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Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, their clinical features are quite similar. Here, we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS patient bone marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. Although inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS and as an effective therapeutic target for a broad spectrum of patients with MDS.Significance: We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. Cancer Discov; 8(11); 1438-57. ©2018 AACR. See related commentary by Chen and Steidl, p. 1355 This article is highlighted in the In This Issue feature, p. 1333.

Carbonates or carbon-bearing materials may release gases under high pressure and high temperature (HP–HT) conditions. Characterizing the species and quantifying the volumes of these carbonaceous gases are critical for understanding carbon chemistry. However, the volatile nature of carbonaceous gas poses technical challenges in their collection, speciation, and quantification during HP–HT experiments. To address these challenges, we have developed a system that integrates sample collection, gas transportation, chemical conversion, and measurement of carbonaceous gases trapped within the large volume press capsules. The system comprises a capsule-crushing device for thorough sample pulverization, a mechanizer coupled with a flame ionization detector, a gas-sealing and transport interface, and gas chromatography for detection. To evaluate the system's capabilities, we quantified the gas volumes released from encapsulated kerogen quenched from 1.9 GPa to 873, 973, and 1073 K. The collected gas chromatography signals were compared to those obtained from standard mixed-gases. The volumes of CO2, CH4, and C2H6 in the samples were successfully derived from the signal peak area through calibration. The relative standard deviation value of two runs at 3 GPa and 1073 K is 1.956%, suggesting good reproducibility. Our system thus provides a robust solution for investigating carbon chemistry under HP–HT conditions. [ABSTRACT FROM AUTHOR]

The next-generation sequencing detecting gene mutation has been recommended for the routine diagnosis of suspicious myelodysplastic symdromes patients. Recently, several pre-MDS conditions, a new subtype MDS with SF3B1, gene mutations integrated prognosis scores and gene mutations-based clinical decision-making and treatment choice were proposed. Nowadays, it is a big problem to standardize the generation, analysis, clinical interpretation and reporting of NGS data in China. It will open new horizons for individualized medicine of patients with MDS in the future by implementing integrated genomics into the diagnostic and treatment algorithms.

Precise quantification of the JAK2V617F mutation using highly sensitive assays is crucial for diagnosis, treatment process monitoring, and prognostic prediction in myeloproliferative neoplasms' (MPNs) patients. Digital droplet polymerase chain reaction (ddPCR) enables precise quantification of low-level mutations amidst a high percentage of wild type alleles without the need for external calibrators or endogenous controls. The objective of this study was to optimize a ddPCR assay for detecting the JAK2V617F mutation and establish it as a laboratory-developed ddPCR assay in our center. The optimization process involved fine-tuning five key parameters: primer/probe sequences and concentrations, annealing temperature, template amount, and PCR cycles. Our ddPCR assay demonstrated exceptional sensitivity, and the limit of quantification (LoQ) was 0.01% variant allele frequency with a coefficient of variation of approximately 76%. A comparative analysis with quantitative PCR on 39 samples showed excellent consistency (r = 0.988). In summary, through rigorous optimization process and comprehensive analytic performance validation, we have established a highly sensitive and discriminative laboratory-developed ddPCR platform for JAK2V617F detection. This optimized assay holds promise for early detection of minimal residual disease, personalized risk stratification, and potentially more effective treatment strategies in MPN patients and non-MPN populations. [ABSTRACT FROM AUTHOR]

Summary: Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion‐dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo‐controlled, randomised study to evaluate the iron chelator deferasirox in patients with low‐ or intermediate‐1–risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk. [ABSTRACT FROM AUTHOR]

Background Several studies have suggested that short-course antibiotic therapy was effective in Pseudomonas aeruginosa (PA) bloodstream infections (BSI) in immunocompetent patients. But similar studies in patients with hematological malignancies were rare. Methods This cohort study included onco-hematology patients at 2 hematology centers in China. Inverse probability of treatment weighting was used to balance the confounding factors. Multivariate regression model was used to evaluate the effect of short-course antibiotic therapy on clinical outcomes. Results In total, 434 patients met eligibility criteria (short-course, 7–11 days, n = 229; prolonged, 12–21 days, n = 205). In the weighted cohort, the univariate and multivariate analysis indicated that short course antibiotic therapy had similar outcomes to the prolonged course. The recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group (P =.979). The recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group (P =.139), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group (P =.957). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital (P <.001). Conclusions In the study, short-course therapy was non-inferior to prolonged-course therapy in terms of clinical outcomes. However, due to its biases and limitations, further prospective randomized controlled trials are needed to generalize our findings. [ABSTRACT FROM AUTHOR]