Role of RPL39 in Metaplastic Breast Cancer

Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer. Methods: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39. Results: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = .006) and iNOS expression (P = .003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor NG-methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = .04 and P = .02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1. Conclusion: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer

The effects on public health of climate change adaptation responses: a systematic review of evidence from low- and middle-income countries.

Climate change adaptation responses are being developed and delivered in many parts of the world in the absence of detailed knowledge of their effects on public health. Here we present the results of a systematic review of peer-reviewed literature reporting the effects on health of climate change adaptation responses in low- and middle-income countries (LMICs). The review used the 'Global Adaptation Mapping Initiative' database (comprising 1682 publications related to climate change adaptation responses) that was constructed through systematic literature searches in Scopus, Web of Science and Google Scholar (2013-2020). For this study, further screening was performed to identify studies from LMICs reporting the effects on human health of climate change adaptation responses. Studies were categorised by study design and data were extracted on geographic region, population under investigation, type of adaptation response and reported health effects. The review identified 99 studies (1117 reported outcomes), reporting evidence from 66 LMICs. Only two studies were ex ante formal evaluations of climate change adaptation responses. Papers reported adaptation responses related to flooding, rainfall, drought and extreme heat, predominantly through behaviour change, and infrastructural and technological improvements. Reported (direct and intermediate) health outcomes included reduction in infectious disease incidence, improved access to water/sanitation and improved food security. All-cause mortality was rarely reported, and no papers were identified reporting on maternal and child health. Reported maladaptations were predominantly related to widening of inequalities and unforeseen co-harms. Reporting and publication-bias seems likely with only 3.5% of all 1117 health outcomes reported to be negative. Our review identified some evidence that climate change adaptation responses may have benefits for human health but the overall paucity of evidence is concerning and represents a major missed opportunity for learning. There is an urgent need for greater focus on the funding, design, evaluation and standardised reporting of the effects on health of climate change adaptation responses to enable evidence-based policy action

The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair

© 2016 Elsevier Ireland Ltd. Triple negative breast cancer (TNBC), characterized by an abundance of treatment-resistant breast cancer stem cells (CSCs), has a poorer prognosis than other types of breast cancers. Despite its aggressiveness, no effective targeted therapy exists for TNBC. Here, we demonstrate that CQ effectively targets CSCs via autophagy inhibition, mitochondrial structural damage, and impairment of double-stranded DNA break repair. Electron microscopy demonstrates CQ-induced mitochondrial cristae damage, which leads to mitochondrial membrane depolarization with a significant reduction in the activity of cytochrome c oxidase and accumulation of superoxide and double-stranded DNA breaks. CQ effectively diminishes the TNBC cells\u27 ability to metastasize in vitro and in a TNBC xenograft model. When administered in combination with carboplatin, CQ effectively inhibits carboplatin-induced autophagy. This combination treatment significantly diminishes the expression of DNA repair proteins in CSC subpopulations, resulting in tumor growth reduction in carboplatin-resistant BRCA1 wild-type TNBC orthotopic xenografts. As TNBC\u27s high treatment failure rate has been attributed to enrichment of CSCs, CQ, an autophagy inhibitor with anti-CSC effects, may be an effective adjunct to current TNBC chemotherapy regimens with carboplatin

Hepatic arterial embolization and chemoembolization for imatinib-resistant gastrointestinal stromal tumors

We evaluated the efficacy of embolotherapy including hepatic arterial embolization and chemoembolization in patients with imatinib-resistant gastrointestinal stromal tumors with progressive liver metastases. Medical records and computed tomography images of patients with imatinib-resistant gastrointestinal stromal tumor with progressive liver metastases who underwent embolotherapy from January 2002 through January 2007 were retrospectively reviewed. Response was assessed by Response Evaluation Criteria in Solid Tumors and modified CT response criteria that assessed tumor density changes. Progression-free survival in the liver and overall survival rates were calculated from the date of the initial embolotherapy session using the Kaplan-Meier method. Correlations between disease status or treatment variables and survival were tested in univariate and multivariate analyses using the log-rank test, and the Cox proportional hazards model, respectively. Fourteen patients with gastrointestinal stromal tumor who had been treated with imatinib for 7 to 61 months underwent 26 sessions of embolotherapy. Radiologic response could be evaluated in 13 patients. On the basis of response evaluation criteria in solid tumors, 1 patient demonstrated a partial response and the remaining 12 patients demonstrated stable disease. On the basis of the modified CT response criteria, 7 patients demonstrated a partial response and 6 patients demonstrated stable disease. Progression-free survival rates in the liver were 78.7%, 31.4%, and 31.4% at 6 months, 1, and 3 years, respectively; the median progression-free survival time was 7.0 months. Overall survival rates were 78.6%, 45.8%, and 45.8% at 6 month, 1 year, and 3 year, respectively; the median overall survival time was 9.7 months. Patients who had progressive extrahepatic metastases at the time of treatment and those who received only 1 embolotherapy treatment had shorter OS than did patients with liver-only progression and those who received 2 or more treatment sessions, respectively. Hepatic arterial embolization and chemoembolization induced radiologic response or disease stabilization in most patients with imatinib-resistant gastrointestinal stromal tumor with progressive liver metastases. Patients with progressive extrahepatic metastases or those who are not amenable to more than 1 embolotherapy sessions, however, did not demonstrate an appreciable survival benefit following embolotherapy