Successful treatment with hyperbaric oxygen therapy for pneumatosis cystoides intestinalis as a complication of granulomatosis with polyangiitis: a case report

Although gastrointestinal involvement in patients with granulomatosis with polyangiitis is uncommon, it is associated with mild to severe life-threatening complications. We present a case of pneumatosis cystoi...

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Margin-free excision of small solid breast carcinomas using the Intact Breast Lesion Excision System ® : is it feasible?

Abstract

Background

The Breast Lesion Excision System^® (BLES^®) is a stereotactic vacuum-assisted breast biopsy device that utilizes radiofrequency in order to excise non-palpable mammographic lesions for pathologic diagnosis. The purpose of this study was to evaluate the efficacy of BLES^® in performing complete, margin-free excisions of small solid carcinomas.

Methods

Our retrospective study of prospectively enrolled patients included 50 cases of non-palpable, BIRADS ≥ 4, solid by means of mammography and sonography, lesions. All these patients underwent a BLES^® breast biopsy procedure from June 2010 to June 2014 and had a malignant diagnosis. According to each patient's pathologic diagnosis, appropriate surgical treatment was recommended. Postoperatively, surgical specimens were histologically analyzed, aiming to determine whether residual malignant disease was present in the specimen cavity formatted by BLES^®.

Results

Ductal carcinoma in situ (DCIS) was diagnosed in 5 patients and invasive carcinoma (IC) in 45 patients, at primary BLES^® pathology report. Tumor-free resection margins (< 0.5 and < 1 mm) were accomplished in only 8/24 subcentimeter cases (33.3%). Absence of residual disease upon surgical excision was confirmed in 23/24 subcentimeter cases (95.8%) and 2/26 of the cases measuring > 1 cm (7.69%). Statistical analysis revealed that mammographic size was the only significant prognostic factor for complete excision (i.e., with no residual disease in the biopsy cavity) of a malignant lesion.

Conclusions

Our results indicate that it is possible, when using the BLES^® device, to completely excise small (≤ 10 mm) breast carcinomas that appear radiologically as solid lesions. This subset of patients should be investigated regarding the therapeutic potential of this method.

http://ift.tt/2y5ZOEN

Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy

Abstract

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high- or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated.

The median follow-up was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10, and percentage of positive biopsy cores > 75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n=16), two (n=74), or one of these risk factors (n=217) were 27.1%, 11.6%, and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (p < 0.001).

CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT.

This article is protected by copyright. All rights reserved.

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The miR-203 inhibits cell proliferation, invasion, and migration of non-small cell lung cancer by downregulating RGS17

Abstract

The involvement of the RGS17 oncogene in promotion of non-small cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of microRNAs in RGS17-induced NSCLC, we showed that miR-203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined if miR-203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR-203 on RGS17, we used lung cancer cell lines, A549 and Calu-1, and the constructed miR-203 and RGS17 overexpression vectors. The CCK8 kit was used to determine the cell proliferation, and the Transwell^® assay was used to measure cell invasion and migration. RT-PCR, western blots, and immunofluorescence were used to analyze the expression of miR-203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR-203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. The expression of miR-203 inhibited the proliferation, invasion, and migration of lung cancer cell lines A549 and Calu-1 by targeting RGS17. The regulatory effect of miR-203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR-203 downregulated RGS17 by direct integration into the 3′-UTR of RGS17 mRNA. In vivo studies showed that the expression of miR-203 significantly inhibited the growth of tumors. Taken together, the results suggested that the expression of miR-203 inhibited tumor growth and metastasis by targeting RGS17.

This article is protected by copyright. All rights reserved.

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Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy

Abstract

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high- or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated.

The median follow-up was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10, and percentage of positive biopsy cores > 75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n=16), two (n=74), or one of these risk factors (n=217) were 27.1%, 11.6%, and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (p < 0.001).

CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT.

This article is protected by copyright. All rights reserved.

http://ift.tt/2fccHtl

The miR-203 inhibits cell proliferation, invasion, and migration of non-small cell lung cancer by downregulating RGS17

Abstract

The involvement of the RGS17 oncogene in promotion of non-small cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of microRNAs in RGS17-induced NSCLC, we showed that miR-203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined if miR-203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR-203 on RGS17, we used lung cancer cell lines, A549 and Calu-1, and the constructed miR-203 and RGS17 overexpression vectors. The CCK8 kit was used to determine the cell proliferation, and the Transwell^® assay was used to measure cell invasion and migration. RT-PCR, western blots, and immunofluorescence were used to analyze the expression of miR-203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR-203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. The expression of miR-203 inhibited the proliferation, invasion, and migration of lung cancer cell lines A549 and Calu-1 by targeting RGS17. The regulatory effect of miR-203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR-203 downregulated RGS17 by direct integration into the 3′-UTR of RGS17 mRNA. In vivo studies showed that the expression of miR-203 significantly inhibited the growth of tumors. Taken together, the results suggested that the expression of miR-203 inhibited tumor growth and metastasis by targeting RGS17.

This article is protected by copyright. All rights reserved.

http://ift.tt/2xpusMl

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

http://ift.tt/2x7d4Kd

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

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In vitro inhibition of HIV-1 replication in autologous CD4 + T cells indicates viral containment by multifactorial mechanisms

Abstract

HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4⁺ T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures. However, the same neutralizing antibody was able to contain viruses by antibody-dependent cell-mediated virus inhibition in vitro, which was mediated by natural killer cells (NKs) and dependent on an Fc-Fc receptor interaction. Meanwhile, bulk CTLs from HIV-1 controllers were more effective in suppression of virus replication than those from progressors. These findings indicate that control of HIV-1 replication in activated CD4⁺ T cells is ineffectively mediated by neutralizing antibodies alone, but that both CTLs and antibody-dependent NK-mediated immune mechanisms contribute to viral containment. Our study systemically compared three major players in controlling HIV-1 infection, CTLs, NAbs, and NKs, in an autologous system and highlighted the multifactorial mechanisms for viral containment and vaccine success.

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HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients

Abstract

Purpose

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients.

Experimental design

A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort.

Results

In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045–2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376–3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294).

Conclusions

Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

http://ift.tt/2x7d4Kd

In vitro inhibition of HIV-1 replication in autologous CD4 + T cells indicates viral containment by multifactorial mechanisms

Abstract

HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4⁺ T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures. However, the same neutralizing antibody was able to contain viruses by antibody-dependent cell-mediated virus inhibition in vitro, which was mediated by natural killer cells (NKs) and dependent on an Fc-Fc receptor interaction. Meanwhile, bulk CTLs from HIV-1 controllers were more effective in suppression of virus replication than those from progressors. These findings indicate that control of HIV-1 replication in activated CD4⁺ T cells is ineffectively mediated by neutralizing antibodies alone, but that both CTLs and antibody-dependent NK-mediated immune mechanisms contribute to viral containment. Our study systemically compared three major players in controlling HIV-1 infection, CTLs, NAbs, and NKs, in an autologous system and highlighted the multifactorial mechanisms for viral containment and vaccine success.

http://ift.tt/2f2pM4N

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study

Abstract

Introduction

Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms.

Methods

This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms.

Results

At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating.

Conclusion

NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted.

Funding

Orexigen Therapeutics, Inc.

http://ift.tt/2fp8cbx

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study

Abstract

Introduction

Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms.

Methods

This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms.

Results

At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating.

Conclusion

NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted.

Funding

Orexigen Therapeutics, Inc.

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Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy

Abstract

Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.

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Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy

Abstract

Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.

http://ift.tt/2w0ltNX

Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and...

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Dosimetric comparison of different treatment modalities for stereotactic radiotherapy

The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) linac, and...

http://ift.tt/2wwN20M

Health-related quality of life in melanoma patients: Impact of melanoma-related limb lymphoedema

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): Caroline A. Gjorup, Mogens Groenvold, Helle W. Hendel, Karin Dahlstroem, Krzysztof T. Drzewiecki, Tobias W. Klausen, Lisbet R. Hölmich
AimTo explore health-related quality of life (HRQoL) in recurrence-free melanoma patients, with a focus on the association between melanoma-related limb lymphoedema and HRQoL.MethodsHRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the breast cancer module (EORTC QLQ-BR23) subscales body image and future perspective, the Functional Assessment for Cancer Therapy-General subscale social/family well-being and the Hospital Anxiety and Depression Scale. Data were analysed using linear and ordinal logistic regression adjusting for age and gender.ResultsA total of 431 melanoma patients who had undergone wide local excision and axillary or inguinal sentinel lymph node biopsy (SLNB) and/or complete lymph node dissection (CLND) participated. No patients had had recurrence of the disease or had received adjuvant radiotherapy. The HRQoL scores improved with time after surgery. Melanoma-related limb lymphoedema was present in 109 patients (25%). Patients with lymphoedema had significantly worse HRQoL scores in the EORTC QLQ-C30 subscales global health status/quality of life, role and social functioning, fatigue, pain and financial difficulties, as well as in the QLQ-BR23 body image subscale. No associations were found between the limb affected (upper or lower limb), clinical stage of lymphoedema, duration of lymphoedema or type of surgery (SLNB or CLND) and HRQoL. We found an interaction with age and gender in the associations between lymphoedema and HRQoL: younger patients and women with lymphoedema had worse social functioning and women had significantly more impaired body image.ConclusionsThe negative impact of melanoma-related limb lymphoedema on HRQoL emphasises the importance of developing strategies for increasing awareness and improving prevention and treatment of lymphoedema.



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Isolated limb perfusion for locally advanced angiosarcoma in extremities: A multi-centre study

Publication date: November 2017
Source:European Journal of Cancer, Volume 85
Author(s): E.A. Huis in 't Veld, D.J. Grünhagen, C. Verhoef, H.G. Smith, A.C.J. van Akkooi, R. Jones, F. van Coevorden, A.J. Hayes, W.J. van Houdt
BackgroundAngiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma.Material and methodsAll patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases.ResultsA total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1–60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%).ConclusionILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS.



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PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and...

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Mutations in context: implications of BRCA testing in diverse populations

Abstract

Cancer is a common non-communicable disease worldwide, although it exhibits differential population trends in incidence and mortality rates. The differences relate to population structure, environmental risk factors as well as health system organization. This article discusses the potential impact of genetic testing on population health, focusing in particular on the mutational spectrum of breast cancer susceptibility genes in diverse populations. We identify the need for improved access to, and increased investment in, comprehensive cancer risk assessment and genetic testing as well as cancer control measures that take into account lifestyle, environmental, and social factors in understudied minority groups.

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Neoisoliquiritigenin inhibits tumor progression by targeting GRP78-β-catenin signaling in breast cancer.

Neoisoliquiritigenin inhibits tumor progression by targeting GRP78-β-catenin signaling in breast cancer.

