Multicenter phase 2 trial of nintedanib in advanced nonpancreatic neuroendocrine tumors.

BACKGROUND: Antiangiogenic-targeting agents have low response rates in patients with nonpancreatic neuroendocrine tumors (NETs). Nintedanib is an oral antiangiogenic agent that has inhibitory effects on the fibroblast growth factor receptor, which is highly expressed in NETs. The authors hypothesized that nintedanib would be active in patients with nonpancreatic NETs. METHODS: Patients with advanced, grade 1 or 2, nonpancreatic NETs who were receiving a stable dose of somatostatin analogue were enrolled. Nintedanib was administered at a dose of 200 mg twice daily in 28-day cycles. The primary endpoint was progression-free survival (PFS) at 16 weeks. RESULTS: Thirty-two patients were enrolled, and 30 were evaluable for the primary outcome. Most had radiographic disease progression within 12 months before enrollment. The 16-week PFS rate was 83%, and the median PFS and overall survival were 11.0 months and 32.7 months, respectively. Nintedanib was well tolerated and delayed deterioration in quality of life. The baseline serotonin level had a strong, positive correlation with activated but exhausted T cells. CONCLUSIONS: Nintedanib is active in nonpancreatic NETs. The immunosuppressive effect of serotonin should be targeted in future clinical trials.

A Translational Hepatic Artery Infusion (HAI) Model for Hepatocellular Carcinoma in Woodchucks.

BACKGROUND: Woodchucks (Marmota monax) are a well-accepted animal model for the investigation of spontaneous hepatocellular carcinoma (HCC). As HCC tumors obtain nutrient blood supply exclusively from the hepatic artery, hepatic artery infusion (HAI) has been applied to HCC. However, there is a scarcity of experimental animal models to standardize drug regimens and examine novel agents. The purpose of this study was to establish an HAI model in woodchucks. MATERIALS AND METHODS: HAI ports were placed in the gastroduodenal artery (GDA) of 11 woodchucks. The ports were infused with either a vehicle (dextrose 5% in water) or an experimental drug, CBL0137, once a week for 3 wk. Technical success rates, anatomical variation, morbidity and mortality, and tumor responses between groups were analyzed. RESULTS: The GDA access was feasible and reproducible in all woodchucks (11/11). The average operation time was 95 ± 20 min with no increase in the levels of liver enzymes detected from either infusate. The most common morbidity of CBL0137 therapy was anorexia after surgery. One woodchuck died due to hemorrhage at the gallbladder removal site from hepatic coagulopathy. Significantly higher CBL0137 concentrations were measured in the liver compared with blood after each HAI. Tumor growth was suppressed after multiple CBL0137 HAI treatments which corresponded to greater T cell infiltration and increased tumor cell apoptosis. CONCLUSIONS: HAI via GDA was a feasible and reproducible approach with low morbidity and mortality in woodchucks. The described techniques serve as a reliable platform for the identification and characterization of therapeutics for HCC.

Assessment of microbial quality of fish processing industrial effluent in bar-mouth at Bhidia landing site, Veraval, Gujarat, India.

The present study was carried out to assess the microbial quality of fish processing industries effluent at Bhidia bar-mouth, Veraval, Gujarat during April, 2012 to March 2013. The total viable bacterial count (TVBC), total Enterobacteriaceae count, E. coli count (EC), Staphylococcus aureus and Fecal Streptococcal count in effluent ranged from 3.0 x 10(-1) to 6.8 x 10(6), 9.0 x 10(1) to 2.9 x 10(4), 0 to 0. 5 x 10(4), 0 to 0. 4 x 102 and 0.3 x 10(1) to 0. 1 x 10(4) cfu.(-1)respectively. Significantly higher load of TEC, E. coli, S.aureus, Fecal Streptococci, Total coliforms and Fecal coliforms were higher during summer whereas, TVBC was higher in the month of Sept.-Oct. Furthermore, the total coliform and fecal coliform counts were found to be higher with 1400+ /100 ml MPN value throughout the year of the study, except in the month of August. Overall occurrence of pathogenic strains of E. coli, S. aureus and Fecal streptococci were 41.67%, 25.00% and 66.67% respectively during this period. The antibiogram of the isolated E. coli isolates show that almost 50% were resistant to Cefazidime/Clavulanic acid (CAC), Amoxyclav (AMC), Ciprofloxacin (CIF) and Ampicillin (AMP). The present study indicated that the effluent of fish processing industry was heavily contaminated with E. coli, S. aureus and Fecal Streptococci which confirmed improper treatment of fish processing effluent. Moreover, the precedence of antibiotic resistant E. coli may pose threat to public health safety.

