Using Social Media at National Meetings in Hematology—Optimal Use, Tips, Strategies, and Limitations

Abstract

Social media has become an important tool for physicians and scientists to rapidly share information with colleagues around the world. Use of social media outlets—in particular, Twitter—has risen rapidly in recent years, and it is now customary for national hematology meetings to have thousands of participants who share photographs and textual summaries of data presentations, as well as personal insights and commentary, with virtual audiences. These messages, or "tweets," can be specifically followed using a hashtag ontology which arose organically over the past several years in the context of medical meetings. This system facilitates communication between meeting attendees and those colleagues near and far with similar interests, thus globalizing the conversation between hematology providers, investigators, patient advocates, professional organizations, regulatory agencies, testing companies, and the pharmaceutical industry about cutting-edge developments in the field.

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Using Social Media at National Meetings in Hematology—Optimal Use, Tips, Strategies, and Limitations

Abstract

Social media has become an important tool for physicians and scientists to rapidly share information with colleagues around the world. Use of social media outlets—in particular, Twitter—has risen rapidly in recent years, and it is now customary for national hematology meetings to have thousands of participants who share photographs and textual summaries of data presentations, as well as personal insights and commentary, with virtual audiences. These messages, or "tweets," can be specifically followed using a hashtag ontology which arose organically over the past several years in the context of medical meetings. This system facilitates communication between meeting attendees and those colleagues near and far with similar interests, thus globalizing the conversation between hematology providers, investigators, patient advocates, professional organizations, regulatory agencies, testing companies, and the pharmaceutical industry about cutting-edge developments in the field.

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Immune-related intestinal pseudo-obstruction associated with nivolumab treatment in a lung cancer patient

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis

Abstract

Patients undergoing radiation therapy for the head and neck are susceptible to a significant and often abrupt deterioration in their oral health. The oral morbidities of radiation therapy include but are not limited to an increased susceptibility to dental caries and periodontal disease. They also include profound and often permanent functional and sensory changes involving the oral soft tissue. These changes range from oral mucositis experienced during and soon after treatment, mucosal opportunistic infections, neurosensory disorders, and tissue fibrosis. Many of the oral soft tissue changes following radiation therapy are difficult challenges to the patients and their caregivers and require life-long strategies to alleviate their deleterious effect on basic life functions and on the quality of life. We discuss the presentation, prognosis, and management strategies of the dental structure and oral soft tissue morbidities resulting from the administration of therapeutic radiation in head and neck patient. A case for a collaborative and integrated multidisciplinary approach to the management of these patients is made, with specific recommendation to include knowledgeable and experienced oral health care professionals in the treatment team.

Oral complications of radiation therapy to the head and neck can result in acute and long-term deterioration in oral soft tissues and dentition. The presentation, prognosis, and strategies to manage the dental and nondental morbidities of radiation therapy to the head and neck are discussed in this manuscript.

http://ift.tt/2zEiQCV

Cancer Registry follow-up for 17 million person-years of a nationwide maternity cohort

Abstract

Population-based Finnish Maternity Cohort (FMC) comprises 2M first trimester sera collected from 1M women during 33 years. Informed consent is by the opt-out principle, and linkages with cancer and population registries provide a base for over time and over generation studies. Follow-up for 17M person-years by the end of 2014 can identify 39,700 cases of invasive cancer and 18,900 cases of premalignant breast and cervix lesions, and basal cell carcinoma diagnosed after serum sampling. For women with multiple pregnancies, serial samples taken before cancer diagnosis are available. Offspring of the women have developed more than 4000 cancers. For 100,000 individuals, samples taken during the pregnancies of both their mothers and grandmothers enable familial cancer studies. FMC continues to collect samples, and surveillance of exposures or interventions like vaccination programs is feasible. In summary, the FMC is a unique, accessible biobank for epidemiological, biomarker, and surveillance studies on cancer.

We announce a biobank comprising virtually the entire population of Finnish females, who have been pregnant since 1983. The Finnish Maternity Cohort (FMC) is linkable with population-based health registers including the Finnish Cancer Registry. Serial prediagnostic serum samples and comprehensive data accessible over three generations provide possibilities for unique study settings. Selected examples on the use of the FMC in cancer studies hopefully stimulate international quest for this open access resource.

http://ift.tt/2h9v7bO

Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis

Abstract

Patients undergoing radiation therapy for the head and neck are susceptible to a significant and often abrupt deterioration in their oral health. The oral morbidities of radiation therapy include but are not limited to an increased susceptibility to dental caries and periodontal disease. They also include profound and often permanent functional and sensory changes involving the oral soft tissue. These changes range from oral mucositis experienced during and soon after treatment, mucosal opportunistic infections, neurosensory disorders, and tissue fibrosis. Many of the oral soft tissue changes following radiation therapy are difficult challenges to the patients and their caregivers and require life-long strategies to alleviate their deleterious effect on basic life functions and on the quality of life. We discuss the presentation, prognosis, and management strategies of the dental structure and oral soft tissue morbidities resulting from the administration of therapeutic radiation in head and neck patient. A case for a collaborative and integrated multidisciplinary approach to the management of these patients is made, with specific recommendation to include knowledgeable and experienced oral health care professionals in the treatment team.

Oral complications of radiation therapy to the head and neck can result in acute and long-term deterioration in oral soft tissues and dentition. The presentation, prognosis, and strategies to manage the dental and nondental morbidities of radiation therapy to the head and neck are discussed in this manuscript.

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Cancer Registry follow-up for 17 million person-years of a nationwide maternity cohort

Abstract

Population-based Finnish Maternity Cohort (FMC) comprises 2M first trimester sera collected from 1M women during 33 years. Informed consent is by the opt-out principle, and linkages with cancer and population registries provide a base for over time and over generation studies. Follow-up for 17M person-years by the end of 2014 can identify 39,700 cases of invasive cancer and 18,900 cases of premalignant breast and cervix lesions, and basal cell carcinoma diagnosed after serum sampling. For women with multiple pregnancies, serial samples taken before cancer diagnosis are available. Offspring of the women have developed more than 4000 cancers. For 100,000 individuals, samples taken during the pregnancies of both their mothers and grandmothers enable familial cancer studies. FMC continues to collect samples, and surveillance of exposures or interventions like vaccination programs is feasible. In summary, the FMC is a unique, accessible biobank for epidemiological, biomarker, and surveillance studies on cancer.

We announce a biobank comprising virtually the entire population of Finnish females, who have been pregnant since 1983. The Finnish Maternity Cohort (FMC) is linkable with population-based health registers including the Finnish Cancer Registry. Serial prediagnostic serum samples and comprehensive data accessible over three generations provide possibilities for unique study settings. Selected examples on the use of the FMC in cancer studies hopefully stimulate international quest for this open access resource.

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A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker

Abstract

Malignant gliomas, the most frequent primary brain tumors, are characterized by a dismal prognosis. Reliable biomarkers complementary to neuroradiology in the differential diagnosis of gliomas and monitoring for post-surgical progression are unmet needs. Altered expression of several microRNAs in tumour tissues from patients with gliomas compared to normal brain tissue have been described, thus supporting the rationale of using microRNA-based biomarkers. Although different circulating microRNAs were proposed in association with gliomas, they have not been introduced into clinical practice so far. Blood samples were collected from patients with high and low grade gliomas, both before and after surgical resection, and the expression of miR-21, miR-222 and miR-124-3p was measured in exosomes isolated from serum. The expression levels of miR-21, miR-222 and miR-124-3p in serum exosomes of patients with high grade gliomas were significantly higher than those of low grade gliomas and healthy controls and were sharply decreased in samples obtained after surgery. The analysis of miR-21, miR-222 and miR-124-3p in serum exosomes of patients affected by gliomas can provide a minimally invasive and innovative tool to help the differential diagnosis of gliomas at their onset in the brain and predict glioma grading and non glial metastases before surgery.

