Myelodysplastic Neoplasms (MDS): The Current and Future Treatment Landscape.

Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality.

A Thrombotic Thrombocytopenic Purpura-Like Syndrome in HIV and Streptococcus pneumoniae Meningitis.

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by the formation of diffuse thromboses in small blood vessels, which can result in neurological and renal impairment, fever, and purpura, among additional sequelae. TTP-like syndromes are disease processes that have similar signs and symptoms as TTP but without a severe deficiency in ADAMTS13 levels. We present a case of a young male with advanced human immunodeficiency virus (HIV) and Streptococcus pneumoniae meningitis presenting with a thrombotic microangiopathy (TMA). Although his ADAMTS13 level was not suggestive of TTP, at 54.4% (normal low ADAMTS13: >66.8% activity; severe ADAMTS13 deficiency: ≤10% activity), he improved only after plasmapheresis was initiated, supporting a diagnosis of a TTP-like syndrome likely due to his streptococcal meningitis. We discuss the importance of treating patients with TTP-like syndromes and advanced HIV with highly active antiretroviral therapy (HAART). We also highlight the increased prevalence of TMA and TTP among HIV patients and that many of these patients do not have a severe deficiency in levels of serum ADAMTS13.

Dietary factors in experimental autoimmune encephalomyelitis and multiple sclerosis: A comprehensive review.

BACKGROUND: Dietary intervention in multiple sclerosis carries potential therapeutic implications. While studies utilizing animal models of multiple sclerosis (MS) have demonstrated intriguing findings, well-designed clinical trials are few in number. OBJECTIVE: The objective of this study is to review the animal model and clinical literature regarding dietary factors in experimental autoimmune encephalitis (EAE) and MS. METHODS: This manuscript provides a comprehensive review of current animal model and clinical knowledge related to dietary factors in MS. RESULTS: While there is currently little data for any specific diet in MS, there is growing evidence that certain dietary factors may influence the disease. CONCLUSIONS: Definitive information regarding dietary factors as a modifiable risk factor in MS will require larger randomized clinical trials.

Maternal perinatal calorie restriction temporally regulates the hepatic autophagy and redox status in male rat.

Intrauterine growth restriction (IUGR) leads to adult obesity, cardiovascular disease, and non-alcoholic fatty liver disease/steatohepatitis. Animal models have shown that combined intrauterine and early postnatal calorie restriction (IPCR) ameliorates these sequelae in adult life. The mechanism by which IPCR protects against adult onset disease is not understood. Autophagy, a lysosomal degradative process, recycles cellular constituents and eliminates damaged organelles, proteins, and oxidants. In this study, we hypothesized that IPCR could regulate autophagy in the liver of male rat offspring. At birth (d1) of male IUGR rat offspring and on day 21 (p21) of life, IPCR male rat offspring had a profound decrease in hepatic autophagy in all three stages of development: initiation, elongation, and maturation. However, upon receiving a normal diet ad-lib throughout adulthood, aged IPCR rats (day 450 of life (p450)), had increased hepatic autophagy, in direct contrast to what was seen in early life. The decreased autophagy at d21 led to the accumulation of ubiquitinated proteins and lipid oxidative products, whereas the increased autophagy in late life had the opposite effect. Oxidized lipids were unchanged at d1 by IUGR treatment indicating that decreased autophagy precedes oxidative stress in early life. When cellular signaling pathways regulating autophagy were examined, the 5' adenosine monophosphate-activated protein kinase pathway (AMPK), and not endoplasmic stress pathways, was found to be altered, suggesting that autophagy is regulated through AMPK signaling pathway in IPCR rats. Taken together, this study reveals that the perinatal nutritional status establishes a nutritionally sensitive memory that enhances hepatic autophagy in late life, a process that perhaps acts as a protective mechanism to limited nutrition.