Noble metal-free CZTS electrocatalysis: synergetic characteristics and emerging applications towards water splitting reactions.

This review provides a comprehensive overview of the production and modification of CZTS nanoparticles (NPs) and their application in electrocatalysis for water splitting. Various aspects, including surface modification, heterostructure design with carbon nanostructured materials, and tunable electrocatalytic studies, are discussed. A key focus is the synthesis of small CZTS nanoparticles with tunable reactivity, emphasizing the sonochemical method's role in their formation. Despite CZTS's affordability, it often exhibits poor hydrogen evolution reaction (HER) behavior. Carbon materials like graphene, carbon nanotubes, and C60 are highlighted for their ability to enhance electrocatalytic activity due to their unique properties. The review also discusses the amine functionalization of graphene oxide/CZTS composites, which enhances overall water splitting performance. Doping with non-noble metals such as Fe, Co., and Ni is presented as an effective strategy to improve catalytic activity. Additionally, the synthesis of heterostructures consisting of CZTS nanoparticles attached to MoS2-reduced graphene oxide (rGO) hybrids is explored, showing enhanced HER activity compared to pure CZTS and MoS2. The growing demand for energy and the need for efficient renewable energy sources, particularly hydrogen generation, are driving research in this field. The review aims to demonstrate the potential of CZTS-based electrocatalysts for high-performance and cost-effective hydrogen generation with low environmental impact. Vacuum-based and non-vacuum-based methods for fabricating CZTS are discussed, with a focus on simplicity and efficiency. Future developments in CZTS-based electrocatalysts include enhancing activity and stability, improving charge transfer mechanisms, ensuring cost-effectiveness and scalability, increasing durability, integrating with renewable energy sources, and gaining deeper insight into reaction processes. Overall, CZTS-based electrocatalysts show great promise for sustainable hydrogen generation, with ongoing research focused on improving performance and advancing their practical applications.

A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.

Evaluation of the serotonin pathway as a biomarker in cholangiocarcinoma.

Background: Cholangiocarcinomas (CCAs) are rare and aggressive malignant tumors of the biliary tract. Serotonin (5HT) has tumor-promoting effects in CCA while inhibition of 5HT synthesis can decrease tumor growth. Methods: In this retrospective study, we evaluated the expression of 5HT and tryptophane hydroxylase-1 (TPH-1) in tumor specimens from patients treated with cisplatin plus gemcitabine (CisGem). We included consecutive patients ≥18 years, with locally advanced unresectable, recurrent, or metastatic CCA who were treated with CisGem and had available archival tumor tissue for immunohistochemistry. Formalin-fixed paraffin (FFPE) sections were stained for 5HT and TPH-1. Specimens were evaluated for neuroendocrine features and tumor-infiltrating lymphocytes (TILs). Serum 5HT was measured. Results: We identified 23 patients fulfilling the inclusion criteria. 5HT expression was absent in almost all tumors examined. TPH-1 expression was neither associated with stage or primary tumor location nor predictive of response to CisGem. There was a trend for improved overall survival (OS) in patients whose tumors had high TPH-1 expression. The examined tumor specimens had no neuroendocrine features. Most sections had no TILs. There was a trend for worse OS in patients with high serum 5HT concentration. Conclusions: Tumor TPH-1 expression was not predictive of response to treatment. There was a trend for improved long-term outcomes in patients with high tumor TPH expression and lower serum 5HT concentration.

Actinomycosis of the Cervix Mimicking Stage II Cervical Cancer.

Actinomycosis is a chronic bacterial infection, characterized by suppurative and granulomatous inflammation. In humans, actinomycosis is most frequently caused by Actinomyces israelii. It is a normal commensal which becomes pathogenic upon any breach in the mucosa. We report the case of cervical actinomycosis in a 45-year-old female who had a mass per vagina for 2 years. There was no history of any intrauterine contraceptive device insertion. The radiological diagnosis was a neoplasm as the lesion is extending into the adjacent structures. Surgery was planned and a biopsy was taken which revealed Actinomyces. The patient was administered long-term penicillins and advised follow-up. Pelvic actinomycosis should be included in the differential diagnosis of pelvic masses. Even though actinomycosis can present as a large pelvic mass invading adjacent structures, it can be treated with medications and without any surgical intervention.

