Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

Probing tumor phenotypes using stable and regulated synthetic microRNA precursors.

RNA interference is a powerful method for suppressing gene expression in mammalian cells. Stable knock-down can be achieved by continuous expression of synthetic short hairpin RNAs, typically from RNA polymerase III promoters. But primary microRNA transcripts, which are endogenous triggers of RNA interference, are normally synthesized by RNA polymerase II. Here we show that RNA polymerase II promoters expressing rationally designed primary microRNA-based short hairpin RNAs produce potent, stable and regulatable gene knock-down in cultured cells and in animals, even when present at a single copy in the genome. Most notably, by tightly regulating Trp53 knock-down using tetracycline-based systems, we show that cultured mouse fibroblasts can be switched between proliferative and senescent states and that tumors induced by Trp53 suppression and cooperating oncogenes regress upon re-expression of Trp53. In practice, this primary microRNA-based short hairpin RNA vector system is markedly similar to cDNA overexpression systems and is a powerful tool for studying gene function in cells and animals.

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma.

KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses.

Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources-including protein structure, gene expression and mutational profiles-via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that OncoSig is generalizable, we first inferred SigMaps for the ten most mutated human oncoproteins and then for the full repertoire of 715 proteins in the COSMIC Cancer Gene Census. Taken together, these SigMaps show that the cell's regulatory and signaling architecture is highly tissue specific.

Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.

Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.

Biofilm processes in biologically active carbon water purification.

This review paper serves to describe the composition and activity of a biologically active carbon (BAC) biofilm used in water purification. An analysis of several physical-chemical, biochemical and microbiological methods (indicators) used to characterize the BAC biofilm's composition and activity is provided. As well, the ability of the biofilm to remove and biodegrade waterborne organic substances and pollutants will be reviewed, with context to other industrial processes such as pre-ozonation and post-membrane filtration. Strategies to control the growth of the BAC biofilm, such as varying the nutrient loading rate, manipulating influent DO and pH levels, altering the frequency of BAC filter backwashing and applying oxidative disinfection, will be described in detail along with their respective process control challenges.

Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase.

KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.

Effectiveness of multidisciplinary patient counselling in reducing cardiovascular disease risk factors through nonpharmacological intervention: results from the Healthy Heart Program.

BACKGROUND: The value of lifestyle modification in reducing physiological cardiovascular disease (CVD) risk factors remains controversial because changes in patient behaviour following CVD prevention counseling have failed to correlate with or impact reductions in physiological variables. OBJECTIVES: To determine whether nonpharmacological CVD prevention counselling significantly reduces behavioural and physiological risk factors, and to examine correlations between changes in these variables. METHODS: At baseline, dyslipidemic individuals with or at risk of developing CVD completed CVD risk factor questionnaires. At baseline and three months, participants submitted dietary logs, self-classified their readiness for behaviour change for eight lifestyles, and had their blood lipid profiles, weight and height assessed. Following CVD risk factor screening, lower and higher risk participants were recommended for multidisciplinary group counselling (GC) or group plus individual counselling (GIC), respectively. A prospective time series design assessed behavioural and physiological risk factor changes. RESULTS: Participants progressed forward (P<0.01) through the stage of change continuum for all behaviours. GIC participants progressed to a higher average stage of behaviour change for achieving optimal body weight (P<0.01), drinking less alcohol (P<0.05) and controlling blood pressure (P<0.05). Significant reductions in body mass index (2.1% and 1.9%), total cholesterol (7.0% and 5.5%), low density lipoprotein cholesterol (6.2% and 5.4%), total cholesterol to high density lipoprotein cholesterol ratio (5.1% and 3.8%) and triglyceride levels (10.8% and 8.5%) were observed in GC and GIC participants, respectively. Furthermore, significant correlations were observed between concurrent changes in lifestyle behaviour and physiological risk factors. CONCLUSIONS: Multidisciplinary CVD prevention counseling positively influenced participant readiness for lifestyle behaviour change which translated into significant reductions in several physiological risk factors.

Cancer deaths and occupational exposure in a group of plutonium workers.

An exploratory epidemiological study was conducted for 319 deceased nuclear workers who had intakes of transuranic radionuclides and histories of employment during the time period from 1943 to 1995. The workers were employed at various facilities throughout the United States, including the Department of Energy defense facilities and uranium mining and milling sites. The majority of individuals were involved in documented radiological incidents during their careers. All had voluntarily agreed to donate their organs or whole body to the United States Transuranium and Uranium Registries. External and internal dose assessments were performed using occupational exposure histories and postmortem concentrations of transuranic radionuclides in critical organs. Statistical data analyses were performed to investigate the potential relationship between radiation exposure and causes of death within this population due to cancers of the lungs, liver, and all sites combined while controlling for the effects of other confounders. No association was found between radiation exposure and death due to cancer (α = 0.05). However, statistically significant associations were found between death due to any type of cancer and smoking (yes or no) (odds ratio = 5.41; 95% CI: 1.42 to 20.67) and rate of cigarette smoking (packs per day) (odds ratio = 2.70; 95% CI: 1.37 to 5.30).

Epithelial cell organization suppresses Myc function by attenuating Myc expression.

c-Myc is an oncogene transcription factor that causes cancer in many settings, including solid tumors that arise in the context of organized tissue structures. Given that disruption of tissue architecture frequently occurs in cancer, there is considerable interest in how cell organization impacts oncogene function. A previous report found that organization of mammary epithelial cells into defined 3-dimensional structures renders them insensitive to the effects of retrovirus-mediated overexpression of Myc, leading to the notion that organization tempers the sensitivity of individual cells to Myc activity. In this article, we report that epithelial cell organization does not profoundly alter Myc activity but, instead, suppresses Myc by modulating its expression. We show that the morphogenesis of mammary epithelial cells into organized acinar structures in vitro is accompanied by widespread changes in gene expression patterns, including a substantial decrease in the expression of Myc. Concomitant with the decrease in endogenous Myc expression, we observe a decrease in transcription from retroviral vectors during morphogenesis and find that Myc transgene expression in acini is much lower than in unorganized cells. This decrease in Myc transgene activity is responsible for the apparent recalcitrance of organized cells to ectopic Myc, as adenovirus-mediated expression of Myc in organized structures potently induces apoptosis. These observations reveal that organization does not alter the inherent response of epithelial cells to Myc and suggest that other tumor suppression mechanisms, apart from structure, antagonize Myc in the development of solid tumors.

A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies.

Cytokine-mobilized peripheral blood is increasingly used instead of bone marrow as the source of cells for allogeneic transplantation. Although cells lead to faster hematologic recovery, their effects on graft-versus-host disease, relapse, and survival are less certain. Between January 1996 and February 2000, 228 patients with chronic myeloid leukemia, acute myeloid leukemia, or myelodysplasia were randomized to receive either bone marrow or peripheral blood allografts from HLA-matched siblings. All patients received busulfan and cyclophosphamide as conditioning chemotherapy and cyclosporine and methotrexate as graft-versus-host disease prophylaxis. We compared the times to neutrophil and platelet recovery, acute and chronic graft-versus-host disease, relapse, and overall survival between the groups. The median times to neutrophil recovery were 19 days and 23 days and the times to platelet recovery were 16 days and 22 days in the peripheral blood and bone marrow groups, respectively (P <.0001 for both comparisons). The cumulative incidence of grades II to IV acute graft-versus-host disease 100 days after transplantation was 44% in both groups (hazard ratio, 0.99; 95% confidence interval, 0.66-1.49; P >.9), and the incidence of extensive chronic graft-versus-host disease at 30 months after transplantation was 40% with peripheral blood and 30% with bone marrow (hazard ratio, 1.23; 95% confidence interval, 0.78-1.96; P =.37). There was no statistically significant difference in the probability of relapse of the underlying disease between the groups. The probabilities of survival at 30 months after transplantation were 68% and 60% in the peripheral blood and bone marrow groups, respectively (hazard ratio, 0.62; 95% confidence interval, 0.39-0.97; P =.04). In patients with chronic myeloid leukemia, acute myeloid leukemia, and myelodysplasia undergoing allogeneic transplantation from matched siblings, the use of peripheral blood instead of bone marrow leads to faster hematologic recovery, similar risk of graft-versus-host disease, and improved survival.