Inactivating mutations in the SETD2 gene, encoding for a nonredundant histone H3 methyltransferase and regulator of transcription, is a frequent molecular feature in clear cell renal cell carcinomas (ccRCC). SETD2 deficiency is associated with recurrence of ccRCC and bears low prognostic values. Targeting autophagy, a conserved catabolic process with critical functions in maintenance of cellular homeostasis and cell conservation under stress condition, is emerging as a potential therapeutic strategy to combat ccRCC. Epigenetics-based pathways are now appreciated as key components in the regulation of autophagy. However, whether loss of function in the SETD2 histone modifying enzyme occurring in ccRCC cells may impact on their ability to undergo autophagy remained to be explored. Here, we report that SETD2 deficiency in RCC cells is associated with the aberrant accumulation of both free ATG12 and of an additional ATG12containing complex, distinct from the ATG5-ATG12 complex. Rescue of SETD2 functions in the SETD2 deficiency in RCC cells, or reduction of SETD2 expression level in RCC cells wild type for this enzyme, demonstrates that SETD2 deficiency in RCC is directly involved in the acquisition of these alterations in the autophagic process. Furthermore, we revealed that deficiency in SETD2, known regulator of alternative splicing, is associated with increased expression of a short ATG12 spliced isoform at the depend of the canonical long ATG12 isoform in RCC cells. The defect in the ATG12dependent conjugation system was found to be associated with a decrease autophagic flux, in accord with the role for this ubiquitin-like protein conjugation system in autophagosome formation and expansion. Finally, we report that SETD2 and ATG12 gene expression levels are associated with favorable respective unfavorable prognosis in ccRCC patients. Collectively, our findings bring further argument for considering the SETD2 gene status of ccRCC tumors, when therapeutic interventions, such as targeting the autophagic process, are considered to combat these kidney cancers.

Retinoblastoma is a rare, intraocular paediatric cancer that originates in the neural retina and is most frequently caused by bi-allelic loss of RB1 gene function. Other oncogenic mutations, such as amplification and increased expression of the MYCN gene, have been found even with proficient RB1 function. In this study, we investigated whether MYCN over-expression can drive carcinogenesis independently of RB1 loss-of-function mutations. The aim was to elucidate the events that result in carcinogenesis and identify the cancer cell-of-origin. We used the chicken retina, a well-established model for studying retinal neurogenesis, and established human embryonic stem cell-derived retinal organoids as model systems. We over-expressed MYCN by electroporation of piggyBac genome-integrating expression vectors. We found that over-expression of MYCN induced tumorigenic growth with high frequency in RB1-proficient chicken retinas and human organoids. In both systems, the tumorigenic cells expressed markers for undifferentiated cone photoreceptor/horizontal cell progenitors. The over-expression resulted in metastatic retinoblastoma within 7–9 weeks in chicken. Cells expressing MYCN could be grown in vitro and, when orthotopically injected, formed tumours that infiltrated the sclera and optic nerve and expressed markers for cone progenitors. Investigation of the tumour cell phenotype determined that the potential for neoplastic growth was embryonic stage-dependent and featured a cell-specific resistance to apoptosis in the cone/horizontal cell lineage, but not in ganglion or amacrine cells. We conclude that MYCN over-expression is sufficient to drive tumorigenesis and that a cell-specific resistance to apoptosis in the cone/horizontal cell lineage mediates the cancer phenotype.

Background: Left ventricular noncompaction (LVNC) is a heterogeneous myocardial disorder with an uncertain prognosis. There was a lack of studies on LVNC subtypes at present. This study sought to identify the prognosis of the overall population of LVNC and to describe the distribution of different subtypes and compare their prognosis.Hypothesis: Patients with different subtypes of LVNC may have different prognoses.Methods: Patients who fulfilled the Jenni criteria and/or Petersen criteria were included. Major adverse cardiovascular events (MACE) were defined as a combination of heart failure (HF) hospitalization and all-cause mortality.Results: A total of 200 patients from four hospitals were included. The mean age at diagnosis was 48.2 years, and 61.5% of the patients were male. Left ventricular ejection fraction (LVEF) < 50% was present in 54% of the patients. Over a mean retrospective time period of 22.2 months, 47 (23.5%) patients experienced MACE.Age (hazard ratio [HR] 1.03; 95% confidence interval [CI] 1.01-1.06; p = .004), LVEF < 50% (HR 2.32; 95% CI 1.09-4.91; p = .028) and ventricular tachycardia/ ventricular fibrillation (HR 2.17; 95% CI 1.08-4.37; p = .03) were significantly associated with the risk of MACE. The most common subtype was dilated LVNC (51.3%), followed by benign LVNC (21.3%) and LVNC with arrhythmias (10.5%).Patients with dilated LVNC had significantly increased cumulative incidence of MACE, HF hospitalization, and all-cause mortality (p < .05).Conclusions: Age, LVEF < 50%, and ventricular tachycardia/ventricular fibrillation were independent risk factors for prognosis of LVNC. The most common subtype was dilated LVNC, which had a worse prognosis.

When a shock wave releases from a metal-vacuum interface, some high velocity metal particles will be ejected from the metal surface which generally produce some tiny grooves on the metal surface. This phenomenon is often called the “micro-ejecta”. In this paper, we numerically investigate the effect of the micro-structures of these tiny grooves on the property of the micro-ejecta. To verify the numerical simulation model, a strict Pb micro-ejecta experiment is carried out, where the breakout pressure is about 40 GPa and the Pb target surface roughness is Ra1.6. The dynamic processes of the micro-ejection caused by the real surface groove of experimental target and simplified isosceles groove (both have a depth of 5 μm and wavelength of 75 μm), are respectively simulated by a two-dimensional smooth particle hydrodynamics method, and the effects of surface groove micro-structure on the micro-ejecta properties are examined. The simulation results of the tip velocity and accumulated mass, obtained from the real surface groove model, are in good agreement with the corresponding experimental results measured via DISAR and Asay foil, implying that the numerical result is exact. The tip velocity and accumulated mass caused by the real surface groove are much larger than those caused by the simplified isosceles groove, and a second ejection phenomenon is found in the micro-ejecta process from the real surface groove model. The process can produce some faster ejecta than a single ejecta process and influence the density distribution of the micro-ejection. It indicates that the micro-ejecta process can also be affected by the micro-structure of the metal surface groove, besides perturbation wavelength and surface groove depth.