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The majority of colorectal cancers (CRCs) present with early mutations in tumor suppressor gene APC. APC mutations result in oncogenic activation of the Wnt pathway, which is associated with hyperproliferation, cytoskeletal remodeling, and a global increase in mRNA translation. To compensate for the increased biosynthetic demand, cancer cells critically depend on protein chaperones to maintain proteostasis, although their function in CRC remains largely unexplored. In order to investigate the role of molecular chaperones in driving CRC initiation, we captured the transcriptomic profiles of murine wild type and Apc‐mutant organoids during active transformation. We discovered a strong transcriptional upregulation of Hspb1, which encodes small heat shock protein 25 (HSP25). We reveal an indispensable role for HSP25 in facilitating Apc‐driven transformation, using both in vitro organoid cultures and mouse models, and demonstrate that chemical inhibition of HSP25 using brivudine reduces the development of premalignant adenomas. These findings uncover a hitherto unknown vulnerability in intestinal transformation that could be exploited for the development of chemopreventive strategies in high‐risk individuals. Synopsis: Upon loss of Apc, the most common early genetic lesion in colorectal cancer, cells upregulate a genetic program involved in buffering proteotoxic stress, including small heat shock protein HSP25. Here, we reveal that inhibition of HSP25 inhibits oncogenic transformation and prevents polyp formation. Intestinal epithelial loss of Apc instructs a Wnt‐driven program for oncogenic transformation that includes the small heat shock protein and chaperone HSP25.Genetic deletion or chemical inhibition of HSP25 using brivudine inhibits transformation and clonal expansion of murine and human APC‐mutant organoids in vitro.Oral administration of brivudine prevents oncogenic transformation and adenoma development in vivo, underscoring the essential role of HSP25 in early tumor formation.This study provides rationale for HSP25 inhibition as a chemoprevention strategy for patients with familial adenomatous polyposis that carry germline mutations in the APC gene. [ABSTRACT FROM AUTHOR]

Limited value of the D-dimer based YEARS algorithm to rule out pulmonary embolism in sickle cell disease and sickle cell trait Further research is needed to establish whether an altered SCD-specific PERC rule might be more suitable in ruling out PE in patients with SCD. Sickle cell disease (SCD) is associated with hypercoagulability and an increased risk of venous thromboembolism (VTE) including pulmonary embolism (PE).1-4 In patients with SCD, overlapping symptoms between PE and acute complications such as vaso-occlusive crisis (VOC) and/or acute chest syndrome lead to diagnostic challenges.5 Therefore, reliable diagnostic algorithms to rule out PE and avoid the frequent use of computed tomography pulmonary angiography (CTPA) are urgently needed for patients with SCD.6 In patients without SCD with clinically suspected PE, D-dimer-based PE algorithms are recommended. CTPA could be withheld in only 7% of patients with SCD and 24% of HbAS individuals, while the YEARS algorithm can safely avoid a CTPA in 48% of unselected individuals with clinically suspected PE.14 It is therefore vital to develop diagnostic algorithms for patients with SCD that are not based on D-dimer levels. [Extracted from the article]

ABSTRACT Background Methods Results Conclusion Relapsed acute myeloid leukemia (AML) and high‐risk myelodysplastic syndrome (HR‐MDS) are associated with a poor prognosis. It is unknown which re‐induction therapy provides the highest chance of durable remission. Commonly used therapies are high dose cytarabine (HiDAC) and triple therapy consisting of fludarabine, cytarabine, and idarubicin combined with granulocyte colony‐stimulating factor (FLAG‐IDA).Two patient cohorts with relapsed AML or HR‐MDS treated with HiDAC or FLAG‐IDA between October 2015 and December 2021 in two academic hospitals in the Netherlands were retrospectively analyzed.Patients were treated with either HiDAC (n=22) or FLAG‐IDA (n=25). Rates of CR (71% vs. 74%, P=0.85), 1‐year OS (47% vs. 51%, P=0.99) and EFS (38% vs. 35%, P=0.71) were comparable between HiDAC and FLAG‐IDA. Durations of neutropenia (median 24 days (IQR 20‐26) vs. 30 days (IQR 22‐39), P=0.014) and thrombocytopenia (22 days (IQR 17‐26) vs. 36 days (IQR 26‐53)) were significantly shorter in the HiDAC group than in the FLAG‐IDA group.While remission rates and survival outcomes were similar, FLAG‐IDA was associated with longer periods of myelosuppression and transfusion dependency compared to HiDAC in these two cohorts. HiDAC can be considered as a salvage chemotherapyfor relapsed AML/HR‐MDS based on our study. [ABSTRACT FROM AUTHOR]

The article discusses a pilot study on the use of low-dose iron chelation as anti-oxidative therapy in patients with sickle cell disease. The study aimed to investigate the potential of iron chelation in reducing oxidative stress and improving various health markers in patients with sickle cell disease. The results showed a decrease in haemolysis markers after treatment, but no significant changes in erythrocyte sickling or adhesion. The study suggests that further research with a larger sample size and longer treatment duration is needed to determine the effectiveness of low-dose iron chelation in managing sickle cell disease. [Extracted from the article]