A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats.

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective ß3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1ß, and IL-6 gene expression and IL-1ß and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.

Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006.

BACKGROUND: Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. PATIENTS AND METHODS: In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. RESULTS: At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). CONCLUSIONS: Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Rich but random: parasite communities of snouted treefrog, Scinax fuscovarius (Anura: Hylidae), in Bodoquena Mountains, western Brazil.

Hosts represent discrete habitats that contain finite parasite communities, and individual hosts can be used as replicates in parasitism studies, such as investigations of the processes that mediate the formation of parasite communities. However, within a single host population, there may be singularities among individuals that affect parasite contact rates. Accordingly, the goals of the present study were to document the parasites associated with the small treefrog Scinax fuscovarius, to verify possible variation and co-occurrences in parasite infracommunities, and to assess the effects of host characteristics (size and sex) on infracommunity structure. Treefrog specimens (n = 75) were collected from the Bodoquena Mountains in Mato Grosso do Sul, Brazil. After collection, the specimens were transported to the laboratory, and examined for parasitic. The parasites found were removed, fixed, and identified. Patterns in parasite infracommunity organization were analyzed using the checkerboard score index, which was calculated using a presence-absence matrix. The matrix was randomized under the null hypothesis that the infracommunities independently represent the component community. Forty-two (56%) of the individuals harbored at least one parasite, and a total of 500 metazoan parasites were recovered, with a particularly rich composite community of 18 taxa, including 13 nematodes, two trematodes, one cestode, one oligochaete, and one mite larvae. The parasite species were randomly distributed among the infracommunities, with no evidence of co-occurrence, segregation, or aggregation. However, both body size and sex influenced infection, with larger hosts harboring more parasites and parasites were more abundant in male specimens and more species rich in female specimens. These results suggest that the parasite infracommunities of S. fuscovarius are shaped by both random factors and individual host characteristics.

Biochar application and summer temperatures reduce N2O and enhance CH4 emissions in a Mediterranean agroecosystem: Role of biologically-induced anoxic microsites.

Biochar applications have been proposed for mitigating some soil greenhouse gas (GHG) emissions. However, results can range from mitigation to no effects. To explain these differences, mechanisms have been proposed but their reliability depends on biochar type, soil and climatic conditions. Furthermore, it is found that the mitigation capacity is dependent on how the biochar is aging under field conditions. The effects on N2O, CH4 and CO2 emission rates of a gasification pine biochar (applied as 0, 5, and 30 t ha-1) were studied between 8 and 21 months of the application in an alkaline soil cropped to barley under Mediterranean climate. Together with GHG, soil chemical and biological properties were assessed, namely, changes in labile organic matter content and nutrient status, and pH, as well as microbial abundance, activity, and functional composition. During the 2 years of the application, significant changes were observed at the highest rate of biochar application such as higher contents of water, K+, Mg2+, SO42-, higher basal respiration, and with non-significant changes in microbial community, though with some temporal effects. Regarding GHG, N2O decreases coupled with CH4 increases in the summer sampling were measured, although only for the highest application rate scenario. Such effects were unrelated to pH, bioavailable nitrogen status, or bulk soil microbial community shifts. We hypothesized that the key is the porous structure of our wood biochar, which is able to provide more and diversified microbial microhabitats in comparison to bulk soil. At higher temperatures in summer, biologically-induced anoxic conditions in biochar pores acting as microsites may be promoted, where total denitrification to N2 occurs which leads to N2O uptake, while CH4 production is promoted.

Incidence and survival of central nervous system tumors in childhood and adolescence in Girona (Spain) 1990-2013: national and international comparisons.

INTRODUCTION: Pediatric central nervous system tumors are one of the most frequent types of neoplasms in children but epidemiological data on these tumors have been sparsely reported in the medical literature. MATERIALS AND METHODS: We analyze the epidemiology of this type of tumors performing a retrospective population-based study in pediatrics and adolescent age in the population of Girona and compare them with series from Spain, Europe and worldwide. Cases were registered using the International Classification of Disease for Oncology, third edition and grouping according the International Classification of Childhood Cancer, third edition (ICCC-3). RESULTS: For all the histologies and the whole population between 0 and 19 years old, ASRw was 41.8 cases per million person-years. In children population, meaning under 14 years old, we found 104 cases with ASRw of 45.6. Males were the most affected by CNS tumors with a 1.2 sex ratio between 0 and 14 years old, and 1.1 between 0 and 19 years old. The analysis of trends in incidence did not find any statistically significant increase or decrease. Five-year observed survival was 68%, both for patients under 19 and 14 years of age. CONCLUSIONS: The incidence in our area was among the highest in Spain and worldwide, while survival was comparable to others reported.

