HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by abnormal hematopoietic cell maturation, increased apoptosis of bone marrow cells, and anemia. They are the most common myeloid blood cancers in American adults. The full complement of gene mutations that contribute to the phenotypes or clinical symptoms in MDS is not fully understood. Around 10%-25% of MDS patients harbor an interstitial heterozygous deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes, including HSPA9. The HSPA9 gene encodes for the protein mortalin, a highly conserved heat shock protein predominantly localized in mitochondria. Our prior study showed that knockdown of HSPA9 induces TP53-dependent apoptosis in human CD34+ hematopoietic progenitor cells. In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that the knockdown of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knockdown, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53.

Evaluation of the Quality and Safety of Venous Thromboembolism Prophylaxis Among Gastroenterology Inpatients at a Tertiary Hospital in Australia.

Background and objective: Hospital acquired venous thromboembolisms (VTEs) are common and preventable. The Queensland Health VTE prophylaxis guidelines, developed in 2018, provide guidance for risk assessment, and prescribing of anticoagulation for prophylaxis and treatment of hospital inpatients. Currently, there are limited recommendations for gastroenterology patients. This study investigated the completion of VTE risk assessments, and the appropriateness of VTE prophylaxis regimens, in accordance with Queensland Health guidelines for gastroenterology patients. The quality and safety of VTE prophylaxis regimens was assessed based on their VTE risk and bleeding risk. Method: A retrospective study was conducted by obtaining a random sample of gastroenterology patients admitted to a tertiary Australian hospital, from 1st May 2019 and 1st May 2020, to determine the compliance of VTE risk assessment and thromboprophylaxis prescribing with state-wide VTE guidelines. The quality and safety of thromboprophylaxis was evaluated using the modified Caprini and HASBLED scores, and subsequent thromboprophylaxis-related complications. Results: Of the 94 patients reviewed, 68 did not have contraindications to thromboprophylaxis. Of these 68 patients, 32 (47%) had no VTE risk assessment recorded in their clinical records and were not prescribed any thromboprophylaxis during the hospitalization. There was no significant difference between thromboprophylaxis prescribing for patients with low VTE risk, compared to moderate to high VTE risk (P = .075). There was a trend for decrease in thromboprophylaxis prescribing as HASBLED bleeding risk score increased, and patients with moderate-high bleed risk were less likely to be prescribed thromboprophylaxis (P = .006). There were no thromboprophylaxis related complications identified. Conclusion: It is essential that all patients have a clearly documented risk assessment and are prescribed thromboprophylaxis according to best practice guidelines. The prescription of venous thromboembolism prophylaxis should continue to be individualized, with each patient assessed holistically.