Curr Cancer Drug Targets. 2017 Sep 14;:

Authors: Tang H, Peng F, Huang X, Xie X, Chen B, Shen J, Gao F, You J, Xie X, Chen J

Abstract
Although breast cancer mortality has been stable or decreasing in the world, its incidence and recurrence rates have sharply risen worldwide in recent years. Identification of novel preventative biomarkers and drugs for breast cancer has become an urgent issue worldwide. Recently, GRP78 demonstrated a critical role in mediating tumorigenesis, metastasis and angiogenesis. However, the impact of GRP78 in breast cancer and clinical characteristics remains unclear. In this study, we found that GRP78 could promote breast cancer initiation and progression, and higher expression of GRP78 indicated poorer state of breast cancer patients, suggesting that GRP78 was a significant oncogene with the potential to be a novel biomarker and target in clinical investigation. Also, according to the analysis of molecular docking, we found a derivative of Isoliquiritigenin, Neoisoliquiritigenin (NISL), showed a vital inhibitory effect on breast cancer through direct binding to GRP78 to regulate β-catenin pathway. Taken together, this study not only highlight the significance of GRP78 in breast cancer development via β-catenin signaling but also suggest NISL as a natural candidate to inhibit breast cancer by targeting GRP78.

PMID: 28914191 [PubMed - as supplied by publisher]

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Clinicopathological significance of HSP27 in gastric cancer: a meta-analysis

http://ift.tt/2jyhUNv

Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

http://ift.tt/2xGIrhS

Dose escalation intensity-modulated radiotherapy–based concurrent chemoradiotherapy is effective for advanced-stage thoracic esophageal squamous cell carcinoma

No studies have investigated the effects of irradiation-dose escalation intensity-modulated radiotherapy (IMRT)-based concurrent chemoradiotherapy (CCRT) in patients with thoracic esophageal squamous cell carcinoma (TESCC).

http://ift.tt/2y56cfx

Radioresistance of the breast tumor is highly correlated to its level of cancer stem cell and its clinical implication for breast irradiation

Growing evidence suggested the coexistence of cancer stem cells (CSCs) within solid tumors. We aimed to study radiosensitivity parameters for the CSCs and differentiated tumor cells (TCs) and the correlation of the fractions of CSCs to the overall tumor radioresistance.

http://ift.tt/2x7bO9Q

A systematic review of health economic evaluation in adjuvant breast radiotherapy: Quality counted by numbers

Evolving practice in adjuvant breast radiotherapy inevitably impacts healthcare budgets. This is reflected in a rise of health economic evaluations (HEE) in this domain. The available HEE literature was analysed qualitatively and quantitatively, using available instruments.

http://ift.tt/2f1KBgv

Clinical update regarding general anesthesia-associated neurotoxicity in infants and children.

Purpose of review: The U.S. Federal Drug Administration (FDA) recently released a warning stating that 'repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains' ( http://ift.tt/2x7Abo0). The goal of this article is to review the most recent clinical studies which provide evidence that these concerns may be overstated for the majority of healthy young children who require surgery and anesthesia. Recent findings: Three large retrospective matched cohort studies published within the past year provide data on a total of 59 814 children exposed to general anesthesia before age 4 (including 30 021

http://ift.tt/2y5r1rb

Complications and unplanned admissions in nonoperating room procedures.

Purpose of review: The purpose of this article is to review complications and unplanned hospital admissions in patients presenting for ambulatory procedures requiring anesthesia care in the gastrointestinal endoscopy, bronchoscopy, and radiology suites. Recent findings: The range of ambulatory diagnostic and therapeutic procedures being undertaken in the gastrointestinal endoscopy, bronchoscopy, and radiology suites is expanding rapidly. Recent observational studies in gastrointestinal endoscopy confirm low incidences of complications and unplanned admissions. Deep propofol-based sedation is associated with more complications than lighter sedation. Older patients suffer more complications but obstructive sleep apnea does not appear to increase risk. Sedation improves patient comfort during bronchoscopy. Propofol-based sedation is associated with fewer complications than benzodiazepine-based sedation, but all combinations are associated with high patient satisfaction. Obesity and obstructive sleep apnea are not associated with worse outcomes in bronchoscopy patients. Sedation is increasingly required for interventions in the radiology suite. When patients are involved in choosing sedation depth, there is a trend to lighter sedation and high patient satisfaction. Summary: Sedation and anesthesia are required for the increasing number of increasingly complex procedures being undertaken outside the operating suite. Large randomized trials are required to define the optimum sedation drugs, sedation depth and sedation provider. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Effects of pregabalin on postoperative pain after hysterectomy under spinal anesthesia with intrathecal morphine: a randomized controlled trial

Abstract

Purpose

To determine if preoperative pregabalin could decrease 24-h postoperative morphine consumption after spinal anesthesia with intrathecal morphine compared with placebo.

Methods

A randomized, double-blind, controlled trial was performed in the tertiary care center. Patients aged between 18 and 65 years who were American Society of Anesthesiologists class I–II and scheduled for abdominal hysterectomy with or without salpingo-oophorectomy were randomly allocated to a placebo or a pregabalin group. Patients received pregabalin 150 mg or placebo 1 h prior to anesthesia. Spinal anesthesia was achieved with 0.5% hyperbaric bupivacaine with morphine 0.2 mg. Intravenous patient-controlled analgesia morphine was provided postoperatively. Postoperative morphine consumption at 6, 12, and 24 h, time to first analgesic rescue, pain scores, adverse effects, and patient satisfaction were evaluated at 24 h after the operation.

Results

One hundred twenty-five patients were recruited and 119 patients (placebo N = 58, pregabalin N = 61) were included in the analysis. Forty-seven (81.0%) patients in the placebo group and 53 (86.9%) patients in the pregabalin group required morphine in the first 24 h. Median [IQR] 24-h morphine consumption was 4.0 [1.8, 10.0] mg in the placebo group and 5.0 [2.0, 11.0] mg in the prebagalin group, p = 0.60. There were no differences in cumulative morphine consumption at 6, 12, and 24 h postoperatively. The two groups also did not differ in time to first analgesic rescue, pain scores at rest and on movement, and side effects.

