Rebound Thrombocytosis after Induction Chemotherapy is a Strong Biomarker for Favorable Outcome in AML Patients

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A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Complexity of CEBPA dysregulation in human acute myeloid leukemia

The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is crucial for normal development of granulocytes. Various mechanisms have been identified how CEBPA function is dysregulated in patients with acute myeloid leukemia (AML). In particular, dominant-negative mutations located either at the N- or the C terminus of the CEBPA gene are observed in roughly 10% of AML patients, either in the combination on separate alleles or as sole mutation. Clinically significant complexity exists among AML with CEBPA mutations, and patients with double CEBPA mutations seem to have a more favorable course of the disease than patients with a single mutation. In addition, myeloid precursor cells of healthy carriers with a single germ-line CEBPA mutation evolve to overt AML by acquiring a second sporadic CEBPA mutation. This review summarizes recent reports on dysregulation of CEBPA function at various levels in human AML and therapeutic concepts targeting correction of CEBPA activity. The currently available data are persuasive evidence that impaired CEBPA function contributes directly to the development of AML, whereas restoring CEBPA function represents a promising target for novel therapeutic strategies in AML

C/EBPalpha and the pathophysiology of acute myeloid leukemia

PURPOSE OF REVIEW: The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. RECENT FINDINGS: Conditional mouse models provide direct evidence that loss of C/EBPalpha function leads to the accumulation of myeloid blasts in the bone marrow. Targeted disruption of the wild type C/EBPalpha protein, while conserving the dominant-negative 30 kDa isoform of C/EBPalpha, induces an AML-like disease in mice. In hematopoietic stem cells C/EBPalpha serves to limit cell self-renewal. Finally, C/EBPalpha function is disrupted at different levels in specific subgroups of acute myeloid leukemia patients. SUMMARY: There is evidence that impaired C/EBPalpha function contributes directly to the development of acute myeloid leukemia. Normal myeloid development and acute myeloid leukemia are now thought to reflect opposite sides of the same hematopoietic coin. Restoring C/EBPalpha function represents a promising target for novel therapeutic strategies in acute myeloid leukemia

The maximum alcohol withdrawal syndrome score associates with worse clinical outcomes - A retrospective cohort study

Background: The Wetterling alcohol withdrawal syndrome (AWS) scale determines withdrawal severity and guides treatment. We investigated associations between maximum AWS scores and clinical outcomes. Methods: This retrospective cohort study considered AWS assessments measured from 8/2015-8/2017. We used multivariable linear and logistic regression to analyze associations between the maximum score and increased length of stay (LOS) and in-hospital mortality, respectively. Firstly, we investigated the maximum score of all AWS assessments any time during the stay, secondly, the maximum measured only within the first 3 days of withdrawal. Results: A total of 2,464 hospital stays showed that, patients with “mild” (9) maximum scores had median LOS of 5.93, 9.35, 14.71 days, mortality was 1.7%, 4.8%, 8.0%, respectively. Regression showed that a higher maximum score was independently associated with increased LOS and mortality (both p < 0.001). Based on the maximum AWS score within the first 3 days, the median LOS was 6.18, 9.00, 12.89 days, mortality was 2.2%, 3.6%, 7.6%, respectively. A higher maximum score in the first 3 days was independently associated with increased LOS (p = 0.036) and mortality (p = 0.001). Severe maximum AWS scores within 3 days of withdrawal had an odds ratio of 2.53 (95% CI: 1.27, 4.82; p = 0.0060) for in-hospital death. Conclusions: Maximum AWS scores associate independently with increased LOS and in-hospital mortality. This association is reproducible within the first 3 days of withdrawal. Development of such a 3-day tool could help clinicians assess the risk of worse clinical outcomes early on and adjust care accordingly

Heterozygous deletion of the PU.1 locus in human AML

The transcription factor PU.1 is essential for myeloid development. Targeted disruption of an upstream regulatory element (URE) decreases PU.1 expression by 80% and leads to acute myeloid leukemia (AML) in mice. Here, we sequenced the URE sequences of PU.1 in 120 AML patients. Four polymorphisms (single nucleotide polymorphisms [SNPs]) in the URE were observed, with homozygosity in all SNPs in 37 patients. Among them, we compared samples at diagnosis and remission, and one patient with cytogenetically normal acute myeloid leukemia M2 was identified with heterozygosity in 3 of the SNPs in the URE at remission. Loss of heterozygosity was further found in this patient at 2 polymorphic sites in the 5' promoter region and in 2 intronic sites flanking exon 4, thus suggesting loss of heterozygosity covering at least 40 kb of the PU.1 locus. Consistently, PU.1 expression in this patient was markedly reduced. Our study suggests that heterozygous deletion of the PU.1 locus can be associated with human AML

Multimorbidity and cardiovascular disease: a perspective on low- and middle-income countries

New and changing patterns of multimorbidity (MM), i.e., multiple concurrent acute or chronic diseases in a person, are emerging in low- and middle-income countries (LMICs). The interplay of underlying population-specific factors and lifestyle habits combined with the colliding epidemics of communicable and non-communicable diseases presents new disease combinations, complexities and risks that are not common in high-income countries (HICs). The complexities and risks include those arising from potentially harmful drug-drug and drug-disease interactions (DDIs), the management of which may be considered as MM in the true sense. A major concern in LMICs is the increasing burden of leading cardiovascular diseases, prevalence of associated risk factors and co-occurrence with other morbidities. New models of MM management and integrated care can respond to the needs of specific multimorbid populations, with some LMICs making substantial progress (e.g., integration of tuberculosis and HIV services in South Africa). But there is a dearth of relevant data on the changing patterns and underlying factors and determinants of MM, the associated complexities and risks of DDIs in MM management, and the barriers to integrated care in LMICs. This requires careful attention