KRAS activation in gastric cancer stem-like cells promotes tumor angiogenesis and metastasis

Abstract Our previous work showed that KRAS activation in gastric cancer cells leads to activation of an epithelial-to-mesenchymal transition (EMT) program and generation of cancer stem-like cells (CSCs). Here we analyze how this KRAS activation in gastric CSCs promotes tumor angiogenesis and metastasis. Gastric cancer CSCs were found to secrete pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A), and inhibition of KRAS markedly reduced secretion of these factors. In a genetically engineered mouse model, gastric tumorigenesis was markedly attenuated when both KRAS and VEGF-A signaling were blocked. In orthotropic implant and experimental metastasis models, silencing of KRAS and VEGF-A using shRNA in gastric CSCs abrogated primary tumor formation, lymph node metastasis, and lung metastasis far greater than individual silencing of KRAS or VEGF-A. Analysis of gastric cancer patient samples using RNA sequencing revealed a clear association between high expression of the gastric CSC marker CD44 and expression of both KRAS and VEGF-A, and high CD44 and VEGF-A expression predicted worse overall survival. In conclusion, KRAS activation in gastric CSCs enhances secretion of pro-angiogenic factors and promotes tumor progression and metastasis.This study was funded by NIH/NCI grant P30 CA008748, the DeGregorio Family Foundation, and Stand Up To Cancer

Health Related Quality of Life among Patients with Tuberculosis and HIV in Thailand

INTRODUCTION: Health utilities of tuberculosis (TB) patients may be diminished by side effects from medication, prolonged treatment duration, physical effects of the disease itself, and social stigma attached to the disease. METHODS: We collected health utility data from Thai patients who were on TB treatment or had been successfully treated for TB for the purpose of economic modeling. Structured questionnaire and EuroQol (EQ-5D) and EuroQol visual analog scale (EQ-VAS) instruments were used as data collection tools. We compared utility of patients with two co-morbidities calculated using multiplicative model (U(CAL)) with the direct measures and fitted Tobit regression models to examine factors predictive of health utility and to assess difference in health utilities of patients in various medical conditions. RESULTS: Of 222 patients analyzed, 138 (62%) were male; median age at enrollment was 40 years (interquartile range [IQR], 35-47). Median monthly household income was 6,000 Baht (187 US$; IQR, 4,000-15,000 Baht [125-469 US$]). Concordance correlation coefficient between utilities measured using EQ-5D and EQ-VAS (U(EQ-5D) and U(VAS), respectively) was 0.6. U(CAL) for HIV-infected TB patients was statistically different from the measured U(EQ-5D) (p-value<0.01) and U(VAS) (p-value<0.01). In tobit regression analysis, factors independently predictive of U(EQ-5D) included age and monthly household income. Patients aged ≥40 years old rated U(EQ-5D) significantly lower than younger persons. Higher U(EQ-5D) was significantly associated with higher monthly household income in a dose response fashion. The median U(EQ-5D) was highest among patients who had been successfully treated for TB and lowest among multi-drug resistant TB (MDR-TB) patients who were on treatment. CONCLUSIONS: U(CAL) of patients with two co-morbidities overestimated the measured utilities, warranting further research of how best to estimate utilities of patients with such conditions. TB and MDR-TB treatments impacted on patients' self perceived health status. This effect diminished after successful treatment

Structural violence and clinical medicine.

Structural violence refers to the social structures that put people in harm's way. Farmer and colleagues describe the impact of social violence upon people living with HIV in the US and Rwanda

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies. The role for immune-based therapies has become clearer as we obtain a greater understanding of the role of the immune system in gastric cancer formation and growth. A variety treatment to augment the immune system are under evaluation in clinical trials, and these include immune checkpoint inhibitors, antibody-drug conjugates, and immune cell-based therapies. Here, we review the immune landscape and immune-based therapies for GC

Components of the Package for Prevention of Mother-to-Child Transmission of HIV Provided by Partners In Health/Inshuti Mu Buzima in Rwanda

<p>Photo: Ophelia Dahl, Partners In Health</p

Factors Affecting Metabolic Outcomes Post Bariatric Surgery: Role of Adipose Tissue

Obesity is an ever-growing public health crisis, and bariatric surgery (BS) has become a valuable tool in ameliorating obesity, along with comorbid conditions such as diabetes, dyslipidemia and hypertension. BS techniques have come a long way, leading to impressive improvements in the health of the majority of patients. Unfortunately, not every patient responds optimally to BS and there is no method that is sufficient to pre-operatively predict who will receive maximum benefit from this surgical intervention. This review focuses on the adipose tissue characteristics and related parameters that may affect outcomes, as well as the potential influences of insulin resistance, BMI, age, psychologic and genetic factors. Understanding the role of these factors may help predict who will benefit the most from BS

Factors Affecting Metabolic Outcomes Post Bariatric Surgery: Role of Adipose Tissue

Obesity is an ever-growing public health crisis, and bariatric surgery (BS) has become a valuable tool in ameliorating obesity, along with comorbid conditions such as diabetes, dyslipidemia and hypertension. BS techniques have come a long way, leading to impressive improvements in the health of the majority of patients. Unfortunately, not every patient responds optimally to BS and there is no method that is sufficient to pre-operatively predict who will receive maximum benefit from this surgical intervention. This review focuses on the adipose tissue characteristics and related parameters that may affect outcomes, as well as the potential influences of insulin resistance, BMI, age, psychologic and genetic factors. Understanding the role of these factors may help predict who will benefit the most from BS