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

BACKGROUND: Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. PATIENTS AND METHODS: Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). RESULTS: KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2-30.4) and 38.6 months (95% CI, 27.2-not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8-11.1) and 16.9 months (95% CI, 9.3-35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. CONCLUSIONS: This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT01295827.

Parasitic infections in relation to practices and knowledge in a rural village in Northern Thailand with emphasis on fish-borne trematode infection.

The present study integrates several aspects of a parasitological survey in a rural community village combining community knowledge of parasites, their potential transmission routes and health risk factors. A rural community located in Northern Thailand was surveyed for intestinal parasites, and an overall prevalence of 45.2% for helminths and 4.8% for protozoan infections was identified. Socio-demographic characteristics, customs and perceptions were compiled using individual questionnaires and interviews for participants surveyed for parasitic screening. The results allowed us to determine the knowledge and perception of local people concerning helminthic infection and transmission. Despite the fact that the participants in this community were aware of parasitic transmission routes, their widespread custom of eating raw fish and meat render the reduction of helminthiasis difficult. A detailed study on the infection of fish-borne parasitic trematodes, the most prevalent helminth, allowed us to determine that the distance from a given household to the river is a determinant of infection intensity. Health education activities organised in the local community resulted in a change in perception of risks associated with parasite transmission.

Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study.

BACKGROUND: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. PATIENTS AND METHODS: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. RESULTS: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. CONCLUSIONS: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. CLINICALTRIALS.GOV: NCT01006980.

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

BACKGROUND: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND METHODS: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. RESULTS: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. CONCLUSIONS: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study.

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care. ClinicalTrials.gov: NCT01689519.

Wild-Caught and Farm-Reared Amphibians are Important Reservoirs of Salmonella, A Study in North-East Thailand.

The role of amphibians as Salmonella reservoirs has not been as well studied as in reptiles, where the literature is abundant. Recent outbreaks of salmonellosis associated with exotic pet frogs have occurred in United States. Frog farming and wild frog harvesting have increased the international trade in these species. This necessitates a better understanding of the risk of salmonellosis transmission from amphibians to humans. We explored the presence of Salmonella in amphibians (frogs and toads) in Thailand, where farmed and wild frogs as well as toads are present. These live animals are easily found in the local markets and are used as food. Exportation of frog meat from Thailand is common. During March-June 2014, ninety-seven frogs were collected from several habitats, including frog farms, urban areas and protected natural areas. The collected amphibians were tested for the presence of Salmonella. The overall prevalence of Salmonella was 69.07% (90.00% in farm animals, 0% in urban area animals and 44.83% in protected area animals). Eight serovars of Salmonella were isolated: subsp. diarizonae ser. 50:k:z, Hvittingfoss, Muenchen, Newport, Stanley, Thompson, Panama and Wandsworth. Six of the identified serovars, Hvittingfoss, Newport, Panama, Stanley, Thompson and Wandsworth, have been detected in humans in Thailand. According to our results, amphibians are reservoirs of Salmonella and can be a public health concern when used as a source of protein for humans.

Anuran helminth communities from contrasting nature reserve and pasture sites in the Pantanal wetland, Brazil.

Studies of amphibian macroparasites are relevant for the investigation of parasite community ecology and disease dynamics. Here, the parasite communities of five anuran species (Hypsiboas raniceps, Phyllomeduza azurea, Pseudis paradoxa, Leptodactylus fuscus and Leptodactylus podicipinus) are described from two habitats with different levels of preservation (pasture versus nature reserve). Specifically, we used mixed-effect models to test whether helminth species richness, prevalence and abundance differ between the two host collection sites. A total of 120 anuran individuals and 25 helminth parasite taxa were collected. Helminth communities differed between collection sites and among host species. In general, helminth species richness, prevalence and abundance were higher in hosts collected in the pond from the nature reserve. In all, these data help fill the gap in parasite biodiversity knowledge in a changing area, within a sensitive group of vertebrate hosts.

Gastrointestinal helminth fauna of rodents from Cambodia: emphasizing the community ecology of host-parasite associations.

Extensive field surveys of rodents were conducted in Cambodia from 2008 to 2014 to study the diversity and ecology of helminth infection in wild rodent populations. Gastrointestinal helminths were isolated from 14 species of rodents (569 individuals) trapped from different habitats (forest, dry land, rain-fed land and human settlements) in four provinces of Cambodia (Krong Preah Sihanouk, Mondolkiri, Pursat and Steung Treng). The average prevalence of parasitic infection was 58.5% (range, 16.0-64.7%), and 19 helminth taxa were identified in total. Trichostrongylid nematodes were the most prevalent (25.8%), followed by Raillietina sp. (14.1%), Gongylonema neoplasticum (10.7%), Syphacia muris (9.8%) and Hymenolepis diminuta (9.6%). Potential rodent-borne zoonotic helminths were also identified, and the risks of helminthiasis were discussed. The status of helminth infection and species diversity in rodents from settlements were significantly lower than in rodents from forest and peri-domesticated habitats, which indicates that habitat alteration might affect helminth infection and diversity in rodent hosts. Generalized linear models revealed that host attributes (host species and maturity) and environmental factors (habitat and geographical location) were explanatory variables for helminth infection in these rodents. Using network analyses, we showed that the oriental house rat, Rattus tanezumi, was the most central host in the rodent-helminth assemblage, based on the number of helminth taxa it shared with other rodent species. Therefore, R. tanezumi could play an important role in rodent-helminth interactions and helminth transmission to other rodent hosts.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Imidazolium salts with antifungal potential for the control of head blight of wheat caused by Fusarium graminearum.

