Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer.

Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics.

Reactive Oxygen Species or "ROS" encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

Navigating Diagnostic Challenges: Severe Pulmonary Hypertension in Acute Exacerbation of Chronic Obstructive Pulmonary Disease vs. Pulmonary Embolism.

A 63-year-old male with an unremarkable medical history presented to the emergency room (ER) with shortness of breath and bilateral lower extremity edema. In the ER, he was found to be hypoxic and hypercapnic on an arterial blood gas. CT angiography of the chest revealed severe emphysematous changes and large right apical bullae. A bedside point-of-care ultrasound demonstrated many bilateral B-lines as well as normal ejection fraction (EF). An echocardiogram revealed a small left ventricular cavity with an EF of 65%, severely dilated right ventricle, severe right ventricular dysfunction, "D" shaped interventricular septum, severely dilated right atrium, and severe pulmonary arterial hypertension (PAH) with a calculated pulmonary artery systolic pressure of 72 mmHg. The patient was initiated on bilevel positive airway pressure, glucocorticoids, bronchodilator nebulization, and diuretics with symptomatic improvement. Herein, this case report discusses similarities and differences between presentations and echocardiographic manifestations of severe PAH in the setting of acute exacerbation of chronic obstructive pulmonary disease and pulmonary embolism in the acute setting.

Towards Optimal Cardiovascular Health: A Comprehensive Review of Preventive Strategies.

Heart disease remains a prominent global health concern, with cardiovascular disease (CVD) standing as a leading cause of death worldwide. Preventing heart disease not only decreases the risk of premature death but also mitigates complications like heart attacks, strokes, and arrhythmias, thereby enhancing overall health and quality of life. The economic burden of heart disease treatment highlights the importance of implementing preventive measures, such as lifestyle changes and early interventions, which can alleviate healthcare costs. These strategies, targeting risk factors like hypertension (HTN), diabetes mellitus (DM), dyslipidemia, and obesity, not only prevent heart disease but also reduce the risk of other health issues. Herein, this review covers various preventive measures, including dietary interventions, exercise, controlling HTN, DM, cholesterol, and weight, smoking cessation, and pharmacological interventions. By critically analyzing the guidelines and leveraging robust data alongside variations in recommendations, this review aims to elucidate effective primary prevention strategies for CVD.

A Rare Case of Bicalutamide-Induced Severe Congestive Heart Failure in a Patient With Advanced Prostate Cancer.

Bicalutamide, a nonsteroidal androgen receptor inhibitor, is an established therapeutic agent for advanced prostate cancer but is associated with severe cardiovascular side effects in rare cases. This case report discusses a rare occurrence of severe systolic congestive heart failure (CHF) in a 68-year-old male undergoing treatment for advanced prostate cancer with bicalutamide, without concurrent use of gonadotropin-releasing hormone antagonists. The patient presented with non-specific abdominal and bilateral foot pain. The initial assessment indicated anemia and severe dyspnea, revealing a significant decrease in left ventricular ejection fraction (LVEF) from 55% to 15% on transthoracic echocardiography (TTE), indicative of severe CHF. Bicalutamide was identified as the likely culprit given the temporal association and lack of other identifiable causes, leading to its discontinuation and initiation of guideline-directed medical therapy (GDMT). A remarkable recovery of cardiac function was subsequently observed, with LVEF improving to 60%. The patient was managed with GDMT, and a gonadotropin-releasing hormone antagonist, degarelix, was later introduced for prostate cancer treatment, along with ongoing cardiac monitoring. The recovery of LVEF and the absence of other etiologies reinforce the likelihood of bicalutamide-induced cardiotoxicity. This report underscores the importance of vigilant cardiovascular monitoring in patients receiving bicalutamide, prompt identification of cardiac dysfunction and possible mechanisms of bicalutamide cardiotoxicity, and the potential for cardiac recovery upon drug discontinuation and initiation of GDMT.

Factors influencing blood pressure fluctuation in pediatric patients with sickle cell disease in Saudi Arabia: A retrospective single-center cohort study.

OBJECTIVES: To investigate changes in blood pressure (BP) among pediatric patients with sickle cell disease (SCD) and determine the variables that might influence these changes. METHODS: A total of 100 pediatric patients with SCD who followed up in the pediatric outpatient clinic were recruited for this retrospective cohort study. Clinical data included anthropometric measures, average systolic and diastolic BP recorded during multiple follow-up visits, hemoglobin (Hb) level, serum creatinine, and hemoglobin S percentage. Blood pressure measurements were categorized according to the guidelines of the American Academy of Pediatrics (AAP, 2017). RESULTS: In this cohort, 68% of the patients had normal systolic BP, 13% had elevated systolic BP, 17% had stage 1 hypertension (HTN), while only 2% reported stage 2 HTN. Patients who were overweight had relatively high systolic BP compared to patients who were underweight (p=0.034) or had normal weight (p=0.023). The average systolic BP significantly correlates with body mass index (r= 0.377, p<0.001) and serum creatinine (r=0.369, p<0.001). CONCLUSION: Pediatric overweight SCD patients exhibited higher average systolic BP than those underweight or normal weight. Body mass index and serum creatinine significantly influenced the average systolic BP more than the Hb level or Hb S percentage.

Comparison of Knowledge of Lactose Intolerance and Cow's Milk Allergy Among the Medical Students at Two Universities in Saudi Arabia.

Lactose intolerance is a condition causing an inability to absorb and digest lactose leading to gastrointestinal symptoms such as abdominal pain, diarrhea, and flatulence. Because of the similarities between lactose intolerance and cow's milk allergy, it is becoming necessary to increase physicians' understanding of these two diseases. Consequently, we aimed to determine the level of knowledge of lactose intolerance and cow's milk allergy among medical students. An electronic survey was distributed to 399 medical students at two universities in Saudi Arabia from October to November 2022. The majority of the respondents had an inadequate knowledge of both lactose intolerance and cow's milk allergy (99.75% and 97.99%, respectively). According to the study's results that showed a lack of awareness among health-related students, further studies and awareness programs are highly recommended.

Metabolomic credentialing of murine carcinogen-induced urothelial cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

Targeting the PI3K/AKT/mTOR/NFκB Axis in Ovarian Cancer.

Ovarian cancer stands as the most lethal gynecologic malignancy and remains the fifth most common gynecologic cancer. Poor prognosis and low five-year survival rate are attributed to nonspecific symptoms at early phases along with a lack of effective treatment at advanced stages. It is thus paramount, that ovarian carcinoma be viewed through several lenses in order to gain a thorough comprehension of its molecular pathogenesis, epidemiology, histological subtypes, hereditary factors, diagnostic approaches, and methods of treatment. Above all, it is crucial to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This short communication seeks to underscore several important aspects of the PI3K/AKT/mTOR/NFκB pathway in the context of ovarian cancer and discuss recent advances in targeting this pathway.

Metabolic Plasticity in Ovarian Cancer Stem Cells.

Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients' specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs.