Metabolomics in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a complex, heterogenous hematological malignancy caused by mutations in myeloid differentiation and proliferation. Response to therapy and long-term outcomes vary widely based on chromosomal and molecular aberrations. Many platforms have been used to characterize and stratify AML. Metabolomics, the global profiling of small molecules in a biological sample, has emerged in the last decade as an important tool for studying the metabolic dependency of cancer cells. Metabolic reprogramming is not only an important manifestation of AML but clinically relevant for diagnosis, risk stratification and targeted drug development. In this review, we discuss notable metabolic studies of the last decade and their application to novel therapies.

Vitamin D Deficiency in a Minnesota-Based Foster Care Population: A Cross Sectional Study.

Children in foster care have complex health concerns that often interplay with their childhood experiences, environment and access to care. Studies suggest that foster care youth are at an increased risk for mental health disorders and physical disabilities. Although traditionally associated with insufficient bone development, the implications of vitamin D deficiency are broadening to encompass behavioral, neurodevelopmental, and psychological phenomena. Due to its association with diet, prenatal factors, and the prevalence of nutrition related deficiencies in foster care patients, we hypothesize that foster care patients exhibit lower levels of total 25-hydroxy vitamin D [25(OH)D] than the general pediatric population. A retrospective cross-sectional chart review of foster care patients and similar-aged non-fostered controls screened for vitamin D deficiency was conducted between January 2013 and May 2018 (n=407). Twenty-five (OH)D levels were comparable between foster care children and controls (p=0.771). A univariate analysis of risk factors within the foster care group found that higher BMI, older age, ADHD, and number of transitions was associated with decreased levels of 25(OH)D. Recognition and treatment of low 25(OH)D in foster care patients with specific risk factors may serve as an adjunct for meeting their medical and psychosocial needs.

Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMß2 integrin-dependent upregulation of Mmp12.

BACKGROUND & AIMS: Acetaminophen (APAP)-induced liver injury is coupled with activation of the blood coagulation cascade and fibrin(ogen) accumulation within APAP-injured livers of experimental mice. We sought to define the role of fibrin(ogen) deposition in APAP-induced liver injury and repair. METHODS: Wild-type, fibrinogen-deficient mice, mutant mice with fibrin(ogen) incapable of binding leukocyte αMß2 integrin (Fibγ390-396A mice) and matrix metalloproteinase 12 (Mmp12)-deficient mice were fasted, injected with 300mg/kg APAP i.p. and evaluated at a range of time-points. Plasma and liver tissue were analyzed. Rescue of Fibγ390-396A mice was carried out with exogenous Mmp12. To examine the effect of the allosteric leukocyte integrin αMß2 activator leukadherin-1 (LA-1), APAP-treated mice were injected with LA-1. RESULTS: In wild-type mice, APAP overdose increased intrahepatic levels of high molecular weight cross-linked fibrin(ogen). Anticoagulation reduced early APAP hepatotoxicity (6h), but increased hepatic injury at 24h, implying a protective role for coagulation at the onset of repair. Complete fibrin(ogen) deficiency delayed liver repair after APAP overdose, evidenced by a reduction of proliferating hepatocytes (24h) and unresolved hepatocellular necrosis (48 and 72h). Fibγ390-396A mice had decreased hepatocyte proliferation and increased multiple indices of liver injury, suggesting a mechanism related to fibrin(ogen)-leukocyte interaction. Induction of Mmp12, was dramatically reduced in APAP-treated Fibγ390-396A mice. Mice lacking Mmp12 displayed exacerbated APAP-induced liver injury, resembling Fibγ390-396A mice. In contrast, administration of LA-1 enhanced hepatic Mmp12 mRNA and reduced necrosis in APAP-treated mice. Further, administration of recombinant Mmp12 protein to APAP-treated Fibγ390-396A mice restored hepatocyte proliferation. CONCLUSIONS: These studies highlight a novel pathway of liver repair after APAP overdose, mediated by fibrin(ogen)-αMß2 integrin engagement, and demonstrate a protective role of Mmp12 expression after APAP overdose. LAY SUMMARY: Acetaminophen overdose leads to activation of coagulation cascade and deposition of high molecular weight cross-linked fibrin(ogen) species in the liver. Fibrin(ogen) is required for stimulating liver repair after acetaminophen overdose. The mechanism whereby fibrin(ogen) drives liver repair after acetaminophen overdose requires engagement of leukocyte αMß2 integrin and subsequent induction of matrix metalloproteinase 12.

Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.

BACKGROUND: Vulvar aphthous ulcers are a rare type of genital lesion most common in non-sexually active adolescents. Vulvar aphthous ulcers are typically associated with viral infections. To date, there have been several cases reported in patients infected with COVID-19. Vulvar aphthous ulcers following vaccination have not been previously reported in the literature. CASE: We present the case of a 16-year-old adolescent who developed vulvar aphthous ulceration following Pfizer-BioNTech (BNT162b2) vaccination. SUMMARY AND CONCLUSION: Through an extensive literature search, we found no previous reports of vulvar aphthous ulcer following vaccination. Our case highlights a potential novel side effect of Pfizer-BioNTech COVID-19 vaccination and a new etiology for vulvar aphthous ulcers. This case suggests that vulvar aphthous ulcers might be associated with COVID-19 vaccination through a yet undetermined mechanism that requires further investigation.

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.