Updates in Biliary Tract Cancers.

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies arising from the epithelium of the biliary tree [...].

Possible intermolecular association in triphenyltin chloride in the solution state as detected by NMR spectroscopy.

NMR measurements ((119)Sn chemical shift, line width and (13)C relaxation) were made on triphenyltin chloride in two solutions, 2.5 and 0.75 mol% in CDCl(3), at several temperatures. The (13)C spin-lattice relaxation time and NOE data for the phenyl carbons provide the corresponding correlation times for the overall molecular reorientational motion and the internal rotation of the phenyl groups. The results are indicative of a weak intermolecular association of the triphenyltin chloride molecules in solution and are discussed with reference to a model for intermolecular phenyl ring π-π stacking interactions.

Pufferfish poisoning from Arothron stellatus: The first confirmed case in India with exact DNA sequencing-based species identification.

A puffer fish poisoning case was reported from the coastal city of Veraval in the Gujarat state of India with patient reporting symptoms of giddiness, vertigo, aphasia and heaviness of head following consumption of cooked fish. Treatment was purely symptomatic and supportive. The patient was discharged from the hospital in a stable condition after 4 days. The suspected fish species was later identified using DNA (Deoxyribonucleic Acid) sequencing as Arothron stellatus with 100% identity.

Hepatocellular Carcinoma: Special Issue Highlights.

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Guidelines for Management of Urgent Symptoms in Patients with Cholangiocarcinoma and Biliary Stents or Catheters using the Modified RAND/UCLA Delphi Process.

Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20-40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1-9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1-3 (inappropriate) and greater than 2 (>2) ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as "appropriate" or "maybe appropriate" based on a patient's bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.

Enhanced Overall Water-Splitting Performance: Oleylamine-Functionalized GO/Cu2ZnSnS4 Composite as a Nobel Metal-Free and NonPrecious Electrocatalyst.

Using emergent highly proficient and inexpensive non-noble metal-based bifunctional electrocatalysts to overall water splitting reaction is a pleasingly optional approach to resolve greenhouse gases and energy anxiety. In this work, oleylamine-functionalized graphene oxide/Cu2ZnSnS4 composite (OAm-GO/CZTS) is prepared and investigated as a higher bifunctional electrocatalyst for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). The OAm-GO/CZTS shows brilliant electrocatalytic performance and durability toward H2 and O2 in both acidic and basic media, with overpotentials of 47 mV for HER and 1.36 V for OER at a current density of 10 mA cm-2 and Tafel slopes of 64 and 91 mV dec-1, respectively, which are extremely higher to those of transition metal chalcogenide and as good as of commercial precious-metal catalysts.

CZTS Decorated on Graphene Oxide as an Efficient Electrocatalyst for High-Performance Hydrogen Evolution Reaction.

Cu2ZnSnS4 (CZTS) was synthesized by the sonochemical method using 2-methoxyethanol as the solvent and subsequently decorated onto graphene oxide (GO synthesized by the modified Hummers' method) using two different approaches such as in situ growth and ex situ synthesis followed by deposition. Preliminary characterizations indicated that the synthesized CZTS belongs to the kesterite structure with a sphere-like morphology. The in situ-synthesized CZTS/GO (I-CZTS/GO) composite is used as an efficient electrocatalyst for hydrogen evolution reaction (HER) which revealed superior electrocatalytic activity with a reduced overpotential (39.3 mV at 2 mA cm-2), Tafel slope (70 mV dec-1), a larger exchange current density of 908 mA cm-2, and charge transfer resistance (5 Ω), significantly different from pure CZTS. Besides, the I-CZTS/GO composite exhibits highest HER performance with high current stability of which shows no noticeable degradation after i-t amperometry. The catalytic activity demonstrates that the I-CZTS/GO composite could be a promising electrocatalyst in hydrogen production from their cooperative interactions.

Enhanced oxygen evolution reaction on amine functionalized graphene oxide in alkaline medium.

