Explainable artificial intelligence analysis of brachytherapy boost receipt in cervical cancer during the COVID-19 era.

PURPOSE: Brachytherapy is a critical component of the standard-of-care curative radiotherapy regimen for women with locally advanced cervical cancer (LACC). However, existing literature suggests that many patients will not receive the brachytherapy boost. We used machine learning (ML) and explainable artificial intelligence to characterize this disparity. MATERIALS AND METHODS: Patients with LACC diagnosed from 2004 to 2020 who received definitive radiation were identified in the National Cancer Database. Five ML models were trained to predict if a patient received a brachytherapy boost. The best-performing model was explained using SHapley Additive exPlanation (SHAP) values. To identify trends that may be attributable to the coronavirus disease 2019 (COVID-19) pandemic, the previous analysis was repeated and limited to 2019 to 2020. RESULTS: A total of 37,564 patients with LACC were identified; 5799 were diagnosed from 2019 to 2020 (COVID cohort). Of these patients, 59.3% received a brachytherapy boost, with 76.4% of patients diagnosed in 2019 to 2020 receiving a boost. The random forest model achieved the best performance for both the overall and COVID cohorts. In the overall cohort, the most important predictive features were the year of diagnosis, stage, age, and insurance status. In the COVID cohort, the most important predictive features were FIGO stage, age, insurance status, and hospital type. Of the 26 patients who tested positive for COVID-19 during their course of radiotherapy, 19 (73.1%) received a brachytherapy boost. CONCLUSIONS: A gradual increase in brachytherapy boost utilization has been noted, which did not seem to be significantly impacted by the onset of the COVID-19 pandemic. ML could be considered to identify patient populations where brachytherapy is underutilized, which can provide actionable feedback for improving access.

Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004). CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Current Status and Future Directions of Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer.

PURPOSE: The standard of care for patients with locally advanced cervical cancer is definitive chemoradiation followed by a brachytherapy boost. This review describes the current status and future directions of image-guided adaptive brachytherapy for locally advanced cervical cancer. METHODS: A systematic search of the PubMed and Clinicaltrials.gov databases was performed, focusing on studies published within the last 10 years. The search queried "cervical cancer [AND] image-guided brachytherapy [OR] magnetic resonance imaging (MRI) [OR] adaptive brachytherapy". DISCUSSION: The retroEMBRACE and EMBRACE-I trials have established the use of MRI as the standard imaging modality for brachytherapy application and planning. Quantitative imaging and radiomics have the potential to improve outcomes, with three ongoing prospective studies examining the use of radiomics to further risk-stratify patients and personalize brachytherapy. Another active area of investigation includes utilizing the superior soft tissue contrast provided by MRI to increase the dose per fraction and decrease the number of fractions needed for brachytherapy, with several retrospective studies demonstrating the safety and feasibility of three-fraction courses. For developing countries with limited access to MRI, trans-rectal ultrasound (TRUS) appears to be an effective alternative, with several retrospective studies demonstrating improved target delineation with the use of TRUS in conjunction with CT guidance. CONCLUSIONS: Further investigation is needed to continue improving outcomes for patients with locally advanced cervical cancer treated with image-guided brachytherapy.

Lithium downregulates phosphorylated acetyl­CoA carboxylase 2 and attenuates mitochondrial fatty acid utilization and oxidative stress in cardiomyocytes.

Acetyl-CoA carboxylase 2 plays a crucial role in regulating mitochondrial fatty acid oxidation in cardiomyocytes. Lithium, a monovalent cation known for its cardioprotective potential, has been investigated for its influence on mitochondrial bioenergetics. The present study explored whether lithium modulated acetyl-CoA carboxylase 2 and mitochondrial fatty acid metabolism in cardiomyocytes and the potential therapeutic applications of lithium in alleviating metabolic stress. Mitochondrial bioenergetic function, fatty acid oxidation, reactive oxygen species production, membrane potential and the expression of proteins involved in fatty acid metabolism in H9c2 cardiomyocytes treated with LiCl for 48 h was measured by using a Seahorse extracellular flux analyzer, fluorescence microscopy and western blotting. Small interfering RNA against glucose transporter type 4 was transfected into H9c2 cardiomyocytes for 48 h to induce metabolic stress mimicking insulin resistance. The results revealed that LiCl at a concentration of 0.3 mM (but not at a concentration of 0.1 or 1.0 mM) upregulated the expression of phosphorylated (p-)glycogen synthase kinase-3 beta and downregulated the expression of p-acetyl-CoA carboxylase 2 but did not affect the expression of adenosine monophosphate-activated protein kinase or calcineurin. Cotreatment with TWS119 (8 µM) and LiCl (0.3 mM) downregulated p-acetyl-CoA carboxylase 2 expression to a similar extent as did treatment with TWS119 (8 µM) alone. Moreover, LiCl (0.3 mM) inhibited mitochondrial fatty acid oxidation, improved coupling efficiency and the cellular respiratory control ratio, hindered reactive oxygen species production and proton leakage and restored mitochondrial membrane potential in glucose transporter type 4 knockdown-H9c2 cardiomyocytes. These findings suggested that low therapeutic levels of lithium can downregulate p-acetyl-CoA carboxylase 2, thus reducing mitochondrial fatty acid oxidation and oxidative stress in cardiomyocytes.