Conclusion

A single preoperative dose of pregabalin 150 mg did not reduce 24-h postoperative morphine consumption or pain scores or prolong the time to first analgesic rescue in spinal anesthesia with intrathecal morphine.

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miR-122 Promotes Metastasis of Clear-Cell Renal Cell Carcinoma by Downregulating Dicer

Abstract

Although overall downregulation of microRNAs (miRNAs) is a general feature of clear-cell renal cell carcinoma (ccRCC), several miRNAs are consistently upregulated, among which miR-122 was markedly increased in ccRCC tissues. This study aims to determine the functional importance and underlying mechanism of miR-122 in ccRCC metastasis. Here we demonstrate that the expression of miR-122 increased in ccRCC tissues, and higher miR-122 expression was found in ccRCC tissues with metastatic disease than in those without metastasis. The increased miR-122 levels were associated with poor metastasis-free survival in ccRCC patients with localized disease. Dicer was validated as a direct functional target of miR-122. Overexpression of miR-122 promoted migration and invasion of ccRCC cells in vitro and metastatic behavior of ccRCC cells in vivo. Inhibition of miR-122 attenuated this metastatic phenotype in vitro. Importantly, miR-122 exerted its pro-metastatic properties in ccRCC cells by downregulating Dicer and its downstream effector, the miR-200 family, thereby inducing epithelial–mesenchymal transition (EMT). Our results suggest an important role of the miR-122/Dicer/miR-200s/EMT pathway in ccRCC metastasis. Furthermore, miR-122 may serve as a biomarker for discriminating ccRCC with metastatic potential. This article is protected by copyright. All rights reserved.

http://ift.tt/2xaddON

Contralateral Breast Cancers: Independent Cancers or Metastases?

Abstract

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in 3 cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all 3 cases. In 3 additional cases there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases. This article is protected by copyright. All rights reserved.

http://ift.tt/2wwB081

The impact of P-glycoprotein and Breast Cancer Resistance Protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors

Abstract

Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC-transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244) and pimasertib (AS703026): PD0325901 was the weakest substrate of P-gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2^-/- mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, this study recommends further development of PD0325901 for the treatment of intracranial neoplasms. This article is protected by copyright. All rights reserved.

http://ift.tt/2x9Q2E0

Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression

Abstract

Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log₂FC|>2). Particularly the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas e.g. genes involved in angiogenesis were down-regulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8x10⁻⁷⁵ log₂FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log₂FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 down-regulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2.

This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected down-regulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. This article is protected by copyright. All rights reserved.

http://ift.tt/2wwpjhB

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women

Abstract

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; nitrate-nitrogen 5mg/L, 40µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N=15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HR_p95vs.Q1=1.16, 95%CI: 0.51-2.64). Associations with average TTHM levels were also null (HR_Q4vsQ1=0.70, 95%CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HR_p95vs.Q1=1.66, 95% CI 1.00-2.75;p_trend=0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2xalEtn

A naive Bayes algorithm for tissue origin diagnosis (TOD-Bayes) of synchronous multifocal tumors in the hepatobiliary and pancreatic system

Abstract

Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ∼1,000 feature genes were used to train and validate the TOD-Bayes algorithm. The accuracy of the model was > 95% based on 10-fold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including 6 negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step towards more precision-based medicine in cancer diagnosis and treatment. This article is protected by copyright. All rights reserved.

http://ift.tt/2wwECXv

Tumor-suppressive miR-145 co-repressed by TCF4-β-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer

Abstract

The frequently dysregulated Wnt/β-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In the present study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA mediated knock-down tests and protein and chromatin immunoprecipitations, we found the TCF4-β-catenin complex can recruit the histone trimethylation complex PRC2 as a co-repressor while binding to the TCF4-binding element (TBE) in the promoter regions of miR-145, miR-132 and miR-212. Thus, upon Wnt signaling activation, the PRC2-mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor-suppressive miR-145 co-repressed by Wnt signaling and histone trimethylation, forms double-negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR-145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/β-catenin signaling and tumor-suppressive miRNAs reciprocally regulate each other in CRC cells. This article is protected by copyright. All rights reserved.

http://ift.tt/2x9VQNZ

Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer

Abstract

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an anti-secretory agent may be an effective intervention. T84 monolayers were treated with 1µM dacomitinib and 10µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n=48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p=0.0003), and did not attenuate weight loss (p<0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting. This article is protected by copyright. All rights reserved.

http://ift.tt/2wwm7Cl

Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype

Abstract

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-94) and wave 2 (2003-07). We included participants diagnosed to 31 August 2015 with incident stage I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stage I/III disease (p for interaction = .01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance. This article is protected by copyright. All rights reserved.

http://ift.tt/2xafc5x

miR-122 Promotes Metastasis of Clear-Cell Renal Cell Carcinoma by Downregulating Dicer

Abstract

Although overall downregulation of microRNAs (miRNAs) is a general feature of clear-cell renal cell carcinoma (ccRCC), several miRNAs are consistently upregulated, among which miR-122 was markedly increased in ccRCC tissues. This study aims to determine the functional importance and underlying mechanism of miR-122 in ccRCC metastasis. Here we demonstrate that the expression of miR-122 increased in ccRCC tissues, and higher miR-122 expression was found in ccRCC tissues with metastatic disease than in those without metastasis. The increased miR-122 levels were associated with poor metastasis-free survival in ccRCC patients with localized disease. Dicer was validated as a direct functional target of miR-122. Overexpression of miR-122 promoted migration and invasion of ccRCC cells in vitro and metastatic behavior of ccRCC cells in vivo. Inhibition of miR-122 attenuated this metastatic phenotype in vitro. Importantly, miR-122 exerted its pro-metastatic properties in ccRCC cells by downregulating Dicer and its downstream effector, the miR-200 family, thereby inducing epithelial–mesenchymal transition (EMT). Our results suggest an important role of the miR-122/Dicer/miR-200s/EMT pathway in ccRCC metastasis. Furthermore, miR-122 may serve as a biomarker for discriminating ccRCC with metastatic potential. This article is protected by copyright. All rights reserved.

