RACK1 Silencing Induces Cell Apoptosis and Inhibits Cell Proliferation in Hepatocellular Carcinoma MHCC97-H Cells

Abstract

This study aimed to explore the effects of RACK1 gene silencing on the apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H cells. After transfecting MHCC97-H cells with siRNA, RACK1 gene silencing model was established. The cells were divided into blank group, siRNA group and empty plasmid group, respectively. The mRNA and protein expressions of RACK1, cyclin D1 and BAX were determined by qRT-PCR and Western blotting. CCK-8 assay, flow cytometry and FITC-Annexin V/PI staining were used to determine cell viability, cell cycle and cell apoptosis, respectively. The results of qRT-PCR and Western blotting suggested that when compared with the blank group and the empty plasmid group, the mRNA and protein expressions of RACK1 and Cyclin D1 decreased significantly while the mRNA and protein BAX expressions increased substantially in the siRNA group (all P < 0.05). The results of CCK-8 assay revealed that the siRNA group exhibited significantly lower cell viability when compared with the blank group and the empty plasmid group (both P < 0.05); and the cell viability in the siRNA group decreased gradually with the increase of time. The results of flow cytometry and FITC-Annexin V/PI staining indicated that when compared with the blank group and the empty plasmid group, the proportion of cells in S phase was markedly lower and the apoptosis rate was significantly higher in the siRNA group (both P < 0.05). Our study suggests that inhibition of RACK1 could suppress cell proliferation and induce apoptosis in HCC MHCC97-H cells.

http://ift.tt/2oYrw5n

RACK1 Silencing Induces Cell Apoptosis and Inhibits Cell Proliferation in Hepatocellular Carcinoma MHCC97-H Cells

Abstract

This study aimed to explore the effects of RACK1 gene silencing on the apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H cells. After transfecting MHCC97-H cells with siRNA, RACK1 gene silencing model was established. The cells were divided into blank group, siRNA group and empty plasmid group, respectively. The mRNA and protein expressions of RACK1, cyclin D1 and BAX were determined by qRT-PCR and Western blotting. CCK-8 assay, flow cytometry and FITC-Annexin V/PI staining were used to determine cell viability, cell cycle and cell apoptosis, respectively. The results of qRT-PCR and Western blotting suggested that when compared with the blank group and the empty plasmid group, the mRNA and protein expressions of RACK1 and Cyclin D1 decreased significantly while the mRNA and protein BAX expressions increased substantially in the siRNA group (all P < 0.05). The results of CCK-8 assay revealed that the siRNA group exhibited significantly lower cell viability when compared with the blank group and the empty plasmid group (both P < 0.05); and the cell viability in the siRNA group decreased gradually with the increase of time. The results of flow cytometry and FITC-Annexin V/PI staining indicated that when compared with the blank group and the empty plasmid group, the proportion of cells in S phase was markedly lower and the apoptosis rate was significantly higher in the siRNA group (both P < 0.05). Our study suggests that inhibition of RACK1 could suppress cell proliferation and induce apoptosis in HCC MHCC97-H cells.

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Cardiotoxicity with Itraconazole

Itraconazole is a commonly used antifungal drug. In addition to commonly described adverse effects, there have been few reports of heart failure with its use. We present two cases that developed acute systolic heart failure with Itraconazole use. A man in his early 30s was admitted with worsening leg swelling and dyspnoea on exertion. He had been on Itraconazole for blastomyces skin ulcer. His ejection fraction (EF) was found to be 10%–15%. Another man in his 50s was admitted with similar symptoms; his EF was 40%–45%. He had been on Itraconazole for forearm cellulitis. No other aetiology was identified in both patients despite extensive work-up including cardiac catheterisation. Itraconazole was stopped in both the cases. Our first patient did not improve even months after cessation of therapy and was referred for heart transplant. Our second patient improved after a few weeks, and his ejection fraction had improved on repeat testing.

http://ift.tt/2nzlc4K

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

We have developed multifunctional nanoparticles (NP) for co-delivery of bortezomib (BTZ) and doxorubicin (DOX) to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar NP was formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a BTZ-conjugating intermediate, and a dendritic DOX-affinitive interior. BTZ-conjugated telodendrimers, together with DOX, self-assembled into monodispersed micelles (NP(BTZ-DOX)) with small particle sizes (20~30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. BTZ release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined BTZ and DOX were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral BTZ and DOX delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including BTZ and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.

http://ift.tt/2oltVWO

Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2+ breast cancer

PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R mice long-term with the drug combination. RNA-sequencing of TPB-resistant tumors revealed that extracellular matrix (ECM) and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when re-introduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate (DHB). Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition.

http://ift.tt/2p17CDZ

Genomic and molecular screenings identify different mechanisms for acquired resistance to MET inhibitors in lung cancer cells

The development of resistance to tyrosine kinase inhibitors (TKIs) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, i.e., phenotypic modifications, specific changes in gene expression and reactivation of AKT, ERK and mTOR. The gene expression, global DNA methylation and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1 and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of NF2 concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER-family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells.

http://ift.tt/2oZwnn0

Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several pro-apoptotic markers (caspase 9, caspase 3 and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the pro-survival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer.

http://ift.tt/2pnt9pU

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

We have developed multifunctional nanoparticles (NP) for co-delivery of bortezomib (BTZ) and doxorubicin (DOX) to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar NP was formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a BTZ-conjugating intermediate, and a dendritic DOX-affinitive interior. BTZ-conjugated telodendrimers, together with DOX, self-assembled into monodispersed micelles (NP(BTZ-DOX)) with small particle sizes (20~30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. BTZ release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined BTZ and DOX were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral BTZ and DOX delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including BTZ and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.

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via IFTTT

Extracellular matrix/integrin signaling promotes resistance to combined inhibition of HER2 and PI3K in HER2+ breast cancer

PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R mice long-term with the drug combination. RNA-sequencing of TPB-resistant tumors revealed that extracellular matrix (ECM) and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when re-introduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate (DHB). Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition.

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A Novel Galectin-1 Inhibitor Discovered through One-Bead-Two-Compounds Library Potentiates the Anti-tumor Effects of Paclitaxel in vivo

Through the one-bead two-compound (OB2C) ultra-high throughput screening method, we discovered a new small molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC MS/MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras, and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro. Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug-screening platform and LLS2 discovered through this method can be further optimized for anti-cancer drug development.

http://ift.tt/2oZoXA9

Acquired MET Y1248H and D1246N mutations mediate resistance to MET inhibitors in non-small cell lung cancer

Purpose: MET amplification, responsible for 20% of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive. <p>Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a Type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasms ctDNA samples to detect and quantify genetic alterations.</p> <p>Results: We identified 2 newly acquired MET mutations Y1248H and D1246N in 2 patients and further confirmed their resistance against Type I MET-TKIs in silco, in vitro and in vivo. Interestingly, NIH3T3 cells harboring either mutation exhibited responses to Type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKIs resistance mechanism.</p> <p>Conclusion Our study provides insight into the diversity of mechanisms underlying MET-TKI induced resistance and highlights the potential of sequential use of MET-TKIs.

http://ift.tt/2ot6go0

Genomic and molecular screenings identify different mechanisms for acquired resistance to MET inhibitors in lung cancer cells

The development of resistance to tyrosine kinase inhibitors (TKIs) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, i.e., phenotypic modifications, specific changes in gene expression and reactivation of AKT, ERK and mTOR. The gene expression, global DNA methylation and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1 and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of NF2 concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER-family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells.

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via IFTTT

Novel indole-based tambjamine-analogues induce apoptotic lung cancer cell death through p38 mitogen-activated protein kinase activation

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5/survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several pro-apoptotic markers (caspase 9, caspase 3 and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the pro-survival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2pnt9pU
via IFTTT

A Novel Galectin-1 Inhibitor Discovered through One-Bead-Two-Compounds Library Potentiates the Anti-tumor Effects of Paclitaxel in vivo

Through the one-bead two-compound (OB2C) ultra-high throughput screening method, we discovered a new small molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC MS/MS indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras, and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells) in vitro. Furthermore, in vivo therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug-screening platform and LLS2 discovered through this method can be further optimized for anti-cancer drug development.

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via IFTTT

Acquired MET Y1248H and D1246N mutations mediate resistance to MET inhibitors in non-small cell lung cancer

Purpose: MET amplification, responsible for 20% of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive. <p>Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a Type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasms ctDNA samples to detect and quantify genetic alterations.</p> <p>Results: We identified 2 newly acquired MET mutations Y1248H and D1246N in 2 patients and further confirmed their resistance against Type I MET-TKIs in silco, in vitro and in vivo. Interestingly, NIH3T3 cells harboring either mutation exhibited responses to Type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKIs resistance mechanism.</p> <p>Conclusion Our study provides insight into the diversity of mechanisms underlying MET-TKI induced resistance and highlights the potential of sequential use of MET-TKIs.

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Radiation therapy quality indicators for invasive breast cancer

Radiation therapy (RT) for breast cancer has evolved considerably over the past two decades. A concise list of optimal care indexes is lacking. The purpose of this project was to generate a suite of quality of care indicators for breast cancer RT.

http://ift.tt/2oZlwcQ

Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies

Abstract

The aim of this systematic review and meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups and risk of type 2 diabetes (T2D). We conducted a systematic search in PubMed, Embase, Medline (Ovid), Cochrane Central, and Google Scholar for prospective studies investigating the association between whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSB) on risk of T2D. Summary relative risks were estimated using a random effects model by contrasting categories, and for linear and non-linear dose–response relationships. Six out of the 12 food-groups showed a significant relation with risk of T2D, three of them a decrease of risk with increasing consumption (whole grains, fruits, and dairy), and three an increase of risk with increasing consumption (red meat, processed meat, and SSB) in the linear dose–response meta-analysis. There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk. Optimal consumption of risk-decreasing foods resulted in a 42% reduction, and consumption of risk-increasing foods was associated with a threefold T2D risk, compared to non-consumption. The meta-evidence was graded "low" for legumes and nuts; "moderate" for refined grains, vegetables, fruit, eggs, dairy, and fish; and "high" for processed meat, red meat, whole grains, and SSB. Among the investigated food groups, selecting specific optimal intakes can lead to a considerable change in risk of T2D.

http://ift.tt/2okWsff

Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies

Abstract

The aim of this systematic review and meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups and risk of type 2 diabetes (T2D). We conducted a systematic search in PubMed, Embase, Medline (Ovid), Cochrane Central, and Google Scholar for prospective studies investigating the association between whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSB) on risk of T2D. Summary relative risks were estimated using a random effects model by contrasting categories, and for linear and non-linear dose–response relationships. Six out of the 12 food-groups showed a significant relation with risk of T2D, three of them a decrease of risk with increasing consumption (whole grains, fruits, and dairy), and three an increase of risk with increasing consumption (red meat, processed meat, and SSB) in the linear dose–response meta-analysis. There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk. Optimal consumption of risk-decreasing foods resulted in a 42% reduction, and consumption of risk-increasing foods was associated with a threefold T2D risk, compared to non-consumption. The meta-evidence was graded "low" for legumes and nuts; "moderate" for refined grains, vegetables, fruit, eggs, dairy, and fish; and "high" for processed meat, red meat, whole grains, and SSB. Among the investigated food groups, selecting specific optimal intakes can lead to a considerable change in risk of T2D.

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FDA Approves Ribociclib, Expands Palbociclib Approval for Metastatic Breast Cancer

The FDA has approved a new targeted therapy, ribociclib, and expanded its earlier approval of another targeted therapy, palbociclib, for some women with metastatic breast cancer.

http://ift.tt/2osuYoz

A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P

Abstract

Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.

http://ift.tt/2nUGoNQ

Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner

Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner

Oncogenesis 6, e314 (April 2017). doi:10.1038/oncsis.2017.12

Authors: J J Wamsley, C Gary, A Biktasova, M Hajek, G Bellinger, R Virk, N Issaeva & W G Yarbrough

http://ift.tt/2osaSKO

A natural food sweetener with anti-pancreatic cancer properties

A natural food sweetener with anti-pancreatic cancer properties

Oncogenesis 6, e316 (April 2017). doi:10.1038/oncsis.2017.19

Authors: C Liu, L-H Dai, D-Q Dou, L-Q Ma & Y-X Sun

http://ift.tt/2osfIIb

Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression

Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression

Oncogenesis 6, e315 (April 2017). doi:10.1038/oncsis.2017.16

Authors: X Zhao, R Deng, Y Wang, H Zhang, J Dou, L Li, Y Du, R Chen, J Cheng & J Yu

http://ift.tt/2okDl4L

FDA Approves Ribociclib, Expands Palbociclib Approval for Metastatic Breast Cancer

The FDA has approved a new targeted therapy, ribociclib, and expanded its earlier approval of another targeted therapy, palbociclib, for some women with metastatic breast cancer.

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Dexamethasone for nerve blocks: Design matters!

