The data and regulatory considerations leading to the U.S. Food and Drug Administration (FDA) January 30, 2012 approval of Erivedge (vismodegib) capsules for the treatment of patients with recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) are described. The FDA's approval decision was based primarily on the results observed in a single-arm, parallel cohort, international trial of vismodegib, administered orally at 150 mg daily until disease progression, in patients with pathologically confirmed, recurrent, locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma (mBCC). An independent review committee confirmed an overall response rate (ORR) of 30.3% [95% confidence interval (CI): 15.6-48.2] in 33 patients with mBCC and an ORR of 42.9% (95% CI: 30.5-56.0) in 63 patients with laBCC; median response durations were 7.6 months and 7.6 months for patients with mBCC and laBCC, respectively. The most common adverse reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, cough, arthralgias, vomiting, headache, ageusia, insomnia, and upper respiratory tract infection. Animal toxicology studies confirmed that vismodegib is a potent teratogenic agent. Approval was based on durable objective tumor responses supported by knowledge of the pathologic role of Hedgehog signaling in BCC and acceptable toxicity in a population without effective alternative therapies.

Abstract-c-kit, the transmembrane tyrosine kinase receptor for stem cell factor, is required for melanocyte and mast cell development, hematopoiesis, and differentiation of spermatogonial stem cells. We show here that in the heart, c-kit is expressed not only by cardiac stem cells but also by cardiomyocytes, commencing immediately after birth and terminating a few days later, coincident with the onset of cardiomyocyte terminal differentiation.

The aryl hydrocarbon receptor (AHR), also known as the dioxin receptor, was originally characterized as a xenobiotic receptor that senses xenotoxicants. Here we investigated the endobiotic and hepatic role of AHR in fatty liver and energy metabolism, and identified the endocrine factor that mediates the metabolic function of AHR. Wild type and liver-specific constitutively activated human AHR transgenic (TG) mice were used to investigate the role of AHR in fatty liver and energy homeostasis. Adenovirus expressing short hairpin RNA targeting the fibroblast growth factor 21 (FGF21) were used to determine the involvement of FGF21 in the metabolic effect of AHR. We showed that despite their severe fatty liver, the TG mice were protected from diet-induced obesity and type 2 diabetes. We identified the endocrine hormone FGF21 as a mediator for the metabolic benefit of AHR and established FGF21 as a direct transcriptional target of AHR. Interestingly, the transactivation of FGF21 by AHR contributed to both hepatic steatosis and systemic insulin hypersensitivity, both of which were largely abolished upon FGF21 knockdown. Conclusions The AHR-FGF21 endocrine signaling pathway establishes AHR as a pivotal environmental modifier that integrates signals from chemical exposure in the regulation of lipid and energy metabolism.

The aim of this study was to evaluate the relationship between type 2 diabetes mellitus (T2DM) and hepatitis C virus (HCV) infection and to examine whether T2DM enhances the risk of HCV infection compared with the risk in the general population. We followed standard guidelines to perform a meta-analysis. The associated literature was selected based on the established inclusion criteria. The summary odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Through electronic database and manual searching, 22 studies were identified for the final analysis, which included a total of 78,051 individuals. Based on the random effects model, the meta-analysis results showed that patients with T2DM were at a higher risk of acquiring HCV infection than non-T2DM patients (summary OR 5 3.50, 95% CI 5 2.54-4.82, I 2 5 82.3%). Based on the current limited evidence, this study suggests that T2DM is associated with increased susceptibility to HCV infection.H epatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM) are two major public health problems associated with increasing complications and mortality rates worldwide 1,2 . HCV infection is a cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in Western countries and affects an estimated total of 170 million individuals worldwide 3,4 . Meanwhile, Data reported by the World Health Organization (WHO) in 2000 showed that the estimated prevalence of T2DM is approximately 2.8% among adults aged over 20 years 5 . Both diseases present a large health care burden. Moreover, HCV infection and T2DM may coexist in an individual 6 .The development of HCV infection is a multi-factorial process associated with a variety of risk factors, as observed with all other infectious diseases 7 . The major risk factors associated with the development of infection include virus-related factors (e.g., viral load or genotype) and host-related factors, such as age, gender, alcohol consumption, blood transfusion status, obesity, immune status, and co-infections 8 . One important cofactor is T2DM. T2DM has been shown to modify the course of hepatitis C, even at the insulin resistance (IR) stage, which precedes the development of overt diabetes 9,10 . And it is now widely recognized that chronic hepatitis C is a metabolic disease that is strongly associated with T2DM and IR 11 .In recent studies, however, several researchers have focused on the seroprevalence of viral hepatitis markers in individuals who suffer from diabetes. They reported an excessive prevalence of HCV infection among patients with T2DM compared with the general population, which was considered to be the result of more frequent exposure to medical interventions and instrumentation and compromised immunity, leading to an increased risk of HCV infection [12][13][14] . The association between T2DM and liver disease was recognized over 30 years ago 15 . Since then, numerous observational studies assessing the association between HCV and T2DM have been ...

Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of N-aryl-2nitrosoaniline synthetic intermediates that enabled functionalization of the 3-position of this scaffold. Several HPs demonstrated potent antibacterial and biofilm-killing activities (e.g., HP 29, against methicillin-resistant Staphylococcus aureus: MIC = 0.075 μM; MBEC = 2.35 μM), and transcriptional analysis revealed that HPs 3, 28, and 29 induce rapid iron starvation in MRSA biofilms. Several HPs demonstrated excellent activities against Mycobacterium tuberculosis (HP 34, MIC = 0.80 μM against CDC1551). This work established new SAR insights, and HP 29 demonstrated efficacy in dorsal wound infection models in mice. Encouraged by these findings, we believe that HPs could lead to significant advances in the treatment of challenging infections.

The Neuropeptide S receptor, a Gs/Gq-coupled GPCR expressed in brain regions involved in mediating drug reward, has recently emerged as a candidate therapeutic target in addictive disorders. Here, we describe the in vitro and in vivo pharmacology of a novel, selective and brain penetrant NPSR antagonist with nanomolar affinity for the NPSR, NCGC00185684. In vitro, NCGC00185684 shows biased antagonist properties, and preferentially blocks ERK-phosphorylation over intracellular cAMP or calcium responses to NPS. In vivo, systemic NCGC00185684 blocks alcohol-induced ERK-phosphorylation in the rat central amygdala, a region involved in regulation of alcohol intake. NCGC00185684 also decreases operant alcohol self-administration, and lowers motivation for alcohol reward as measured using progressive ratio responding. These effects are behaviorally specific, in that they are observed at doses that do not influence locomotor activity or reinstatement responding following extinction. Together, these data provide an initial validation of the NPSR as a therapeutic target in alcoholism.

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Overdose of isoniazid (INH), an antituberculosis drug, can be life-threatening because of neurotoxicity. In clinical practice for management of INH overdose and acute toxicity, the potential of INH-induced hepatotoxicity is also considered. However, the biochemical basis of acute INH toxicity in the liver remains elusive. In the current study, we used an untargeted metabolomic approach to explore the acute effects of INH on endobiotic homeostasis in mouse liver. We found that overdose of INH resulted in accumulation of oleoyl-l-carnitine and linoleoyl-l-carnitine in the liver, indicating mitochondrial dysfunction. We also revealed the interactions between INH and fatty acyl-CoAs by identifying INH-fatty acid amides. In addition, we found that overdose of INH led to the accumulation of heme and oxidized NAD in the liver. We also identified an INH and NAD adduct in the liver. In this adduct, the nicotinamide moiety in NAD was replaced by INH. Furthermore, we illustrated that overdose of INH depleted vitamin B6 in the liver and blocked vitamin B6-dependent cystathionine degradation. These data suggest that INH interacts with multiple biochemical pathways in the liver during acute poisoning caused by INH overdose.