services, and well-informed patients. [ABSTRACT FROM AUTHOR]

These tumors have a very favorable prognosis, but treatment is often complicated by two factors; their unexpected discovery during surgery, and the patient's desire to preserve her fertility. [ABSTRACT FROM AUTHOR]

Background: Aedes aegypti is a widespread mosquito in tropical and subtropical regions that causes significant mortality and morbidity in humans by transmitting diseases, such as dengue fever and Zika virus disease. Synthetic insecticides, such as pyrethroids, have been used to control Ae. aegypti, but these insecticides can also affect nontarget organisms and contaminate soil and water. This study aimed to investigate the mosquitocidal activity of Pseudomonas mosselii isolated from pond sludge against larvae of Ae. aegypti., Results: Based on the initial results, similar time-course profiles were obtained for the mosquitocidal activity of the bacterial culture and its supernatant, and the pellet resuspended in Luria-Bertani (LB) medium also showed delayed toxicity. These results imply that the toxic component can be released into the medium from live bacteria. Further research indicated that the toxic component appeared in the supernatant approximately 4 h after a 3-mL stock was cultured in 200 mL of LB medium. The stabilities of the P. mosselii culture and supernatant stored at different temperatures were also evaluated, and the best culture stability was obtained at 28 °C and supernatant stability at 4 °C. The bacterial culture and supernatant were toxic to larvae and pupae of not only susceptible Ae. aegypti but also pyrethroid-resistant strains., Conclusion: This study highlights the value of the mosquitocidal activity of P. mosselii, which has potential as an alternative insecticide to control pyrethroid-resistant Ae. aegypti in the field. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape., (© 2024. Springer Nature Limited.)

Background: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood., Methods: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples., Findings: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling., Conclusions: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker., Funding: This investigator-initiated trial was funded by Merck., Competing Interests: Declaration of interests S.N.W. reports grants from NIH, GOG Foundation, Cotinga Pharmaceuticals, Bayer, and ArQule during the conduct of the study. She also reports grants and personal fees from AstraZeneca, Clovis Oncology, GlaxoSmithKline/Tesaro, Roche/Genentech, and Novartis. She reports personal fees from Merck, Pfizer, Eisai, CIrculogene, Zentalis, and Agenus outside the submitted work. N.D.F. reports personal fees from Tesaro, Pfizer, Bristol Myers Squibb, and GlaxoSmithKline outside the submitted work. A.K.S. discloses the following competing interests: consulting (Merck, GSK, ImmunoGen, Iylon, Kiyatec, Astra Zeneca, Onxeo) and shareholder (BioPath). R.C. reports the following competing interests: consulting (Clovis Oncology, Genentech/Roche, AstraZeneca/MedImmune, Genmab, OncoMed, Immunogen, AbbVie, Agenus, Novocure, Merck, OncXerna Therapeutics, Alkermes, Gradalis, GlaxoSmithKline, Alkermes, Eisai, GOG Foundation, Karyopharm Therapeutics), employment (Vanium Group, US Oncology Network), leadership (Onsexo), stock and other ownership interests (McKesson/US Oncology Network), and research funding (AstraZeneca/MedImmune, Clovis Oncology, Merck, Roche/Genentech, Immunogen, Mirati Therapeutics, Amgen, Pfizer, Lilly, Regeneron, Alkermes, Karyopharm Therapeutics). A.A.J. reports personal fees from Gerson Lehrman Group, Guidepoint, Iovance advisory board, NuProbe, Simcere, PACT Pharma, Genentech-Roche, Eisai, Agenus, and Macrogenics. He also reports grants from AstraZeneca, Bristol Myers Squibb, Iovance, Aravive, Pfizer, Immatics US, Eli Lilly, and Merck, and stock/stock options from AvengeBio outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

