Clinical Syndromes and Genetic Screening Strategies of Pheochromocytoma and Paraganglioma

Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells of the adrenal medulla, and paragangliomas (PGLs) are extra-adrenal pheochromocytomas. These can be mainly found in clinical syndromes including multiple endocrine neoplasia (MEN), von Hippel–Lindau (VHL) syndrome, neurofibromatosis-1 (NF-1) and familial paraganglioma (FPGL). PCCs and PGLs are thought to have the highest degree of heritability among human tumors, and it has been estimated that 60% of the patients have genetic abnormalities. This review provides an overview of the clinical syndrome and the genetic screening strategies of PCCs and PGLs. Comprehensive screening principles and strategies, along with specific screening based on clinical symptoms, biochemical tests and immunohistochemistry, are discussed

Survey of Tyrosine Kinase Signaling Reveals ROS Kinase Fusions in Human Cholangiocarcinoma

Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted

Restoration of Shallow Lakes in Subtropical and Tropical China: Response of Nutrients and Water Clarity to Biomanipulation by Fish Removal and Submerged Plant Transplantation

Fish removal has been used to restore temperate lakes, and positive effects on ecological state and water clarity have frequently been recorded in many lakes. Recently, a supplementary measure, transplantation of submerged macrophytes after fish removal, has been applied to restore warm Chinese shallow lakes in order to compensate for the expected lack of increasing grazing control of phytoplankton after the biomanipulation. These measures have successfully shifted turbid warm lakes to a clear water state, but little is known about the responses to restoration of key physico-chemical variables. We analyzed the seasonal variation in nutrient concentrations in two subtropical and one tropical biomanipulated shallow Chinese lakes subjected to restoration. In all three lakes, a marked decline occurred in the concentrations of lake total nitrogen (TN), total phosphorus (TP), total suspended solids (TSS), and chlorophyll a (Chl a), while the transparency (SD: WD ratio, Secchi depth to water depth ratio) increased. A clear water state was established, lasting so far for 7 to 23 months, and TN, TP, Chl a, and TSS levels in the three restored lakes decreased to, on average, 49%, 58%, 41%, and 18% of the level prior to restoration and/or the level in a reference lake, respectively, while the annual mean SD: WD ratio exhibited a 1.5-4 fold increase. In conclusion, lake restoration by transplantation of submerged macrophytes after fish removal had major positive effects on the physico-chemical variables in our study lakes. However, continuous control of omnivorous and herbivorous fish biomass is recommended as the fish typically present in warm, shallow lakes to some extent feed on submerged macrophytes, when available

Human Activity Coupled With Climate Change Strengthens the Role of Lakes as an Active Pipe of Dissolved Organic Matter

Abstract Dissolved organic matter (DOM) composition in lakes is controlled by multiple environmental drivers, but the relative importance of various drivers remains poorly understood at the continental scale. Here, we established a model resolving possible influencing pathways of climate, land cover, societal development, and water retention time of lakes on the quantity and quality of chromophoric DOM (CDOM) from 182 lakes spanning across strong climatic and economic gradients in China. Our results indicate that land cover and societal development both exhibit positive direct effects on lake CDOM quantity, highlighting the significant role of well‐vegetated soils and anthropogenic activities as sources of lake DOM on a continental scale. Climate has two strong but opposite effects—a warming and wet climate facilitates soil OM production and export, while it also enhances CDOM in‐lake transformation. Three proxies are proposed as indicators of the magnitude of biogeochemical drivers influencing lake DOM across different ecoclimatic zones, including fluorescent DOM/DOC indicating economic activity, percentages of a degraded fluorescent DOM component indicating solar irradiation, and percent tyrosine‐like DOM reflecting DOM processing time within the watershed and lake. Collectively, our findings indicate that the effects of climate change and rapid societal development will result in increased loadings of terrestrial and anthropogenic DOM into lakes and drive higher rates of within‐lake processing of DOM. Consequently, lakes will play a more important role as an “active pipe” in mediating the flux and transformation of organic carbon, intensifying the coupling between terrestrial and aquatic carbon cycles on a continental scale

Cyclin-Dependent Kinase 9 (CDK9) Inhibitor Atuveciclib Suppresses Intervertebral Disk Degeneration via the Inhibition of the NF-κB Signaling Pathway.

Intervertebral disk degeneration (IVDD) is a spinal disk condition caused by an inflammatory response induced by various proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many diseases, especially in regulating the activation of primary inflammatory response genes. Our study investigated a highly selective CDK9 inhibitor, atuveciclib, which protects nucleus pulposus (NP) cells from proinflammatory stimuli-induced catabolism. The effects of CDK9 inhibition were determined in human and rat NP cells treated with IL-1β in the presence or absence of atuveciclib or small interfering RNA target CDK9. Inhibition of CDK9 led to the attenuation of inflammatory response. In addition, rat intervertebral disk (IVD) explants were used to determine the role of CDK9 inhibition in extracellular matrix degradation. The rat IVDD model also proved that CDK9 inhibition attenuated IVDD, as validated using magnetic resonance imaging and immunohistochemistry. Taken together, CDK9 is a potential therapeutic target to prevent IVDD

Circulating miR-106b-3p, miR-101-3p and miR-1246 as diagnostic biomarkers of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common liver cancer and second leading cause of cancer related death worldwide. Most HCCs occur in a damaged liver cirrhotic background. No dependable molecular biomarkers exist for the early detection of HCC, one of the reasons of its poor prognosis. MicroRNAs (miRNAs) have attracted attention as potential blood-based biomarkers. To identify circulating miRNAs with diagnostic potential in HCC, based on preliminary RNAseq studies on plasma samples from a small set of HCC patients, cirrhotic patients and healthy controls, we validated 4 miRNAs by the use of droplet digital PCR (ddPCR) in independent plasma and serum cohorts of patients and controls. The analyses established the differential level of miR-101-3p, and miR-106-3p in plasma or serum samples of HCC vs. cirrhotic patients or control subjects. The diagnostic accuracy was measured using ROC curve analyses: a combined classifier consisting of miR-101-3p and miR-106b-3p produced the best diagnostic precision both in plasma and serum. Plasma HCC vs. control exhibited an AUC=0.95 (sensitivity 92.9% and specificity 90.0%); serum HCC vs. cirrhosis exhibited an AUC=0.96 (sensitivity 94.1% and specificity 84.6%). Thus, miR-101-3p/miR-106b-3p two-miRNAs classifier exhibits a considerable clinical value in the diagnosis of HCC, when assayed either in plasma or serum