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A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker

Abstract

Malignant gliomas, the most frequent primary brain tumors, are characterized by a dismal prognosis. Reliable biomarkers complementary to neuroradiology in the differential diagnosis of gliomas and monitoring for post-surgical progression are unmet needs. Altered expression of several microRNAs in tumour tissues from patients with gliomas compared to normal brain tissue have been described, thus supporting the rationale of using microRNA-based biomarkers. Although different circulating microRNAs were proposed in association with gliomas, they have not been introduced into clinical practice so far. Blood samples were collected from patients with high and low grade gliomas, both before and after surgical resection, and the expression of miR-21, miR-222 and miR-124-3p was measured in exosomes isolated from serum. The expression levels of miR-21, miR-222 and miR-124-3p in serum exosomes of patients with high grade gliomas were significantly higher than those of low grade gliomas and healthy controls and were sharply decreased in samples obtained after surgery. The analysis of miR-21, miR-222 and miR-124-3p in serum exosomes of patients affected by gliomas can provide a minimally invasive and innovative tool to help the differential diagnosis of gliomas at their onset in the brain and predict glioma grading and non glial metastases before surgery.

http://ift.tt/2yRpCIk

A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker

Abstract

Malignant gliomas, the most frequent primary brain tumors, are characterized by a dismal prognosis. Reliable biomarkers complementary to neuroradiology in the differential diagnosis of gliomas and monitoring for post-surgical progression are unmet needs. Altered expression of several microRNAs in tumour tissues from patients with gliomas compared to normal brain tissue have been described, thus supporting the rationale of using microRNA-based biomarkers. Although different circulating microRNAs were proposed in association with gliomas, they have not been introduced into clinical practice so far. Blood samples were collected from patients with high and low grade gliomas, both before and after surgical resection, and the expression of miR-21, miR-222 and miR-124-3p was measured in exosomes isolated from serum. The expression levels of miR-21, miR-222 and miR-124-3p in serum exosomes of patients with high grade gliomas were significantly higher than those of low grade gliomas and healthy controls and were sharply decreased in samples obtained after surgery. The analysis of miR-21, miR-222 and miR-124-3p in serum exosomes of patients affected by gliomas can provide a minimally invasive and innovative tool to help the differential diagnosis of gliomas at their onset in the brain and predict glioma grading and non glial metastases before surgery.

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Passive smoking, NAT2 polymorphism, and breast cancer risk in Israeli Arab women: a case–control study

Abstract

Background

The effect of passive smoking (PS) on breast cancer (BC) is controversial, and may be modified by polymorphism of the N-Acetyl-transferase (NAT) 2 enzyme which is involved in tobacco carcinogen metabolism. We aimed to evaluate the relationship between PS and BC by NAT2 variants in Arab–Israeli women, a unique population with low active smoking rates, and high exposure to PS.

Methods

A population-based case-control study was carried out on non-smoking 137 prevalent breast cancer patients and 274 population-based controls, aged 30–70 years. Data on past and current PS, sociodemographic, and other characteristics were retrieved through interviews, and buccal smears were provided for NAT2 analyses. Logistic regression models adjusting for potential confounders assessed the odds ratios (ORs) and 95% confidence intervals (95% CI) of the association between PS and BC.

Results

Ever PS was associated with increased BC risk: OR = 2.22, 95% CI 1.28–3.87. Higher lifetime PS exposure was associated with higher BC risk: Compared to never exposed women, women exposed to PS most of their lives had a threefold higher BC risk (OR = 3.16, 95% CI 1.70–5.87, P _trend < 0.001). NAT2 polymorphism did not modify these associations.

Conclusions

PS exposure in non-smoking Israeli Arab women is significantly associated with increased risk for BC, potentially allowing for specific intervention; NAT2 polymorphism does not modify this association.

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Dietary Patterns and Cardiovascular Disease Prevention among Patients with Diabetes

Abstract

Purpose of Review

This review summarizes the most recent literature on dietary patterns and their effects on cardiovascular health among patients with diabetes.

Recent Findings

Studies identified examined low-fat, low-carbohydrate, low-glycemic index, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean dietary patterns. A limited number of short-term studies showed that intake of low-fat, low-carbohydrate, and low-glycemic index dietary patterns reduced body weight and blood pressure among individuals with diabetes. Short-term consumption of the DASH dietary pattern reduced blood pressure, low-density lipoprotein cholesterol, and triglyceride levels in patients with diabetes. Most convincing evidence supports the effectiveness of Mediterranean dietary patterns in cardiovascular disease prevention by reducing cardiovascular risk factors and mortality among patients with diabetes, as supported by a prospective cohort study, randomized controlled trials, and meta-analyses.

Summary

Among the dietary patterns identified, Mediterranean dietary patterns should be considered as primary nutritional recommendation for cardiovascular disease prevention among individuals with diabetes.

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Dietary Patterns and Cardiovascular Disease Prevention among Patients with Diabetes

Abstract

Purpose of Review

This review summarizes the most recent literature on dietary patterns and their effects on cardiovascular health among patients with diabetes.

Recent Findings

Studies identified examined low-fat, low-carbohydrate, low-glycemic index, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean dietary patterns. A limited number of short-term studies showed that intake of low-fat, low-carbohydrate, and low-glycemic index dietary patterns reduced body weight and blood pressure among individuals with diabetes. Short-term consumption of the DASH dietary pattern reduced blood pressure, low-density lipoprotein cholesterol, and triglyceride levels in patients with diabetes. Most convincing evidence supports the effectiveness of Mediterranean dietary patterns in cardiovascular disease prevention by reducing cardiovascular risk factors and mortality among patients with diabetes, as supported by a prospective cohort study, randomized controlled trials, and meta-analyses.

Summary

Among the dietary patterns identified, Mediterranean dietary patterns should be considered as primary nutritional recommendation for cardiovascular disease prevention among individuals with diabetes.

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Pancreatic Metastases of Rectal Cancer—Case Report and Literature Review

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Pancreatic Metastases of Rectal Cancer—Case Report and Literature Review

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Copanlisib Produces Prolonged Responses in Lymphoma [News in Brief]

More than half of patients respond to the PI3K inhibitor, which may be safer than idelalisib.

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Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) link vitamin B6 catabolism and lung cancer risk

Circulating pyridoxal-5'-phosphate (PLP) has been linked to lung cancer risk. The PAr index, defined as the ratio 4-pyridoxic acid / (pyridoxal + PLP), reflects increased vitamin B6 catabolism during inflammation. PAr has been defined as a marker of lung cancer risk in a prospective cohort study, but analysis of a larger numbers of cases are needed to deepen the significance of this study. Here we conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC, n = 521,330), which included 892 incident lung cancer cases and 1748 controls matched by center, gender, date of blood collection and date of birth. The association of PAr with risk of lung cancer was evaluated by using conditional logistic regression. Study participants with elevated PAr experienced higher risk of lung cancer in a dose-response fashion, with a doubling in PAr levels associated with 52% higher odds of lung cancer after adjustment for tobacco smoking, serum cotinine levels, educational attainment, and BMI (OR=1.52, 95% CI=1.27 to 1.81, P < 0.001). Additional adjustment for intake of vegetables and fruits and physical activity did not materially affect risk association. The association of PAr with lung cancer risk was similar in both genders but slightly stronger in former smokers and in participants diagnosed with squamous cell carcinoma. This study provides robust evidence that increased vitamin B6 catabolism is independently associated with a higher risk of future lung cancer.

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Type I IFN receptor signalling controls IL-7-dependent accumulation and activity of protumoral IL-17A-producing {gamma}{delta}T cells in breast cancer

The protumoral activity of γδT17 cells has recently emerged in a wide variety of solid malignancies including breast cancer. These cells promote tumor growth, angiogenesis, and subsequent metastasis development. However, the factors that regulate the biology of γδT17 cells within the tumor microenvironment are poorly understood. Here we use two experimental models of breast cancer to reinforce the concept that tumor-infiltrating γδT17 cells are endowed with protumoral functions that promote tumor progression and metastasis development. We also demonstrated a critical role for type I interferon signaling in controlling the preferential accumulation of a peculiar subset of γδT17 cells displaying a CD27- CD3bright phenotype in the tumor bed, previously associated with the invariant Vγ6Vδ1+ TCR. This effect was indirect and relied partially on IFNAR1-dependent control of IL-7 secretion, a factor that triggers proliferation and activating functions of deleterious γδT17 cells. Our work identifies a key role of the type I interferon/IL-7 axis in the regulation of intratumoral γδT17 cell functions and in the development of primary breast tumor growth and metastasis.

http://ift.tt/2gKJeY6

APRIL gene expression in a cohort of egyptian acute myeloid leukemia patients: clinical and prognostic significance

Publication date: Available online 24 October 2017
Source:Cancer Genetics
Author(s): Amira Ahmed Hammam, Shereen Mohamed Elhoseiny, Rania El-Sayed Sheir, Hisham Issa
BackgroundAPRIL (A Proliferation Inducing Ligand) is a member of the tumor necrosis factor (TNF) family. It is essential for the survival of normal and malignant B lymphocytes. Increased expression of APRIL is noted in most of hematological malignancies and auto immune diseases.Patients and methodsWe investigated the expression level of APRIL mRNA in 50 de novo acute myeloid leukemia (AML) patients, together with 20 healthy controls using a Real-Time Quantitative Reverse-Transcriptase Polymerase Chain Reaction (RTQ-PCR) with a specific aim of determining its relation to clinical features and laboratory findings at diagnosis and its impact on the response to therapy.ResultsAPRIL mRNA expression level was significantly higher in AML patients than in controls (p=< 0.001). APRIL expression level was significantly higher in patients who didn't achieve CR compared to those who achieved CR (p<0.001).Patients who didn't achieve CR also had higher TLC, lower platelets and older age than CR patients. The difference was statistically significant (p<0.001, p=0.047, p=0.019) respectively. APRIL levels showed significant positive correlation with TLC (r=0.743.p<0.001), with age (r=0.296,p=0.037)and a negative correlation with platelets count (r= -0.443,p=0.001) and no correlation with gender, Hb level, BM blast, HSM or LNs enlargement .ConclusionOur study has shown that APRIL is overexpressed in AML patients, its level might serve as an indicator for disease progression. APRIL might be an indicator for poor prognosis and treatment resistance in AML patient; therefore, APRIL antagonists may represent a novel therapeutic approach for the treatment of AML.



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Comprehensive BRCA mutation analysis in the greek population. Experience from a single clinical diagnostic center

Publication date: Available online 19 October 2017
Source:Cancer Genetics
Author(s): Angela Apessos, Konstantinos Agiannitopoulos, Georgia Pepe, Georgios N. Tsaousis, Eirini Papadopoulou, Vasiliki Metaxa-Mariatou, Angeliki Tsirigoti, Chrysoula Efstathiadou, Christos Markopoulos, Grigorios Xepapadakis, Vasileios Venizelos, Aris Tsiftsoglou, Ioannis Natsiopoulos, George Nasioulas
Germline mutations in the BRCA1 and BRCA2 genes are associated with hereditary predisposition to breast and ovarian cancer. Sensitive and accurate detection of BRCA1 and BRCA2 mutations is crucial for personalized clinical management of individuals affected by breast or ovarian cancer, and for the identification of at-risk healthy relatives.We performed molecular analysis of the BRCA1 and BRCA2 genes in 898 Greek families, using Sanger sequencing or Next Generation Sequencing for the detection of small insertion/deletion frameshift, nonsynonymous, truncating and splice-site alterations and MLPA for the detection of large genomic rearrangements.In total, a pathogenic mutation was identified in 12.9% of 898 families analyzed. Of the 116 mutations identified in total 9% were novel and 14.7% were large genomic rearrangements.Our results indicate that different types of mutational events in the BRCA1 and BRCA2 genes are responsible for the hereditary component of breast / ovarian cancer in the Greek population. Therefore the methodology used in the analysis of Greek patients must be able to detect both point and small frameshift mutations in addition to large genomic rearrangements across the entire coding region of the two genes.



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B-cell acute lymphoblastic leukemia with +der(1)t(1;19) (p13;p13.1) arising in the setting of CALR exon 9 mutated essential thrombocythemia

Publication date: Available online 19 October 2017
Source:Cancer Genetics
Author(s): Talal Hilal, Christopher R. Conley




http://ift.tt/2z6jAVb

Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) link vitamin B6 catabolism and lung cancer risk

Circulating pyridoxal-5'-phosphate (PLP) has been linked to lung cancer risk. The PAr index, defined as the ratio 4-pyridoxic acid / (pyridoxal + PLP), reflects increased vitamin B6 catabolism during inflammation. PAr has been defined as a marker of lung cancer risk in a prospective cohort study, but analysis of a larger numbers of cases are needed to deepen the significance of this study. Here we conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC, n = 521,330), which included 892 incident lung cancer cases and 1748 controls matched by center, gender, date of blood collection and date of birth. The association of PAr with risk of lung cancer was evaluated by using conditional logistic regression. Study participants with elevated PAr experienced higher risk of lung cancer in a dose-response fashion, with a doubling in PAr levels associated with 52% higher odds of lung cancer after adjustment for tobacco smoking, serum cotinine levels, educational attainment, and BMI (OR=1.52, 95% CI=1.27 to 1.81, P < 0.001). Additional adjustment for intake of vegetables and fruits and physical activity did not materially affect risk association. The association of PAr with lung cancer risk was similar in both genders but slightly stronger in former smokers and in participants diagnosed with squamous cell carcinoma. This study provides robust evidence that increased vitamin B6 catabolism is independently associated with a higher risk of future lung cancer.

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Mitochondrial haplotype alters mammary cancer tumorigenicity and metastasis in an oncogenic driver- dependent manner

Using a novel mouse model, a mitochondrial nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA and either FVB/NJ, C57BL/6J or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e. females crossed with Her2 males) showed significantly (p<0.001) longer tumor latency (262 v 293 v 225 days), fewer pulmonary metastases (5 v 7 v 15) and differences in size of lung metastases (1.2 v 1.4 v 1.0 mm diameter) compared to FVB/NJ mtDNA. Although PyMT-driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis.

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Type I IFN receptor signalling controls IL-7-dependent accumulation and activity of protumoral IL-17A-producing {gamma}{delta}T cells in breast cancer

The protumoral activity of γδT17 cells has recently emerged in a wide variety of solid malignancies including breast cancer. These cells promote tumor growth, angiogenesis, and subsequent metastasis development. However, the factors that regulate the biology of γδT17 cells within the tumor microenvironment are poorly understood. Here we use two experimental models of breast cancer to reinforce the concept that tumor-infiltrating γδT17 cells are endowed with protumoral functions that promote tumor progression and metastasis development. We also demonstrated a critical role for type I interferon signaling in controlling the preferential accumulation of a peculiar subset of γδT17 cells displaying a CD27- CD3bright phenotype in the tumor bed, previously associated with the invariant Vγ6Vδ1+ TCR. This effect was indirect and relied partially on IFNAR1-dependent control of IL-7 secretion, a factor that triggers proliferation and activating functions of deleterious γδT17 cells. Our work identifies a key role of the type I interferon/IL-7 axis in the regulation of intratumoral γδT17 cell functions and in the development of primary breast tumor growth and metastasis.

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Long-term Safety of Pregnancy Following Breast Cancer According to Estrogen Receptor Status

Abstract

Safety of pregnancy in women with history of estrogen receptor (ER)–positive breast cancer remains controversial. In this multicenter case–control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaranteed time bias. Survival estimates were calculated using the Kaplan-Meier analysis; groups were compared with the log-rank test. All reported P values were two-sided. At a median follow-up of 7.2 years after pregnancy, no difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.70 to 1.26, P = .68) or ER-negative (HR = 0.75, 95% CI = 0.53 to 1.06, P = .10) disease. No overall survival (OS) difference was observed in ER-positive patients (HR = 0.84, 95% CI = 0.60 to 1.18, P = .32); ER-negative patients in the pregnant cohort had better OS (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). Abortion, time to pregnancy, breastfeeding, and type of adjuvant therapy had no impact on patients' outcomes. This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.

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Extracellular vesicles released by cardiomyocytes in a doxorubicin-induced cardiac injury mouse model contain protein biomarkers of early cardiac injury

Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EVs) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury. Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content. Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EVs) compared to saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury. Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury.

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PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia

Purpose:Leukemia stem cells (LSCs) are important source of tyrosine kinase inhibitor (TKI) resistance and disease relapse in chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism. Experimental Design：Human primary CML CD34+ cells and retrovirally-BCR-ABL-driven CML mouse model were employed to evaluate the effects of suppression of EZH2 by GSK126 or EZH2 specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation (ChIP) assay. Results: Our results showed that pharmacological inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow (NBM) CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown. Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs, and warrants clinical trial of GSK126 in refractory patients with CML.

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Circulating Tumors Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma

Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC).  Experimental Design: In 73 localized HCC patients, blood was drawn from peripheral vein (PV), peripheral artery (PA), hepatic veins (HV), infrahepatic inferior vena cava (IHIVC) and portal vein (PoV) before tumor resection. Epithelial and mesenchymal transition (EMT) phenotype in CTCs were analyzed by a 4-channel immunofluorescence CellSearch assay and microfluidic quantitative RT-PCR. The clinical significance of CTCs from different vascular sites was evaluated. Results: The CTC number and size gradient between tumor efferent vessels and post-pulmonary peripheral vessels was marked. Tracking the fate of CTC clusters revealed that CTCs displayed an aggregated-singular-aggregated manner of spreading. Single-cell characterization demonstrated that EMT status of CTCs was heterogeneous across different vascular compartments. CTCs were predominantly epithelial at release, but switched to EMT-activated phenotype during hematogeneous transit via Smad2 and β-catenin signaling pathways. EMT activation in primary tumor correlated with total CTC number at HV, rather than epithelial or EMT-activated subsets of CTCs. Follow-up analysis suggested that CTC and circulating tumor microemboli burden in hepatic veins and peripheral circulation prognosticated postoperative lung metastasis and intrahepatic recurrence, respectively. Conclusions: The current data suggested that a profound spatial heterogeneity in cellular distribution and biological features existed among CTCs during circulation. Multi-vascular measurement of CTCs could help to reveal novel mechanisms of metastasis and facilitate prediction of postoperative relapse pattern in HCC.

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Extracellular vesicles released by cardiomyocytes in a doxorubicin-induced cardiac injury mouse model contain protein biomarkers of early cardiac injury

Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EVs) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury. Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content. Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EVs) compared to saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury. Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury.

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PTEN is fundamental for elimination of leukemia stem cells mediated by GSK126 targeting EZH2 in chronic myelogenous leukemia

Purpose:Leukemia stem cells (LSCs) are important source of tyrosine kinase inhibitor (TKI) resistance and disease relapse in chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism. Experimental Design：Human primary CML CD34+ cells and retrovirally-BCR-ABL-driven CML mouse model were employed to evaluate the effects of suppression of EZH2 by GSK126 or EZH2 specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation (ChIP) assay. Results: Our results showed that pharmacological inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow (NBM) CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown. Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs, and warrants clinical trial of GSK126 in refractory patients with CML.

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Circulating Tumors Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma

Purpose: The spatial heterogeneity of phenotypic and molecular characteristics of CTCs within circulatory system remains unclear. Herein, we mapped the distribution and characterized biological features of CTCs along the transportation route in hepatocellular carcinoma (HCC).  Experimental Design: In 73 localized HCC patients, blood was drawn from peripheral vein (PV), peripheral artery (PA), hepatic veins (HV), infrahepatic inferior vena cava (IHIVC) and portal vein (PoV) before tumor resection. Epithelial and mesenchymal transition (EMT) phenotype in CTCs were analyzed by a 4-channel immunofluorescence CellSearch assay and microfluidic quantitative RT-PCR. The clinical significance of CTCs from different vascular sites was evaluated. Results: The CTC number and size gradient between tumor efferent vessels and post-pulmonary peripheral vessels was marked. Tracking the fate of CTC clusters revealed that CTCs displayed an aggregated-singular-aggregated manner of spreading. Single-cell characterization demonstrated that EMT status of CTCs was heterogeneous across different vascular compartments. CTCs were predominantly epithelial at release, but switched to EMT-activated phenotype during hematogeneous transit via Smad2 and β-catenin signaling pathways. EMT activation in primary tumor correlated with total CTC number at HV, rather than epithelial or EMT-activated subsets of CTCs. Follow-up analysis suggested that CTC and circulating tumor microemboli burden in hepatic veins and peripheral circulation prognosticated postoperative lung metastasis and intrahepatic recurrence, respectively. Conclusions: The current data suggested that a profound spatial heterogeneity in cellular distribution and biological features existed among CTCs during circulation. Multi-vascular measurement of CTCs could help to reveal novel mechanisms of metastasis and facilitate prediction of postoperative relapse pattern in HCC.

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Radiation toxicity in patients with collagen vascular disease and intrathoracic malignancy treated with modern radiation techniques

There is concern that patients with collagen vascular disease (CVD) are at higher risk of developing radiation toxicity. We analyzed radiation toxicities in patients with intrathoracic malignancy and CVD treated using modern radiotherapy.

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Gender and age make no difference in the re-irradiation of painful bone metastases: A secondary analysis of the NCIC CTG SC.20 randomized trial

Patient's gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation.

http://ift.tt/2iApsis

The influence of stage at diagnosis and molecular subtype on breast cancer patient survival: a hospital-based multi-center study

Stage at diagnosis and molecular subtype are important clinical factors associated with breast cancer patient survival. However, subgroup survival data from a large study sample are limited in China. To estima...

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The influence of stage at diagnosis and molecular subtype on breast cancer patient survival: a hospital-based multi-center study

Stage at diagnosis and molecular subtype are important clinical factors associated with breast cancer patient survival. However, subgroup survival data from a large study sample are limited in China. To estima...

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With FDA Approval for Advanced Lymphoma, Second CAR T-Cell Therapy Moves to the Clinic

One month after approving the first CAR T-cell therapy for cancer, FDA has approved a second such therapy. The treatment, axicabtagene ciloleucel (Yescarta™), was approved for some patients with advanced non-Hodgkin lymphoma.

