HDL-inflammatory index correlates with poor outcome in hemodialysis patients.

Oxidative stress and cardiovascular disease are risk factor of patients with chronic kidney disease (CKD) on maintenance hemodialysis. We used the fluorescence of low-density lipoprotein as an index of its proinflammatory potential to examine any role that high-density lipoprotein (HDL) might have in promoting this effect. The total body fat of the patients was measured by means of near-infrared interactance and their quality of life by means of SF36 questionnaires. In 189 randomly selected patients, followed for 30 months, HDL was found to be significantly anti-inflammatory but with a large standard deviation. Fully 17% of the patients had a decidedly proinflammatory index along with inferior SF36 scores. The patients were divided into 10% increments of total body fat percentages up to 40%. HDL was found to be progressively proinflammatory the higher the body fat content. Patients with a higher HDL proinflammatory index had a higher 30-month adjusted hazard ratio for death than those whose HDL were seen to be anti-inflammatory. Our findings suggest an important role of inflammatory HDL in patients with CKD leading to poor outcome

HDL-inflammatory index correlates with poor outcome in hemodialysis patients

Oxidative stress and cardiovascular disease are risk factor of patients with chronic kidney disease (CKD) on maintenance hemodialysis. We used the fluorescence of low-density lipoprotein as an index of its proinflammatory potential to examine any role that high-density lipoprotein (HDL) might have in promoting this effect. The total body fat of the patients was measured by means of near-infrared interactance and their quality of life by means of SF36 questionnaires. In 189 randomly selected patients, followed for 30 months, HDL was found to be significantly anti-inflammatory but with a large standard deviation. Fully 17% of the patients had a decidedly proinflammatory index along with inferior SF36 scores. The patients were divided into 10% increments of total body fat percentages up to 40%. HDL was found to be progressively proinflammatory the higher the body fat content. Patients with a higher HDL proinflammatory index had a higher 30-month adjusted hazard ratio for death than those whose HDL were seen to be anti-inflammatory. Our findings suggest an important role of inflammatory HDL in patients with CKD leading to poor outcome

The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth

Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. We sought to define effects of the HSP90 inhibitor NVP-AUY922 in NSCLC cell lines, and identify predictors of response by in vitro and in vivo evaluation. NVP-AUY922 potently inhibited growth in all 41 NSCLC cell lines evaluated in vitro with IC50 < 100 nM. In 36 lines, IC100 (complete inhibition of proliferation) was below 40 nM. Greatest sensitivity was in lines with low baseline HSP70 protein levels. In vitro comparison of gene expression before and after NVP-AUY922 exposure demonstrated consistent changes in expression of genes involved in a wide range of cellular functions, including consistently decreased expression of dihydrofolate reductase after exposure. Expression of the co-chaperone AHA1 increased in response to exposure, and this effect was disproportionately seen in less sensitive lines. NVP-AUY922 slowed growth of A549 (KRAS mutant) xenografts, and achieved tumor stability and decreased epidermal growth factor receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR tyrosine kinase inhibitors in the EGFR gene. This impressive preclinical efficacy in a broad range of NSCLC cell lines led to clinical evaluation of NVP-AUY922 in NSCLC patients with tumors bearing known driver mutations as well as tumors without such abnormalities. An ongoing phase II NSCLC trial will incorporate correlative data to confirm our observations and guide further development of NVP-AUY922 in NSCLC. Word Count: 249 of (max 250

Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer.

ObjectivesDichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical cancer studies. We designed this open-label phase II trial to determine the response rate, safety, and tolerability of oral DCA in patients with metastatic breast cancer and advanced stage non-small cell lung cancer (NSCLC).Materials and methodsThis trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV NSCLC or stage IV breast cancer. Growth inhibition by DCA was also evaluated in a panel of 54 NSCLC cell lines with and without cytotoxic chemotherapeutics (cisplatin and docetaxel) in normoxic and hypoxic conditions.Results and conclusionsUnder normoxic conditions in vitro, single-agent IC50 was &gt;2 mM for all evaluated cell lines. Synergy with cisplatin was seen in some cell lines under hypoxic conditions. In the clinical trial, after seven patients were enrolled, the study was closed based on safety concerns. The only breast cancer patient had stable disease after 8 weeks, quickly followed by progression in the brain. Two patients withdrew consent within a week of enrollment. Two patients had disease progression prior to the first scheduled scans. Within 1 week of initiating DCA, one patient died suddenly of unknown cause and one experienced a fatal pulmonary embolism. We conclude that patients with previously treated advanced NSCLC did not benefit from oral DCA. In the absence of a larger controlled trial, firm conclusions regarding the association between these adverse events and DCA are unclear. Further development of DCA should be in patients with longer life expectancy, in whom sustained therapeutic levels can be achieved, and potentially in combination with cisplatin

The HSP90 Inhibitor NVP-AUY922 Potently Inhibits Non–Small Cell Lung Cancer Growth

Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC(50) < 100 nM. IC(100) (complete inhibition of proliferation) < 40 nM was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase (DHFR) after exposure. NVP-AUY922 slowed growth of A549 (KRAS mutant) xenografts, and achieved tumor stability and decreased epidermal growth factor receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR tyrosine kinase inhibitors in the EGFR gene. This data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLC