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Immune checkpoint inhibitors (ICIs) have changed the landscape of advanced cancer treatment. However, immune checkpoint inhibitors can trigger effector T cells against self-antigens as well as tumor antigens, resulting in immune-related toxicities in normal organs, referred to as immune-related adverse events (irAEs).A 56-year-old man with undifferentiated gastric carcinoma received sintilimab plus paclitaxel and tegafur therapy. After five cycles of treatment, the patient was referred to the hospital for sudden onset urinary frequency, micturition pain, and urinary incontinence. Cystoscopy revealed the entire bladder mucosa was red and edematous but there was no evidence of tumor. Oral administration of Chai-Ling-Tang (Sairei-To) alleviated lower urinary tract symptoms (LUTS). Histological analysis revealed numerous infiltrates of CD3-positive and CD8-positive cells into the urothelium but no atypia, indicating a diagnosis of immune-related cystitis. Interestingly, the urothelial epithelium infiltrated by lymphocytes and subepithelial inflammatory cells strongly expressed cell boundary PD-L1. The dose of Chai-Ling-Tang was maintained and stopped 2 months later without recurrence of LUTS. Since recovering from cystitis, the patient remains alive with no disease progression.This report shows that Chai-Ling-Tang is safe and effective for treating immune-related cystitis. The detailed mechanism of action requires further investigation.

This work presents an integrated application of potential field data to discover potash-bearing evaporite sources in Aji-Chai salt deposit, located in east Azerbaijan province, northwest of Iran. Low density and diamagnetic effect of salt minerals, i.e. potash, give rise to promising potential field anomalies that assist to localize sought blind targets. The halokinetic-type potash-bearing salts in the prospect zone have flowed upward and intruded into surrounded sedimentary sequences dominated frequently by marl, gypsum and alluvium terraces. Processed gravity and magnetic data delineated a main potash source with negative gravity and magnetic amplitude responses. To better visualize these evaporite deposits, 3D model of density contrast and magnetic susceptibility was constructed through constrained inversion of potential field data. A mixed-norm regularization technique was taken into account to generate sharp and compact geophysical models. Since tectonic pressure causes vertical movement of the potash in the studied region, a simple vertical cylindrical shape is an appropriate geometry to simulate these geological targets. Therefore, structural index (i.e. decay rate of potential field amplitude with distance) of such assumed source was embedded in the inversion program as a geometrical constraint to image these geologically plausible sources. In addition, the top depth of the main and the adjacent sources were estimated 39 m and 22 m, respectively, via the combination of the analytic signal and the Euler deconvolution techniques. Drilling result also indicated that the main source of potash starts at a depth of 38 m. The 3D models of the density contrast and the magnetic susceptibility (assuming a superficial sedimentary cover as a hard constraint in the inversion algorithm) demonstrated that potash source has an extension in depth less than 150 m.

Background Depressive symptoms are thought to promote cancer development and depressive remission has been reported to be effective for defeating cancer. The herbal formula Xiao-Chai-Hu-Tang (XCHT), that has an anti-depressive efficacy, has been widely utilized in China. However, its anti-cancer effect and underlying mechanisms remain unclear. Purpose The present study aims to investigate the effects of XCHT on the depression-associated tumor and its potential mechanisms. Methods A placebo-controlled trial was conducted in cancer patients comorbid with depressive symptoms to evaluate the effects of XCHT on depressive scales, tumor-related immune indicators, and gut microbial composition. A xenografted colorectal cancer (CRC) mouse model exposure to chronic restraint stress (CRS) was established to examine XCHT effects on tumorigenesis in vivo. Further, by manipulating gut bacteria with fecal microbial transplantation (FMT) or antibiotics-induced bacterial elimination in CRS-associated xenografted model, gut microbiota-mediated anti-tumor mechanism was explored. Results In cancer patients comorbid with depressive symptoms, XCHT showed substantial effects on improvement of depressive scales, system inflammatory levels and gut dysbiosis. In vivo, XCHT inhibited tumor growth and prolonged survival time in addition to showing anti-depressive effect. Similarly, in our clinical trial, XCHT partially reversed gut dysbiosis, particularly through reducing abundances of Parabacteroides, Blautia and Ruminococcaceae bacterium. Manipulation of gut bacteria in CRS-associated xenografted model further proved that the inhibition of XCHT on tumor progression was mediated by gut microbiota and that the underlying mechanism involves in downregulation of TLR4/MyD88/NF-κB signaling. Conclusions We demonstrated that gut microbiota mediates the anti-tumor action of the formula XCHT in cancer patients and models that were comorbid with depressive symptoms. This study implies a novel clinical significance of anti-depressive herbal medicine in the cancer treatment and clarifies the important role of gut microbiota in treating cancer accompanied by depressive symptoms.

