A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: Case Series and Review of the Literature

The development of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced stage cancers. However, immune-related adverse events are frequently observed. Cardiac toxicity from ICI therapy can range from asymptomatic troponin-I elevations to conduction abnormalities of the heart and even fulminant myocarditis. Although rare, myocarditis is a potentially fatal adverse effect of ICI therapy. We present a series of five cases of ICI-related cardio-toxicity diagnosed and managed at Roswell Park Comprehensive Cancer Center along with a review of published case reports in the literature. Our series highlights the importance of high clinical suspicion, early diagnosis of myocarditis, and prompt initiation of immunosuppressive therapy

Long-Term Survivors of Metastatic Colorectal Cancer Treated with Systemic Chemotherapy Alone: A North Central Cancer Treatment Group Review of 3811 Patients, N0144

Although systemic chemotherapy in patients with unresectable metastatic colorectal cancer (mCRC) is palliative in nature, some patients experience long-term remission beyond 5 years consequent to treatment with chemotherapy alone

How Human Brucellosis Incidence in Urban Kampala Can Be Reduced Most Efficiently? A Stochastic Risk Assessment of Informally-Marketed Milk

In Kampala, Uganda, studies have shown a significant incidence of human brucellosis. A stochastic risk assessment involving two field surveys (cattle farms and milk shops) and a medical record survey was conducted to assess the risk of human brucellosis infection through consumption of informally marketed raw milk potentially infected with Brucella abortus in Kampala and to identify the best control options.In the cattle farm survey, sera of 425 cows in 177 herds in the Kampala economic zone were sampled and tested for brucellosis using a competitive enzyme-linked immunosorbent assay (CELISA). Farmers were interviewed for dairy information. In the milk shop surveys, 135 milk sellers in the urban areas were interviewed and 117 milk samples were collected and tested using an indirect enzyme-linked immunosorbent assay (IELISA). A medical record survey was conducted in Mulago National Referral Hospital for serological test results. A risk model was developed synthesizing data from these three surveys. Possible control options were prepared based on the model and the reduction of risk was simulated for each scenario. Overall, 12.6% (6.8-18.9: 90%CI) of informally marketed milk in urban Kampala was contaminated with B.abortus at purchase and the annual incidence rate was estimated to be 5.8 (90% CI: 5.3-6.2) per 10,000 people. The best control option would be the construction of a milk boiling centre either in Mbarara, the largest source of milk, or in peri-urban Kampala and to ensure that milk traders always sell milk to the boiling centre; 90% success in enforcing these two options would reduce risk by 47.4% (21.6-70.1: 90%CI) and 82.0% (71.0-89.0: 90%CI), respectively.This study quantifies the risk of human brucellosis infection through informally marketed milk and estimates the incidence rate in Kampala for the first time; risk-based mitigation strategies are outlined to assist in developing policy

Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]

BACKGROUND: Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. METHODS: 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. RESULTS: During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. CONCLUSION: In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding risk. Although sclerotherapy lowered mortality attributable to variceal bleeding, overall survival was not affected. The effect of prophylactic sclerotherapy seems dependent on the underlying bleeding risk. A beneficial effect can only be expected for patients with a high risk for bleeding

Evidence for Female-Biased Dispersal in the Protandrous Hermaphroditic Asian Seabass, Lates calcarifer

Movement of individuals influences individual reproductive success, fitness, genetic diversity and relationships among individuals within populations and gene exchange among populations. Competition between males or females for mating opportunities and/or local resources predicts a female bias in taxa with monogamous mating systems and a male-biased dispersal in polygynous species. In birds and mammals, the patterns of dispersal between sexes are well explored, while dispersal patterns in protandrous hermaphroditic fish species have not been studied. We collected 549 adult individuals of Asian seabass (Lates calcarifer) from four locations in the South China Sea. To assess the difference in patterns of dispersal between sexes, we genotyped all individuals with 18 microsatellites. Significant genetic differentiation was detected among and within sampling locations. The parameters of population structure (FST), relatedness (r) and the mean assignment index (mAIC), in combination with data on tagging-recapture, supplied strong evidences for female-biased dispersal in the Asian seabass. This result contradicts our initial hypothesis of no sex difference in dispersal. We suggest that inbreeding avoidance of females, female mate choice under the condition of low mate competition among males, and male resource competition create a female-biased dispersal. The bigger body size of females may be a cause of the female-biased movement. Studies of dispersal using data from DNA markers and tagging-recapture in hermaphroditic fish species could enhance our understanding of patterns of dispersal in fish

A novel glucagon-related peptide (GCRP) and its receptor GCRPR account for coevolution of their family members in vertebrates

The glucagon (GCG) peptide family consists of GCG, glucagon-like peptide 1 (GLP1), and GLP2, which are derived from a common GCG precursor, and the glucose-dependent insulinotropic polypeptide (GIP). These peptides interact with cognate receptors, GCGR, GLP1R, GLP2R, and GIPR, which belong to the secretin-like G protein-coupled receptor (GPCR) family. We used bioinformatics to identify genes encoding a novel GCG-related peptide (GCRP) and its cognate receptor, GCRPR. The GCRP and GCRPR genes were found in representative tetrapod taxa such as anole lizard, chicken, and Xenopus, and in teleosts including medaka, fugu, tetraodon, and stickleback. However, they were not present in mammals and zebrafish. Phylogenetic and genome synteny analyses showed that GCRP emerged through two rounds of whole genome duplication (2R) during early vertebrate evolution. GCRPR appears to have arisen by local tandem gene duplications from a common ancestor of GCRPR, GCGR, and GLP2R after 2R. Biochemical ligand-receptor interaction analyses revealed that GCRP had the highest affinity for GCRPR in comparison to other GCGR family members. Stimulation of chicken, Xenopus, and medaka GCRPRs activated Gαs-mediated signaling. In contrast to chicken and Xenopus GCRPRs, medaka GCRPR also induced Gαq/11-mediated signaling. Chimeric peptides and receptors showed that the K(16)M(17)K(18) and G(16)Q(17)A(18) motifs in GCRP and GLP1, respectively, may at least in part contribute to specific recognition of their cognate receptors through interaction with the receptor core domain. In conclusion, we present novel data demonstrating that GCRP and GCRPR evolved through gene/genome duplications followed by specific modifications that conferred selective recognition to this ligand-receptor pair