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Contralateral Breast Cancers: Independent Cancers or Metastases?

Abstract

A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in 3 cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all 3 cases. In 3 additional cases there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases. This article is protected by copyright. All rights reserved.

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The impact of P-glycoprotein and Breast Cancer Resistance Protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors

Abstract

Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC-transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244) and pimasertib (AS703026): PD0325901 was the weakest substrate of P-gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2^-/- mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, this study recommends further development of PD0325901 for the treatment of intracranial neoplasms. This article is protected by copyright. All rights reserved.

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Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression

Abstract

Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log₂FC|>2). Particularly the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas e.g. genes involved in angiogenesis were down-regulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8x10⁻⁷⁵ log₂FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log₂FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 down-regulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2.

This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected down-regulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. This article is protected by copyright. All rights reserved.

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via IFTTT

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women

Abstract

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; nitrate-nitrogen 5mg/L, 40µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N=15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HR_p95vs.Q1=1.16, 95%CI: 0.51-2.64). Associations with average TTHM levels were also null (HR_Q4vsQ1=0.70, 95%CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HR_p95vs.Q1=1.66, 95% CI 1.00-2.75;p_trend=0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.

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

A naive Bayes algorithm for tissue origin diagnosis (TOD-Bayes) of synchronous multifocal tumors in the hepatobiliary and pancreatic system

Abstract

Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ∼1,000 feature genes were used to train and validate the TOD-Bayes algorithm. The accuracy of the model was > 95% based on 10-fold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including 6 negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step towards more precision-based medicine in cancer diagnosis and treatment. This article is protected by copyright. All rights reserved.

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via IFTTT

Tumor-suppressive miR-145 co-repressed by TCF4-β-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer

Abstract

The frequently dysregulated Wnt/β-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In the present study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA mediated knock-down tests and protein and chromatin immunoprecipitations, we found the TCF4-β-catenin complex can recruit the histone trimethylation complex PRC2 as a co-repressor while binding to the TCF4-binding element (TBE) in the promoter regions of miR-145, miR-132 and miR-212. Thus, upon Wnt signaling activation, the PRC2-mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor-suppressive miR-145 co-repressed by Wnt signaling and histone trimethylation, forms double-negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR-145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/β-catenin signaling and tumor-suppressive miRNAs reciprocally regulate each other in CRC cells. This article is protected by copyright. All rights reserved.

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Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer

Abstract

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an anti-secretory agent may be an effective intervention. T84 monolayers were treated with 1µM dacomitinib and 10µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n=48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p=0.0003), and did not attenuate weight loss (p<0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting. This article is protected by copyright. All rights reserved.

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Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype

Abstract

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-94) and wave 2 (2003-07). We included participants diagnosed to 31 August 2015 with incident stage I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stage I/III disease (p for interaction = .01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance. This article is protected by copyright. All rights reserved.

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Unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report

We describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity.

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Current chemotherapeutic regimens for brain metastases treatment

Abstract

Brain metastasis is a common complication in advanced systemic cancer, with an increasing incidence. The diagnosis of brain metastasis historically portended a dismal prognosis. The successful development of effective treatments for patients with brain metastasis is complicated by the differences among cancer subtypes, the limited understanding of the underlying pathophysiology of BM, the impact of the blood-brain barrier, and other factors. There is now renewed interest in treating this often devastating complication of cancer, and in understanding the underlying mechanisms of disease in this "sanctuary" site. Promising treatment strategies include brain-penetrant targeted therapies and immunotherapy, and strategies for enhanced delivery of therapy. This review highlights a selection of these approaches.

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Current chemotherapeutic regimens for brain metastases treatment

Abstract

Brain metastasis is a common complication in advanced systemic cancer, with an increasing incidence. The diagnosis of brain metastasis historically portended a dismal prognosis. The successful development of effective treatments for patients with brain metastasis is complicated by the differences among cancer subtypes, the limited understanding of the underlying pathophysiology of BM, the impact of the blood-brain barrier, and other factors. There is now renewed interest in treating this often devastating complication of cancer, and in understanding the underlying mechanisms of disease in this "sanctuary" site. Promising treatment strategies include brain-penetrant targeted therapies and immunotherapy, and strategies for enhanced delivery of therapy. This review highlights a selection of these approaches.

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Prim-O-glucosylcimifugin induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells

Prim-O-glucosylcimifugin is a major constituent in Radix Saposhnikovia that has been long used for the treatment of pyrexia, rheumatism, and cancer in traditional Chinese medicine. However, the molecular and cellular mechanisms remain unknown regarding the therapeutic effect of prim-O-lucosylcimifugin. Here, we investigated the effects of prim-O-glucosylcimifugin on cell cycle progression and apoptosis in human acute lymphoblastic leukemia cells. Prim-O-glucosylcimifugin treatment resulted in marked increases in cell apoptosis and cell cycle arrest at the G2/M phase. Mechanistically, prim-O-glucosylcimifugin induced the degradation of β-tubulin and downregulated phosphorylated CDK1 levels, a molecular indicator in the G2/M cell cycle arrest. Furthermore, activation of caspase-3, caspase-8, and caspase-9 was involved in the prim-O-glucosylcimifugin-induced apoptosis. Our study reveals the anticancer activity of prim-O-glucosylcimifugin and the potential underlying mechanisms.

