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Introduction Cancer cells reprogram their metabolism to meet their bioenergetic and biosynthetic needs for rapid growth and proliferation (1-3). Increased serine biosynthesis is an important metabolic adaptation in many human [...], Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.

Introduction Amplified-HER2 breast cancer is an aggressive disease that until recently had the worst overall survival prognosis among breast cancer subtypes (1, 2). The clinical implementation of HER2-targeted therapies, including [...], The c-MYC (MYC) oncoprotein is often overexpressed in human breast cancer; however, its role in driving disease phenotypes is poorly understood. Here, we investigate the role of MYC in [HER2.sup.+] disease, examining the relationship between HER2 expression and MYC phosphorylation in [HER2.sup.+] patient tumors and characterizing the functional effects of deregulating MYC expression in the murine NeuNT model of amplified-HER2 breast cancer. Deregulated MYC alone was not tumorigenic, but coexpression with NeuNT resulted in increased MYC Ser62 phosphorylation and accelerated tumorigenesis. The resulting tumors were metastatic and associated with decreased survival compared with NeuNT alone. MYC; NeuNT tumors had increased intertumoral heterogeneity including a subtype of tumors not observed in NeuNT tumors, which showed distinct metaplastic histology and worse survival. The distinct subtypes of MYC; NeuNT tumors match existing subtypes of amplified-HER2, estrogen receptor-negative human tumors by molecular expression, identifying the preclinical utility of this murine model to interrogate subtype-specific differences in amplified-HER2 breast cancer. We show that these subtypes have differential sensitivity to clinical HER2/EGFR-targeted therapeutics, but small-molecule activators of PP2A, the phosphatase that regulates MYC Ser62 phosphorylation, circumvents these subtype-specific differences and ubiquitously suppresses tumor growth, demonstrating the therapeutic utility of this approach in targeting deregulated MYC breast cancers.

Background: A low appropriate therapy rate indicates that a minority of patients will benefit from their implantable cardioverter defibrillator (ICD). Quantitative measurements from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) may predict ventricular arrhythmia (VA) occurrence after ICD placement.Methods: We performed a prospective observational study and recruited patients who required ICD placement. Pre-procedure image scans were performed. Patients were followed up for VA occurrence. Associations between image results and VA were analyzed.Results: In 51 patients (33 males, 53.9 ± 17.2 years) analyzed, 17 (33.3%) developed VA. Compared with patients without VA, patients with VA had significantly larger values in scar area (17.7 ± 12.4% vs. 7.0 ± 7.9%), phase standard deviation (51.4° ± 14.0° vs. 34.0° ± 15.0°), bandwidth (172.9° ± 39.8° vs. 128.7° ± 49.9°), sum thickening score (STS, 29.5 ± 11.1 vs. 17.8 ± 13.2), and sum motion score (42.9 ± 11.5 vs. 33.0 ± 19.0). Cox regression analysis and receiver operating characteristic curve analysis showed that scar size, dyssynchrony, and STS were associated with VA occurrence (HR, 4.956, 95% CI 1.70-14.46).Conclusion: Larger left ventricular scar burden, increased dyssynchrony, and higher STS quantified by 18F-FDG PET may indicate a higher VA incidence after ICD placement. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the accuracy of gated-SPECT (GSPECT) and gated-PET (GPET) in the assessment of left ventricular (LV) end-diastolic volumes (EDVs), end-systolic volumes (ESVs) and LV ejection fractions (LVEFs) among patients with prior myocardial infarction (MI).Methods: One hundred and sixty-eight consecutive patients with MI who underwent GSPECT and GPET were included. Of them, 76 patients underwent CMR in addition to the two imaging modalities. The measurements of LV volumes and LVEF were performed using Quantitative Gated SPECT (QGS), Emory Cardiac Toolbox (ECTB), and 4D-MSPECT (4DM).Results: The correlation between GPET, GSPECT, and CMR were excellent for LV EDV (r = 0.855 to 0.914), ESV (r = 0.852 to 0.949), and LVEF (r = 0.618 to 0.820), as calculated from QGS, ECTB, and 4DM. In addition, subgroup analysis revealed that EDV, ESV, and LVEF measured by GPET were accurate in patients with different extents of total perfusion defect (TPD), viable myocardium, and perfusion/metabolic mismatch. Furthermore, multivariate regression analysis identified that mismatch score was associated with the difference in EDV (P < 0.05) measurements between GPET and CMR.Conclusions: In patients with MI, LV volumes and LVEF scores measured by both GSPECT and GPET imaging were comparable to those determined by CMR, but should not be interchangeable in individual patients. [ABSTRACT FROM AUTHOR]