PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.

The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic-specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D -driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP-binding sites severely impair the tumor-promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1-PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF-SOS1 axis, and provides a promising therapeutic target for PDAC.

The role of imaging features and resection status in the survival outcome of sporadic optic pathway glioma children receiving different adjuvant treatments.

Optic pathway glioma (OPG) is a rare brain tumor affecting children, with no standard treatment strategy. This study described the sporadic OPG survival outcomes after surgical treatment and analyzed the role of imaging features and resection status in children receiving different adjuvant treatments. This retrospective study included 165 OPG patients whose clinical information were obtained from the hospital record system. Tumor volume and residual tumor volume were calculated by delineating the lesion area. Kaplan-Meier method and Cox proportional hazards model were conducted to analyze the independent prognosis factor. A total of 165 patients were included in this study. Respectively, the 5-year overall survival (OS) and progression-free survival (PFS) were 87.58% and 77.87%. Residual tumor size and first adjuvant treatment (AT) after surgery were both associated with PFS. In patients with small-size residual tumors, there was no significant difference in PFS between the AT treatment groups. Moreover, age, exophytic cystic components, leptomeningeal metastases, and AT were associated with OS. In patients with exophytic cystic components and those with leptomeningeal metastases, there was no significant difference in OS. Our results revealed that OPG patients could avoid or defer AT by maximized resection. Age ≤ 2 years was a disadvantageous factor for OS. Patients with exophytic cystic components were more likely to benefit from primary surgery, and CT or RT was not beneficial for these patients. Patients with leptomeningeal metastases had a poor prognosis regardless of the treatment they received. Future prospective clinical studies are needed to develop more effective treatment regimens.

[Effects of increased planting density with reduced nitrogen fertilizer application on greenhouse gas emission in double-season rice fields under water saving and simple cultivation mode]. / èŠ‚æ°´è½»ç®€æ ½åŸ¹æ¨¡å¼ä¸‹å¢žå¯†å‡æ°®å¯¹åŒå­£ç¨»ç”°æ¸©å®¤æ°”ä½“æŽ’æ”¾çš„å½±å“.

To clarify the effects of increased density and reduced nitrogen on greenhouse gas emission in double-season paddy fields under the water-saving and simple cultivation mode, we used Luliangyou 996 (early rice) and Fengyuanyou 299 (late rice) as materials to collect greenhouse gas by closed static box method, monitored the dynamics of CH4 and N2O emissions from different combinations of increased density and reduced nitrogen for early and late rice, and explored changes in cumulative CH4 and N2O emissions, global warming potential (GWP) and greenhouse gas intensity (GHGI) as affected by different combinations of increased density and reduced nitrogen from double-season rice fields. The results showed that the cumulative emissions of CH4 and N2O from different combinations were significantly different. Compared with the control (CK), cumulative CH4 emission, GWP and GHGI in the two seasons decreased by 50.8%, 37.3%, and 42.9% for the combination of increased density and reduced nitrogen IR2(the amount of nitrogen applied of early rice was 86.4 kg·hm-2, the density was 360000 holes·hm-2; the amount of nitrogen applied of late rice was 108 kg·hm-2, the density was 320000 holes·hm-2), respectively. IR2 of early rice had the lowest N2O cumulative emission, being 33.7% lower than CK. IR1(the amount of nitrogen applied of early rice was 103.2 kg·hm-2, the density was 320000 holes·hm-2; the amount of nitrogen applied of late rice was 129 kg·hm-2, the density was 280000 holes·hm-2) of late rice had the lowest N2O cumulative emission, being decreased by 94.9%. IR2 had the lowest annual total GWP and GHGI of double-season paddy fields. Compared with other treatments of increased density and reduced nitrogen, the IR2 treatment, where nitrogen fertilizer in both early and late rice was reduced by 28.0%, the density of early rice was increased by 28.6%, and the density of late rice was increased by 33.3%, was an effective and safe option for simultaneously ensuring high yield and reducing greenhouse gas emissions.

METH-Induced Neurotoxicity Is Alleviated by Lactulose Pretreatment Through Suppressing Oxidative Stress and Neuroinflammation in Rat Striatum.

Abuse of methamphetamine (METH) results in neurological and psychiatric abnormalities. Lactulose is a poorly absorbed derivative of lactose and can effectively alleviate METH-induced neurotoxicity in rats. The present study was designed to investigate the effects of lactulose on METH-induced neurotoxicity. Rats received METH (15 mg/kg, 8 intraperitoneal injections, 12-h interval) or saline and received lactulose (5.3 g/kg, oral gavage, 12-h interval) or vehicle 2 days prior to the METH administration. Reactive oxygen species (ROS) and malondialdehyde (MDA) were measured. Protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), nuclear factor κB (NFκB), interleukin (IL)-1ß, IL-6, TNF-α, cleaved caspase 3, and poly(ADP-ribose) polymerase-1 (PARP-1) were determined by western blotting. mRNA expressions of nuclear factor erythroid 2-relatted factor-2 (Nrf2), p62, and heme oxygenase-1 (HO-1) were assessed by RT-qPCR. The lactulose pretreatment decreased METH-induced cytoplasmic damage in rat livers according to histopathological observation. Compared to the control group, overproduction of ROS and MDA were observed in rat striatums in the METH alone-treated group, while the lactulose pretreatment significantly attenuated the METH-induced up-regulation of oxidative stress. The lactulose pretreatment significantly repressed over-expressions of proteins of TLR4, MyD88, TRAF6, NFκB, IL-1ß, IL-6, TNF-α, cleaved caspase 3, PARP-1. The lactulose pretreatment increased mRNA expressions of Nrf2, p62, and HO-1. These findings suggest that lactulose pretreatment can alleviate METH-induced neurotoxicity through suppressing neuroinflammation and oxidative stress, which might be attributed to the activation of the Nrf2/HO-1 axis.

PCB28 and PCB52 induce hepatotoxicity by impairing the autophagic flux and stimulating cell apoptosis in vitro.

Hepatotoxicity is one of the adverse health effects induced by polychlorinated biphenyls (PCBs). Recently, autophagy was revealed to play an important role in PCBs-induced toxicology, however, its precise role in PCBs-induced hepatotoxicity is as yet unknown. In this study, treatment of PCB28/PCB52 for 48 h dose-dependently induced hepatotoxicity at doses of 10, 20, 40 and 80 µM in homo and rattus hepatocytes. Expressions of proteins of BECN1, LC3-II and ULK1 significantly increased in PCB28/PCB52-treated cells at a dose of 40 µM, implying initiation of autophagy. Over-expression of p62 suggested deficient clearance of autophagosome. Consistently, accumulation of autophagosome was observed by transmission-electron microscopy and confocal fluorescence microscopy using adenovirus expressing mRFP-GFP-LC3, which may initiate apoptosis. Furthermore, increased reactive oxygen species levels might also induce autophagy and apoptosis. Consistently, cell apoptosis was evoked by the treatment of PCB28/PCB52 compared to the respective controls, which coincided with obvious hepatotoxicity. Subsequently, an inhibitor (3-methlyadenine) and an initiator (rapamycin) of autophagy were used. Compared to PCB28/PCB52 alone-treated cells, initiation of autophagy, blocked autophagic flux, cell apoptosis and hepatotoxicity were alleviated by 3-methlyadenine and aggravated by rapamycin, respectively. Taken together, PCB28 and PCB52 induced hepatotoxicity by impairing autophagic flux and stimulating cell apoptosis in vitro.