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Liver X receptors agonist T0901317 downregulates matrix metalloproteinase-9 expression in non-small-cell lung cancer by repressing nuclear factor-κB

The liver X receptors (LXRs) is an important component of the nuclear receptor (NR) superfamily. Previous studies have shown that the LXRs possessed antitumor activity in various types of tumor cells. However, the complicated mechanisms underlying the antitumor activity remain largely unexplored. In this study, we incubated A549 cells with the compound T0901317, a specific LXRs agonist, for 24 h. The MTT assay was used to assess cell viability. Transwell assays were used to evaluate cell migration and invasion. The shRNA was utilized for RNA interference. The target gene and protein expression levels were assessed using reverse transcription-PCR and western blot assay. The DNA-binding activity of nuclear factor κB (NF-κB) was examined using electrophoretic mobility shift assays. Luciferase reporter assay was used to detect the binding of NF-κB to the matrix metalloproteinase-9 (MMP-9) promoter. We found that T0901317 inhibited the invasion and migration of A549 cells in a dose-dependent manner. Meanwhile, we further indicated that activation of LXRβ, one subtype of LXRs, can downregulate MMP-9 expression. More importantly, activation of LXRβ triggered by T0901317 inhibited the invasion and metastasis of A549 cells by repressing NF-κB/MMP-9 signaling pathway. Taken together, our study shows that activation of LXRs triggered by T0901317 inhibits the invasion and metastasis of human non-small-cell lung cancer by repressing the NF-κB/MMP-9 signaling pathway.

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Clinical activity of eribulin in advanced desmoplastic small round-cell tumor

Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy – that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them.

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Geraniin inhibits migration and invasion of human osteosarcoma cancer cells through regulation of PI3K/Akt and ERK1/2 signaling pathways

Geraniin, an active compound isolated from Geranium sibiricum, was found to inhibit proliferation and induce apoptosis of tumor cells. However, the antimetastatic effects of geraniin remain elusive. Our study found the potential antitumor mechanisms of geraniin through inhibiting the migration and invasion of human osteosarcoma U2OS cells. The western blot, gelatin zymography, and reversed transcription-PCR analysis showed that geraniin suppressed matrix metalloproteinase-9 (MMP-9) expression in a concentration-dependent manner. Geraniin potently suppressed the phosphorylation of extracellular signal regulating kinase (ERK)1/2, phosphatidylinositide-3-kinase (PI3K), and Akt, but did not affect phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. Furthermore, when transforming growth factor-β1 (TGF-β1) was used as an agonist, geraniin inhibited TGF-β1-mediated cell invasion and upregulation of MMP-9. These results suggested that geraniin inhibited U2OS cell migration and invasion by reducing the expression of MMP-9 through the PI3K/Akt and ERK1/2 signaling pathways.

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Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil: a prospective cohort study

5-Fluorouracil (5-FU) has long been used for the treatment of gastrointestinal tumors harboring interindividual variability in both the pharmacokinetic and the pharmacogenetic profiles, which in turn may lead to life-threatening toxicities. We carried out a prospective cohort study of adult patients initiating treatment with 5-FU between 2013 and 2015. Primary exposures of interest were the methylenetetrahydrofolate reductase single nucleotide polymorphism in exons 4 and 7 and 5′-untranslated region-thymidylate synthase VNTR genotypes, in addition to baseline clinical and demographic variables. The primary outcome was the time to the occurrence of severe toxicity. We used a Cox regression model to evaluate patients' survival and toxicity experience and its association with baseline characteristics and a priori determined genetic polymorphisms. A total of 197 patients were included, 40.1% developed severe toxicity during follow-up. Variables that were significantly associated with developing severe toxicity were the European Organization for Research and Treatment of Cancer functional score [hazard ratio (HR): 0.98; 95% confidence interval (CI): 0.97–0.99]; type of tumor [anus (HR: 2.50; 95% CI: 1.07–5.82), head and neck/esophagus/stomach (HR: 2.95; 95% CI: 1.64–5.33)] and 5-FU continuous infusion regimens over 4–5 days (HR: 9.35; 95% CI: 2.68–32.59). We found a significant association between baseline functional status, type of tumor and continuous infusion regimens and the occurrence of severe toxicity during the follow-up of patients receiving 5-FU. No association was found with the genotypic variants evaluated. Future validation and modeling of an everyday easy-to-use score to predict toxicity among these subgroup of patients remains warranted.

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Andrographolide enhances cisplatin-mediated anticancer effects in lung cancer cells through blockade of autophagy

Lung cancer is the most common cause of cancer-related death worldwide and the platinum-based drugs such as cisplatin have been used as the first line of the treatment. However, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance. In this study, we found that cisplatin induced autophagy that attenuated the sensitivity of both A549 and Lewis lung cancer (LLC) cells to cisplatin. In contrast, the clinical drug andrographolide (Andro) suppressed autophagy and enhanced cisplatin-mediated apoptosis in these cells. Using two murine lung cancer models, including a subcutaneously inoculated LLC model and an orthotopic LLC implantation model, we investigated the therapeutic efficacy of the combined treatment of cisplatin and Andro. Compared with the sole cisplatin treatment, combining cisplatin with Andro potentially inhibited tumor growth, reduced the incidence of lung metastases, and relieved renal tubular damage. Moreover, the combined treatment prolonged the life span of tumor-bearing mice. TUNEL and immunohistochemistry assays showed the increase in apoptotic cells and the decrease in both conversion of LC3B-I to LC3B-II and Atg5 protein expression in the tumor tissues from mice with the combined treatment. These results suggest that Andro offers an ideal candidate of autophagy inhibitors in clinical application, and combination of cisplatin with Andro could be a promising strategy for the treatment of lung cancer.

