ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP.

Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics.

Personalized Medicine in Pancreatic Cancer: The Promise of Biomarkers and Molecular Targeting with Dr. Michael J. Pishvaian.

Pancreatic cancer, with its alarming rising incidence, is predicted to become the second deadliest type of solid tumor by 2040, highlighting the urgent need for improved diagnostic and treatment strategies. Despite medical advancements, the five-year survival rate for pancreatic cancer remains about 14%, dropping further when metastasized. This review explores the promise of biomarkers for early detection, personalized treatment, and disease monitoring. Molecular classification of pancreatic cancer into subtypes based on genetic mutations, gene expression, and protein markers guides treatment decisions, potentially improving outcomes. A plethora of clinical trials investigating different strategies are currently ongoing. Targeted therapies, among which those against CLAUDIN 18.2 and inhibitors of Claudin 18.1, have shown promise. Next-generation sequencing (NGS) has emerged as a powerful tool for the comprehensive genomic analysis of pancreatic tumors, revealing unique genetic alterations that drive cancer progression. This allows oncologists to tailor therapies to target specific molecular abnormalities. However, challenges remain, including limited awareness and uptake of biomarker-guided therapies. Continued research into the molecular mechanisms of pancreatic cancer is essential for developing more effective treatments and improving patient survival rates.

Reviewing the Landscape of Cancer Survivorship: Insights from Dr. Lidia Schapira's Programs and Beyond.

The constantly escalating population of cancer survivors worldwide has prompted a focused exploration of their unique needs and experiences within the context of healthcare medicine. This review initiates its analysis inspired by Dr. Lidia Schapira's insightful keynote conference on the Survivorship 1.0 and Survivorship 2.0 Programs, shedding light on their implementation challenges and setting the stage for a comprehensive analysis of cancer survivorship initiatives. Within the transformed landscape of cancer care, patient-centric strategies embedded in cancer survivorship programs comprising vital elements such as connection, support, and education are presented. While placing cancer recurrence surveillance at the forefront, the review underlines concern regarding the potential oversight of the enduring impact on mental and physical health. Dr. Schapira's insights further extend into the exploration of mental health challenges faced by survivors, promoting an examination of diverse strategies to address these concerns. Furthermore, the discussion continues toward promising areas of research, notably Precision Medicine's role in de-escalating cancer therapies, and advocates for measures such as early cancer awareness and timely referrals to supportive services. Highlighting the significance of education, the role of online resources in enhancing the knowledge of healthcare practitioners and future generations in cancer care is then explored. The paper concludes by presenting some of the most prominent global current survivorship programs, identifying critical knowledge gaps in cancer care and projecting future developments aimed at delivering accurate and holistic care, improving the quality of life for survivors, and enhancing both mental and physical well-being. Drawing upon the insights from Dr. Schapira, this review lays the groundwork for a nuanced exploration of cancer survivorship and its multifaceted implications.

Heart failure in patients with metabolic syndrome X.

Metabolic syndrome X has been known to be a risk factor for the development of cardiovascular dysfunction. Insulin resistance, diabetes mellitus and serum lipid abnormalities, which are all seen in metabolic syndrome X, have been found to negatively impact heart function, leading to heart failure in particular. Heart failure is a condition resulting when the heart is unable to perform its function of providing sufficient blood flow to meet the body's requirements. The treatment of heart failure in metabolic syndrome X varies based on the various components of metabolic syndrome X, which include obesity, hyperglycemia, hypertension and dyslipidemia. Obesity is regarded as one of the derangements seen in patients with metabolic syndrome X. It is a significant risk factor in the development of cardiovascular disease, which may eventually lead to heart failure. However, the obesity paradox suggests that obesity provides a higher chance of survival in patients with metabolic syndrome and heart failure. This review article focuses on the pathophysiology of heart failure in patients who already have metabolic syndrome X, as well as the therapeutic management complexity of the two conditions taking into consideration the protective role provided by obesity.

Echocardiographic screening for rheumatic heart disease in 4 515 Sudanese school children: marked disparity between two communities.

INTRODUCTION: Echocardiographic (echo) screening has unmasked a high prevalence of subclinical rheumatic heart disease (RHD) in many countries, and it can be used as a surveillance tool to control the disease. METHODS: School children of 10 to 15 years of age were selected in two areas of Sudan, Khartoum, the capital, and Niyala in western Sudan. Echo screening using a hand-held echo (HHE) was conducted in Khartoum using a three-view protocol, and in Niyala, a one-view protocol, both modified from the World Heart Federation protocol. Suspected cases were referred for standard echo study. Training of health personnel was conducted and health education sessions were delivered to the public. RESULTS: In Khartoum, a total of 3 000 school children were screened; seven cases were positive for RHD using HHE and one case was confirmed by standard echocardiography. The prevalence of RHD using echocardiography was 0.3 per 1 000 children. In Niyala, a total of 1 515 school children were screened. Using HHE, 59 cases were positive for RHD; 44 had definite and 15 borderline disease. Out of 34 who underwent standard echocardiography, 29 (85.2%) were found to have RHD; 22 had definite and seven borderline disease. The prevalence using echocardiography was 19 per 1 000 children. A total of 779 health workers were trained in South Darfur and 50 000 posters and pamphlets were distributed. CONCLUSION: Using echocardiography, there was a significant disparity in RHD prevalence between the two communities in Sudan. Efforts to control RHD should be directed to this area, and other rural communities should be investigated.