The sulfamide moiety affords higher inhibitory activity and oral bioavailability to a series of coumarin dual selective RAF/MEK inhibitors

Introducing a sulfamide moiety to our coumarin derivatives afforded enhanced Raf/MEK inhibitory activity concomitantly with an acceptable PK profile. Novel sulfamide 17 showed potent HCT116 cell growth inhibition (IC₅₀ = 8 nM) and good PK profile (bioavailability of 51% in mouse), resulting in high in vivo antitumor efficacy in the HCT116 xenograft (ED₅₀ = 4.8 mg/kg). We confirmed the sulfamide moiety showed no negative impact on tests run on the compound to evaluate DMPK (PK profiles in three animal species, CYP inhibition and CYP induction) and the safety profile (hERG and AMES tests). Sulfamide 17 had favorable properties that warranted further preclinical assessment     

Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1

We recently identified a novel metastasis suppressor gene, BRMS1, in breast cancer. Since the BRMS1 gene maps to chromosome 11q13.1-q13.2 and since chromosome 11q defects have been described in various stages of human melanoma progression, we hypothesized that BRMS1 may function as a tumor or metastasis suppressor in melanomas as well. Quantitative real-time RT-PCR revealed that BRMS1 mRNA expression was high in melanocytes, considerably reduced in early melanoma-derived cell lines, and barely detectable in advanced/metastatic cell lines. Stable transfectants of BRMS1 in the human melanoma cell lines MelJuSo and C8161.9 did not alter the tumorigenicity of either cell line, but significantly suppressed metastasis compared to vector-only transfectants. Orthotopic tumors continued to express BRMS1, but expression was lost in lung metastases. In vitro morphology, growth rate, and histology of BRMS1 transfectants were similar to controls. BRMS1 transfectants were less invasive in a collagen sandwich assay and had restored homotypic gap junctional intercellular communication (GJIC). Thus, BRMS1 functions as a metastasis suppressor in more than one tumor type (i.e., breast carcinoma and cutaneous melanoma) by modifying several metastasis-associated phenotypes.     

Increased Risk of Sudden Cardiac Arrest in Obstructive Pulmonary Disease: A Case-Control Study

Background

We aimed to determine whether (1) patients with obstructive pulmonary disease (OPD) have an increased risk of sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF), and (2) the SCA risk is mediated by cardiovascular risk-profile and/or respiratory drug use.

Methods

A community-based case-control study was performed, with 1310 cases of SCA of the ARREST study and 5793 age, sex and SCA-date matched non-SCA controls from the PHARMO database. Only incident SCA cases, age older than 40 years, that resulted from unequivocal cardiac causes with electrocardiographic documentation of VT/VF were included. Conditional logistic regression analysis was used to assess the association between SCA and OPD. Pre-specified subgroup analyses were performed regarding age, sex, cardiovascular risk-profile, disease severity, and current use of respiratory drugs.

Results

A higher risk of SCA was observed in patients with OPD (n = 190 cases [15%], 622 controls [11%]) than in those without OPD (OR adjusted for cardiovascular risk-profile 1.4 [1.2–1.6]). In OPD patients with a high cardiovascular risk-profile (OR 3.5 [2.7–4.4]) a higher risk of SCA was observed than in those with a low cardiovascular risk-profile (OR 1.3 [0.9–1.9]) The observed SCA risk was highest among OPD patients who received short-acting β2-adrenoreceptor agonists (SABA) or anticholinergics (AC) at the time of SCA (SABA OR: 3.9 [1.7–8.8], AC OR: 2.7 [1.5–4.8] compared to those without OPD).

Conclusions

OPD is associated with an increased observed risk of SCA. The most increased risk was observed in patients with a high cardiovascular risk-profile, and in those who received SABA and, possibly, those who received AC at the time of SCA.     

Botanical Knowledge and its Differentiation by Age,Gender and Ethnicity in Southwestern Niger

Indigenous knowledge is unevenly distributed. Individual knowledge level may be affected by many factors such as gender, age, ethnicity, profession, religious and cultural beliefs, abundance and usefulness of the species. This study documents indigenous knowledge of herbaceous and woody plant species of farmers and herders in southwestern Niger. Specifically, we examine the effects of age, gender, and ethnicity on knowledge of local vegetation. Results from the study showed that on average a higher proportion of woody species was identified by the respondents compared to herbaceous species. Both gender and ethnicity had a significant effect on the identification of herbaceous species but no effect on identification of woody species. Respondents in lower age group (10 to 30 years) identified lower number of species compared to other age classes. There seems to be a curvilinear relationship between age of respondents and number of plant species identified. Results from this study reaffirm the uneven distribution of indigenous knowledge within a given area due to social factors. The main challenge is how to incorporate these social differences in knowledge of native plant species into sustainable management and conservation of community natural resources.

Herders’ Perceptions on Ruminant Livestock Breeds and Breeding Management in Southwestern Niger

This study documents indigenous knowledge of breeds of cattle, sheep and goats in southwestern Niger, and includes both pastoralists and agropastoralists. Our study included sheep and goats in view of the increasing importance of small ruminants in livestock production systems in the Sahel since the drought of the 1970s and 1980s. This study was carried out under the Desert Margins Program (DMP) project on arresting land degradation and the conservation of biodiversity in desert margins of sub-Saharan Africa, partly funded by the Global Environment Facility (GEF).     

Innate antiviral immunity of human PBLs and immunoregulatory activity of EGb 761

Background

The aim of the studies was to examine the potential immunoregulatory activity of Ginkgo biloba extract (EGb 761) on cytokine production, one of the mechanisms of innate antiviral immunity, by human peripheral blood leukocytes (PBLs) ex vivo.

Methodology

PBLs isolated from healthy blood donors were treated with different, nontoxic concentrations of EGb 761. Levels of different cytokines (TNF-α, IFN-α, IFN-Γ, IL-10 and IL-12), important in innate immunity development, were determined by ELISA.

Results

EGb 761, apart from strengthening of antiviral response, showed a differential impact on cytokine production by human PBLs ex vivo. It decreased the level of TNF-α and IFN-α but strongly increased the level of IFN-γ in PBLs stimulated by vesicular stomatitis virus (VSV) and non-stimulated PBLs. The extract reduced the production of IL-10 and IL-12 by human PBLs. The results were discussed and compared with previously published findings on the activity of the synthetic drug donepezil.

Conclusions

According to the results from the present study and our previous investigations, we report immunoregulatory activity of EGb 761 on different cytokine production by human PBLs ex vivo, which indicates the possibility of using the drug for the treatment of many immune deficiencies or infectious diseases through strengthening of innate immunity reactions.     

Polycystin-1 interacts with intermediate filaments

Polycystin-1, the protein defective in a majority of patients with autosomal dominant polycystic kidney disease, is a ubiquitously expressed multi-span transmembrane protein of unknown function. Subcellular localization studies found this protein to be a component of various cell junctional complexes and to be associated with the cytoskeleton, but the specificity and nature of such associations are not known. To identify proteins that interact with the polycystin-1 C-tail (P1CT), this segment was used as bait in a yeast two-hybrid screening of a kidney epithelial cell library. The intermediate filament (IF) protein vimentin was identified as a strong polycystin-1-interacting partner. Cytokeratins K8 and K18 and desmin were also found to interact with P1CT. These interactions were mediated by coiled-coil motifs in polycystin-1 and IF proteins. Vimentin, cytokeratins K8 and K18, and desmin also bound directly to P1CT in GST pull-down and in in vitro filament assembly assays. Two observations confirmed these interactions in vivo: (i) a cell membrane-anchored form of recombinant P1CT decorated the IF network and was found to associate with the cytoskeleton in detergent-solubilized cells and (ii) endogenous polycystin-1 distributed with IF at desmosomal junctions. Polycystin-1 may utilize this association for structural, storage, or signaling functions.     

Are Salmonella-Induced Gastroenteritis Neglected in Developing Countries? Feedback from Microbiological Investigations in N’Djamena Hospitals,Chad

Salmonella is considered to be one of the main pathogens causing human gastroenteritis worldwide. Looking for Salmonella in Africa in patients suffering from gastroenteritis is rather unusual, and the use of antibiotics is not subject to any regulation. This study intends for stressing the possible prominent importance of Salmonella in digestive diseases in Africa as well as identifying antimicrobial resistance of Salmonella isolates from faeces samples of human origin. All samples were collected from five N’Djamena hospitals, from patients suffering from diarrhoea. The collecting was undertaken over two periods of six months each: from August 2010 to January 2011 and from September 2011 to February 2012. Salmonella isolates were obtained by standard cultivation and serotyping methods. A total of 43 Salmonella isolates were identified, belonging to 21 different serovars. The most prevalent serovar was Salmonella Stanleyville (n = 7), followed by S. Anatum (n = 4) and S. Kottbus (n = 3). The other serovars were under-represented. The majority of these isolates were susceptible to all antibiotics tested (CLSI Standards), except two S. Enteritidis isolates that exhibited resistance to fluoroquinolones. The different serovars and antibiotic resistance profiles that were observed highlight the substantial diversity of Salmonella in N’Djamena, Chad. Roughly, one out of ten patients who consulted for gastroenteritis was shedding Salmonella spp. and none of them would have been diagnosed outside the context of this research program. This study may encourage local clinicians to explore more often salmonellosis suspicion in their daily practice.