NK2 Homeobox 1 (NKX2-1) is a well-characterized pathological marker that delineates lung adenocarcinoma (LUAD) progression. The advancement of LUAD is influenced by the immune tumor microenvironment through paracrine signaling. However, the involvement of NKX2-1 in modeling the tumor immune microenvironment is still unclear. Here, the downregulation of NKX2-1 is observed in high-grade LUAD. Meanwhile, single-cell RNA sequencing and Visium in situ capturing profiling revealed the recruitment and infiltration of neutrophils in orthotopic syngeneic tumors exhibiting strong cell-cell communication through the activation of CXCLs/CXCR2 signaling. The depletion of NKX2-1 triggered the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Chemokine secretion is analyzed by chemokine array and validated by qRT-PCR. ATAC-seq revealed the restrictive regulation of NKX2-1 on the promoters of CXCL1, CXCL2, and CXCL5 genes. This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2-1 modulates the infiltration of tumor-promoting neutrophils by inhibiting CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that may improve LUAD patient outcomes., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Ovarian cancer is among the leading causes of gynecologic cancer-related death. Past ovarian cancer screening trials using combination of cancer antigen 125 testing and transvaginal ultrasound failed to yield statistically significant mortality reduction. Estimates of ovarian cancer sojourn time-that is, the period from when the cancer is first screen detectable until clinical detection-may inform future screening programs., Methods: We modeled ovarian cancer progression as a continuous time Markov chain and estimated screening modality-specific sojourn time and sensitivity using a Bayesian approach. Model inputs were derived from the screening arms (multimodal and ultrasound) of the UK Collaborative Trial of Ovarian Cancer Screening and the Prostate, Lung, Colorectal and Ovarian cancer screening trials. We assessed the quality of our estimates by using the posterior predictive P value. We derived histology-specific sojourn times by adjusting the overall sojourn time based on the corresponding histology-specific survival from the Surveillance, Epidemiology, and End Results Program., Results: The overall ovarian cancer sojourn time was 2.1 years (posterior predictive P value = .469) in the Prostate, Lung, Colorectal and Ovarian studies, with 65.7% screening sensitivity. The sojourn time was 2.0 years (posterior predictive P value = .532) in the United Kingdom Collaborative Trial of Ovarian Cancer Screening's multimodal screening arm and 2.4 years (posterior predictive P value = .640) in the ultrasound screening arm, with sensitivities of 93.2% and 64.5%, respectively. Stage-specific screening sensitivities in the Prostate, Lung, Colorectal and Ovarian studies were 39.1% and 82.9% for early-stage and advanced-stage disease, respectively. The histology-specific sojourn times ranged from 0.8 to 1.8 years for type II ovarian cancer and 2.9 to 6.6 years for type I ovarian cancer., Conclusions: Annual screening is not effective for all ovarian cancer subtypes. Screening sensitivity for early-stage ovarian cancers is not sufficient for substantial mortality reduction., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications., Experimental Design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model., Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis., Conclusions: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered., (©2024 American Association for Cancer Research.)

Objective: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic., Methods: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data., Results: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing., Conclusions: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts., Competing Interests: Competing interests: The following authors declare no potential conflict of interest: EMB, KAP, KHL, APSDDS, GO, CeEMdCA, LG, JR-C, DC-d-L. JAR-H reports consulting fees from Guidepoint Consulting and Schlesinger Group., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited., Methods: Follow-up data from patients in our prospective phase II trial of LIUD for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse., Results: Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at six months, premenopausal status, and Hispanic ethnicity (p<0.05), but only six-month response status remained a significant predictor in a multivariate model (p=0.023). LIUD increased abundance of NK cells (DMCP-counter score=46.13, FDR=0.004) and cytotoxic lymphocytes (DMCP-counter score=277.67, FDR=0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC=1.62, FDR=0.025) and GZMA (log2FC=2.47, FDR=0.008). NK cells were reduced at relapse (DMCP-counter score=-55.96, FDR=0.02). Immune-related pathways (IFNα-response and TGFβ-signaling) were enriched at relapse (FDR<0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR<0.05)., Conclusions: Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for non-surgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion.