Interleukin-33/ST2 axis involvement in atrial remodeling and arrhythmogenesis.

Interleukin (IL)-33, a cytokine involved in immune responses, can activate its receptor, suppression of tumorigenicity 2 (ST2), is elevated during atrial fibrillation (AF). However, the role of IL-33/ST2 signaling in atrial arrhythmia is unclear. This study explored the pathological effects of the IL-33/ST2 axis on atrial remodeling and arrhythmogenesis. Patch clamping, confocal microscopy, and Western blotting were used to analyze the electrical characteristics of and protein activity in atrial myocytes (HL-1) treated with recombinant IL-33 protein and/or ST2-neutralizing antibodies for 48 hrs. Telemetric electrocardiographic recordings, Masson's trichrome staining, and immunohistochemistry staining of the atrium were performed in mice receiving tail vein injections with nonspecific immunoglobulin (control), IL-33, and IL-33 combined with anti-ST2 antibody for 2 weeks. IL-33-treated HL-1 cells had a reduced action potential duration, lower L-type Ca2+ current, greater sarcoplasmic reticulum (SR) Ca2+ content, increased Na+/Ca2+ exchanger (NCX) current, elevation of K+ currents, and increased intracellular calcium transient. IL-33-treated HL-1 myocytes had greater activation of the calcium-calmodulin-dependent protein kinase II (CaMKII)/ryanodine receptor 2 (RyR2) axis and nuclear factor kappa B (NF-κB) / NLR family pyrin domain containing 3 (NLRP3) signaling than did control cells. IL-33 treated cells also had greater expression of Nav1.5, Kv1.5, NCX, and NLRP3 than did control cells. Pretreatment with neutralizing anti-ST2 antibody attenuated IL-33-mediated activation of CaMKII/RyR2 and NF-κB/NLRP3 signaling. IL-33-injected mice had more atrial ectopic beats and increased AF episodes, greater atrial fibrosis, and elevation of NF-κB/NLRP3 signaling than did controls or mice treated with IL-33 combined with anti-ST2 antibody. Thus, IL-33 recombinant protein treatment promotes atrial remodeling through ST2 signaling. Blocking the IL-33/ST2 axis might be an innovative therapeutic approach for patients with atrial arrhythmia and elevated serum IL-33.

Adenosine monophosphate-regulated protein kinase inhibition modulates electrophysiological characteristics and calcium homeostasis of rabbit right ventricular outflow tract.

BACKGROUND: Metabolic stress predisposes to ventricular arrhythmias and sudden cardiac death. Right ventricular outflow tract (RVOT) is the common origin of ventricular arrhythmias. Adenosine monophosphate-regulated protein kinase (AMPK) activation is an important compensatory mechanism for cardiac remodeling during metabolic stress. OBJECTIVES: The purpose of this study was to access whether AMPK inhibition would modulate RVOT electrophysiology, calcium (Ca2+ ) regulation, and RVOT arrhythmogenesis or not. METHODS: Conventional microelectrodes were used to record electrical activity before and after compound C (10 µM, an AMPK inhibitor) in isoproterenol (1 µM)-treated rabbit RVOT tissue preparations under electrical pacing. Whole-cell patch-clamp and confocal microscopic examinations were performed in baseline and compound C-treated rabbit RVOT cardiomyocytes to investigate ionic currents and intracellular Ca2+ transients in isolated rabbit RVOT cardiomyocytes. RESULTS: Compound C decreased RVOT contractility, and reversed isoproterenol increased RVOT contractility. Compound C decreased the incidence, rate, and duration of isoproterenol-induced RVOT burst firing under rapid pacing. Compared to baseline, compound C-treated RVOT cardiomyocytes had a longer action potential duration, smaller intracellular Ca2+ transients, late sodium (Na+ ), peak L-type Ca2+ current density, Na+ -Ca2+ exchanger, transient outward potassium (K+ ) current, and rapid and slow delayed rectifier K+ currents. CONCLUSION: AMPK inhibition modulates RVOT electrophysiological characteristics and Ca2+ homeostasis, contributing to lower RVOT arrhythmogenic activity. Accordingly, AMPK inhibition might potentially reduce ventricular tachyarrhythmias.

Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 µM, an inhibitor of protein kinase A, PKA), KN93 (1 µM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 µM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.

The relationship between serum CA-125 level and recurrence in surgical stage I endometrial cancer patients.

BACKGROUND: The majority of patients diagnosed with early stage endometrial cancer have a favorable prognosis; however, approximately 10% to 15% experience a recurrence. Therefore, the aim of the present study was to evaluate whether postoperative carbohydrate antigen 125 (CA-125) levels could be used to predict recurrence and recurrence-free survival (RFS) in patients with surgical stage I endometrial cancer. METHODS: We enrolled a total of 518 patients with stage I endometrial cancer who underwent surgical treatment between January 2010 and March 2019. Serum CA-125 levels were measured prior to surgery, as well as 6 to 12 months after surgery. Subsequently, the correlations between the CA-125 levels, cancer recurrence, and RFS were analyzed. RESULTS: Although the preoperative CA-125 level was not associated with the risk of cancer recurrence, the postoperative CA-125 level was found to be the only independent predictor of recurrence in both univariate and multivariate analyses. Additionally, we found that a postoperative CA-125 cutoff value of 13.75 U/mL yielded the best sensitivity and specificity for predicting cancer recurrence. Patients with a postoperative CA-125 level ≥13.75 U/mL, and those with a level <13.75 U/mL, had a median time to recurrence and a 5-year RFS rate of 35.5 vs 50.5 months and 84.7 vs 94.4%, respectively. Additionally, postoperative CA-125 levels were not found to be correlated with preoperative levels. CONCLUSION: In patients with stage I endometrial cancer, a postoperative CA-125 level ≥13.75 U/mL was found to be significantly correlated with a higher recurrence rate, as well as a shorter RFS. Therefore, obtaining a follow-up CA-125 level within 6 to 12 months after staging surgery may be a promising noninvasive biomarker for predicting recurrence.

Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

The Complex Interplay between Imbalanced Mitochondrial Dynamics and Metabolic Disorders in Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a global burden, with an increasing number of people affected and increasing treatment costs. The advances in research and guidelines improve the management of blood glucose and related diseases, but T2DM and its complications are still a big challenge in clinical practice. T2DM is a metabolic disorder in which insulin signaling is impaired from reaching its effectors. Mitochondria are the "powerhouses" that not only generate the energy as adenosine triphosphate (ATP) using pyruvate supplied from glucose, free fatty acid (FFA), and amino acids (AA) but also regulate multiple cellular processes such as calcium homeostasis, redox balance, and apoptosis. Mitochondrial dysfunction leads to various diseases, including cardiovascular diseases, metabolic disorders, and cancer. The mitochondria are highly dynamic in adjusting their functions according to cellular conditions. The shape, morphology, distribution, and number of mitochondria reflect their function through various processes, collectively known as mitochondrial dynamics, including mitochondrial fusion, fission, biogenesis, transport, and mitophagy. These processes determine the overall mitochondrial health and vitality. More evidence supports the idea that dysregulated mitochondrial dynamics play essential roles in the pathophysiology of insulin resistance, obesity, and T2DM, as well as imbalanced mitochondrial dynamics found in T2DM. This review updates and discusses mitochondrial dynamics and the complex interactions between it and metabolic disorders.

Cardiopulmonary functional capacity in Taiwanese children with ventricular septal defects.

BACKGROUND: Children with ventricular septal defects (VSDs) are considered to have no difference in cardiopulmonary functional capacity with healthy children of the same age; however, studies have shown contradictory findings. The aim of this study was to assess whether Taiwanese children with VSDs exhibited cardiopulmonary deficits. METHODS: This is a retrospective cohort study with the data collected from January 2010 to December 2021. All patients and controls (age-, sex-, and body mass index -matched) underwent cardiopulmonary exercise testing (CPET) and pulmonary function test. RESULTS: In total, 157 VSD patients (80 patients with surgically closed VSDs, 77 patients with unrepaired VSDs) and 157 healthy controls were recruited. Pulmonary function test showed significant among-group differences in maximal voluntary ventilation (MVV) (p = 0.015). The surgically closed group had lower MVV compared to the control group. Regarding CPET, we found VSD patients had lower peak oxygen uptake than the controls (surgically closed group: 30.84 ± 6.27 ml/kg/min; unrepaired group: 32.00 ± 5.95 ml/kg/min; control group: 36.76 ± 6.50 ml/kg/min, p < 0.001). There was also significant among-group differences in aerobic capacity (surgically closed group: 21.20 ± 4.39 ml/kg/min; unrepaired group: 21.68 ± 4.47 ml/kg/min; control group: 26.25 ± 4.33 ml/kg/min, p < 0.001). In addition, the surgically closed group had lower heart rate average at anaerobic threshold than the control group (surgically closed group: 138.11 ± 16.42 bpm; control group: 145.78 ± 15.53 bpm, p = 0.002). CONCLUSION: Taiwanese children with VSD, whether surgically closed or not, have poorer cardiopulmonary performance than age-matched healthy children, and the results of the surgically closed group were even worse.

Patterns of Care for Patients With Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy at Predominately Academic Centers between 2016-2020: An NCDB Analysis.

Total neoadjuvant therapy (TNT) has emerged as the preferred approach for locally advanced rectal cancer (LARC), defined as T3/4 or any T with N+ disease. Our objective was to (1) determine the proportion of patients with LARC receiving TNT over time, (2) determine the most common method in which TNT is being delivered, and (3) determine what factors are associated with a greater likelihood of receiving TNT in the United States. Retrospective data was obtained from the National Cancer Database (NCDB) for patients diagnosed with rectal cancer between 2016 and 2020. Patients were excluded if they had M1 disease, T1-2 N0 disease, incomplete staging information, nonadenocarcinoma histology, received RT to a nonrectum site, or received a nondefinitive RT dose. Data were analyzed using linear regression, χ2 test, and binary logistic regression. Of the 26,375 patients included, most patients were treated at an academic facility (94.6%). Five thousand three (19.0%) patients received TNT, and 21,372 (81.0%) patients did not receive TNT. The proportion of patients receiving TNT increased significantly over time, from 6.1% in 2016 to 34.6% in 2020 (slope = 7.36, 95% CI 4.58-10.15, R2 = 0.96, P = .040). The most common TNT regimen was multiagent chemotherapy followed by long-course chemoradiation (73.2% of cases from 2016-2020). There was a significant increase in utilization of short-course RT as part of TNT from 2.8% in 2016 to 13.7% in 2020 (slope = 2.74, 95% CI 0.37-5.11, R2 = 0.82, P = .035). Factors associated with a lower likelihood of TNT usage included age >65, female gender, Black race, and T3 N0 disease. TNT use in the United States has increased significantly from 2016-2020, with approximately 34.6% of patients with LARC receiving TNT in 2020. The observed trend appears to be in line with the recent National Comprehensive Cancer Network guidelines recommending TNT as the preferred approach.

Robot-assisted sacrohysteropexy vs robot-assisted sacrocolpopexy in women with primary advanced apical prolapse: A retrospective cohort study.

