Citations

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13 C stable isotope resolved metabolomics (SIRM) using U[ 13 C 6 ]Glucose and U[ 13 C 5 ]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13 C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention.

Transcatheter pulmonary valve placement is emerging as a standard therapy for dysfunctional right ventricular outflow tract conduits. The Melody transcatheter pulmonary valve is indicated for use in the management of pediatric and adult patients with right ventricular outflow tract conduits measuring at least 16 mm in diameter. This is the first reported case of placement in a patient with a left ventricular assist device. We outline the preprocedural evaluation process, the procedural methods, and the outcomes of a successful implantation in a complex patient. With a team-based approach including thoughtful preprocedural evaluation, and close monitoring, successful deployment of a transcatheter pulmonary valve is possible in complex patients in the setting of mechanical circulatory support.

his study was designed to characterize left ventricular (LV) function and mass in a modified cardiomyopathy model in the dog in which right ventricular pacing rates are gradually increased throughout 38 days. On the last day of the pacing protocol, ejection fraction was reduced (25 +/- 3 vs. 60 +/- 1%) and LV end-diastolic diameter index (a ratio of LV end-diastolic diameter to body weight, 2.09 +/- 0.02 vs. 1.79 +/- 0.08 mm/kg) and LV mass index (a ratio of LV mass to body weight, 5.2 +/- 0.3 vs. 4.3 +/- 0.2 g/kg) were greater than in the normal dogs (P < 0.05, respectively). Cardiac filling pressures increased, and LV diastolic function and coronary blood flow were impaired. After 4 wk of recovery from the progressive pacing protocol, LV end-diastolic diameter index (2.12 +/- 0.06 mm/kg) and LV mass index (5.6 +/- 0.2 g/kg) remained increased. Ejection fraction was improved (38 +/- 4%) but still depressed. LV diastolic function, coronary blood flow, and cardiac filling pressures returned to levels seen in the normal dogs. This modified cardiomyopathy model associated with LV hypertrophy complements the conventional tachycardia-induced cardiomyopathy model without LV hypertrophy.

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

The purpose of this guideline is to provide information for the interpretation of clinical dihydropyrimidine dehydrogenase ( DPYD ) genotype tests so that the results can be used to guide dosing of fluoropyrimidines (5‐fluorouracil and capecitabine). Detailed guidelines for the use of fluoropyrimidines, their clinical pharmacology, as well as analyses of cost‐effectiveness are beyond the scope of this document. The Clinical Pharmacogenetics Implementation Consortium (CPIC ® ) guidelines consider the situation of patients for which genotype data are already available (updates available at https://cpicpgx.org/guidelines/guideline‐for‐fluoropyrimidines‐and‐dpyd/ ).

Key Points Buccal epithelial cells harbor an MPN-associated CALR mutation in a patient with CALR-mutant essential thrombocytosis, Ph+ CML, and no germ line CALR mutation.

The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in‐tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness.