The inhibition of invasion of human melanoma cells through N-cadherin knock-down

Abstract

N-cadherin seems to promote cell migration and invasion in many types of cancers. The object of this study is recognition of the possible role of N-cadherin and selected downstream protein kinases: PI3K, ERK1/2, and mTOR in cell invasion in malignant melanoma. Melanoma cells were transfected with the small interfering RNA (siRNA) that targets human N–cadherin gene (CDH2). Inhibitors LY294002 (PI3K), U0126 (ERK1/2), and everolimus (mTOR) were used to inhibit selected kinases of signalling pathways. In vitro cell invasion was studied using Matrigel and an analysis of matrix metalloproteinases MMP-2 and MMP-9 activity by gelatinase zymogram assay. Treatment of melanoma cell with either siRNA against N-cadherin or protein kinase inhibitors led to significantly decreased MMPs expression and activity, as well as diminished invasion. Both the current and the former results suggest that activation of PI3/AKT, mTOR, and ERK kinase, following N-cadherin expression, contributes not only to increased proliferation but also invasive potential of melanoma cells. The results also indicate that N-cadherin, as well as the studied kinases, should be considered as a potential target in melanoma therapy.

http://ift.tt/2BX7yOv

The inhibition of invasion of human melanoma cells through N-cadherin knock-down

Abstract

N-cadherin seems to promote cell migration and invasion in many types of cancers. The object of this study is recognition of the possible role of N-cadherin and selected downstream protein kinases: PI3K, ERK1/2, and mTOR in cell invasion in malignant melanoma. Melanoma cells were transfected with the small interfering RNA (siRNA) that targets human N–cadherin gene (CDH2). Inhibitors LY294002 (PI3K), U0126 (ERK1/2), and everolimus (mTOR) were used to inhibit selected kinases of signalling pathways. In vitro cell invasion was studied using Matrigel and an analysis of matrix metalloproteinases MMP-2 and MMP-9 activity by gelatinase zymogram assay. Treatment of melanoma cell with either siRNA against N-cadherin or protein kinase inhibitors led to significantly decreased MMPs expression and activity, as well as diminished invasion. Both the current and the former results suggest that activation of PI3/AKT, mTOR, and ERK kinase, following N-cadherin expression, contributes not only to increased proliferation but also invasive potential of melanoma cells. The results also indicate that N-cadherin, as well as the studied kinases, should be considered as a potential target in melanoma therapy.

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The risk of cardiovascular disease following breast cancer by Framingham risk score

Abstract

Objectives

This study evaluates the risk of cardiovascular disease (CVD) following breast cancer, accounting for baseline CVD risk.

Methods

Within the EPIC-NL (Dutch part of the European Prospective Investigation into Nutrition and Cancer) cohort, 1103 women were diagnosed with breast cancer. For every breast cancer patient, 3–4 women without breast cancer (n = 4328) were selected matched for age, year, and time since cohort enrollment. Based on CVD risk factors at cohort enrollment, 10-year risk of CVD was calculated and categorized: low (< 10%), intermediate (10–20%), high (> 20%). Cox proportional hazard models assessed the risk of CVD events (hospitalization or mortality) and CVD mortality of women with versus without breast cancer, adjusted for baseline CVD risk.

Results

After median follow-up of 5 and 6 years, 92 (8.3%) and 325 (7.5%) CVD events occurred in women with and without breast cancer, respectively. In the low CVD risk group, women with breast cancer had 1.44 (95% CI 1.00–2.06) times higher risk of CVD events than women without breast cancer. In the intermediate and high CVD risk categories, risk of CVD events was similar in women with and without breast cancer. Overall, women with breast cancer had 1.77 (95% CI 1.10–2.86) times higher risk of CVD mortality than women without breast cancer.

Conclusions

Among women with low CVD risk, women with breast cancer have a higher risk of CVD event than women without breast cancer. Overall, women with breast cancer have a higher risk of CVD mortality than women without breast cancer.

http://ift.tt/2EZnSxa

Associations of Metabolic syndrome and C-reactive protein with Mortality from total cancer, obesity-linked cancers and Breast Cancer among Women in NHANES III

Abstract

Although metabolic syndrome (MetS) is a prognostic factor for cancer occurrence, the association of MetS and cancer mortality remains unclear. The purpose of this study was to evaluate whether MetS, components of MetS and C-reactive protein (CRP) are associated with cancer mortality in women.

A total of 400 cancer deaths, with 140 deaths from obesity-linked-cancers (OLCas), [breast (BCa), colorectal, pancreatic and endometrial], linked through the National Death Index, were identified from 10,104 eligible subjects aged ≥18 years. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) for cancer mortality.

MetS was associated with increased deaths for total-cancer [HR=1.33, 95% confidence interval (CI) 1.04-1.70] and BCa [HR=2.1, 95% CI, 1.09-4.11]. The risk of total-cancer [HR=1.7, 95% CI, 1.12-2.68], OLCas [HR=2.1, 95% CI, 1.00-4.37] and BCa [HR=3.8, 95% CI, 1.34-10.91] mortality was highest for women with all MetS components abnormal, compared to those without MetS. Linear associations of blood-pressure [HR=2.5, 1.02-6.12, Quartile (Q) 4 vs Q1, p-trend=0.004] and blood-glucose [HR=2.2, 1.04-4.60, Q4 vs Q1, p-trend=0.04] with total-OLCas mortality were observed. A three-fold increased risk of BCa mortality was observed for women with enlarged waist circumference, ≥100.9cm, [HR=3.5, 1.14-10.51, p-trend=0.008] and in those with increased blood glucose, ≥101mg/dL, [HR=3.2, 1.11-9.20, p-trend=0.03] compared to those in Q1. None of the components of MetS were associated with total-cancer mortality. CRP was not associated with cancer mortality.

In conclusion, MetS is associated with total-cancer and breast-cancer mortality, with waist circumference, blood pressure and blood glucose as independent predictors of OLCas and BCa mortality. This article is protected by copyright. All rights reserved.

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Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women

Abstract

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes, and homeostasis model-insulin resistance (HOMA-IR – a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0, and ≥30.0 kg/m²) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. This article is protected by copyright. All rights reserved.

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Pharmacological Inhibition of the Notch Pathway Enhances the Efficacy of Androgen Deprivation Therapy for Prostate Cancer

Abstract

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In this study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch Pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. This article is protected by copyright. All rights reserved.

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Associations of Metabolic syndrome and C-reactive protein with Mortality from total cancer, obesity-linked cancers and Breast Cancer among Women in NHANES III

Abstract

Although metabolic syndrome (MetS) is a prognostic factor for cancer occurrence, the association of MetS and cancer mortality remains unclear. The purpose of this study was to evaluate whether MetS, components of MetS and C-reactive protein (CRP) are associated with cancer mortality in women.

A total of 400 cancer deaths, with 140 deaths from obesity-linked-cancers (OLCas), [breast (BCa), colorectal, pancreatic and endometrial], linked through the National Death Index, were identified from 10,104 eligible subjects aged ≥18 years. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios (HR) for cancer mortality.

MetS was associated with increased deaths for total-cancer [HR=1.33, 95% confidence interval (CI) 1.04-1.70] and BCa [HR=2.1, 95% CI, 1.09-4.11]. The risk of total-cancer [HR=1.7, 95% CI, 1.12-2.68], OLCas [HR=2.1, 95% CI, 1.00-4.37] and BCa [HR=3.8, 95% CI, 1.34-10.91] mortality was highest for women with all MetS components abnormal, compared to those without MetS. Linear associations of blood-pressure [HR=2.5, 1.02-6.12, Quartile (Q) 4 vs Q1, p-trend=0.004] and blood-glucose [HR=2.2, 1.04-4.60, Q4 vs Q1, p-trend=0.04] with total-OLCas mortality were observed. A three-fold increased risk of BCa mortality was observed for women with enlarged waist circumference, ≥100.9cm, [HR=3.5, 1.14-10.51, p-trend=0.008] and in those with increased blood glucose, ≥101mg/dL, [HR=3.2, 1.11-9.20, p-trend=0.03] compared to those in Q1. None of the components of MetS were associated with total-cancer mortality. CRP was not associated with cancer mortality.

In conclusion, MetS is associated with total-cancer and breast-cancer mortality, with waist circumference, blood pressure and blood glucose as independent predictors of OLCas and BCa mortality. This article is protected by copyright. All rights reserved.

http://ift.tt/2ovwpBD

Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women

Abstract

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes, and homeostasis model-insulin resistance (HOMA-IR – a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0, and ≥30.0 kg/m²) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. This article is protected by copyright. All rights reserved.

http://ift.tt/2oBIV1J

Pharmacological Inhibition of the Notch Pathway Enhances the Efficacy of Androgen Deprivation Therapy for Prostate Cancer

Abstract

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In this study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch Pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. This article is protected by copyright. All rights reserved.

http://ift.tt/2Co63KB

Efficacy and safety of the trastuzumab biosimilar candidate CT-P6

Future Oncology, Ahead of Print.


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Efficacy and safety of the trastuzumab biosimilar candidate CT-P6

Future Oncology, Ahead of Print.


http://ift.tt/2F3F7gN

Heterochromatin protein 1{alpha} mediates development and aggressiveness of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.

http://ift.tt/2oy9a9g

Interleukin-30/IL-27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization

Prostate cancer (PC) stem-like cells (PCSLCs) are believed to be responsible for PC onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In PC patients, interleukin(IL)-30/IL-27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here we asked whether IL-30 may favor PC progression by conditioning PCSLCs and assessed the value of blocking IL-30 to suppress tumor growth. IL-30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL-30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL-30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL-30 knockdown or knockout in PCSLCs. Collectively, these results mark IL-30 as a key driver of PCSLC behavior. Targeting IL-30 signaling may be a potential therapeutic strategy against PC progression and recurrence.

http://ift.tt/2CpPYnE

Targeting the SUMO pathway primes all-trans retinoic acid-induced differentiation of non-promyelocytic acute myeloid leukemias

Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a post-translational modification related to ubiquitination, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with pharmacological inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA-induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-APL AML cells. This activated ATRA-induced terminal myeloid differentiation and reduced cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation via overexpression of SUMO-conjugating enzyme Ubc9 dampened expression of ATRA-responsive genes and prevented differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor-prognosis cancer.

http://ift.tt/2oAK9dz

Lutetium Lu 177 Dotatate Approved by FDA [News in Brief]

Radiopharmaceutical becomes treatment option for patients with certain neuroendocrine tumors.

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NIH Offers Funding for Genome-Editing Projects [News in Brief]

Agency to award $190 million for technology development over next 6 years.

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Heterochromatin protein 1{alpha} mediates development and aggressiveness of neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer (PCa) arising mostly from adenocarcinoma via NE transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathological feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor (AR) and RE1 silencing transcription factor (REST) and enriched the repressive trimethylated histone H3 at Lys9 (H3K9me3) mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.

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A Resource for Managing Immunotherapy Side Effects [News in Brief]

Comprehensive guidelines aim to help clinicians diagnose and treat side effects of checkpoint inhibitors.

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Interleukin-30/IL-27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization

Prostate cancer (PC) stem-like cells (PCSLCs) are believed to be responsible for PC onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In PC patients, interleukin(IL)-30/IL-27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here we asked whether IL-30 may favor PC progression by conditioning PCSLCs and assessed the value of blocking IL-30 to suppress tumor growth. IL-30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL-30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL-30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL-30 knockdown or knockout in PCSLCs. Collectively, these results mark IL-30 as a key driver of PCSLC behavior. Targeting IL-30 signaling may be a potential therapeutic strategy against PC progression and recurrence.

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Targeting the SUMO pathway primes all-trans retinoic acid-induced differentiation of non-promyelocytic acute myeloid leukemias

Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a post-translational modification related to ubiquitination, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with pharmacological inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA-induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-APL AML cells. This activated ATRA-induced terminal myeloid differentiation and reduced cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation via overexpression of SUMO-conjugating enzyme Ubc9 dampened expression of ATRA-responsive genes and prevented differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor-prognosis cancer.

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Landiolol hydrochloride to successfully treat refractory ventricular arrhythmia during weaning from cardiopulmonary bypass

We effectively treated refractory ventricular arrhythmia (RVA) at the time of weaning from the cardiopulmonary bypass (CPB) during aortic valve replacement with landiolol for three patients who failed to respond to electrical defibrillation. Demographic data, comorbid factors, and preoperative finding were noted [Table 1].

http://ift.tt/2oss0iX

Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy

Abstract

Background

To evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients.

Methods

Two groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re-planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test.

Results

Both SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V₂₀, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST.

Conclusions

This study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice.

http://ift.tt/2ovfr6y

Response criteria in solid tumors (PERCIST/RECIST) and SUV max in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy

Abstract

Background

The purpose of this study was to evaluate the prognostic impact of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) and of pre- and post-treatment maximum Standard Uptake Value (SUV_max) in regards to survival and tumor control for patients treated for early-stage non-small cell lung cancer (ES-NSCLC) with stereotactic body radiotherapy (SBRT).

Methods

This is a retrospective review of patients with ES-NSCLC treated at our institution using SBRT. Lobar, locoregional, and distant failures were evaluated based on PERCIST/RECIST and clinical course. Univariate analysis of the Kaplan-Meier curves for overall survival (OS), progression free survival (PFS), lobar control (LC), locoregional control (LRC), and distant control (DC) was conducted using the log-rank test. Pre- and post-treatment SUV_max were evaluated using cutoffs of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3. ∆SUV_max was also evaluated at various cutoffs. Cox regression analysis was conducted to evaluate survival outcomes based on age, gender, pre-treatment gross tumor volume (GTV), longest tumor dimension on imaging, and Charlson Comorbidity Index (CCI).

Results

This study included 95 patients (53 female, 42 male), median age 75. Lung SBRT was delivered in 3–5 fractions to a total of 48–60 Gy, with a BED_{α/β = 10Gy} of at least 100 Gy. Median OS and PFS from the end of SBRT was 15.4 and 11.9 months, respectively. On univariate analysis, PERCIST/RECIST response correlated with PFS (p = 0.039), LC (p = 0.007), and LRC (p = 0.015) but not OS (p = 0.21) or DC (p = 0.94). Pre-treatment SUV_max and post-treatment SUV_max with cutoff values of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3 did not predict for OS, PFS, LC, LRC, or DC. ∆SUV_max did not predict for OS, PFS, LC, LRC, or DC. On multivariate analysis, pre-treatment GTV ≥ 30 cm³ was significantly associated with worse survival outcomes when accounting for other confounding variables.

Conclusions

PERCIST/RECIST response is associated with improved LC and PFS in patients treated for ES-NSCLC with SBRT. In contrast, pre- and post-treatment SUV_max is not predictive of disease control or survival.

http://ift.tt/2ozZc7a

Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy

Abstract

Background

To evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients.

Methods

Two groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re-planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test.

Results

Both SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V₂₀, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST.

Conclusions

This study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice.

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Response criteria in solid tumors (PERCIST/RECIST) and SUV max in early-stage non-small cell lung cancer patients treated with stereotactic body radiotherapy

Abstract

Background

The purpose of this study was to evaluate the prognostic impact of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) and of pre- and post-treatment maximum Standard Uptake Value (SUV_max) in regards to survival and tumor control for patients treated for early-stage non-small cell lung cancer (ES-NSCLC) with stereotactic body radiotherapy (SBRT).

Methods

This is a retrospective review of patients with ES-NSCLC treated at our institution using SBRT. Lobar, locoregional, and distant failures were evaluated based on PERCIST/RECIST and clinical course. Univariate analysis of the Kaplan-Meier curves for overall survival (OS), progression free survival (PFS), lobar control (LC), locoregional control (LRC), and distant control (DC) was conducted using the log-rank test. Pre- and post-treatment SUV_max were evaluated using cutoffs of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3. ∆SUV_max was also evaluated at various cutoffs. Cox regression analysis was conducted to evaluate survival outcomes based on age, gender, pre-treatment gross tumor volume (GTV), longest tumor dimension on imaging, and Charlson Comorbidity Index (CCI).

Results

This study included 95 patients (53 female, 42 male), median age 75. Lung SBRT was delivered in 3–5 fractions to a total of 48–60 Gy, with a BED_{α/β = 10Gy} of at least 100 Gy. Median OS and PFS from the end of SBRT was 15.4 and 11.9 months, respectively. On univariate analysis, PERCIST/RECIST response correlated with PFS (p = 0.039), LC (p = 0.007), and LRC (p = 0.015) but not OS (p = 0.21) or DC (p = 0.94). Pre-treatment SUV_max and post-treatment SUV_max with cutoff values of < 5 and ≥ 5, < 4 and ≥ 4, and < 3 and ≥ 3 did not predict for OS, PFS, LC, LRC, or DC. ∆SUV_max did not predict for OS, PFS, LC, LRC, or DC. On multivariate analysis, pre-treatment GTV ≥ 30 cm³ was significantly associated with worse survival outcomes when accounting for other confounding variables.

Conclusions

PERCIST/RECIST response is associated with improved LC and PFS in patients treated for ES-NSCLC with SBRT. In contrast, pre- and post-treatment SUV_max is not predictive of disease control or survival.

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Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy

Abstract

Background

Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy.

Methods

We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (≤ 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year).

Results

Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA.

Conclusions

In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor.

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Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy

Abstract

Background

Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy.

Methods

We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (≤ 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year).

Results

Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA.

Conclusions

In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor.

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Copyright

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2





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Contributors

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2





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Contents

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2





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Forthcoming Issues

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2





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Colon Cancer

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2
Author(s): Mark W. Arnold




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Minimally Invasive Surgical Approaches to Colon Cancer

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2
Author(s): Jean F. Salem, Sriharsha Gummadi, John H. Marks

Teaser

Colon cancer remains the most common abdominal visceral malignancy affecting both men and women in America. Open colectomy has been the standard of care for colon cancer patients the past 100 years; although highly effective, the major trauma associated with it has a significant morbidity rate and represents a large operation for patients to recover from. Minimally invasive colon surgery was developed as a new and alternative option, and surgeons aim to continue to make it simpler, more reproducible, and easier to teach and learn. We describe herein the current state of minimally invasive colorectal surgery for colon cancer and compare it with open surgery to offer insights to future directions.


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Population Screening for Hereditary Colorectal Cancer

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2
Author(s): Heather Hampel

Teaser

Colorectal cancer can be caused by hereditary cancer syndromes such as Lynch syndrome and the polyposis syndromes. Tumor screening for Lynch syndrome has been recommended by several professional organizations. In addition, it has been shown that patients with microsatellite unstable colorectal cancer can benefit from immunotherapy. Unfortunately, universal tumor screening for Lynch syndrome has not been implemented at all hospitals yet. More recent studies have found that the prevalence of all hereditary cancer syndromes is around 10%, and for those diagnosed under age 50, it is closer to 16%. It may be time to consider offering genetic counseling and testing to all colorectal cancer patients.


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Clinical Trials and Progress in Metastatic Colon Cancer

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2
Author(s): Kabir Mody, Tanios Bekaii-Saab

Teaser

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide but associated mortality has declined in recent decades. Genomic profiling of the disease has resulted in the definition of subsets of patients—for example, KRAS, NRAS, or BRAF mutated; Her2 amplified; and mismatch repair deficient—which has enabled personalization of therapeutic decision making. These subsets are guiding drug development and combination therapy approaches using both targeted therapies and immunotherapies. Further refinement based on molecular discoveries and the emergence of newer technologies to enable new discoveries allow for great optimism for the future on behalf of patients with colon cancer.


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Maximizing the Effectiveness of Colonoscopy in the Prevention of Colorectal Cancer

Publication date: April 2018
Source:Surgical Oncology Clinics of North America, Volume 27, Issue 2
Author(s): John F. Sullivan, John A. Dumot

Teaser

Colonoscopy is a proven screening test for colorectal cancer; maximizing its effectiveness is the best way to decrease interval colorectal cancer. The adenoma detection rate can be improved by monitoring physician detection rates. Assistive devices and innovative endoscopic equipment may also decrease adenoma miss rates. Complete polypectomy of adenomatous lesions and recommending the proper date for the next examination are important considerations. Advanced polypectomy techniques including endoscopic mucosal resection and endoscopic mucosal dissection have a clear role in the nonsurgical management of large laterally spreading adenomatous polyps that previously would have required surgical resection.


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Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy, Published online: 27 February 2018; doi:10.1038/bjc.2017.467

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

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Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours, Published online: 27 February 2018; doi:10.1038/bjc.2017.460

Systemic immune-inflammation index in germ-cell tumours

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Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker, Published online: 27 February 2018; doi:10.1038/bjc.2018.7

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

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Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy, Published online: 27 February 2018; doi:10.1038/bjc.2017.467

Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

http://ift.tt/2t0EOSf

Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours

Systemic immune-inflammation index in germ-cell tumours, Published online: 27 February 2018; doi:10.1038/bjc.2017.460

Systemic immune-inflammation index in germ-cell tumours

http://ift.tt/2Cq5qA6

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker, Published online: 27 February 2018; doi:10.1038/bjc.2018.7

Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

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Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel

.


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Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel

.


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Imaging biomarkers of outcome after radiotherapy for pediatric ependymoma

Ependymoma is the third most common brain tumor in children. Radiation therapy (RT) is systematically administered after maximum surgical resection, utilizing recent advances in radiation delivery. Imaging can make a significant contribution to improving treatment outcome. This prompted us to look for significant preoperative and postoperative imaging markers for survival.

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Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

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Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

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Systemic immune-inflammation index in germ-cell tumours

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Systemic immune-inflammation index in germ-cell tumours: search for a biological prognostic biomarker

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Systemic inflammatory markers have independent prognostic value in patients with metastatic testicular germ cell tumours undergoing first-line chemotherapy

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Systemic immune-inflammation index in germ-cell tumours

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Hepatitis C: When high drug prices preclude patient benefit

Currently, there are at least 6 drug companies that have developed curative treatments for hepatitis C. Drugs that cure hepatitis C can save up to one-half million individuals every year, but these therapies are neither accessible nor affordable. See also pages 000-000.

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Prevention of liver cancer with new curative hepatitis C antivirals: Real-world challenges

New antiviral therapies cure most patients with hepatitis C and prevent the development of cirrhosis and hepatocellular carcinoma. The major challenges for global hepatitis C virus eradication are the identification of patients with chronic hepatitis C, referrals to treatment, and elevated drug prices. See also pages 000-000.

http://ift.tt/2EWwnNj

Hepatitis C: When high drug prices preclude patient benefit

Currently, there are at least 6 drug companies that have developed curative treatments for hepatitis C. Drugs that cure hepatitis C can save up to one-half million individuals every year, but these therapies are neither accessible nor affordable. See also pages 000-000.

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Prevention of liver cancer with new curative hepatitis C antivirals: Real-world challenges

New antiviral therapies cure most patients with hepatitis C and prevent the development of cirrhosis and hepatocellular carcinoma. The major challenges for global hepatitis C virus eradication are the identification of patients with chronic hepatitis C, referrals to treatment, and elevated drug prices. See also pages 000-000.

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Cabozantinib Approval Expands Initial Treatment Options for Advanced Kidney Cancer

The Food and Drug Administration has approved cabozantinib (Cabometyx®) as an initial treatment for patients with advanced renal cell carcinoma, the most common type of kidney cancer.

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Cabozantinib Approval Expands Initial Treatment Options for Advanced Kidney Cancer

The Food and Drug Administration has approved cabozantinib (Cabometyx®) as an initial treatment for patients with advanced renal cell carcinoma, the most common type of kidney cancer.

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Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers doi: 10.3390/cancers10030061

Authors: Sergio Lamprecht Ina Sigal-Batikoff Shraga Shany Naim Abu-Freha Eduard Ling George Delinasios Keren Moyal-Atias John Delinasios Alexander Fich

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells.

http://ift.tt/2BUbHCR

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers doi: 10.3390/cancers10030060

Authors: Urska Kamensek Natasa Tesic Gregor Sersa Maja Cemazar

Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU.

http://ift.tt/2EXtiwG

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers doi: 10.3390/cancers10030059

Authors: David Corujo Marcus Buschbeck

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.

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Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers, Vol. 10, Pages 59: Post-Translational Modifications of H2A Histone Variants and Their Role in Cancer

Cancers doi: 10.3390/cancers10030059

Authors: David Corujo Marcus Buschbeck

Histone variants are chromatin components that replace replication-coupled histones in a fraction of nucleosomes and confer particular characteristics to chromatin. H2A variants represent the most numerous and diverse group among histone protein families. In the nucleosomal structure, H2A-H2B dimers can be removed and exchanged more easily than the stable H3-H4 core. The unstructured N-terminal histone tails of all histones, but also the C-terminal tails of H2A histones protrude out of the compact structure of the nucleosome core. These accessible tails are the preferential target sites for a large number of post-translational modifications (PTMs). While some PTMs are shared between replication-coupled H2A and H2A variants, many modifications are limited to a specific histone variant. The present review focuses on the H2A variants H2A.Z, H2A.X, and macroH2A, and summarizes their functions in chromatin and how these are linked to cancer development and progression. H2A.Z primarily acts as an oncogene and macroH2A and H2A.X as tumour suppressors. We further focus on the regulation by PTMs, which helps to understand a degree of context dependency.

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Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers, Vol. 10, Pages 61: Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-β1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts

Cancers doi: 10.3390/cancers10030061

Authors: Sergio Lamprecht Ina Sigal-Batikoff Shraga Shany Naim Abu-Freha Eduard Ling George Delinasios Keren Moyal-Atias John Delinasios Alexander Fich

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-β1 (TGFβ-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFβ-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs—the most abundant cell population of the tumor microenvironment (TME)—as target cells.

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Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers, Vol. 10, Pages 60: Clinically Usable Interleukin 12 Plasmid without an Antibiotic Resistance Gene: Functionality and Toxicity Study in Murine Melanoma Model

Cancers doi: 10.3390/cancers10030060

Authors: Urska Kamensek Natasa Tesic Gregor Sersa Maja Cemazar

Plasmids, which are currently used in interleukin 12 (IL-12) gene electrotransfer (GET) clinical trials in the USA, contain antibiotic resistance genes and are thus, according to the safety recommendation of the European Medicines Agency (EMA), not suitable for clinical trials in the EU. In the current study, our aim was to prepare an IL-12 plasmid without an antibiotic resistance gene and test its functionality and toxicity after GET in a preclinical B16F10 mouse melanoma model. The antibiotic resistance-free plasmid encoding the human IL-12 fusion gene linked to the p21 promoter, i.e., p21-hIL-12-ORT, was constructed using operator-repressor titration (ORT) technology. Next, the expression profile of the plasmid after GET was determined in B16F10 cells and tumors. Additionally, blood chemistry, hematological and histological changes, and antitumor response were evaluated after GET of the plasmid in melanoma tumors. The results demonstrated a good expression and safety profile of the p21-hIL-12-ORT GET and indications of efficacy. We hope that the obtained results will help to accelerate the transfer of this promising treatment from preclinical studies to clinical application in the EU.

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Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Abstract

Background

In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results

Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions

This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.

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Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis

Abstract

Background

Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis.

Results

Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h.

No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO₃⁻ were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h.

Conclusion

Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

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Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging

Abstract

Background

In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results

Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions

This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.

http://ift.tt/2oumtIK

Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis

Abstract

Background

Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis.

Results

Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h.

No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO₃⁻ were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h.

Conclusion

Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

http://ift.tt/2CLGWwO

Cardiopulmonary resuscitation