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KRAS Alleles: The Devil Is in the Detail.

ABSTRACT: KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathways or in stress response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between the many distinct KRAS activating mutations. This review draws upon insights from both clinical and experimental studies to explore similarities and differences among KRAS alleles. Historical and emerging evidence supports the notion that the specific biology related to each allele might be exploitable for allele-specific therapy.

SUBMITTER: Haigis KM

PROVIDER: S-EPMC5824632 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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KRAS Alleles: The Devil Is in the Detail.

Haigis Kevin M KM

Trends in cancer 20170912 10

KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathways or in stress response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between ...[more]

PMID: 28958387

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Project description:BackgroundFemicide is a very important public health problem in Ecuador. Since regional and country-level femicide rates can obscure significant variations at the sub-national level, it is important to provide information at the lowest relevant level of disaggregation to be able to develop targeted preventive policies. The aim of this study was to assess the spatial distribution of the femicide rate and to examine its spatial clustering at the canton level in Ecuador in the period 2018-2019.MethodsData on cases were collected by a national network of non-governmental organizations. Two age-disaggregated analyses were done, one for the 15 to 24 years-olds and the other for the female population of 15 and older. Age-specific population data were obtained from the National Institute of Statistics for the study period. Standardized mortality ratios for mapping the mortality were calculated using hierarchical Bayesian models and spatial scan statistics were applied to identify local clusters. Thematic maps of age-specific femicide rates were also constructed.ResultsDuring the two-year period, 61 and 183 women were killed in the age ranges 15-24 and 15 years and older, respectively. The annual rate of femicides in Ecuador was 1.0 and 0.8 per 100,000 in the female population aged 15-24 and 15+, respectively, with substantial variations among cantons. The spatial analysis contributed to visualize high risk cantons, which were mainly located in a small area in the central part of the country (for those 15+) but especially in the Amazon region, for both of the studied age groups.ConclusionsThis study has shown the usefulness of applying spatial analysis to the problem of femicides in Ecuador. The study has revealed important variations among cantons but also a spatial clustering, mainly in the Amazon region of the country. The results should help policymakers to focus on current prevention programmes for violence against women into these high-risk areas. Continuous monitoring of femicides at low-level geographical areas is highly recommended.

Project description:Simple Summary Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are the preferred anti-viral agents used as first-line treatments for chronic hepatitis B. Despite many meta-analyses being conducted, it is still not clear whether TDF is more effective than ETV at reducing the risk of HCC due to the inconsistent statistical methodologies employed in previous observational studies. To reduce heterogeneity, we analysed only hospital cohort data studies with anti-viral naive patients. Additionally, unlike previous studies, we conducted subgroup analyses with enrolment criteria and socioeconomic factors that could not be corrected with statistical techniques. There is no difference between the two drugs in terms of reducing the risk of HCC in a pooled analysis of PS-matched patients. In the subgroup analysis, if there was interval of over three years from the start point of patient enrolment, we found that TDF was associated with significantly lower HCC risk. This result will provide new perspectives for future research. Abstract Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are the preferred anti-viral agents used as first-line treatments for chronic hepatitis B (CHB). However, the efficacy of these agents in reducing the incidence of hepatocellular carcinoma (HCC) remains unclear. We conducted this meta-analysis to assess the efficacy of anti-viral agent on preventing HCC in CHB. Two investigators independently searched all relevant studies that examined the efficacy of anti-viral agent for preventing HCC using MEDLINE, Embase, and Cochrane Library databases through August 2021. The extracted data were analysed using a random-effects meta-analysis model based on the inverse-variance method (DerSimonian–Laird) and expressed as hazard ratio (HR) and 95% confidence interval (95% CI). We included 19 retrospective studies in the analysis. Although there was substantial heterogeneity between the studies, the overall pooled HR indicated that TDF significantly lowered the risk of HCC (HR: 0.72, 95% CI: 0.58–0.90, I2 = 66.29%). However, the pooled analysis of propensity score (PS)-matched subpopulations showed no significant differences (HR, 0.83; 95% CI, 0.65–1.06; I2 = 52.30%) between TDF and ETV. In a subgroup analysis, an interval of over three years in the start point of patient enrolment and excluding alcoholic liver disease patients significantly lowered the HCC risk associated with TDF. In conclusion, TDF may be more effective than ETV at reducing HCC incidence in treatment-naive CHB patients, but this effect was not consistent in the PS-matched subpopulation that reduced heterogeneity. As a result of subgroup analysis, the conflicting findings of previous studies may result from heterogeneous inclusion criteria. Further studies with standardised protocols are needed to reduce the residual heterogeneity.

Dataset Information

KRAS Alleles: The Devil Is in the Detail.

Publications

KRAS Alleles: The Devil Is in the Detail.

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