Metabolic Dysfunction-Associated Steatotic Liver Disease and Polycystic Ovary Syndrome: A Complex Interplay.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) are prevalent conditions that have been correlated with infertility through overlapped pathophysiological mechanisms. MASLD is associated with metabolic syndrome and is considered among the major causes of chronic liver disease, while PCOS, which is characterized by ovulatory dysfunction and hyperandrogenism, is one of the leading causes of female infertility. The pathophysiological links between PCOS and MASLD have not yet been fully elucidated, with insulin resistance, hyperandrogenemia, obesity, and dyslipidemia being among the key pathways that contribute to liver lipid accumulation, inflammation, and fibrosis, aggravating liver dysfunction. On the other hand, MASLD exacerbates insulin resistance and metabolic dysregulation in women with PCOS, creating a vicious cycle of disease progression. Understanding the intricate relationship between MASLD and PCOS is crucial to improving clinical management, while collaborative efforts between different medical specialties are essential to optimize fertility and liver health outcomes in individuals with MASLD and PCOS. In this review, we summarize the complex interplay between MASLD and PCOS, highlighting the importance of increasing clinical attention to the prevention, diagnosis, and treatment of both entities.

Exploring the Role of GITR/GITRL Signaling: From Liver Disease to Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and presents a continuously growing incidence and high mortality rates worldwide. Besides advances in diagnosis and promising results of pre-clinical studies, established curative therapeutic options for HCC are not currently available. Recent progress in understanding the tumor microenvironment (TME) interactions has turned the scientific interest to immunotherapy, revolutionizing the treatment of patients with advanced HCC. However, the limited number of HCC patients who benefit from current immunotherapeutic options creates the need to explore novel targets associated with improved patient response rates and potentially establish them as a part of novel combinatorial treatment options. Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and promotes CD8+ and CD4+ effector T-cell function with simultaneous inhibition of Tregs function, when activated by its ligand, GITRL. GITR is currently considered a potential immunotherapy target in various kinds of neoplasms, especially with the concomitant use of programmed cell-death protein-1 (PD-1) blockade. Regarding liver disease, a high GITR expression in liver progenitor cells has been observed, associated with impaired hepatocyte differentiation, and decreased progenitor cell-mediated liver regeneration. Considering real-world data proving its anti-tumor effect and recently published evidence in pre-clinical models proving its involvement in pre-cancerous liver disease, the idea of its inclusion in HCC therapeutic options theoretically arises. In this review, we aim to summarize the current evidence supporting targeting GITR/GITRL signaling as a potential treatment strategy for advanced HCC.

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies.

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell-cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell-cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications.

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.

The immune microenvironment of cancer of the uterine cervix.

While several treatment choices exist for cervical cancer, such as surgical therapy, chemotherapy, and radiotherapy, some patients will still show poor prognosis. HPV infection is a principal factor for cervical cancer development, from early inflammation to proliferation, angiogenesis, and neoplastic growth. While HPV T-cell responses exist, the tumor seems to evade the immune system upon its tolerance. The latter suggests the existence of a confluent tumor microenvironment responsible for the evasion tactics employed by the neoplasm. Therefore, novel biomarkers governing prognosis and treatment planning must be developed, with several studies tackling the significance of the tumor microenvironment in the genesis, development, proliferation, and overall response of cervical cancer during neoplastic processes. This review aims to analyze and contemplate the characteristics of the tumor microenvironment and its role in prognosis, progression, evasion, and invasion, including therapeutic outcome and overall survival.

New-onset aplastic anemia after SARS-CoV-2 vaccination.

Aplastic anemia (AA) is a rare autoimmune disease. Drugs, viruses, and radiation are among the most common etiologic factors, and most cases have immune pathophysiology. SARS-CoV-2 vaccines have been linked with rare side effects, including cases of acquired aplastic anemia. Here we review all the reported cases of new-onset AA after SARS-CoV-2 vaccination, and discuss their clinical characteristics and management. 18 patients in these case reports had a median age of 58 years. The time from vaccination to onset of aplastic anemia ranged from 1 day to 7 months, with a median of 2.5 weeks. Seventeen patients were diagnosed with severe or very severe aplastic anemia post-vaccination and all patients received standard treatments for acquired aplastic anemia. Seventeen patients achieved a complete or partial response and only 1 patient died. Aplastic anemia can be considered a very rare SARS-CoV-2 vaccine-related adverse event, although a causative relationship has not been proven. Reporting cases of such uncommon post-vaccination events could help clinicians to consider aplastic anemia when pancytopenia is observed after vaccination. The benefits of SARS-Cov-2 vaccination are established, and reports of rare events serve only to increase awareness in daily clinical practice.

Paving the Way Towards Precision Vaccinology: The Paradigm of Myocarditis After Coronavirus Disease 2019 (COVID-19) Vaccination.

Systems vaccinology approaches have introduced novel tools for the evaluation of the safety profile of novel vaccine antigens by developing biomarkers of vaccine reactogenicity associated with potential adverse events. The use of such approaches may prove extremely advantageous in the context of a global pandemic where accelerated approval of new vaccine formulations for all ages is essential for the containment of the epidemic. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had devastating effects on global health, but the emergency authorization of mRNA vaccines significantly reduced SARS-CoV-2-associated morbidity and mortality. Despite their favorable safety profile in adult populations, recent reports have raised concerns about an association of the mRNA-based vaccines with acute myocarditis, predominantly among male adolescents and young adults following the second vaccine dose. Here, we review data on myocarditis epidemiology following SARS-CoV-2 mRNA vaccination and describe potential mechanisms involved that may explain the sex- and age-related differences, focusing on mRNA immune reactivity. The case of vaccine-associated myocarditis highlights the need to incorporate precision vaccinology approaches for the development of safe and effective vaccines for everyone.

Pneumococcal Immunization Strategies for High-Risk Pediatric Populations Worldwide: One Size Does Not Fit All.

Despite the significant reduction in pneumococcal disease due to pneumococcal vaccines, protection of vulnerable high-risk individuals, especially pediatric populations, remains a great challenge. In an effort to maximize the protection of high-risk children against pneumococcal disease, a combined schedule that includes both conjugate and polysaccharide vaccines is recommended by several countries in the developed world. On the other hand, middle- and low-income countries do not have in place established policies for pneumococcal immunization of children at risk. Pneumococcal conjugate vaccines, despite their benefits, have several limitations, mainly associated with serotype replacement and the wide range of serotype coverage worldwide. In addition, PPV23-impaired immunogenicity and the hyporesponsiveness effect among populations at risk have been well-documented. Therefore, the added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among high-risk children in both developed and developing countries, assessing the optimization of current recommendations for their vaccination against pneumococcal disease.