Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxia-inducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis.

BackgroundThe aim of this study was to assess the effect of combined use of Astragaloside IV(AsIV) and atorvastatin (AV) on the expression of PPAR-γ and inflammation-associated cytokines in atherosclerosis rats.Material/MethodsHigh-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma were detected through automatic biochemical analyzer and the histopathological analysis was performed via HE staining. The levels of oxidized low-density lipoprotein (oxLDL) and tumor necrosis factor-α (TNF-α), and interleukins (IL)-6 and IL-18 in serum were detected by ELISA. The expressions of proliferator-activated receptor-gamma (PPAR-γ), cluster of differentiation 36 (CD36), matrix metalloprotein-9 (MMP-9), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1), and p38 and P-p38 levels were detected by Western blot. RT-PCR was used to detect the mRNA expressions of nuclear factor-κB (NF-κB), PPAR-γ, CD36, MMP-9, ICAM-1, and VCAM-1.ResultsAdministration of AsIV and AV significantly decreased the lipid content and oxLDL in plasma. The levels of TNF-α, IL-6, and IL-18 were significantly decreased in AsIV, AV, and AsIV + AV groups, especially in the AsIV + AV group. Administration decreased the levels of NF-κB, CD36, MMP-9, ICAM-1, VCAM-1, and P-p38 expression and increased the expression of peroxisome PPAR-γ. Compared with the NC group, the atherosclerotic lesions significantly increased in the HD group, while the combined administration significantly inhibited the development of atherosclerotic disease.ConclusionsCombined administration of AV and AsIV showed potent effects against atherosclerosis through the NF-κB/PPARγ pathway, which may be a new therapy for treatment of atherosclerosis in the future.

Cancer-causing genome instability is a major concern during space travel due to exposure of astronauts to potent sources of high-linear energy transfer (LET) ionizing radiation. Hematopoietic stem cells (HSCs) are particularly susceptible to genotoxic stress, and accumulation of damage can lead to HSC dysfunction and oncogenesis. Our group recently demonstrated that aging human HSCs accumulate microsatellite instability coincident with loss of MLH1 , a DNA Mismatch Repair (MMR) protein, which could reasonably predispose to radiation-induced HSC malignancies. Therefore, in an effort to reduce risk uncertainty for cancer development during deep space travel, we employed an Mlh1 +/− mouse model to study the effects high-LET 56 Fe ion space-like radiation. Irradiated Mlh1 +/− mice showed a significantly higher incidence of lymphomagenesis with 56 Fe ions compared to γ-rays and unirradiated mice, and malignancy correlated with increased MSI in the tumors. In addition, whole exome sequencing analysis revealed high SNVs and INDELs in lymphomas being driven by loss of Mlh1 and frequently mutated genes had a strong correlation with human leukemias. Therefore, the data suggest that age-related MMR deficiencies could lead to HSC malignancies after space radiation, and that countermeasure strategies will be required to adequately protect the astronaut population on the journey to Mars.

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ObjectiveMinimally invasive McKeown esophagectomy (McKeown MIE) is performed at many hospitals in esophageal cancer(EC) treatment. However, secure and quick methods for dissecting the esophagus and dissecting lymph nodes in this surgery are lacking. This study introduces a simple, secure and feasible esophagus dissecting technique named two-rope method. Two mobile traction ropes are placed around the esophagus and we tow these ropes to free the esophagus, dissect the lymph nodes, and decrease the operative trauma.Materials and MethodsRetrospective analysis was performed on 112 patients who underwent McKeown MIE in our center from January 2019 to September 2021. They were assigned into two groups based on the method of dissecting the esophagus: Group A (two-rope method, 45 cases) and Group B (regular method, 67 cases). Operation time, thoracic operation time, the number of dissected thoracic lymph nodes, and postoperative complications were compared between the two groups after propensity score matching.ResultsUsing 1:1 nearest neighbor matching, we successfully matched 41 pairs of patients. Operation time, thoracic operation time, and the duration (ac to as) was significantly shorter and the size of the abdominal incision was significantly smaller in the Group A than Group B (p < 0.05). There was no statistically significant difference in the number of dissected thoracic lymph nodes, pulmonary infection, anastomotic leak, recurrent laryngeal (RLN) injury, and chylothorax between the two groups (p > 0.05).ConclusionsTwo-rope method to free the esophagus and dissect thoracic lymph nodes in McKeown MIE has significant advantages compared with the regular method. The technique is, therefore suitable for widespread adoption by surgeons.