This study aimed to investigate the prevalence of cercarial infections in freshwater snails collected from the Chai Nat province of Central Thailand. Moreover, we aimed to develop a duplex PCR technique, using the ITS2 and candidate MT-ND1 gene, to determine the dissemination of H. taichui and H. pumilio, respectively. Six types of cercariae were discovered with an overall prevalence of 4.71% (59/1,252). The parapleurolophocercous cercariae were demonstrated to be the dominant type, infecting only Melanoides tuberculata snails. The duplex PCR was optimized for specific amplification of ITS2 for H. taichui (115 bp) and MT-ND1 for H. pumilio (335 bp). Both specific primers confirmed the specificity of the duplex PCR reaction, with no cross-reactivity with other heterophyids or related species. In addition, this duplex PCR could be used to detect co-infection at a concentration of 3.0 ng/µL. For the molecular identification, 9 of 22 parapleurolophocercous cercaria specimens in Chai Nat province generated the specific DNA fragment of H. pumilio. These results proved that the MT-ND1 gene is a species-specific method for heterophyid detection and provides a rapid method for identification based on larval and adult stages of H. taichui and H. pumilio in their intermediate and/or definitive hosts in the infected area.

Many waters in Tanzania exhibit high concentrations of organic matter and dissolved contaminants such as fluoride. Due to bacteria and virus removal, ultrafiltration (UF) is an attractive option for drinking water treatment, and when coupled with adsorbents, may compete with other established processes like nanofiltration (NF) for lower contaminant concentrations. The results presented here examine the characteristics and treatability of tropical natural organic matter (NOM) by UF as a function of seasonal variation. The Tanzanian river Maji ya Chai was sampled monthly during one year. The composition of NOM in Maji ya Chai River is influenced strongly by precipitation. Total organic carbon (TOC), specific ultraviolet absorbance (SUVA) and concentration of allochthonous organics substances (such as humic substances (HS)) are elevated in periods following high precipitation, while TOC is lower and contains more biopolymers in the dry seasons. UF experiments with two regenerated cellulose membranes of different molecular weight cut-off (MWCO, 5 and 10 kDa) were conducted. UF is able to remove 50-95% of TOC with a seasonal variability of 10-20%. Due to the remaining NOM in the water that would contribute to disinfection by-product formation and bacterial regrowth, the physically disinfected water is more applicable for point of use systems than distribution or storage.

The effects of Chai-hu-gui-zhi-tang (TJ-10) on the development of liver lesions induced by N-nitrosomorpholine and on labeling and apoptotic indices were investigated in male Sprague-Dawley rats. Rats were given chow pellets containing 0.5 or 1.0% TJ-10 and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Visible white liver nodules, cellular alteration foci, and hepatic foci staining positively for glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 16, TJ-10 at both dosages significantly reduced the incidence, and/or number of visible white nodules and hepatic lesions. Quantitative histologic analysis also showed that prolonged feeding of TJ-10 at both dosages significantly reduced the number of hepatic foci positive for glutathione-S-transferase, placental type. Administration of TJ-10 at both dosages also significantly decreased the labeling index of adjacent liver and significantly increased the apoptotic index of adjacent liver but had no significant effect on those of neoplastic lesions. These findings indicate that TJ-10 suppresses the development of liver lesions and suggest that this effect might be related to TJ-10's inhibition of cell proliferation and induction of apoptosis in adjacent hepatocytes.

The purpose of this study is to develop and validate an UPLC-MS/MS method to quantify different marker compounds from Xiao-Chai-Hu-Tang (XCHT, a Chinese traditional herbal) in biological samples and apply the method to pharmacokinetic study. A Waters BEH C18UPLC column was used with acetonitrile/0.1% formic acid mobile phases. The mass analysis was performed in a triple quadrupole mass spectrometer using multiple reaction monitoring (MRM) with positive scan mode. A one-step protein precipitation by methanol was used to extract the analytes from blood. Seventeen commercially available compounds from the different compositing herbals were selected as markers. The results revealed that all of the calibration curves showed good linear regression (r2 > 0.9918). The intra-day and inter-day precisions (RSD) of all of these markers at three different levels were less than 15.0% and the bias of the accuracies ranged from −13.5% to 16.6%. The extraction recoveries of all of these 17 markers were from 70.8% to 113.7% and the matrix effects ranged from 71.8% to 114.8%. The stabilities of these compounds in blood were evaluated by analyzing three replicates of QC samples at three different concentrations following storage at 25°C for 6 h, 4°C for 24 h, and −80°C for 30 days. All the samples displayed 85–15% precision and accuracy after various stability tests. The validated method was successfully applied to pharmacokinetic study in A/J mouse with oral administration of XCHT. All of these markers were detected and the pharmacokinetic parameters of 8 compounds were able to be calculated. This method is sensitive and reproducible that can be used for XCHT’s in vivo study.

s / Pancreatology 16 (2016) S1eS63 S40 Background: Prediction of the malignancy of intraductal papillary mucinous neoplasm (IPMN) remains difficult, especially for themixed type. Objective: The aim of this study was to evaluate the usefulness of EUS to predict malignancy for resection of branch duct-type (BD)-IPMN and to compare them with spiral CT and MRCP. Methods: A prospectively collected database of patients with resected BD-IPMN who receive EUS, CT and MRCP before the operation was analyzed to compare factors as predictors of malignancy. Results: Of 42 patients with BD-IPMN, 14 were diagnosed as malignancy according to surgical pathology. The sensitivity (0.72) and specificity (0.75) of EUS were superior to those of CT (0.62 and 0.72) and MRCP (0.52 and 0.68). Multiple logistic regression analysis showed that main pancreatic duct dilatation greater than 5mm (HR 5.56, 95% CI 2.45 ~ 9.62; P < 0.001), mural nodules (HR 4.28, 2.15 to 10.21; P < 0.001) and carbohydrate antigen 19-9 level above 37 units/ml (HR 3.02, 1.25 to 10.90; P 1⁄4 0.001) were independent predictors of BD-IPMN malignancy. Conclusion: EUS has better performance to classify BD-IPMN than CT andMRCP. Clinical significance of the variable factors associatedwith a risk of malignancy indicates the need for a tailored approach in the management of patients with BD-IPMN.

A simple and quick quantitative analysis of saikosaponins a, c and d, the major bioactive principles contained in Bupleurum species, by TLC scanner is described. Results with Bupleurum kaoi, the species native to Taiwan, showed that the roots, rhizomes and aerial parts (leaves and stem) have greater quantities of saikosaponins than cultivated B. falcatum var. komarowi and imported B. chinense. The liver protective effects of water extracts of "Xiao-Chai-Hu-Tang" (XCHT), a mixture of seven crude drugs, prepared using roots of the three different Bupleurum species and aerial parts of B. kaoi and B. falcatum var. komarowi, were evaluated using CCl4-induced toxicity in rats. The acute increase of serum transaminase (SGOT and SGPT) levels caused by CCl4 administration (3.0 ml/kg, s.c.) was dramatically reduced when treated with XCHT prepared with the roots of B. kaoi. The histological metamorphoses such as fatty changes, ballooning degeneration, cell necrosis and lymphocyte and Kupffer cell increases around the central vein, were clearly decreased by XCHT prepared with B. kaoi. Furthermore, water extracts of aerial parts of both B. kaoi and cultivated B. falcatum var. komarowi decreased SGOT and SGPT levels and moderately reduced the pathological changes.

Xiao Chai Hu Tang (XCHT) is sold as traditional medicine or dietary supplement in worldwide. To understand metabolism profile of traditional medicine is key point in their logical pharmacological research and clinical application. Based on our previous research of the chemical and absorption signature of XCHT in vitro, we proposed a novel strategy to identify the bioactive components of XCHT in vivo. This strategy have two steps: firstly, based on the parents' database in vitro, built-in and editable biotransformations for phase I and phase II metabolism reactions with MassHunter Metabolite ID software (building metabolites database). Secondly, mouse plasma, bile and urine samples were analyzed by UHPLC-ESI-Q-TOF/MS technique, and the absorbed parents and metabolites were compared and identified with the XCHT's digital library using MassHunter Metabolite ID software. In total, 27 parent compounds and 26 metabolites of XCHT were identified in vivo, 2'-O-xylosyl saikosaponin b2 or b1 was reported for the first time. Saponins and their related metabolites were predominantly excreted into the bile, but flavonoids were excreted by both hepatic as well as renal excretion. Flavonoids, saponins, gingerol and their related metabolites were the absorbed components in cardiovascular system and bioactive components of XCHT. Phase I reactions (hydrolysis, hydroxylation and oxidation) and phase II reactions (glucuronidation) were identified and involved in the mouse metabolism of XCHT.