No abstract

While the nephrotoxicity of high-dose nano-TiO 2 has been demonstrated, very little is known about the mechanism of oxidative stress to the animal kidney. In order to understand the nephrotoxicity of nano-anatase TiO 2 particles, various biochemical and chemical parameters were assayed in mouse kidneys. Abdominal exposures of high-dose nano-anatase TiO 2 caused nephritis and oxidative stress to kidney. An increase in coefficients of the kidney, Ti accumulation and histopathological changes in kidney could be observed, followed by increased reactive oxygen species generation and lipid peroxidation, and decreased activities of superoxide dismutase, catalase, ascorbate peroxidase and total antioxidant capacity as well as antioxidants such as glutathione and ascorbic acid content. In addition, kidney functions were disrupted, including increase of the creatinine, calcium and phosphonium, and reduction of uric acid and blood urea nitrogen. Our results suggest that nephritis generation in mice caused by nano-anatase TiO 2 particles is closely related to oxidative stress.

BackgroundTo evaluate the safety and efficacy of particle therapy (PT) using pencil beam scanning (PBS) technique for early stage non-small cell lung cancer (NSCLC).MethodsFrom 08/2014 to 03/2018, 31 consecutive patients with sum of the longest diameters of primary tumor and hilar lymph node < 5 cm, N0–1, M0 NSCLC treated with PT were retrospectively analyzed. Gating/active breathing control techniques were used to control tumor motion in 20 and 7 patients. PBS-based proton radiotherapy (PRT) or carbon ion radiotherapy (CIRT) plans were designed via Syngo® planning system. PRT, PRT + CIRT boost, and CIRT were used in 6, 6 and 19 patients, respectively. Prescriptions were categorized to 3 levels: 5–7.5 GyE * 8–10 Fx, 4–5 GyE * 15–16 Fx and 2.25–3.5 GyE * 20–31 Fx.ResultsThirty-one patients (20 males and 11 females) with a median age of 71 (50–80) years were enrolled with a median follow-up time of 12.1 (2.9–45.2) months. Fourteen were adenocarcinomas, 7 squamous cell carcinomas, 4 non-specified NSCLC and 6 had no histological diagnosis (4/6 had previous resected lung cancer). The median tumor size was 3.1 (1.1–4.7) cm. No grade 4–5 toxicities were observed. One patient experienced grade 3 (per the Common Terminology Criteria for Adverse Events version 4.03) radiation-induced lung injury (RILI) at 6.7 months from radiation started. Grade 2 acute toxicities included hematological toxicities (5 cases), RILI (2), plural pain (1) and dermatitis (1). Grade 2 late toxicities included RILI (3) and asymptomatic rib fracture (1). Three patients had progressed disease at 4.0~10.6 months after the initiation of PT. One experienced local failure with simultaneous distant failure and died of brain metastasis at 10.8 months; one developed regional and distant failure and died of lung infection at 8.7 months; the other experienced isolated distant failure only and his disease was well controlled after salvage systemic therapy. The estimated rates of progression-free survival, local control, cause-specific survival and overall survival at 1, 2 years were 85.5% and 85.5%, 95.2% and 95.2%, 95.0% and 95.0%, 90.7% and 90.7%, respectively.ConclusionsPBS-based PT appears safe and effective for early stage NSCLC. Further follow-up and investigation is warranted.Trial registrationISRCTN, ISRCTN78973763. Registered 14 August 2018- Retrospectively registered, http://www.isrctn.com/ISRCTN78973763.

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67–87% and decreased WAS-induced-FPO by 23–53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.