Biophysical and Biochemical Characterization of Structurally Diverse Small Molecule Hits for KRAS Inhibition.

We describe six compounds as early hits for the development of direct inhibitors of KRAS, an important anticancer drug target. We show that these compounds bind to KRAS with affinities in the low micromolar range and exert different effects on its interactions with binding partners. Some of the compounds exhibit selective binding to the activated form of KRAS and inhibit signal transduction through both the MAPK or the phosphatidylinositide 3-kinase PI3K-protein kinase B (AKT) pathway in cells expressing mutant KRAS. Most inhibit intrinsic and/or SOS-mediated KRAS activation while others inhibit RAS-effector interaction. We propose these compounds as starting points for the development of non-covalent allosteric KRAS inhibitors.

Demographic, Clinical and Laboratory Profiles of HIV Infected Patients Admitted into Imam Khomeini Hospital of Tehran, Iran.

OBJECTIVE: The aim of this study was to report the epidemiological, clinical and laboratory profiles of HIV-infected patients who admitted to HIV/AIDS laboratory of Imam Khomeini Hospital in Tehran, Iran. METHODS: HIV positive patients referred to the HIV/AIDS reference laboratory between December 2012 to March 2013 were included in the study. Their demographic characteristics, behavioral and personal history were assessed. Ninety nine patients' files from the medical records at the Voluntary Counseling and Testing Center (VCT) were selected and evaluated. Data was analyzed using SPSS for Windows Version 16. We used Pearson's chi-squared, one-way ANOVA and post hoc tests to examine differences in proportions. RESULTS: Of 99 participants in the present study, 68.7% were males, the mean age of the patients was 36±1.2 years and about 60% were married and almost half of them were self-employed. The most common transmission route was injection drug use. There was a statistically significant difference in CD4 count among different age groups (P = 0.028). Also, there was significant association between CD4 count and narcotic types (F=3.71, P = 0.012). Patients who used opium, had significantly higher CD4 than who used two or more narcotics (P = 0.005). CONCLUSION: Our findings are helpful in understanding the demographic, clinical and laboratory profile of people living with HIV/AIDS. Consideration of useful interventions for high- risk groups and paying more attention to socio demographic background are needed for health care providers.

Assessment of the Effects of a Novel Herbal Immunomodulator Drug (IMOD) on Cytokine Profiles in Experimental Canine Visceral Leishmaniasis: a Preliminary Survey.

BACKGROUND: Cytokines play a fundamental role in the regulation of immune responses in remission and/or relapsing of leishmaniasis. Therefore, immunotherapy for the treatment of canine visceral leishmaniasis (CVL) has represented a principle approach in control of the infection. The present research aimed to evaluating the immunotherapeutic potential of a novel herbal immunomodulator drug (IMOD) on CVL. METHODS: Twelve mongrel dogs were intravenously infected with Iranian strain of L. infantum and randomly divided into three groups; 1: negative control (non-infected), 2: immunotherapy with IMOD and 3: positive control (non-treated). Cell proliferation and Th1-/Th2-type cytokines were measured in peripheral blood mononuclear cell (PBMC) by cell proliferation kit I (MTT) and enzyme-linked immunospot (ELISpot) assays, respectively. RESULTS: At the 60 days follow-up assessment, no adverse effects were observed in treated interventional group. Cellular proliferation assay indicated that PBMCs of IMOD group had higher stimulation index (SI) than positive control group (p < 0.05). Enhancement of CD4+T cells such as IL-2, IL-4 & IL-10 were detected in negative control group due to in vitro IMOD stimulation 30 days post-treatment. In accordance to decreasing trends of Th1 & Th2 cytokines in positive control group, the mean number of IFN-γ IL-2, IL-4 and IL-10 spot forming cells (SFCs) down regulated for IMOD group during the study. CONCLUSION: These data indicate that IMOD had immunomodulatory potential but is not sufficient for total parasitic cure due to balance of Th1/Th2 cytokines. This is a preliminary study and we propose to undertake a series of experiments to evaluate the CVL due to in vitro modulatory effects of IMOD.