The European Society for Clinical Microbiology and Infectious Diseases recommends 3rd generation cephalosporins and metronidazole for empirical treatment of community-acquired brain abscesses. In 53 retrospectively analyzed pediatric patients with community-acquired brain abscesses at a German University Hospital Staphylococcus aureus was identified as a relevant pathogen (21%). Therefore, it may be reasonable to cover S. aureus when selecting empirical therapy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: To assess the health state utilities of ovarian cancer patients, clinicians, and non-cancer controls regarding surgical complications in ovarian cancer., Methods: Utilities for 14 surgical complications were assessed from patients with recently diagnosed or recurrent ovarian cancer, clinicians, and non-cancer controls using the visual analog scale (VAS) and time trade-off (TTO) methods. Health state utilities were converted to a 0-to-1 scale, where 0 represents the least favorable outcome and 1 represents the most favorable outcome., Results: Fifty patients, 50 clinicians, and 50 controls participated. Median VAS scores were lower than TTO scores across all groups (p < 0.01). Patients viewed 'bleeding requiring transfusion' most favorably (VAS utility 0.75), followed in order by less favorable utility scores for hernia, thromboembolism, pleural effusion, abscess, ileus/bowel obstruction, wound infection, bowel obstruction requiring surgery, anastomotic leak requiring drain, temporary ostomy, anastomotic leak requiring surgery, genito-urinary fistula, permanent ostomy, and genito-intestinal fistula (VAS utility 0.2). Overall, clinicians perceived complications more favorably than patients by VAS (overall utility score 0.49 vs 0.43, p < 0.01), but not by the TTO. There were no differences in overall utility scores between patients and controls. Patients who had not experienced certain surgical complications had less favorable scores than patients who did (utility score for ostomy = 0.2 for patients without ostomy vs. 0.7 for patients with ostomy, p = 0.02)., Conclusions: This study establishes health state utilities for surgical complications associated with ovarian cancer. These utilities can be used in future cost-effectiveness evaluations to determine quality-adjusted outcomes and may help in counseling patients during the shared decision-making process., Competing Interests: Declaration of competing interest This research was supported in part by the Duncan Family Institute, and the MD Anderson Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health (NIH/NCI P30 CA016672). Dr. Suidan received research support from the National Institutes of Health T32 grant (5T32 CA101642). Dr. Meyer received research support from the Cancer Prevention and Research Institute of Texas grant (RP140020) and the National Cancer Institute (K07 CA201013). Dr. Giordano received research support from the Cancer Prevention and Research Institute of Texas grant (RP160674) and Komen grant (SAC150061)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Programmed cell death (PCD) plays a pivotal role in tumor initiation and progression. However, the prognostic value and clinical characteristics of PCD-related genes (PRGs) remain unclear. We collected and analyzed genes associated with twelve PCD patterns, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis to construct a gene signature. Our analysis identified 215 differentially expressed PRGs out of 1254 in lung adenocarcinoma (LUAD) and normal lung tissues. Subsequently, we performed univariate Cox regression analysis and identified 58 prognostic PRGs. Based on LASSO Cox regression analysis, we constructed a risk score using the expression levels of seven genes: DAPK2, DDIT4, E2F2, GAPDH, MET, PIM2, and FOXF1 . Patients with lower risk scores showed earlier stages of cancer, longer survival times, and better immune infiltrations and functions. Notably, we found that knockdown of DDIT4 significantly increased apoptosis and impaired the proliferation of human LUAD cell lines. Our study proposes a PRG-based prognostic signature that sheds light on the potential role of PCD-related genes in LUAD and provides valuable insights into future therapeutic strategies., Competing Interests: None., (AJTR Copyright © 2024.)

Background: Chaperonin Containing TCP1 Subunit 6 A (CCT6A) is a prominent protein involved in the folding and stabilization of newly synthesized proteins. However, its roles and underlying mechanisms in lung adenocarcinoma (LUAD), one of the most aggressive cancers, remain elusive., Methods: Our study utilized in vitro cell phenotype experiments to assess CCT6A's impact on the proliferation and invasion capabilities of LUAD cell lines. To delve into CCT6A's intrinsic mechanisms affecting glycolysis and proliferation in lung adenocarcinoma, we employed transcriptomic sequencing and liquid chromatography-mass spectrometry analysis. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (CHIP) assays were also conducted to substantiate the mechanism., Results: CCT6A was found to be significantly overexpressed in LUAD and associated with a poorer prognosis. The silencing of CCT6A inhibited the proliferation and migration of LUAD cells and elevated apoptosis rates. Mechanistically, CCT6A interacted with STAT1 protein, forming a complex that enhances the stability of STAT1 by protecting it from ubiquitin-mediated degradation. This, in turn, facilitated the transcription of hexokinase 2 (HK2), a critical enzyme in aerobic glycolysis, thereby stimulating LUAD's aerobic glycolysis and progression., Conclusion: Our findings reveal that the CCT6A/STAT1/HK2 axis orchestrated a reprogramming of glucose metabolism and thus promoted LUAD progression. These insights position CCT6A as a promising candidate for therapeutic intervention in LUAD treatment., (© 2024. The Author(s).)

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6 + T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor-treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell-dependent immune checkpoint that regulates human T cell function.

Objective: Although pure titanium (PT) and its alloys exhibit excellent mechanical properties, they lack biological activity as implants. The purpose of this study was to improve the biological activity of titanium implants through surface modification., Materials and Methods: Titanium was processed into titanium discs, where the titanium discs served as anodes and stainless steel served as cathodes, and a copper- and cobalt-doped porous coating [pure titanium model (PTM)] was prepared on the surface of titanium via plasma electrolytic oxidation. The surface characteristics of the coating were evaluated using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and profilometry. The corrosion resistance of PTM was evaluated with an electrochemical workstation. The biocompatibility and bioactivity of coated bone marrow mesenchymal stem cells (BMSCs) were evaluated through in vitro cell experiments., Results: A copper- and cobalt-doped porous coating was successfully prepared on the surface of titanium, and the doping of copper and cobalt did not change the surface topography of the coating. The porous coating increased the surface roughness of titanium and improved its resistance to corrosion. In addition, the porous coating doped with copper and cobalt promoted the adhesion and spreading of BMSCs., Conclusions: A porous coating doped with copper and cobalt was prepared on the surface of titanium through plasma electrolytic oxidation. The coating not only improved the roughness and corrosion resistance of titanium but also exhibited good biological activity.

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC., Competing Interests: E.G. is an Expert in Residence at General Inception and provides guidance for oncology programs. R.R. was previously the chief medical officer at Aravive and is currently the chief medical officer at Karyopharm. A.K.S. reports consulting for KIYATEC, Merck & Co., GSK, Onxeo, ImmunoGen, Iylon, and AstraZeneca; being a stockholder in Bio-Path Holdings. S.N.W. reports consulting for AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, SeaGen, Verastem, Vincerx, Zentalis, ZielBio and research funds to institution from Astra Zeneca, AvengeBio, Bayer, Bio-Path, Clovis Oncology, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, Roche/Genentech, Zentalis. A.A.J. reports consulting for Guidepoint, Gerson Lehrman Group, Macrogenics, Xencor, Theolytics, Avenge Bio, and Green Fire Bio, and clinical trial funding to the Institution from Merck, AstraZeneca, Bristol Myers Squibb, Iovance, Macrogenics, Eli Lilly, Alaunos, Immatics, Xencor, Break Through Cancer, and Imunon. Y.Y. reports consulting for AbbVie, Amgen, Bexion, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, Century, Enliven, GT Medical, NeoImmueTech, Merck, NGM, Repare, Servier, Transthera, Xinthera, and Vertex., (© 2024 The Author(s).)

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity., Methods: In this phase 1b study, registered at Clinical., Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Findings: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients., Conclusions: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks., Funding: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642)., Competing Interests: Declaration of interests S.N.W. reports grants/contracts to the institution from AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis Oncology, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, Roche/Genentech, and Zentalis; she also reports consulting with AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Verastem, Vincerx, Zentalis, and ZielBio. A.K.S. reports consulting for Kiyatec, Merck & Co., GSK, Valerio Therapeutics (formerly Onxeo), ImmunoGen, Iylon, and AstraZeneca; being a stockholder in BioPath Holdings; and a licensed patent (EGFL6 antibody). A.A.J. received institutional research funding from Bristol Myers Squibb, Iovance, Merck, Pfizer, Imunon, Aravive, MacroGenics, AstraZeneca, Avenge Bio, Greenfire Bio, and Break Through Cancer and consulting fees from Guidepoint, Alkermes, Gerson Lehrman Group, Adicet Bio, Theolytics, Avenge Bio, NuProbe, and Greenfire Bio., (Copyright © 2024 Elsevier Inc. All rights reserved.)