AIMS: Evaluate the in vitro effect of imidazolium salts (IMS) on the conidia germination and mycelial growth of Fusarium graminearum and their in vivo efficacy for suppressing the symptoms of the disease and infection of kernels in wheat plants. METHODS AND RESULTS: The minimum inhibitory concentrations (MIC) of three IMS (C16 MImCl, C16 MImMeS and C16 MImNTf2 ) were determined for four F. graminearum isolates using serial broth dilution method. The MICs found for all IMS were either 3·12 or 6·25 µg ml(-1) across the isolates, with the former as the most frequent. In the mycelial growth assay on potato dextrose agar media, only the C16 MImCl among the IMS reduced 50% of mycelial growth of one isolate at an estimated concentration of 0·32 mg ml(-1) . The time-kill curves showed a strong fungicidal effect starting 1 h after incubation at a concentration of 12·5 µg ml(-1) , representing a fourfold increase in the most frequent MIC. The C16 MImCl sprayed onto the spikes of potted wheat plants during the flowering stage reduced disease intensity at levels comparable to the commercial fungicide when applied preventatively (1 h prior to fungal inoculation), rather than curatively, and at the higher dosage (2 mg ml(-1) ) rather than lower dosage (0·5 mg ml(-1) ). CONCLUSIONS: C16 MImCl proved to be a potent inhibitor of F. graminearum growth and provided good levels of control of the disease at levels comparable to a commercial fungicide, in wheat plants treated prior to fungal infection during flowering stages. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests the potential of using IMS as alternative to the hazardous standard fungicides in the management of Fusarium head blight of wheat.

Association between HLA-C*04 and American cutaneous leishmaniasis in endemic region of southern Brazil.

Leishmaniasis is a parasitic infectious disease with global repercussions. American cutaneous leishmaniasis (ACL) is endemic in southern Brazil and its pathogenesis varies according to parasite species, immune response, and host genetics. In terms of immunogenetics, many host genes, including HLA (human leukocyte antigen), could be involved in susceptibility to and protection against ACL. Accordingly, the aim of this study was to investigate the association between HLA class I genes (HLA-A, -B, and -C) and ACL in an endemic region of southern Brazil. The allele frequencies of 186 patients diagnosed with ACL and 278 healthy individuals were compared. HLA class I (HLA-A, -B, and -C) typing was carried out by PCR-SSO using Luminex technology. The results revealed an association between the HLA-C*04 allele and the patient study group, in which it appeared more frequently than in the control group [21.5 vs 13.49% (P = 0.0016 and Pc = 0.0258; OR = 1.7560; 95%CI = 1.2227-2.5240)], thereby suggesting an increased susceptibility to ACL. Additional allelic groups such as HLA-A*02, HLA-B*35, HLA-B*45, HLA-C*01, and HLA-C*15 were also implicated; however, further investigation is necessary to confirm their association with ACL. Therefore, the results obtained in this study demonstrate the involvement of HLA class I genes in the susceptibility or resistance to ACL, with significant association between HLA-C*04 and ACL susceptibility.

Diversity and patterns of interaction of an anuran-parasite network in a neotropical wetland.

We describe the diversity and structure of a host-parasite network of 11 anuran species and their helminth parasites in the Pantanal wetland, Brazil. Specifically, we investigate how the heterogeneous use of space by hosts changes parasite community diversity, and how the local pool of parasites exploits sympatric host species of different habits. We examined 229 anuran specimens, interacting with 32 helminth parasite taxa. Mixed effect models indicated the influence of anuran body size, but not habit, as a determinant of parasite species richness. Variation in parasite taxonomic diversity, however, was not significantly correlated with host size or habit. Parasite community composition was not correlated with host phylogeny, indicating no strong effect of the evolutionary relationships among anurans on the similarities in their parasite communities. Host-parasite network showed a nested and non-modular pattern of interaction, which is probably a result of the low host specificity observed for most helminths in this study. Overall, we found host body size was important in determining parasite community richness, whereas low parasite specificity was important to network structure.