Development of highly efficient oxygen evolution reaction (OER) electrocatalysts is a critical challenge in the cost-effective generation of clean fuels. Here, a metal-free tyramine functionalized graphene oxide (T-GO) electrocatalyst is proposed to use in alkaline electrolytes for enhanced OER. Moreover, the T-GO and GO nanomaterials are well characterized by SEM, XRD, FTIR, XPS and Raman spectroscopy. T-GO exhibits an electrocatalytic OER with a current density of 2 mA cm-2 at a low onset potential of ∼1.39 V and a small Tafel slope of about 69 mV dec-1 and GO exhibits an onset potential of 1.51 V and Tafel slope of about 92 mV dec-1. Additionally, the current stability and RRDE based diffusion controlled response of the T-GO electrocatalyst are outstanding compared to GO. This study establishes metal free T-GO as an efficient electrocatalyst for the OER and used for cathodic production of hydrogen as a counter reaction in the field of water splitting.

Heterostructural CuO-ZnO Nanocomposites: A Highly Selective Chemical and Electrochemical NO2 Sensor.

A simple one-step chemical method is employed for the successful synthesis of CuO(50%)-ZnO(50%) nanocomposites (NCs) and investigation of their gas sensing properties. The X-ray diffraction studies revealed that these CuO-ZnO NCs display a hexagonal wurtzite-type crystal structure. The average width of 50-100 nm and length of 200-600 nm of the NCs were confirmed by transmission electron microscopic images, and the 1:1 proportion of Cu and Zn composition was confirmed by energy-dispersive spectra, i.e., CuO(50%)-ZnO(50%) NC studies. The CuO(50%)-ZnO(50%) NCs exhibit superior gas sensing performance with outstanding selectivity toward NO2 gas at a working temperature of 200 °C. Moreover, these NCs were used for the indirect evaluation of NO2 via electrochemical detection of NO2 - (as NO2 converts into NO2 - once it reacts with moisture, resulting into acid rain, i.e., indirect evaluation of NO2). As compared with other known modified electrodes, CuO(50%)-ZnO(50%) NCs show an apparent oxidation of NO2 - with a larger peak current for a wider linear range of nitrite concentration from 20 to 100 mM. We thus demonstrate that the as-synthesized CuO(50%)-ZnO(50%) NCs act as a promising low-cost NO2 sensor and further confirm their potential toward tunable gas sensors (electrochemical and solid state) (Scheme 1).

Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells.

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials.

Celecoxib and mucosal protection: translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil.

PURPOSE: Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study. EXPERIMENTAL DESIGN: In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography. RESULTS: Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set. CONCLUSIONS: Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.

Extraction and characterization of polysaccharides from tamarind seeds, rice mill residue, okra waste and sugarcane bagasse for its Bio-thermoplastic properties.

The aim of the present study is to extract potential thermoplastic polysaccharides from agricultural industrial wastes. Polysaccharides were extracted from renewable agro industrial wastes such as tamarind seeds [rich in starch (TSS)], okra head waste [rich in mucilage polysaccharide (OMP)], sugarcane bagasse [rich in cellulose (SBC)] and residual rice mill wastes [rich in starch and fiber (RS)]. Urigam variety of tamarind seed starch found to be an amylose rich starch. Different polysaccharides extracted from agro wastes were found to be having high thermal stability, except okra polysaccharide (comparatively low). X-ray diffraction pattern of tamarind seed starch proved its high crystallinity index. Crystallinity index of investigated polysaccharides were found to be in the order of SBC > TSS > RS > OMP. Chemical nature of extracted polysaccharides was confirmed by Fourier transform infrared spectroscopic analysis. Residual rice bran starch granules and tamarind seed starch globules were found to be having comparatively reduced particle size than sugarcane bagasse cellulose and okra mucilage. Scanning electron microscopic analysis revealed the cluster formations of RS granules and TSS globules. Residual rice bran starch found to be associated with other fibers (present in outer coat of rice). Okra mucilage and SBC were examined to be having linear sheets and linear bundles structures, respectively.

Enhanced electrocatalytic hydrogen generation from water via cobalt-doped Cu2ZnSnS4 nanoparticles.

Herein, we adopted a novel noble metal-free Co-doped CZTS-based electrocatalyst for the hydrogen evolution reaction (HER), which was fabricated using a facile, effective, and scalable strategy by employing a sonochemical method. The optimized Co-doped CZTS electrocatalyst shows a superior HER performance with a small overpotential of 200 and 298 mV at 2 and 10 mA-1, respectively, and Tafel slope of 73 mV dec-1, and also exhibits excellent stability up to 700 cycles with negligible loss of the cathodic current. The ease of synthesis and high activity of the Co-doped CZTS-based cost-effective catalytic system appear to be promising for HER catalysis.