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Tumour growth increased following antiangiogenic interruption: the challenge of tumour evaluation

Vascular endothelial growth factor inhibitors, led by bevacizumab, are considered the cornerstone of the therapy in metastatic colorectal carcinoma. We present the case of a patient with metastatic colorectal cancer who experienced rapid tumour growth with liver broad invasion after the withdrawal of an antivascular endothelial growth factor therapy, aflibercept. The rebound effect caused by the residual tumour inducing a regrowth after an initial controlled disease has already been stressed in mice and metastatic colorectal cancer patients following bevacizumab interruption. The use of liver volume evaluation was consistent with the Response Evaluation Criteria in Solid Tumours 1.1 criteria evaluation and might be a useful tool in patients with more than a half liver invasion. We describe for the first time the case of a major liver disease progression, confirmed by Response Evaluation Criteria in Solid Tumours 1.1 criteria and liver volume evaluation, after an antiangiogenic interruption in second line.

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Solid lipid nanoparticles improve octyl gallate antimetastatic activity and ameliorate its renal and hepatic toxic effects

Metastasis is the main cause of cancer-related death and requires the development of effective treatments with reduced toxicity and effective anticancer activity. Gallic acid derivatives have shown significant biological properties including antitumoral activity as shown in a previous study with octyl gallate (G8) in vitro. Thus, the aim of this work was to evaluate the antimetastatic effect of free and solid lipid nanoparticle-loaded G8 in mice in a lung metastasis model. Animals inoculated with melanoma cells presented metastasis in lungs, which was significantly inhibited by treatment with G8 and solid lipid nanoparticle-loaded G8, named G8-NVM. However, G8-treated mice showed an increase in several toxicological parameters, which were almost completely circumvented by G8-NVM treatment. This study supports the need for pharmacological studies on new potential medicinal plants to treat cancer and can provide new perspectives on using nanotechnology to improve biological activities while decreasing the chemotherapy toxicological effects of anticancer drugs.

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Screening of medicinal plant phytochemicals as natural antagonists of p53–MDM2 interaction to reactivate p53 functioning

In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. The crystal structure of MDM2, with a 109-residue amino-terminal domain, reveals that MDM2 has a core hydrophobic region to which p53 binds as an amphipathic α helix. The interface depends on the steric complementarity between MDM2 and the hydrophobic region of p53. Especially, on p53's triad, amino acids Phe19, Trp23 and Leu26 bind to the MDM2 core. Results from studies suggest that the structural motif of both p53 and MDM2 can be attributed to similarities in the amphipathic α helix. Thus, in the current investigation it is hypothesized that the similarity in the structural motif might be the cause of p53 inactivation by MDM2. Hence, molecular docking and phytochemical screening approaches are appraised to inhibit the hydrophobic cleft of MDM2 and to stop p53–MDM2 interaction, resulting in reactivation of p53 activity. For this purpose, a library of 2295 phytochemicals were screened against p53–MDM2 to find potential candidates. Of these, four phytochemicals including epigallocatechin gallate, alvaradoin M, alvaradoin E and nordihydroguaiaretic acid were found to be potential inhibitors of p53–MDM2 interaction. The screened phytochemicals, derived from natural extracts, may have negligible side effects and can be explored as potent antagonists of p53–MDM2 interactions, resulting in reactivation of the normal transcription of p53.

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Codelivery of salinomycin and docetaxel using poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles to target both gastric cancer cells and cancer stem cells

Cancer stem cells (CSCs) in gastric cancer (GC) have been established recently as key therapeutic targets for the successful treatment of GC. Emerging evidence suggests that both CSCs and cancer cells should be eradicated to achieve optimal therapeutic efficacy. In the present study, salinomycin, which has been reported to kill CSCs, was used in combination with docetaxel, a chemotherapeutic drug that is used as first-line therapy in GC, to eradicate both GC stem cells (SCs) and cancer cells. Salinomycin and docetaxel were loaded separately into poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles of ∼140 nm with a narrow size distribution, high drug loading, and sustained drug release. GC SCs were isolated by magnetic-activated cell sorting on the basis of CD44 expression as the CSC phenotype. CD44+ GC SCs showed the characteristics of CSCs, including increased SC gene expression, tumorsphere formation capacity, and tumorigenicity in nude mice. We found that both salinomycin and salinomycin-loaded nanoparticles (salinomycin-NPs) could selectively eradicate GC SCs, as reflected by reduced tumorsphere formation capacity and the frequency of CD44+ GC cells, whereas docetaxel and docetaxel-loaded nanoparticles (docetaxel-NPs) could significantly eradicate GC cells. In nude mice bearing GC xenografts, salinomycin-NPs and salinomycin significantly decreased the intratumor population of GC SCs. Notably, salinomycin-NPs combined with docetaxel-NPs suppressed tumor growth more effectively than did salinomycin combined with docetaxel, single salinomycin-NPs, or docetaxel-NPs. Therefore, salinomycin-NPs combined with docetaxel-NPs represent a promising strategy for the treatment of GC by eradicating both GC SCs and cancer cells.

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Treatment with abiraterone in metastatic castration-resistant prostate cancer patients progressing after docetaxel: a retrospective study

The aim of this study was to evaluate abiraterone's efficacy in Italian patients affected with metastatic prostate cancer progressing after treatment with docetaxel. We conducted a retrospective analysis of 60 patients. Prostate-specific antigen (PSA) reduction in serum was the primary endpoint for evaluating the efficacy of abiraterone in combination with prednisone treatment, whereas reduced pain, safety, progression-free survival, response rate, and overall survival (OS) were secondary endpoints. A significant correlation was noticed between PSA response and OS. Further, the Index Bravais–Pearson (r) correlation allowed us to observe a significant negative interdependence between PSA response and reduction in pain of 0.57 (95% confidence interval: −0.30 to 0.80) (P=0.005). Meanwhile, regression analysis revealed that PSA levels are predictive of OS. There was a positive correlation with OS, which showed a value of R2 to 0.50 with a slope of 1.44 (P=0.0021). Abiraterone is a well-tolerated and effective treatment modality for patients affected with metastatic castration-resistant prostate cancer. The drug has a better tolerability profile, gives significant pain relief, and increases the survival rate.

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Enhanced anticancer efficacy of histone deacetyl inhibitor, suberoylanilide hydroxamic acid, in combination with a phosphodiesterase inhibitor, pentoxifylline, in human cancer cell lines and in-vivo tumor xenografts

Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo.

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A case of resistance to tyrosine kinase inhibitor therapy: small cell carcinoma transformation concomitant with plasma-genotyped T790M positivity

Although non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors, drug resistances are always inevitable. The secondary somatic EGFR threonine–methionine substitution at position 790 (T790M) mutation accounts for ∼50% of acquired resistance mechanisms. Small cell lung cancer (SCLC) transformation is a relatively rare mechanism, but has recently attracted considerable attention. The coexistence of both the mechanisms in one patient is much more scarce in clinic. In this case report, we described a 37-year-old woman who underwent refractory after second-line gefitinib therapy and was confirmed to have SCLC transformation without the T790M mutation in the left lobar nodule, but concomitant with the plasma-genotyped EGFR T790M mutation. Our case report uncovered the underling relationship between SCLC transformation and the T790M mutation, and the fluid biopsy approach may help overcome the problem of heterogeneity in acquired resistance to EGFR-tyrosine kinase inhibitors.

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Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein

Androgen receptor (AR) expression and activity is highly linked to the development and progression of prostate cancer and is a target of therapeutic strategies for this disease. We investigated whether the antimalarial drug artemisinin, which is a sesquiterpene lactone isolated from the sweet wormwood plant Artemisia annua, could alter AR expression and responsiveness in cultured human prostate cancer cell lines. Artemisinin treatment induced the 26S proteasome-mediated degradation of the receptor protein, without altering AR transcript levels, in androgen-responsive LNCaP prostate cancer cells or PC-3 prostate cancer cells expressing exogenous wild-type AR. Furthermore, artemisinin stimulated AR ubiquitination and AR receptor interactions with the E3 ubiquitin ligase MDM2 in LNCaP cells. The artemisinin-induced loss of AR protein prevented androgen-responsive cell proliferation and ablated total AR transcriptional activity. The serine/threonine protein kinase AKT-1 was shown to be highly associated with artemisinin-induced proteasome-mediated degradation of AR protein. Artemisinin treatment activated AKT-1 enzymatic activity, enhanced receptor association with AKT-1, and induced AR serine phosphorylation. Treatment of LNCaP cells with the PI3-kinase inhibitor LY294002, which inhibits the PI3-kinase-dependent activation of AKT-1, prevented the artemisinin-induced AR degradation. Furthermore, in transfected receptor-negative PC-3 cells, artemisinin failed to stimulate the degradation of an altered receptor protein (S215A/S792A) with mutations in its two consensus AKT-1 serine phosphorylation sites. Taken together, our results indicate that artemisinin induces the degradation of AR protein and disrupts androgen responsiveness of human prostate cancer cells, suggesting that this natural compound represents a new potential therapeutic molecule that selectively targets AR levels.

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CXCR4 blockade with AMD3100 enhances Taxol chemotherapy to limit ovarian cancer cell growth

The standard of care for ovarian cancer includes initial treatment with chemotherapy. Despite initial efficacy, over 70% of patients develop recurrence; thus, there is a need to identify novel approaches that can improve therapeutic outcomes. We evaluated AMD3100 (Plerixafor), an FDA-approved CXCR4 inhibitor, as a potential adjunctive therapy for low-dose Taxol (Paclitaxel) by assessing the impact on in-vitro ovarian cancer cell proliferation. Proliferation was a measure for both human TOV-112D and murine ID8 ovarian cancer cells incubated with AMD3100 and Taxol, either individually or in combination. Impact of treatment was first determined for the simultaneous administration of AMD3100 and Taxol. We next assessed a sequential application of AMD3100 pretreatment, followed by AMD3100, Taxol, or a combination to test for sensitization to Taxol. In addition, we measured the impact of AMD3100 and Taxol, individually and in combination, on colony formation, an in-vitro model assay of tumor growth. Expression data, as measured by flow cytometry, show that both ID8 and TOV-112D cells are positive for CXCR4, CXCR7, and CXCL12. Combination treatment with AMD3100 (≤10 μmol/l) sensitized both ID8 and TOV-112D cells to low concentrations of Taxol (≤5 nmol/l), limiting cell proliferation and colony formation in vitro. Pretreatment with AMD3100 significantly increased the sensitivity of human ovarian cancer to low-dose Taxol or the combination of AMD3100 and Taxol, although this effect was not evident in murine cells. Importantly, for both human and murine cells, incubation with a combination of AMD3100 and Taxol had the largest impact on limiting cell proliferation. AMD3100 in combination with low-dose Taxol offers improved efficacy and the potential of reduced toxicity for the treatment of ovarian cancer.

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