With a few notable exceptions, efforts to prolong peripheral nerve blocks with adjuvant drugs have been generally disappointing. One prime exception is dexamethasone: it has been demonstrated to prolong analgesia as well as sensory and motor block in multiple contexts, although numbers are too low to make definitive statements about safety [1]. All the early studies, however, assumed the action of dexamethasone was on the peripheral nerve and therefore did not include systemic controls. Desmet and colleagues upset the apple cart in 2013 with their report that 10mg of systemic dexamethasone appears to prolong the time to first analgesic request as much as perineural administration [2].

http://ift.tt/2p0kfiX

Occupational stress of anesthesia: Effects on aging

Anesthesiology has been identified as a stressful specialty. Chronic psychological stress may lead to biological aging and skin aging.

http://ift.tt/2nyNFHM

Labetalol, nitroglycerin, controlled hypotension, sinus endoscopic surgery

To assess the efficacy of labetalol versus nitroglycerin for induction of controlled hypotension during sinus endoscopic surgery.

http://ift.tt/2p0khaz

A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P

Abstract

Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.

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Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner

Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner

Oncogenesis 6, e314 (April 2017). doi:10.1038/oncsis.2017.12

Authors: J J Wamsley, C Gary, A Biktasova, M Hajek, G Bellinger, R Virk, N Issaeva & W G Yarbrough

from Cancer via ola Kala on Inoreader http://ift.tt/2osaSKO
via IFTTT

A natural food sweetener with anti-pancreatic cancer properties

A natural food sweetener with anti-pancreatic cancer properties

Oncogenesis 6, e316 (April 2017). doi:10.1038/oncsis.2017.19

Authors: C Liu, L-H Dai, D-Q Dou, L-Q Ma & Y-X Sun

from Cancer via ola Kala on Inoreader http://ift.tt/2osfIIb
via IFTTT

Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression

Twist1/Dnmt3a and miR186 establish a regulatory circuit that controls inflammation-associated prostate cancer progression

Oncogenesis 6, e315 (April 2017). doi:10.1038/oncsis.2017.16

Authors: X Zhao, R Deng, Y Wang, H Zhang, J Dou, L Li, Y Du, R Chen, J Cheng & J Yu

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Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oncogenesis 6, e313 (April 2017). doi:10.1038/oncsis.2017.13

Authors: H-Y Tseng, Y-A Chen, J Jen, P-C Shen, L-M Chen, T-D Lin, Y-C Wang & H-L Hsu

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MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation

MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation

Oncogenesis 6, e312 (April 2017). doi:10.1038/oncsis.2017.21

Authors: X Jin, Y Pan, L Wang, L Zhang, R Ravichandran, P R Potts, J Jiang, H Wu & H Huang

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Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Oncogenesis 6, e313 (April 2017). doi:10.1038/oncsis.2017.13

Authors: H-Y Tseng, Y-A Chen, J Jen, P-C Shen, L-M Chen, T-D Lin, Y-C Wang & H-L Hsu

http://ift.tt/2okDhSz

MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation

MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation

Oncogenesis 6, e312 (April 2017). doi:10.1038/oncsis.2017.21

Authors: X Jin, Y Pan, L Wang, L Zhang, R Ravichandran, P R Potts, J Jiang, H Wu & H Huang

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MicroRNA-9 promotes the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1

Abstract

Purpose

The objective of the study was to investigate the role of microRNA-9 (miR-9) targeting forkhead box O1 (FOXO1) in the proliferation, migration, and invasion of breast cancer cells.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expressions of miR-9 and FOXO1 mRNA in breast cancer tissues, normal breast tissues, breast cancer cell lines, and normal breast epithelial cells. After the up-regulation of miR-9 expression, qRT-PCR and Western blotting were used to determine the expression of FOXO1. The luciferase reporter gene assay was used to validate the target gene. The CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay were used to investigate the changes in the proliferation, migration, and invasion of breast cancer cells, respectively.

Results

MicroRNA-9 expression was significantly up-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). FOXO1 mRNA and protein expressions were substantially down-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). There can be a negative correlation between miR-9 and FOXO1 mRNA in breast cancer. Luciferase reporter gene assay indicated that miR-9 can down-regulate FOXO1 expression at a post-transcriptional level through binding specifically to FOXO1 3′UTR. The results of CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay revealed that the inhibition of miR-9 can suppress MCF7 cell proliferation, migration, and invasion. Additionally, the expression of miR-9 increased significantly whilst that of FOXO1 decreased substantially as the disease progressed (P < 0.05).

Conclusions

Our study provides evidence that miR-9 can promote the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1.

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MicroRNA-9 promotes the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1

Abstract

Purpose

The objective of the study was to investigate the role of microRNA-9 (miR-9) targeting forkhead box O1 (FOXO1) in the proliferation, migration, and invasion of breast cancer cells.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expressions of miR-9 and FOXO1 mRNA in breast cancer tissues, normal breast tissues, breast cancer cell lines, and normal breast epithelial cells. After the up-regulation of miR-9 expression, qRT-PCR and Western blotting were used to determine the expression of FOXO1. The luciferase reporter gene assay was used to validate the target gene. The CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay were used to investigate the changes in the proliferation, migration, and invasion of breast cancer cells, respectively.

Results

MicroRNA-9 expression was significantly up-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). FOXO1 mRNA and protein expressions were substantially down-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). There can be a negative correlation between miR-9 and FOXO1 mRNA in breast cancer. Luciferase reporter gene assay indicated that miR-9 can down-regulate FOXO1 expression at a post-transcriptional level through binding specifically to FOXO1 3′UTR. The results of CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay revealed that the inhibition of miR-9 can suppress MCF7 cell proliferation, migration, and invasion. Additionally, the expression of miR-9 increased significantly whilst that of FOXO1 decreased substantially as the disease progressed (P < 0.05).

Conclusions

Our study provides evidence that miR-9 can promote the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1.

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Extrahepatic metastasectomy for hepatocellular carcinoma: Predictors of long-term survival

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Extrahepatic metastasectomy for hepatocellular carcinoma: Predictors of long-term survival

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Resection of colorectal liver metastases after second-line chemotherapy: is it worthwhile? A LiverMetSurvey analysis of 6415 patients

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): René Adam, Bin Yi, Pasquale F. Innominato, Eduardo Barroso, Christophe Laurent, Felice Giuliante, Lorenzo Capussotti, Réal Lapointe, Jean-Marc Regimbeau, Santiago Lopez-Ben, Helena Isoniemi, Catherine Hubert, Jen-Kou Lin, Thomas Gruenberger, Dominique Elias, Oleg G. Skipenko, Alfredo Guglielmi
PurposePatient outcome after resection of colorectal liver metastases (CLM) following second-line preoperative chemotherapy (PCT) performed for insufficient response or toxicity of the first-line, is little known and has here been compared to the outcome following first-line.Patients and methodsFrom January 2005 to June 2013, 5624 and 791 consecutive patients of a prospective international cohort received 1 and 2 PCT lines before CLM resection (group 1 and 2, respectively). Survival and prognostic factors were analysed.ResultsAfter a mean follow-up of 30.1 months, there was no difference in survival from CLM diagnosis (median, 3-, and 5-year overall survival [OS]: 58.6 months, 76% and 49% in group 2 versus 58.9 months, 71% and 49% in group 1, respectively, P = 0.32). After hepatectomy, disease-free survival (DFS) was however shorter in group 2: 17.2 months, 27% and 15% versus 19.4 months, 32% and 23%, respectively (P = 0.001). Among the initially unresectable patients of group 1 and 2, no statistical difference in OS or DFS was observed. Independent predictors of worse OS in group 2 were positive primary lymph nodes, extrahepatic disease, tumour progression on second line, R2 resection and number of hepatectomies/year <50. Positive primary nodes, synchronous and bilateral metastases were predictors of shorter DFS. Initial unresectability did not impact OS or DFS in group 2.ConclusionCLM resection following second-line PCT, after oncosurgically favourable selection, could bring similar OS compared to what observed after first-line. For initially unresectable patients, OS or DFS is comparable between first- and second-line PCT. Surgery should not be denied after the failure of first-line chemotherapy.



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Extrahepatic metastasectomy for hepatocellular carcinoma: Predictors of long-term survival

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Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury

Abstract

Introduction

A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF.

Patients and methods

To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI−), and further subdivided into three groups according to AKI severity (stage 1–5).

Results

Of 38 patients, 29 (76%) were AKI−, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI−, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF–CB vs. VMF monotherapy was reduced by 60%.

Conclusion

We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.

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ETV6/RUNX1-like acute lymphoblastic leukemia: A novel B-cell precursor leukemia subtype associated with the CD27/CD44 immunophenotype

Abstract

We have shown previously that ETV6/RUNX1-positive acute lymphoblastic leukemia (ALL) is distinguishable from other ALL subtypes by CD27^p°^s/CD44^l°^w-neg immunophenotype. During diagnostic immunophenotyping of 573 childhood B-cell precursor ALL (BCP-ALL), we identified eight cases with this immunophenotype among "B-other ALL" (BCP-ALL cases negative for routinely tested chromosomal/genetic aberrations). We aimed to elucidate whether these cases belong to the recently described ETV6/RUNX1-like ALL defined by the ETV6/RUNX1-specific gene expression profile, harboring concurrent ETV6 and IKZF1 lesions. We performed comprehensive genomic analysis using single nucleotide polymorphism arrays, whole exome and transcriptome sequencing and gene expression profiling (GEP) on microarrays. In unsupervised hierarchical clustering based on GEP, five out of seven analyzed CD27^p°^s/CD44^l°^w-neg B-other cases clustered with ETV6/RUNX1-positive ALL and were thus classified as ETV6/RUNX1-like ALL. The two cases clustering outside ETV6/RUNX1-positive ALL harbored a P2RY8/CRLF2 fusion with activating JAK2 mutations and a TCF3/ZNF384 fusion, respectively, assigning them to other ALL subtypes. All five ETV6/RUNX1-like cases harbored ETV6 deletions; uniform intragenic ARPP21 deletions and various IKZF1 lesions were each found in three ETV6/RUNX1-like cases. The frequency of ETV6 and ARPP21 deletions was significantly higher in ETV6/RUNX1-like ALL compared with a reference cohort of 42 B-other ALL. In conclusion, we show that ETV6/RUNX1-like ALL is associated with CD27^p°^s/CD44^l°^w-neg immunophenotype and identify ARPP21 deletions to contribute to its specific genomic profile enriched for ETV6 and IKZF1 lesions. In conjunction with previously published data, our study identifies the ETV6 lesion as the only common genetic aberration and thus the most likely key driver of ETV6/RUNX1-like ALL. This article is protected by copyright. All rights reserved.

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ETV6/RUNX1-like acute lymphoblastic leukemia: A novel B-cell precursor leukemia subtype associated with the CD27/CD44 immunophenotype

Abstract

We have shown previously that ETV6/RUNX1-positive acute lymphoblastic leukemia (ALL) is distinguishable from other ALL subtypes by CD27^p°^s/CD44^l°^w-neg immunophenotype. During diagnostic immunophenotyping of 573 childhood B-cell precursor ALL (BCP-ALL), we identified eight cases with this immunophenotype among "B-other ALL" (BCP-ALL cases negative for routinely tested chromosomal/genetic aberrations). We aimed to elucidate whether these cases belong to the recently described ETV6/RUNX1-like ALL defined by the ETV6/RUNX1-specific gene expression profile, harboring concurrent ETV6 and IKZF1 lesions. We performed comprehensive genomic analysis using single nucleotide polymorphism arrays, whole exome and transcriptome sequencing and gene expression profiling (GEP) on microarrays. In unsupervised hierarchical clustering based on GEP, five out of seven analyzed CD27^p°^s/CD44^l°^w-neg B-other cases clustered with ETV6/RUNX1-positive ALL and were thus classified as ETV6/RUNX1-like ALL. The two cases clustering outside ETV6/RUNX1-positive ALL harbored a P2RY8/CRLF2 fusion with activating JAK2 mutations and a TCF3/ZNF384 fusion, respectively, assigning them to other ALL subtypes. All five ETV6/RUNX1-like cases harbored ETV6 deletions; uniform intragenic ARPP21 deletions and various IKZF1 lesions were each found in three ETV6/RUNX1-like cases. The frequency of ETV6 and ARPP21 deletions was significantly higher in ETV6/RUNX1-like ALL compared with a reference cohort of 42 B-other ALL. In conclusion, we show that ETV6/RUNX1-like ALL is associated with CD27^p°^s/CD44^l°^w-neg immunophenotype and identify ARPP21 deletions to contribute to its specific genomic profile enriched for ETV6 and IKZF1 lesions. In conjunction with previously published data, our study identifies the ETV6 lesion as the only common genetic aberration and thus the most likely key driver of ETV6/RUNX1-like ALL. This article is protected by copyright. All rights reserved.