BACKGROUND: This study aimed to evaluate the anatomic and clinical outcomes of robot-assisted sacrohysteropexy (RASH) against robot-assisted sacrocolpopexy (RASC) for the treatment of primary advanced apical prolapse. METHODS: We conducted a retrospective cohort study of all robot-assisted pelvic organ prolapse surgeries for primary advanced apical prolapse (stage ≥II) between January 2011 and May 2021 at an academic tertiary hospital. Surgical outcomes and pelvic organ function were evaluated using the Pelvic Organ Prolapse Quantitative (POP-Q) stage and validated questionnaires (POPDI-6) during preoperative and postoperative 12-month follow-up evaluations. All data were obtained from electronic medical records. RESULTS: A total of 2368 women underwent surgery for apical prolapse repair, and 18 women underwent either RASH (n = 11) or RASC (n = 7). Compared to the RASC group, the RASH group was significantly younger, premenopausal, and less parous. Preoperative prolapse stage, operative time, estimated blood loss, and hospitalization length was comparable between the groups. No intraoperative complications were observed. All women had a median follow-up duration of 24 months (range: 12-108 months). During the 12-month follow-up period, women in the RASH group reported higher satisfaction with the surgery than those in the RASC group (100% vs. 71.4%, p = 0.137). The mesh exposure rate was significantly higher in the RASC group (3/7, 42.9%) than in the RASH group (0/11, 0%) ( p = 0.043), which was found at 12 to 36 months postoperatively and was successfully managed with vaginal estrogen cream. In the RASH group, one woman required reoperation with anterior colporrhaphy for recurrent anterior prolapse at 60 months postoperatively. The apical success rate was 100% at one year postoperatively, without apical recurrence in either group during the follow-up period. CONCLUSION: RASH represents an effective and feasible option for the surgical treatment of advanced primary apical prolapse in women who desire uterine preservation and have a significantly lower risk of mesh erosion than RASC.

Trichomonas tenax induces barrier defects and modulates the inflammatory cytotoxicity of gingival and pulmonary epithelial cells.

BACKGROUND: Trichomonas tenax is a single-cell flagellated anaerobic organism, commensal in the human oral cavity. Although a previous study indicated that T. tenax could cause cell damage and phagocytose host epithelial cells, its pathological effects on gum cells remain unknown. Furthermore, several case reports have detected T. tenax in several patients with empyema and/or pleural effusion, which may have been aspirated from the oral cavity. However, the cytotoxic effects and immune responses of alveolar cells are unknown. Therefore, we aimed to determine the cytotoxic and immune effects of T. tenax on gums and pulmonary cell lines. The cytopathic effect and lactate dehydrogenase (LDH) cytotoxicity assays were used to determine the level of cell damage in gum and lung epithelial cells. Western blot was used to determine the disruption of cell junctions. Finally, epithelial cell cytokines were measured using ELISA to elucidate the immune response to T. tenax. RESULTS: We found that T. tenax induced a cytotoxic effect on gum epithelial cells by disrupting cell junctions; however, it hardly triggered cellular damage in alveolar A549 cells and mucoepidermoid NCI-H292 cells. Furthermore, T. tenax induced the production of IL-6 at a low multiplicity of infection (MOI) in gum, A549, and NCI-H292 cells. CONCLUSIONS: Our results suggest that T. tenax can trigger gingival cell cytotoxicity, disrupt cell junctions, and induce IL-6 production in gingival and pulmonary cell lines.

Title: Trichomonas tenax induit des défauts de barrière et module la cytotoxicité inflammatoire des cellules épithéliales gingivales et pulmonaires. Abstract: Contexte : Trichomonas tenax est un organisme anaérobie unicellulaire flagellé, commensal dans la cavité buccale humaine. Bien qu'une étude précédente ait indiqué que T. tenax pouvait endommager les cellules et phagocyter les cellules épithéliales de l'hôte, ses effets pathogènes sur les cellules gingivales restent inconnus. En outre, plusieurs rapports ont détecté T. tenax chez des patients présentant un empyème et/ou un épanchement pleural, qui peut avoir été aspiré de la cavité buccale. Cependant, les effets cytotoxiques et les réponses immunitaires des cellules alvéolaires sont inconnus. Par conséquent, nous avons cherché à déterminer les effets cytotoxiques et immunitaires de T. tenax sur des lignées cellulaires de gencives et de poumons. Les tests d'effet cytopathique et de cytotoxicité de la lactate déshydrogénase (LDH) ont été utilisés pour déterminer le niveau de dommages cellulaires dans les cellules. Le Western Blot a été utilisé pour déterminer la perturbation des jonctions cellulaires. Enfin, les cytokines des cellules épithéliales ont été mesurées par ELISA pour élucider la réponse immunitaire à T. tenax. Résultats : Nous avons constaté que T. tenax induisait un effet cytotoxique sur les cellules épithéliales gingivales en perturbant les jonctions cellulaires. Cependant, T. tenax a déclenché des dommages cellulaires seulement mineurs dans les cellules alvéolaires A549 et les cellules mucoépidermoïdes NCI-H292. De plus, T. tenax a induit la production d'IL-6 à une faible multiplicité d'infection (MOI) dans les cellules de gencives, A549 et NCI-H292. Conclusions : Nos résultats suggèrent que T. tenax peut déclencher la cytotoxicité des cellules gingivales, perturber les jonctions cellulaires et induire la production d'IL-6 dans les lignées cellulaires gingivales et pulmonaires.

Spike Protein Impairs Mitochondrial Function in Human Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID-19.

BACKGROUND: COVID-19 has a major impact on cardiovascular diseases and may lead to myocarditis or cardiac failure. The clove-like spike (S) protein of SARS-CoV-2 facilitates its transmission and pathogenesis. Cardiac mitochondria produce energy for key heart functions. We hypothesized that S1 would directly impair the functions of cardiomyocyte mitochondria, thus causing cardiac dysfunction. METHODS: Through the Seahorse Mito Stress Test and real-time ATP rate assays, we explored the mitochondrial bioenergetics in human cardiomyocytes (AC16). The cells were treated without (control) or with S1 (1 nM) for 24, 48, and 72 h and we observed the mitochondrial morphology using transmission electron microscopy and confocal fluorescence microscopy. Western blotting, XRhod-1, and MitoSOX Red staining were performed to evaluate the expression of proteins related to energetic metabolism and relevant signaling cascades, mitochondrial Ca2+ levels, and ROS production. RESULTS: The 24 h S1 treatment increased ATP production and mitochondrial respiration by increasing the expression of fatty-acid-transporting regulators and inducing more negative mitochondrial membrane potential (Δψm). The 72 h S1 treatment decreased mitochondrial respiration rates and Δψm, but increased levels of reactive oxygen species (ROS), mCa2+, and intracellular Ca2+. Electron microscopy revealed increased mitochondrial fragmentation/fission in AC16 cells treated for 72 h. The effects of S1 on ATP production were completely blocked by neutralizing ACE2 but not CD147 antibodies, and were partly attenuated by Mitotempo (1 µM). CONCLUSION: S1 might impair mitochondrial function in human cardiomyocytes by altering Δψm, mCa2+ overload, ROS accumulation, and mitochondrial dynamics via ACE2.

Effects of photobiomodulation as an adjunctive treatment in chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic airway inflammation and remodeling and lung parenchymal inflammation and destruction, which result in many pulmonary and extrapulmonary manifestations. The anti-inflammatory effect of photobiomodulation (PBM) has been reported in previous studies. This review was conducted to evaluate the direct effect of PBM on lung inflammation in COPD. The other effects of PBM on modulation of peripheral and respiratory muscle metabolism and angiogenesis in lung tissues were also discussed. The databases of PubMed, Cochrane Library, and Google Scholar were searched to find the relevant studies. Keywords included PBM and related terms, COPD-related signs, and lung inflammation. A total of 12 articles were selected and reviewed in this study. Based on the present review, PBM is helpful in reducing lung inflammation through decreasing the inflammatory cytokines and chemokines at multiple levels and increasing anti-inflammatory cytokines. In addition, PBM also improves both peripheral and respiratory muscle metabolism and promote angiogenesis. This review demonstrated that PBM is a promising adjunctive treatment modality for COPD management which merits further validation.

Maintenance dienogest therapy following adjuvant gonadotropin-releasing hormone agonist treatment after uterus-sparing surgery in adenomyosis: A retrospective cohort study.

OBJECTIVE: To investigate the safety and efficacy of adjuvant gonadotropin-releasing hormone agonist (GnRH-a) treatment followed by maintenance dienogest (DNG) therapy after uterus-sparing surgery. METHODS: Retrospective cohort study. A total of 190 patients with severe adenomyosis underwent uterus-sparing surgery between January 2010 and June 2020. Of these patients, 90 were analyzed. Forty-six patients (control group) received adjuvant 6-month GnRH-a therapy alone after uterus-sparing surgery, and 44 patients (maintenance group) received postoperative 6-month GnRH-a treatment followed by maintenance DNG therapy (2 mg/day orally). The median follow-up period was 18 months. The study was analyzed using generalized estimating equations. RESULTS: At baseline, the characteristics of patients in each group were comparable. Compared with the control group, the maintenance group had a significant improvement in the visual analog scale score of dysmenorrhea (P < 0.001), hemoglobin level (P = 0.004), and uterine volume (P = 0.004) from baseline to 18 months after uterus-sparing surgery. The symptom recurrence rate was significantly lower in the maintenance group than in the control group (4.6% vs. 37.0%, P < 0.001). CONCLUSIONS: The findings of this study suggest that combinatorial treatment with GnRH-a (adjuvant treatment) and DNG (maintenance therapy) represents a safe and effective short-term therapy after uterus-sparing surgery for adenomyosis.

Loss of Major Histocompatibility Complex Class I, CD8 + Tumor-infiltrating Lymphocytes, and PD-L1 Expression in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC), a chemoresistant ovarian cancer, shows a modest response to anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) therapies. The effects of anti-PD-1/PD-L1 therapies rely on cytotoxic T-cell response, which is triggered by antigen presentation mediated by major histocompatibility complex (MHC) class I. The loss of MHC class I with simultaneous PD-L1 expression has been noted in several cancer types; however, these findings and their prognostic value have rarely been evaluated in OCCC. We collected data from 76 patients with OCCC for clinicopathologic analysis. Loss of MHC class I expression was seen in 44.7% of the cases including 39.3% to 47.4% of the PD-L1 + cases and was associated with fewer CD8 + tumor-infiltrating lymphocytes (TILs). PD-L1 positivity was associated with a higher number of CD8 + TILs. Cox proportional hazard models showed that high (≥50/mm 2 ) CD8 + TILs was associated with shorter disease-specific survival (hazard ratio [HR]=3.447, 95% confidence interval [CI]: 1.222-9.720, P =0.019) and overall survival (HR=3.053, 95% CI: 1.105-8.43, P =0.031). PD-L1 positivity using Combined Positive Score was associated with shorter progression-free survival (HR=3.246, 95% CI: 1.435-7.339, P =0.005), disease-specific survival (HR=4.124, 95% CI: 1.403-12.116, P =0.010), and overall survival (HR=4.489, 95% CI: 1.553-12.972, P =0.006). Loss of MHC class I may contribute to immune evasion and resistance to anti-PD-1/PD-L1 therapies in OCCC, and CD8 + TILs and PD-L1 positivity using Combined Positive Score may have a negative prognostic value.

Long-term pelvic fracture and overall mortality risk after pelvic cancer and pelvic radiation.

BACKGROUND: The association of pelvic radiation with pelvic fracture risk has not been examined in prospective cohort settings with comprehensive fracture risk assessment, cancer-free comparison populations, and long-term follow-up. Our objective is to better characterize pelvic fracture and overall mortality risks in postmenopausal women participating in the Women's Health Initiative. METHODS: A total of 135 743 Women's Health Initiative participants aged 50 to 79 years enrolled from 40 US clinical centers from 1993 to 1998 who had entry Fracture Risk Assessment Tool scores were eligible. Outcomes included pelvic cancer diagnosis, pelvic fracture occurrence, and mortality. Cox proportional hazards regression models were used to examine associations of pelvic cancer and pelvic radiation with pelvic fracture and mortality risk. RESULTS: After 17.7 years (median) follow-up, 4451 pelvic cancers, 10 139 pelvic fractures, and 33 040 deaths occurred. In multivariable analyses, women with incident pelvic cancer, compared with women who remained pelvic cancer free, had higher pelvic fracture risk (hazard ratio [HR] = 1.26, 95% confidence interval [CI] = 1.11 to 1.43) and higher overall mortality risk (HR = 2.91, 95% CI = 2.77 to 3.05). Women with pelvic cancer treated with pelvic radiation, compared with women with pelvic cancer not treated with pelvic radiation, had higher pelvic fracture risk (HR = 1.98, 95% CI = 1.41 to 2.78) and higher overall mortality after pelvic cancer (HR = 1.32, 95% CI = 1.15 to 1.52). CONCLUSIONS: Postmenopausal women with pelvic cancer, especially those receiving pelvic radiation, are at higher pelvic fracture risk and higher overall mortality risk. As therapeutic advances have reduced cancer mortality, attention to and interventions for pelvic fracture prevention may be important in pelvic cancer survivors.

MEX3A Mediates p53 Degradation to Suppress Ferroptosis and Facilitate Ovarian Cancer Tumorigenesis.

Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian cancer histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other ovarian cancer subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing ovarian cancer remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing ovarian cancer. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53. SIGNIFICANCE: Degradation of p53 mediated by MEX3A drives ovarian cancer growth by circumventing p53 tumor suppressive functions, suggesting targeting MEX3A as a potential strategy for treating of ovarian cancer expressing WT p53.