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Molecular detection of viruses in Kenyan bats and discovery of novel astroviruses, caliciviruses and rotaviruses

Abstract

This is the first country-wide surveillance of bat-borne viruses in Kenya spanning from 2012–2015 covering sites perceived to have medium to high level bat-human interaction. The objective of this surveillance study was to apply a non-invasive approach using fresh feces to detect viruses circulating within the diverse species of Kenyan bats. We screened for both DNA and RNA viruses; specifically, astroviruses (AstVs), adenoviruses (ADVs), caliciviruses (CalVs), coronaviruses (CoVs), flaviviruses, filoviruses, paramyxoviruses (PMVs), polyomaviruses (PYVs) and rotaviruses. We used family-specific primers, amplicon sequencing and further characterization by phylogenetic analysis. Except for filoviruses, eight virus families were detected with varying distributions and positive rates across the five regions (former provinces) studied. AstVs (12.83%), CoVs (3.97%), PMV (2.4%), ADV (2.26%), PYV (1.65%), CalVs (0.29%), rotavirus (0.19%) and flavivirus (0.19%). Novel CalVs were detected in Rousettus aegyptiacus and Mops condylurus while novel Rotavirus-A-related viruses were detected in Taphozous bats and R. aegyptiacus. The two Rotavirus A (RVA) strains detected were highly related to human strains with VP6 genotypes I2 and I16. Genotype I16 has previously been assigned to human RVA-strain B10 from Kenya only, which raises public health concern, particularly considering increased human-bat interaction. Additionally, 229E-like bat CoVs were detected in samples originating from Hipposideros bats roosting in sites with high human activity. Our findings confirm the presence of diverse viruses in Kenyan bats while providing extended knowledge on bat virus distribution. The detection of viruses highly related to human strains and hence of public health concern, underscores the importance of continuous surveillance.

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Molecular detection of viruses in Kenyan bats and discovery of novel astroviruses, caliciviruses and rotaviruses

Abstract

This is the first country-wide surveillance of bat-borne viruses in Kenya spanning from 2012–2015 covering sites perceived to have medium to high level bat-human interaction. The objective of this surveillance study was to apply a non-invasive approach using fresh feces to detect viruses circulating within the diverse species of Kenyan bats. We screened for both DNA and RNA viruses; specifically, astroviruses (AstVs), adenoviruses (ADVs), caliciviruses (CalVs), coronaviruses (CoVs), flaviviruses, filoviruses, paramyxoviruses (PMVs), polyomaviruses (PYVs) and rotaviruses. We used family-specific primers, amplicon sequencing and further characterization by phylogenetic analysis. Except for filoviruses, eight virus families were detected with varying distributions and positive rates across the five regions (former provinces) studied. AstVs (12.83%), CoVs (3.97%), PMV (2.4%), ADV (2.26%), PYV (1.65%), CalVs (0.29%), rotavirus (0.19%) and flavivirus (0.19%). Novel CalVs were detected in Rousettus aegyptiacus and Mops condylurus while novel Rotavirus-A-related viruses were detected in Taphozous bats and R. aegyptiacus. The two Rotavirus A (RVA) strains detected were highly related to human strains with VP6 genotypes I2 and I16. Genotype I16 has previously been assigned to human RVA-strain B10 from Kenya only, which raises public health concern, particularly considering increased human-bat interaction. Additionally, 229E-like bat CoVs were detected in samples originating from Hipposideros bats roosting in sites with high human activity. Our findings confirm the presence of diverse viruses in Kenyan bats while providing extended knowledge on bat virus distribution. The detection of viruses highly related to human strains and hence of public health concern, underscores the importance of continuous surveillance.

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RACK1 Silencing Induces Cell Apoptosis and Inhibits Cell Proliferation in Hepatocellular Carcinoma MHCC97-H Cells

Abstract

This study aimed to explore the effects of RACK1 gene silencing on the apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H cells. After transfecting MHCC97-H cells with siRNA, RACK1 gene silencing model was established. The cells were divided into blank group, siRNA group and empty plasmid group, respectively. The mRNA and protein expressions of RACK1, cyclin D1 and BAX were determined by qRT-PCR and Western blotting. CCK-8 assay, flow cytometry and FITC-Annexin V/PI staining were used to determine cell viability, cell cycle and cell apoptosis, respectively. The results of qRT-PCR and Western blotting suggested that when compared with the blank group and the empty plasmid group, the mRNA and protein expressions of RACK1 and Cyclin D1 decreased significantly while the mRNA and protein BAX expressions increased substantially in the siRNA group (all P < 0.05). The results of CCK-8 assay revealed that the siRNA group exhibited significantly lower cell viability when compared with the blank group and the empty plasmid group (both P < 0.05); and the cell viability in the siRNA group decreased gradually with the increase of time. The results of flow cytometry and FITC-Annexin V/PI staining indicated that when compared with the blank group and the empty plasmid group, the proportion of cells in S phase was markedly lower and the apoptosis rate was significantly higher in the siRNA group (both P < 0.05). Our study suggests that inhibition of RACK1 could suppress cell proliferation and induce apoptosis in HCC MHCC97-H cells.

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A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy

Abstract

Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40–50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.

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Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

Abstract

Thyroid hormone as L-thyroxine (T₄) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T₄ on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T₄ action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.

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A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy

Abstract

Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40–50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.

http://ift.tt/2ojQTh6

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

Abstract

Thyroid hormone as L-thyroxine (T₄) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T₄ on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T₄ action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.

http://ift.tt/2nyuQV2

Radiotherapy for the Primary Tumor in Patients with Metastatic Rectal Cancer

Abstract

Patients with metastatic rectal cancer (mRC) have a poor prognosis and suffer from several symptoms like bleeding, pain, and obstruction. Radiation therapy (RT) has been used both for palliation and improvement of overall survival (OS) in potentially curable patients. However, treatment in this setting is debated and a recent literature review included only studies published before 2000. Therefore, an analysis of literature was performed including only studies published in recent years (2010–2016) to better evaluate the effect of modern RT in these patients.

The analysis of nine reviewed studies (six retrospective and three phase II) showed that RT is able to achieve pain, bleeding, and obstruction response rate of 79, 87, and 78%, respectively. Moreover, in patients receiving radio-chemo-surgical combined modality treatment, median survivals ranging between 30 and 38 months were recorded, with 5-year survival up to 55% of patients. RT was generally well tolerated with the most common reported side effect being diarrhea/proctitis.

Further studies in this field are needed to establish the best therapeutic sequences, to define the optimal RT dose and fractionation, and to evaluate the clinical results in terms of quality of life (QoL).

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Detecting asymptomatic recurrence after radical cystectomy contributes to better prognosis in patients with muscle-invasive bladder cancer

Abstract

The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. We retrospectively analyzed 581 RC cases for muscle-invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log-rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death was significantly longer in the asymptomatic group than in the symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.

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Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

Abstract

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC₅₀, cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC₅₀:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

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Identification and characterization of biomarkers and their functions for Lapatinib-resistant breast cancer

Abstract

Lapatinib, a novel oral dual tyrosine kinase inhibitor blocking HER1 and HER2 pathways, has presented beneficial effects on breast cancer with positive HER2. However, its efficacy is largely limited by the occurrence of acquired drug resistance. In this study, we aimed to explore the underlying molecular mechanisms of Lapatinib resistance using bioinformatics strategies. The gene expression profile of SKBR3-R (acquired Lapatinib-resistant) and SKBR3 (Lapatinib-sensitive) cell line was downloaded from gene expression omnibus database. Then, the differentially expressed genes (DEGs) were selected using dChip software. Furthermore, gene ontology (GO) and pathway enrichment analyses were carried out by using DAVID database. Finally, the protein–protein interaction network was constructed, and the hub genes in the network were analyzed by using STRING database. A total of 300 DEGs, such as HSPA5, MAP1LC3A and RASSF2, were screened out. GO functional enrichment analysis showed that the genes were associated with cell membrane component-related, stimulus-related and binding-related items. KEGG pathway analysis indicated that three dysfunctional pathways, including PPAR signaling pathway, cytokine–cytokine receptor interaction and pathways in cancer, were enriched. Protein–protein interaction network construction revealed that some hub genes, such as PPARG, TGFBI, TGFBR2, TIMP1, CTGF, UBA52 and JUN, might have an association with Lapatinib resistance. The present study offered new insights into the molecular mechanisms of Lapatinib resistance and identified a series of important hub genes that have the potential to be the targets for treatment of Lapatinib-resistant breast cancer.

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Detecting asymptomatic recurrence after radical cystectomy contributes to better prognosis in patients with muscle-invasive bladder cancer

Abstract

The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. We retrospectively analyzed 581 RC cases for muscle-invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log-rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death was significantly longer in the asymptomatic group than in the symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.

http://ift.tt/2ojrfJn

Efficacy of neratinib in the treatment of HER2/neu-amplified epithelial ovarian carcinoma in vitro and in vivo

Abstract

Epithelial ovarian carcinoma is the most lethal of gynecologic malignancies. There is a need to optimize the currently available treatment strategies and to urgently develop novel therapeutic agents against chemotherapy-resistant disease. The objective of our study was to evaluate neratinib's preclinical efficacy in treating HER2-amplified ovarian cancer. Neratinib's efficacy in treating HER2-amplified ovarian cancer was studied in vitro utilizing six primary tumor cell lines with differential HER2/neu expression. Flow cytometry was utilized to assess IC₅₀, cell signaling changes, and cell cycle distribution. Neratinib's in vivo efficacy was evaluated in HER2-amplified epithelial ovarian carcinoma xenografts. Three of six (50%) ovarian cancer cell lines were HER2/neu-amplified. Neratinib showed significantly higher efficacy in treating HER2/neu-amplified cell lines when compared to the non-HER2/neu-amplified tumor cell lines (mean ± SEM IC₅₀:0.010 μM ± 0.0003 vs. 0.076 μM ± 0.005 p < 0.0001). Neratinib treatment significantly decreased the phosphorylation of the transcription factor S6, leading to arrest of the cell cycle in G0/G1 phase. Neratinib prolonged survival in mice harboring HER2-amplified epithelial ovarian carcinoma xenografts (p = 0.003). Neratinib inhibits proliferation, signaling, cell cycle progression and tumor growth of HER2-amplified epithelial ovarian carcinoma in vitro. Neratinib inhibits xenograft growth and improves overall survival in HER2/neu-amplified ovarian cancer in vivo. Clinical trials are warranted.

http://ift.tt/2pmoHrx

Identification and characterization of biomarkers and their functions for Lapatinib-resistant breast cancer

Abstract

Lapatinib, a novel oral dual tyrosine kinase inhibitor blocking HER1 and HER2 pathways, has presented beneficial effects on breast cancer with positive HER2. However, its efficacy is largely limited by the occurrence of acquired drug resistance. In this study, we aimed to explore the underlying molecular mechanisms of Lapatinib resistance using bioinformatics strategies. The gene expression profile of SKBR3-R (acquired Lapatinib-resistant) and SKBR3 (Lapatinib-sensitive) cell line was downloaded from gene expression omnibus database. Then, the differentially expressed genes (DEGs) were selected using dChip software. Furthermore, gene ontology (GO) and pathway enrichment analyses were carried out by using DAVID database. Finally, the protein–protein interaction network was constructed, and the hub genes in the network were analyzed by using STRING database. A total of 300 DEGs, such as HSPA5, MAP1LC3A and RASSF2, were screened out. GO functional enrichment analysis showed that the genes were associated with cell membrane component-related, stimulus-related and binding-related items. KEGG pathway analysis indicated that three dysfunctional pathways, including PPAR signaling pathway, cytokine–cytokine receptor interaction and pathways in cancer, were enriched. Protein–protein interaction network construction revealed that some hub genes, such as PPARG, TGFBI, TGFBR2, TIMP1, CTGF, UBA52 and JUN, might have an association with Lapatinib resistance. The present study offered new insights into the molecular mechanisms of Lapatinib resistance and identified a series of important hub genes that have the potential to be the targets for treatment of Lapatinib-resistant breast cancer.

http://ift.tt/2piNCfs

BCL2 genotypes and prostate cancer survival

Abstract

Purpose

The antiapoptotic B‑cell lymphoma 2 (BCL2) gene is a key player in cancer development and progression. A functional single-nucleotide polymorphism (c.-938C>A, rs2279115) in the inhibitory P2 BCL2 gene promoter has been associated with clinical outcomes in various types of cancer. Aim of the present study was to analyze the role of BCL2-938C>A genotypes in prostate cancer mortality.

Methods

The association between BCL2-938C>A (rs2279115) genotypes and prostate cancer outcome was studied within the prospective PROCAGENE study comprising 702 prostate cancer patients.

Results

During a median follow-up time of 92 months, 120 (17.1%) patients died. A univariate Cox regression model showed a significant association of the CC genotype with reduced cancer-specific survival (CSS; hazard ratio, HR, 2.13, 95% confidence interval, CI, 1.10–4.12; p = 0.024) and overall survival (OS; HR 2.34, 95% CI 1.58–3.47; p < 0.001). In a multivariate Cox regression model including age at diagnosis, risk group, and androgen deprivation therapy, the CC genotype remained a significant predictor of poor CSS (HR 2.05, 95% CI 1.05–3.99; p = 0.034) and OS (HR 2.25, 95% CI 1.51–3.36; p < 0.001).

Conclusion

This study provides evidence that the homozygous BCL2-938 CC genotype is associated with OS and C in prostate cancer patients.

http://ift.tt/2nyaY4m

Relationship Between Dual Time Point FDG PET/CT and Clinical Prognostic Indexes in Patients with High Grade Lymphoma: a Pilot Study

Abstract

Purpose

This study investigated the correlative relationship between metabolic parameters estimated from dual time point 2-deoxy-2-[¹⁸F] fluoro-D-glucose (¹⁸F-FDG) positron emission tomography/computerized tomography (PET/CT) and the clinical tools predicting the outcome of a lymphoma. We also measured metabolic and volumetric alterations between early and delayed ¹⁸F-FDG PET/CT in patients with high grade lymphoma (HGL).

Methods

The samples were 122 lymph nodes and extralymphatic lesions from 26 patients diagnosed with HGL. All patients were applied to the International Prognostic Index (IPI), Ann Arbor stage, and revised IPI as clinical prognostic parameters. ¹⁸F-FDG dual time point PET/CT (DTPFP) consisted of an early scan 1 h after ¹⁸F-FDG injection and a delayed scan 2 h after the early scan. Based on an analysis of DTPFP, we estimated the standardized uptake value (SUV) of tumors from the early and delayed scans, retention index (RI) representing the percentage change between early and delayed SUV, and metabolic volume different index (MVDI) calculated using metabolic tumor volumes (MTV).

Results

RI_max showed a multiple positive correlative relationship with stage and IPI in lesion-by-lesion analysis (p < 0.01). In the case of IPI, the high risk group exhibited higher RI_max than the low risk group (p = 0.004). In the case of revised IPI, the RI_max of the low risk group were significantly lower than the intermediate and high risk groups, respectively (p < 0.01). The MVDIs of the best outcome group were decreased in comparison to the moderate outcome group (p = 0.029). There was a significant negative correlative relationship between RI_max and MVDI, and the inclinations for decreased MVDIs were slightly associated with increased RIs.

Conclusions

RI_max extracted from DTPFP had a significant relationship to extranodal involvement, staging, IPI, and revised IPI. MVDI showed significant negative correlation with RI_max. Further large scale studies are warranted to support and extend these preliminary results.

http://ift.tt/2ojtnAF

Relationship Between Dual Time Point FDG PET/CT and Clinical Prognostic Indexes in Patients with High Grade Lymphoma: a Pilot Study

Abstract

Purpose

This study investigated the correlative relationship between metabolic parameters estimated from dual time point 2-deoxy-2-[¹⁸F] fluoro-D-glucose (¹⁸F-FDG) positron emission tomography/computerized tomography (PET/CT) and the clinical tools predicting the outcome of a lymphoma. We also measured metabolic and volumetric alterations between early and delayed ¹⁸F-FDG PET/CT in patients with high grade lymphoma (HGL).

Methods

The samples were 122 lymph nodes and extralymphatic lesions from 26 patients diagnosed with HGL. All patients were applied to the International Prognostic Index (IPI), Ann Arbor stage, and revised IPI as clinical prognostic parameters. ¹⁸F-FDG dual time point PET/CT (DTPFP) consisted of an early scan 1 h after ¹⁸F-FDG injection and a delayed scan 2 h after the early scan. Based on an analysis of DTPFP, we estimated the standardized uptake value (SUV) of tumors from the early and delayed scans, retention index (RI) representing the percentage change between early and delayed SUV, and metabolic volume different index (MVDI) calculated using metabolic tumor volumes (MTV).

Results

RI_max showed a multiple positive correlative relationship with stage and IPI in lesion-by-lesion analysis (p < 0.01). In the case of IPI, the high risk group exhibited higher RI_max than the low risk group (p = 0.004). In the case of revised IPI, the RI_max of the low risk group were significantly lower than the intermediate and high risk groups, respectively (p < 0.01). The MVDIs of the best outcome group were decreased in comparison to the moderate outcome group (p = 0.029). There was a significant negative correlative relationship between RI_max and MVDI, and the inclinations for decreased MVDIs were slightly associated with increased RIs.

Conclusions

RI_max extracted from DTPFP had a significant relationship to extranodal involvement, staging, IPI, and revised IPI. MVDI showed significant negative correlation with RI_max. Further large scale studies are warranted to support and extend these preliminary results.

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MicroRNA-9 promotes the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1

Abstract

Purpose

The objective of the study was to investigate the role of microRNA-9 (miR-9) targeting forkhead box O1 (FOXO1) in the proliferation, migration, and invasion of breast cancer cells.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expressions of miR-9 and FOXO1 mRNA in breast cancer tissues, normal breast tissues, breast cancer cell lines, and normal breast epithelial cells. After the up-regulation of miR-9 expression, qRT-PCR and Western blotting were used to determine the expression of FOXO1. The luciferase reporter gene assay was used to validate the target gene. The CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay were used to investigate the changes in the proliferation, migration, and invasion of breast cancer cells, respectively.

Results

MicroRNA-9 expression was significantly up-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). FOXO1 mRNA and protein expressions were substantially down-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). There can be a negative correlation between miR-9 and FOXO1 mRNA in breast cancer. Luciferase reporter gene assay indicated that miR-9 can down-regulate FOXO1 expression at a post-transcriptional level through binding specifically to FOXO1 3′UTR. The results of CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay revealed that the inhibition of miR-9 can suppress MCF7 cell proliferation, migration, and invasion. Additionally, the expression of miR-9 increased significantly whilst that of FOXO1 decreased substantially as the disease progressed (P < 0.05).

Conclusions

Our study provides evidence that miR-9 can promote the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1.

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MicroRNA-9 promotes the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1

Abstract

Purpose

The objective of the study was to investigate the role of microRNA-9 (miR-9) targeting forkhead box O1 (FOXO1) in the proliferation, migration, and invasion of breast cancer cells.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expressions of miR-9 and FOXO1 mRNA in breast cancer tissues, normal breast tissues, breast cancer cell lines, and normal breast epithelial cells. After the up-regulation of miR-9 expression, qRT-PCR and Western blotting were used to determine the expression of FOXO1. The luciferase reporter gene assay was used to validate the target gene. The CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay were used to investigate the changes in the proliferation, migration, and invasion of breast cancer cells, respectively.

Results

MicroRNA-9 expression was significantly up-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). FOXO1 mRNA and protein expressions were substantially down-regulated in breast cancer tissues and breast cancer cell lines when compared with normal breast tissues and normal breast epithelial cells (both P < 0.05). There can be a negative correlation between miR-9 and FOXO1 mRNA in breast cancer. Luciferase reporter gene assay indicated that miR-9 can down-regulate FOXO1 expression at a post-transcriptional level through binding specifically to FOXO1 3′UTR. The results of CCK-8 assay, scratch-wound healing assay, and Transwell invasion assay revealed that the inhibition of miR-9 can suppress MCF7 cell proliferation, migration, and invasion. Additionally, the expression of miR-9 increased significantly whilst that of FOXO1 decreased substantially as the disease progressed (P < 0.05).

Conclusions

Our study provides evidence that miR-9 can promote the proliferation, migration, and invasion of breast cancer cells via down-regulating FOXO1.

http://ift.tt/2o0cCYY

Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients

Summary

Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m²) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m² and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m². For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m²; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.

http://ift.tt/2ojjpPQ

Secukinumab is Efficacious and Safe in Hispanic Patients with Moderate-to-Severe Plaque Psoriasis: Pooled Analysis of Four Phase 3 Trials

Abstract

Introduction

There is little evidence available on the efficacy and safety of biologic therapies for the treatment of psoriasis in Hispanic patients. Secukinumab is demonstrated to be highly effective for clearing psoriasis. The aim of this study was to compare the efficacy and safety of secukinumab in Hispanic and non-Hispanic patients.

Methods

Data were pooled from four phase 3 studies of secukinumab in patients with moderate-to-severe plaque psoriasis. Patients who self-identified as Hispanic were included in the Hispanic subgroup.

Results

Efficacy responses (Psoriasis Area and Severity Index [PASI] 75/90/100 and Investigator's Global Assessment 2011 modified version 0/1) for secukinumab 300 mg were greater than for etanercept at week 12 in the Hispanic and non-Hispanic patient subgroups. At week 12 with secukinumab 300 mg, PASI 90/100 responses were achieved by 70.6%/35.9% of Hispanic patients and 58.0%/28.1% of non-Hispanic patients. At week 12 with secukinumab 150 mg, PASI 90/100 responses were achieved by 59.5%/25.1% of Hispanic patients and 41.2%/13.4% of non-Hispanic patients. In both subgroups, peak efficacy responses with secukinumab were observed at week 16 and were maintained to week 52.

Conclusions

Secukinumab is highly effective for clearing psoriasis in both Hispanic and non-Hispanic patients.

Funding

Novartis Pharmaceutical Corporation.

http://ift.tt/2oqZ1ga

The Rituximab Biosimilar CT-P10 in Rheumatology and Cancer: A Budget Impact Analysis in 28 European Countries

Abstract

Introduction

New biosimilars of monoclonal antibodies are anticipated to bring significant cost savings and increase access to treatment. The rituximab biosimilar CT-P10 has recently been approved in Europe in all indications held by reference rituximab (RTX), including rheumatoid arthritis, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. We analyzed the budgetary impact of the introduction of CT-P10 into the European Union (EU) for use in patients with rheumatoid arthritis and cancer diagnoses, using a budget impact analysis model.

Methods

The model used a base case scenario in which the 1-year uptake of CT-P10 was estimated at 30%, and the cost of CT-P10 was assumed to be 70% of the cost of RTX. A second 1-year scenario was also modeled, in which the market share of CT-P10 was assumed to be 50% (scenario 2). Finally, 3-year time horizon outcomes were calculated, in which the market share of CT-P10 was assumed to be 30%, 40%, and 50% in the first, second, and third years, respectively.

Results

In the base case scenario, the introduction of CT-P10 was associated with projected savings of €90.04 million in the first year, which would allow 7531 additional patients to access rituximab treatment. This was equivalent to a 6.4% increase in the number of rituximab-treated patients. In scenario 2, budget savings were €150.10 million, with a total of 12,551 additional patients able to access rituximab, equivalent to a 10.7% increase. Over a 3-year time horizon, projected budget savings were approximately €570 million, equating to 47,695 additional patients able to access rituximab.

Conclusions

The model predicted that the introduction of CT-P10 in the EU will be associated with significant budget savings, the reallocation of which will enable many more patients to access rituximab treatment. This is likely to have a significant impact on health gains at patient and societal levels.

Funding: CELLTRION Healthcare Co., Ltd. sponsored the development and analysis of the budget impact analysis model.

http://ift.tt/2nUXJ9e

Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury

Abstract

Introduction

A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF.

Patients and methods

To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI−), and further subdivided into three groups according to AKI severity (stage 1–5).

Results

Of 38 patients, 29 (76%) were AKI−, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI−, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF–CB vs. VMF monotherapy was reduced by 60%.

Conclusion

We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.

http://ift.tt/2nUT1bF

A novel classification scheme for advanced laryngeal cancer midline involvement: implications for the contralateral neck

Abstract

Purpose

There are insufficient data concerning risk factors for contralateral regional metastases in laryngeal cancer. The aim of this study was to investigate the frequency and risk factors for contralateral lymph node metastases and their dependence on midline involvement of the primary tumor in patients with advanced laryngeal squamous cell carcinoma.

Methods

58 consecutive patients (8 females, 50 males; mean age 64.2 ± 9.8 years; AJCC stage III disease in 43.1%, IVA disease in 54.4%) undergoing primary total laryngectomy with bilateral neck dissection between 2002 and 2016 have been retrospectively investigated at one of the largest university medical centers in Europe. Preoperative staging computed tomography (CT) scans were analyzed for midline involvement of the primary laryngeal cancer. As a result, a classification scheme has been established (type A: clear, type B: involved, type C: exceeded, and type D: bilateral/origin side indeterminable).

Results

Contralateral lymph node metastases (pN2c necks) were found in six cases (10.3%), from which four were diagnosed with type D (23.5% of type D cases), and one each with type B and type C midline involvement. In cases with no midline involvement (type A), a risk ratio reduction of 100% was seen. CT-based midline typing resulted in fourfold increased sensitivity for predicting contralateral metastases compared to conventional staging. Positive nodal status (pN+) significantly reduced overall and disease-free survival (HR 2.706, p < 0.05).

Conclusions

As a consequence, for type A category, a contralateral neck dissection might be avoidable accompanied by a reduction in surgical complications and operating time.

http://ift.tt/2or8EeJ

Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients

Summary

Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m²) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m² and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m². For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m²; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.

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Secukinumab is Efficacious and Safe in Hispanic Patients with Moderate-to-Severe Plaque Psoriasis: Pooled Analysis of Four Phase 3 Trials

Abstract

Introduction

There is little evidence available on the efficacy and safety of biologic therapies for the treatment of psoriasis in Hispanic patients. Secukinumab is demonstrated to be highly effective for clearing psoriasis. The aim of this study was to compare the efficacy and safety of secukinumab in Hispanic and non-Hispanic patients.

Methods

Data were pooled from four phase 3 studies of secukinumab in patients with moderate-to-severe plaque psoriasis. Patients who self-identified as Hispanic were included in the Hispanic subgroup.

Results

Efficacy responses (Psoriasis Area and Severity Index [PASI] 75/90/100 and Investigator's Global Assessment 2011 modified version 0/1) for secukinumab 300 mg were greater than for etanercept at week 12 in the Hispanic and non-Hispanic patient subgroups. At week 12 with secukinumab 300 mg, PASI 90/100 responses were achieved by 70.6%/35.9% of Hispanic patients and 58.0%/28.1% of non-Hispanic patients. At week 12 with secukinumab 150 mg, PASI 90/100 responses were achieved by 59.5%/25.1% of Hispanic patients and 41.2%/13.4% of non-Hispanic patients. In both subgroups, peak efficacy responses with secukinumab were observed at week 16 and were maintained to week 52.

Conclusions

Secukinumab is highly effective for clearing psoriasis in both Hispanic and non-Hispanic patients.

Funding

Novartis Pharmaceutical Corporation.

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