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With FDA Approval for Advanced Lymphoma, Second CAR T-Cell Therapy Moves to the Clinic

One month after approving the first CAR T-cell therapy for cancer, FDA has approved a second such therapy. The treatment, axicabtagene ciloleucel (Yescarta™), was approved for some patients with advanced non-Hodgkin lymphoma.

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Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer?

Publication date: Available online 25 October 2017
Source:Cancer Treatment Reviews
Author(s): Yi-Long Wu, Ross Andrew Soo, Giuseppe Locatelli, Uz Stammberger, Giorgio Scagliotti, Keunchil Park
Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5–20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c–Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and -independent c-Met activity, with a reduced risk of toxicity compared to non-selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered.



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Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors

Abstract

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for > 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials.

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Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors

Abstract

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for > 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials.

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The Changing Face of Surgical Oncology

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The Role of Intersphincteric Resection in Very Low Rectal Cancer

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Reply to: Partial Verification Distorts Estimates of Sensitivity in Diagnostic Accuracy Studies for Fine-Needle Aspiration Cytology

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Impact of RAS Mutations in Metastatic Colorectal Cancer After Potentially Curative Resection: Does Site of Metastases Matter?

Abstract

Background

RAS mutation status is an important prognostic factor after resection of liver metastases (LiM) from colorectal cancer (CRC). The prognostic significance of RAS after resection of lung (LuM) and peritoneal (PM) metastases from CRC is unknown.

Methods

Between 2005 and 2014, all consecutive patients with known RAS status who underwent potentially curative resection for LiM, LuM, or PM were evaluated.

Results

A total of 720 patients with known RAS status underwent resection of LiM (n = 468), LuM (n = 102), and PM (n = 150). RAS mutations were identified in 63 and 58% of patients with LuM and PM, respectively, compared with 41% of patients with LiM (p < 0.001). Five-year overall survival (OS) after resection of PM was 45%, compared with 52% after resection of LiM (p = 0.018) and 64% after resection of LuM (p = 0.005). RAS mutations were associated with significantly worse OS after resection of LiM (p < 0.001), but did not affect OS among patients undergoing resection of LuM (p = 0.41) and PM (p = 0.65).

Conclusions

RAS mutations are more prevalent among patients undergoing resection of LuM and PM than LiM but do not affect survival after lung and peritoneal metastasectomy, as they do after hepatectomy. These results suggest that the prognostic significance of RAS mutations after resection of metastatic CRC depends on the specific site of metastases.

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Vitamin D Levels Affect Breast Cancer Survival Rates: A Reply

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The Changing Face of Surgical Oncology

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The Role of Intersphincteric Resection in Very Low Rectal Cancer

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Reply to: Partial Verification Distorts Estimates of Sensitivity in Diagnostic Accuracy Studies for Fine-Needle Aspiration Cytology

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Impact of RAS Mutations in Metastatic Colorectal Cancer After Potentially Curative Resection: Does Site of Metastases Matter?

Abstract

Background

RAS mutation status is an important prognostic factor after resection of liver metastases (LiM) from colorectal cancer (CRC). The prognostic significance of RAS after resection of lung (LuM) and peritoneal (PM) metastases from CRC is unknown.

Methods

Between 2005 and 2014, all consecutive patients with known RAS status who underwent potentially curative resection for LiM, LuM, or PM were evaluated.

Results

A total of 720 patients with known RAS status underwent resection of LiM (n = 468), LuM (n = 102), and PM (n = 150). RAS mutations were identified in 63 and 58% of patients with LuM and PM, respectively, compared with 41% of patients with LiM (p < 0.001). Five-year overall survival (OS) after resection of PM was 45%, compared with 52% after resection of LiM (p = 0.018) and 64% after resection of LuM (p = 0.005). RAS mutations were associated with significantly worse OS after resection of LiM (p < 0.001), but did not affect OS among patients undergoing resection of LuM (p = 0.41) and PM (p = 0.65).

Conclusions

RAS mutations are more prevalent among patients undergoing resection of LuM and PM than LiM but do not affect survival after lung and peritoneal metastasectomy, as they do after hepatectomy. These results suggest that the prognostic significance of RAS mutations after resection of metastatic CRC depends on the specific site of metastases.

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Vitamin D Levels Affect Breast Cancer Survival Rates: A Reply

http://ift.tt/2yPKfog

The American Society of Pediatric Hematology/Oncology workforce assessment: Part 1—Current state of the workforce

Abstract

The American Society of Pediatric Hematology/Oncology (ASPHO) recognized recent changes in medical practice and the potential impact on pediatric hematology–oncology (PHO) workforce. ASPHO surveyed society members and PHO Division Directors between 2010 and 2016 and studied PHO workforce data collected by the American Board of Pediatrics and the American Medical Association to characterize the current state of the PHO workforce. The analysis of this information has led to a comprehensive description of PHO physicians, professional activities, and workplace. It is important to continue to collect data to identify changes in composition and needs of the PHO workforce.

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Workforce data and uncertainty: Uneasy but unavoidable partners

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The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2—Implications for fellowship training

Abstract

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010–2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

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Training

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The American Society of Pediatric Hematology/Oncology workforce assessment: Part 1—Current state of the workforce

Abstract

The American Society of Pediatric Hematology/Oncology (ASPHO) recognized recent changes in medical practice and the potential impact on pediatric hematology–oncology (PHO) workforce. ASPHO surveyed society members and PHO Division Directors between 2010 and 2016 and studied PHO workforce data collected by the American Board of Pediatrics and the American Medical Association to characterize the current state of the PHO workforce. The analysis of this information has led to a comprehensive description of PHO physicians, professional activities, and workplace. It is important to continue to collect data to identify changes in composition and needs of the PHO workforce.

http://ift.tt/2z6lp4A

Workforce data and uncertainty: Uneasy but unavoidable partners

http://ift.tt/2iAspzv

The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2—Implications for fellowship training

Abstract

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010–2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

http://ift.tt/2z7dHqT

Training

http://ift.tt/2iAsnrn

Prognostic value of change in anti-thyroglobulin antibodies after thyroidectomy in patients with papillary thyroid carcinoma

Abstract

Purpose

Anti-thyroglobulin antibodies (TgAb) can be used as a surrogate tumor marker in the follow-up of papillary thyroid carcinoma (PTC). We try to determine if the change in TgAb levels in the first post-operative year is a good predictor of persistence/recurrence risk in TgAb-positive PTC patients.

Methods/patients

105 patients with PTC who underwent thyroidectomy between 1988 and 2014 were enrolled. We calculated the percentage of change in TgAb levels with the first measurement at 1–2 months after surgery and the second one at 12–14 months.

Results

TgAb negativization was observed in 29 patients (27.6%), a decrease of more than 50% was observed in 57 patients (54.3%), less than 50% in 12 patients (11.4%) and in 7 patients (6.7%) the TgAb level had increased. The percentage of persistence/recurrence was 0, 8.8, 16.7 and 71.4% in each group, respectively (p < 0.001). In the multivariate analysis, only the percentage of change in TgAb showed a significant association with the risk of persistence/recurrence, regardless of other factors such as age, size and TNM stages.

Conclusions

Changes in TgAb levels in the first year after surgery can predict the risk of persistence/recurrence of TgAb-positive PTC patients. Patients who achieved negativization of TgAb presented an excellent prognosis.

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A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer

Abstract

Purpose

Mesenchymal–epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling.

Methods

This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size.

Results

Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33–0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3–not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated.

Conclusion

Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.

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Prognostic value of change in anti-thyroglobulin antibodies after thyroidectomy in patients with papillary thyroid carcinoma

Abstract

Purpose

Anti-thyroglobulin antibodies (TgAb) can be used as a surrogate tumor marker in the follow-up of papillary thyroid carcinoma (PTC). We try to determine if the change in TgAb levels in the first post-operative year is a good predictor of persistence/recurrence risk in TgAb-positive PTC patients.

Methods/patients

105 patients with PTC who underwent thyroidectomy between 1988 and 2014 were enrolled. We calculated the percentage of change in TgAb levels with the first measurement at 1–2 months after surgery and the second one at 12–14 months.

Results

TgAb negativization was observed in 29 patients (27.6%), a decrease of more than 50% was observed in 57 patients (54.3%), less than 50% in 12 patients (11.4%) and in 7 patients (6.7%) the TgAb level had increased. The percentage of persistence/recurrence was 0, 8.8, 16.7 and 71.4% in each group, respectively (p < 0.001). In the multivariate analysis, only the percentage of change in TgAb showed a significant association with the risk of persistence/recurrence, regardless of other factors such as age, size and TNM stages.

Conclusions

Changes in TgAb levels in the first year after surgery can predict the risk of persistence/recurrence of TgAb-positive PTC patients. Patients who achieved negativization of TgAb presented an excellent prognosis.

http://ift.tt/2zC7AqT

A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer

Abstract

Purpose

Mesenchymal–epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling.

Methods

This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size.

Results

Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33–0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3–not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated.

Conclusion

Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.

http://ift.tt/2y6w2zy

Tumor-infiltrating lymphocytes in breast cancer and implications for clinical practice

Publication date: Available online 20 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Debora de Melo Gagliato, Javier Cortes, Giuseppe Curigliano, Sherene Loi, Carsten Denkert, Jose Perez-Garcia, Esther Holgado
Breast Cancer (BC) can be classified using pathologic features, such as grade and tumor size. It can be categorized based on the gene expression profile, which identifies the distinct molecular subtype. More recently, stromal tissue has been recognized as an important modulator of tumor cell growth, pathogenesis, and progression. Immune cells could drive important clinical characteristics that affect BC outcomes. Subgroups of patients who have tumor-infiltrating lymphocytes in the stroma may have better response to chemotherapy and favorable long-term prognosis. Accumulating evidence shows that the immune system plays a crucial role in the outcomes of some BC subgroups, especially more aggressive, proliferative ones such as triple-negative and HER2-positive BC. This review article will present data on the role of lymphocyte infiltration in BC prognosis and response to therapy. This review will also introduce the reader to the challenges of applying this promising prognostic and predictive biomarker in clinical practice.



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The role of RAS mutations in MLL-rearranged leukaemia: A path to intervention?

Publication date: Available online 19 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Marcela B. Mansur, Anthony M. Ford, Mariana Emerenciano
Childhood acute lymphoblastic leukaemia (ALL) with MLL rearrangement (MLL-r) is an aggressive disease still associated with a high mortality rate. Recent investigations have identified co-operating mutations in the RAS pathway and although the functional consequences of these mutations are not yet fully understood, aberrant regulation of RAS pathway signalling at both transcriptional and protein levels is observed. Studies investigating the efficacy of specific inhibitors of this pathway, e.g. MEK-inhibitors, have also achieved encouraging results. In this context, this mini-review summarizes the available data surrounding MLL-r infant ALL with RAS mutation in relation to other well-known features of this intriguing disease.



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Tumor cell-associated immune checkpoint molecules – Drivers of malignancy and stemness

Publication date: Available online 19 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Fabrizio Marcucci, Cristiano Rumio, Angelo Corti
Inhibitory or stimulatory immune checkpoint molecules are expressed on a sizeable fraction of tumor cells in different tumor types. It was thought that the main function of tumor cell-associated immune checkpoint molecules would be the modulation (down- or upregulation) of antitumor immune responses. In recent years, however, it became clear that the expression of immune checkpoint molecules on tumor cells has important consequences on the biology of the tumor cells themselves. In particular, a causal relationship between the expression of these molecules and the acquisition of malignant traits has been demonstrated. Thus, immune checkpoint molecules have been shown to promote the epithelial-mesenchymal transition of tumor cells, the acquisition of tumor-initiating potential and resistance to apoptosis and antitumor drugs, and the propensity to disseminate and metastasize. Herein, we review this evidence, with a main focus on PD-L1, the most intensively investigated tumor cell-associated immune checkpoint molecule and for which most information is available. Then, we discuss more concisely other tumor-associated immune checkpoint molecules that have also been shown to induce the acquisition of malignant traits, such as PD-1, B7-H3, B7-H4, Tim-3, CD70, CD28, CD137, CD40 and CD47. Open questions in this field as well as some therapeutic approaches that can be derived from this knowledge, are also addressed.



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Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside

Publication date: Available online 18 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Kerui Wu, Fei Xing, Shih-Ying Wu, Kounosuke Watabe
Extracellular vesicles (EVs) have emerged as important players of cancer initiation and progression through cell-cell communication. They have been recognized as critical mediators of extracellular communications, which promote transformation, growth invasion, and drug-resistance of cancer cells. Interestingly, the secretion and uptake of EVs are regulated in a more controlled manner than previously anticipated. EVs are classified into three groups, (i) exosomes, (ii) microvesicles (MVs), and (iii) apoptotic bodies (ABs), based on their sizes and origins, and novel technologies to isolate and distinguish these EVs are evolving. The biologically functional molecules harbored in these EVs, including nucleic acids, lipids, and proteins, have been shown to induce key signaling pathways in both tumor and tumor microenvironment (TME) cells for exacerbating tumor development. While tumor cell-derived EVs are capable of reprogramming stromal cells to generate a proper tumor cell niche, stromal-derived EVs profoundly affect the growth, resistance, and stem cell properties of tumor cells. This review summarizes and discusses these reciprocal communications through EVs in different types of cancers. Further understanding of the pathophysiological roles of different EVs in tumor progression is expected to lead to the discovery of novel biomarkers in liquid biopsy and development of tumor specific therapeutics. This review will also discuss the translational aspects of EVs and therapeutic opportunities of utilizing EVs in different cancer types.



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Deubiquitylating enzymes as cancer stem cell therapeutics

Publication date: Available online 18 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Saba Haq, Bharathi Suresh, Suresh Ramakrishna
The focus of basic and applied research on core stem cell transcription factors has paved the way to initial delineation of their characteristics, their regulatory mechanisms, and the applicability of their regulatory proteins for protein-induced pluripotent stem cells (protein-IPSC) generation and in further clinical settings. Striking parallels have been observed between cancer stem cells (CSCs) and stem cells. For the maintenance of stem cells and CSC pluripotency and differentiation, post translational modifications (i.e., ubiquitylation and deubiquitylation) are tightly regulated, as these modifications result in a variety of stem cell fates. The identification of deubiquitylating enzymes (DUBs) involved in the regulation of core stem cell transcription factors and CSC-related proteins might contribute to providing novel insights into the implications of DUB regulatory mechanisms for governing cellular reprogramming and carcinogenesis. Moreover, we propose the novel possibility of applying DUBs coupled with core transcription factors to improve protein-iPSC generation efficiency. Additionally, this review article further illustrates the potential of applying DUB inhibitors as a novel therapeutic intervention for targeting CSCs. Thus, defining DUBs as core pharmacological targets implies that future endeavors to develop their inhibitors may revolutionize our ability to regulate stem cell maintenance and differentiation, somatic cell reprogramming, and cancer stem cells.

Graphical abstract

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New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies

Publication date: Available online 17 October 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Leilei Niu, Liping Liu, Shengli Yang, Jianwei Ren, Paul B.S. Lai, George G. Chen
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.



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A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer

Abstract

Purpose

Mesenchymal–epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling.

Methods

This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size.

Results

Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33–0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3–not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated.

Conclusion

Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.

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Prognostic value of change in anti-thyroglobulin antibodies after thyroidectomy in patients with papillary thyroid carcinoma

Abstract

Purpose

Anti-thyroglobulin antibodies (TgAb) can be used as a surrogate tumor marker in the follow-up of papillary thyroid carcinoma (PTC). We try to determine if the change in TgAb levels in the first post-operative year is a good predictor of persistence/recurrence risk in TgAb-positive PTC patients.

Methods/patients

105 patients with PTC who underwent thyroidectomy between 1988 and 2014 were enrolled. We calculated the percentage of change in TgAb levels with the first measurement at 1–2 months after surgery and the second one at 12–14 months.

Results

TgAb negativization was observed in 29 patients (27.6%), a decrease of more than 50% was observed in 57 patients (54.3%), less than 50% in 12 patients (11.4%) and in 7 patients (6.7%) the TgAb level had increased. The percentage of persistence/recurrence was 0, 8.8, 16.7 and 71.4% in each group, respectively (p < 0.001). In the multivariate analysis, only the percentage of change in TgAb showed a significant association with the risk of persistence/recurrence, regardless of other factors such as age, size and TNM stages.

Conclusions

Changes in TgAb levels in the first year after surgery can predict the risk of persistence/recurrence of TgAb-positive PTC patients. Patients who achieved negativization of TgAb presented an excellent prognosis.

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Prognostic value of change in anti-thyroglobulin antibodies after thyroidectomy in patients with papillary thyroid carcinoma

Abstract

Purpose

Anti-thyroglobulin antibodies (TgAb) can be used as a surrogate tumor marker in the follow-up of papillary thyroid carcinoma (PTC). We try to determine if the change in TgAb levels in the first post-operative year is a good predictor of persistence/recurrence risk in TgAb-positive PTC patients.

Methods/patients

105 patients with PTC who underwent thyroidectomy between 1988 and 2014 were enrolled. We calculated the percentage of change in TgAb levels with the first measurement at 1–2 months after surgery and the second one at 12–14 months.

Results

TgAb negativization was observed in 29 patients (27.6%), a decrease of more than 50% was observed in 57 patients (54.3%), less than 50% in 12 patients (11.4%) and in 7 patients (6.7%) the TgAb level had increased. The percentage of persistence/recurrence was 0, 8.8, 16.7 and 71.4% in each group, respectively (p < 0.001). In the multivariate analysis, only the percentage of change in TgAb showed a significant association with the risk of persistence/recurrence, regardless of other factors such as age, size and TNM stages.

Conclusions

Changes in TgAb levels in the first year after surgery can predict the risk of persistence/recurrence of TgAb-positive PTC patients. Patients who achieved negativization of TgAb presented an excellent prognosis.

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Prognostic value of change in anti-thyroglobulin antibodies after thyroidectomy in patients with papillary thyroid carcinoma

Abstract

Purpose

Anti-thyroglobulin antibodies (TgAb) can be used as a surrogate tumor marker in the follow-up of papillary thyroid carcinoma (PTC). We try to determine if the change in TgAb levels in the first post-operative year is a good predictor of persistence/recurrence risk in TgAb-positive PTC patients.

Methods/patients

105 patients with PTC who underwent thyroidectomy between 1988 and 2014 were enrolled. We calculated the percentage of change in TgAb levels with the first measurement at 1–2 months after surgery and the second one at 12–14 months.

Results

TgAb negativization was observed in 29 patients (27.6%), a decrease of more than 50% was observed in 57 patients (54.3%), less than 50% in 12 patients (11.4%) and in 7 patients (6.7%) the TgAb level had increased. The percentage of persistence/recurrence was 0, 8.8, 16.7 and 71.4% in each group, respectively (p < 0.001). In the multivariate analysis, only the percentage of change in TgAb showed a significant association with the risk of persistence/recurrence, regardless of other factors such as age, size and TNM stages.

Conclusions

Changes in TgAb levels in the first year after surgery can predict the risk of persistence/recurrence of TgAb-positive PTC patients. Patients who achieved negativization of TgAb presented an excellent prognosis.

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Intrauterine device embedded in omentum of postpartum patient with a markedly retroverted uterus: a case report

The intrauterine device is a popular form of long-acting reversible contraception. Although generally safe, one of the most serious complications of intrauterine device use is uterine perforation. Risk factors...

http://ift.tt/2i4nTFL

Treatment of orofacial granulomatosis: a case report

Orofacial granulomatosis is a relatively recent term coined by Wiesenfield et al. in 1985 to define granulomatous lesions of oral mucosa without intestinal involvement. When it presents in a triad encompassing fa...

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Hydroxyethyl starch 130/0.4 versus crystalloid co-loading during general anesthesia induction: a randomized controlled trial

Abstract

Purpose

Hypotension and decreased cardiac output (CO) are common adverse effects during anesthesia induction depending on the patient's pre-anesthetic cardiac condition. The aim of this study was to assess the ability of hydroxyethyl starch (HES) 130/0.4 to prevent hypotension and decreased CO during the induction of general anesthesia.

Methods

Ninety patients undergoing laparoscopic surgery were randomly divided into a HES group and a crystalloid group. Following the insertion of an intravenous line, fluid was administered to each patient at a rate of 25 ml/min using either crystalloid or HES 130/0.4. Five minutes after the initiation of fluid loading, anesthesia was induced using propofol (1.5 mg/kg), rocuronium (0.9 mg/kg), and remifentanil (0.3 mcg/kg/min). Tracheal intubation was performed 5 min after the induction of anesthesia. Following tracheal intubation, general anesthesia was maintained using remifentanil and sevoflurane. Non-invasive blood pressure (BP) level was measured at 1-min intervals and CO was measured continuously using electrical cardiometry from the start of fluid loading until 5 min after tracheal intubation.

Results

The number of patients with hypotension (systolic BP < 90 mmHg or 80% of baseline) was significantly lower in the HES group (p < 0.001) than in the crystalloid group. Patients in the HES group showed smaller CO decreases than did patients in the crystalloid group (p < 0.001). The Kaplan–Meier method showed a lower incidence and significantly slower onset of hypotension in the HES group (p = 0.009). Multivariate logistic regression models indicated that the use of HES is an independent factor for the prevention of both hypotension and decreased CO (below 85% of baseline; p < 0.005 for both).

Conclusions

Co-loading using HES 130/0.4 prevented hypotension and decreased CO during general anesthesia induction.

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Matrix metallopeptidase 9 targeted by hsa-miR-494 promotes silybin-inhibited osteosarcoma

Abstract

Osteosarcoma (OS) is the most common malignant tumor that develops in bone. Its mortality is very high. Therefore, study of mechanisms of pathogenesis of the OS is urgently required. Previous studies of microarray showed that the expression levels of matrix metallopeptidase 9 (MMP-9) altered significantly in OS. In addition, overexpression of MMP-9 is recognized as an indicator in cancer. However, the exact roles of MMP-9 in OS are not fully investigated. Thus, we firstly studied the roles of MMP-9 in OS and revealed that silence of MMP-9 inhibited OS cell proliferation as determined by MTT assay and colony formation assay. Secondly, we conducted TUNEL assay and confirmed loss of functions of MMP-9 induced OS cell apoptosis. Next, we used lentivector packaging method to overexpress MMP-9 and found that overexpression of MMP-9 promoted OS cell migration. Fourthly, the results of luciferase assay showed that MMP-9 was targeted by hsa-miR-494, which inhibited OS. Fifthly, we revealed that the levels of hsa-miR-494 were upregulated by the drug silybin which inhibited OS. Finally, we revealed that silybin inhibited OS cell viability by altering the protein levels of β-catenin and Runt-related transcription factor 2 (RUNX2) as determined by western blot and immunocytochemistry (ICC). This article is protected by copyright. All rights reserved

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Long non-coding RNA AGER-1 functionally upregulates the innate immunity gene AGER and approximates its anti-tumor effect in lung cancer

Abstract

Background: Little is known about long non-coding RNA (lncRNA) related to innate immunity in lung cancer. The advanced glycosylation end-product specific receptor (AGER) belongs to the immunoglobulin superfamily, and currently, is the only innate immune pattern-recognition receptor whose abnormal expression has been detected in lung cancer. We aimed to explore the lncRNA that is related to AGER and test its effect on lung carcinogenesis.

Methods: We selected one lncRNA whose chromosome location is in close proximity to AGER namely lnc-AGER-1 (defined as lncAGER). The expression of lncAGER was tested in 276 pairs of lung cancer tissues and adjacent lung normal tissues, and its correlation with lung cancer clinical progress was analyzed. A series of assays were further used to assess the biological function of lncAGER on lung cancer development, tumor immunity and autophagy.

Results: LncAGER expression was moderately correlated with AGER expression (r = 0.360, P = 2.15 × 10⁻¹⁸) underlying a mechanism that lncAGER upregulates AGER by competitively binding to miRNA-185. LncAGER was significantly down-regulated in 76.4% of lung cancer tissues compared to adjacent normal tissues due to promoter hypermethylation. Over-expression of the lncRNA resulted in significant decreases in proliferation rate, migration ability, colony formation efficiency of lung cancer cells and tumor growth in nude mice. Notably, lncAGER possibly conduced to enhancement of cytotoxic effects of THP1. Additionally, the lncRNA also promoted cell apoptosis by strengthening autophagy.

Conclusions: Taken together, these observations suggest that lncAGER has an inhibitory effect on lung cancer development via AGER, which may serve as a target for lung cancer treatment. This article is protected by copyright. All rights reserved

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BAG3-dependent expression of Mcl-1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

Abstract

Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer. This article is protected by copyright. All rights reserved

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Expression of the FGFR2c mesenchymal splicing variant in human keratinocytes inhibits differentiation and promotes invasion

ABSTRACT

The altered isoform switching of the fibroblast growth factor receptor 2 (FGFR2) and aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells is involved in cancer progression. We have recently described that the ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth. Here we extended our analysis to the effects of this FGFR2c forced expression on human keratinocyte differentiation and stratification. Our findings demonstrated that, differently from cells overexpressing the epithelial splicing variant FGFR2b, keratinocytes ectopically expressing FGFR2c are not able to form a monolayer and display decreased expression of early differentiation markers. This impaired ability to enter the differentiation program is related to the up-modulation of the transcription factor ΔNp63. In addition, FGFR2c-expressing keratinocytes undergo defective stratification and invasion of the collagen matrix in 3D organotypic cultures, further suggesting their tumorigenic potential. Taken together, our results support the hypothesis that the receptor switching and the consequent appearance of the mesenchymal FGFR2c variant in the epithelial context would drive early steps of carcinogenesis, unbalancing the p63/FGFR interplay and altering the paracrine response to the microenvironment. This article is protected by copyright. All rights reserved

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The PI3K/AKT Signaling Pathway: associations of miRNAs with dysregulated gene expression in colorectal cancer

Abstract

The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC).

We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons.

Of the 304 genes evaluated, 76 had a FC of <0.67 and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks.

Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner. This article is protected by copyright. All rights reserved

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Matrix metallopeptidase 9 targeted by hsa-miR-494 promotes silybin-inhibited osteosarcoma

Abstract

Osteosarcoma (OS) is the most common malignant tumor that develops in bone. Its mortality is very high. Therefore, study of mechanisms of pathogenesis of the OS is urgently required. Previous studies of microarray showed that the expression levels of matrix metallopeptidase 9 (MMP-9) altered significantly in OS. In addition, overexpression of MMP-9 is recognized as an indicator in cancer. However, the exact roles of MMP-9 in OS are not fully investigated. Thus, we firstly studied the roles of MMP-9 in OS and revealed that silence of MMP-9 inhibited OS cell proliferation as determined by MTT assay and colony formation assay. Secondly, we conducted TUNEL assay and confirmed loss of functions of MMP-9 induced OS cell apoptosis. Next, we used lentivector packaging method to overexpress MMP-9 and found that overexpression of MMP-9 promoted OS cell migration. Fourthly, the results of luciferase assay showed that MMP-9 was targeted by hsa-miR-494, which inhibited OS. Fifthly, we revealed that the levels of hsa-miR-494 were upregulated by the drug silybin which inhibited OS. Finally, we revealed that silybin inhibited OS cell viability by altering the protein levels of β-catenin and Runt-related transcription factor 2 (RUNX2) as determined by western blot and immunocytochemistry (ICC). This article is protected by copyright. All rights reserved

http://ift.tt/2yRykGH

Long non-coding RNA AGER-1 functionally upregulates the innate immunity gene AGER and approximates its anti-tumor effect in lung cancer

Abstract

Background: Little is known about long non-coding RNA (lncRNA) related to innate immunity in lung cancer. The advanced glycosylation end-product specific receptor (AGER) belongs to the immunoglobulin superfamily, and currently, is the only innate immune pattern-recognition receptor whose abnormal expression has been detected in lung cancer. We aimed to explore the lncRNA that is related to AGER and test its effect on lung carcinogenesis.

Methods: We selected one lncRNA whose chromosome location is in close proximity to AGER namely lnc-AGER-1 (defined as lncAGER). The expression of lncAGER was tested in 276 pairs of lung cancer tissues and adjacent lung normal tissues, and its correlation with lung cancer clinical progress was analyzed. A series of assays were further used to assess the biological function of lncAGER on lung cancer development, tumor immunity and autophagy.

Results: LncAGER expression was moderately correlated with AGER expression (r = 0.360, P = 2.15 × 10⁻¹⁸) underlying a mechanism that lncAGER upregulates AGER by competitively binding to miRNA-185. LncAGER was significantly down-regulated in 76.4% of lung cancer tissues compared to adjacent normal tissues due to promoter hypermethylation. Over-expression of the lncRNA resulted in significant decreases in proliferation rate, migration ability, colony formation efficiency of lung cancer cells and tumor growth in nude mice. Notably, lncAGER possibly conduced to enhancement of cytotoxic effects of THP1. Additionally, the lncRNA also promoted cell apoptosis by strengthening autophagy.

Conclusions: Taken together, these observations suggest that lncAGER has an inhibitory effect on lung cancer development via AGER, which may serve as a target for lung cancer treatment. This article is protected by copyright. All rights reserved

http://ift.tt/2yKSRKQ

BAG3-dependent expression of Mcl-1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

Abstract

Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer. This article is protected by copyright. All rights reserved

http://ift.tt/2yPA7vY

Expression of the FGFR2c mesenchymal splicing variant in human keratinocytes inhibits differentiation and promotes invasion

ABSTRACT

The altered isoform switching of the fibroblast growth factor receptor 2 (FGFR2) and aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells is involved in cancer progression. We have recently described that the ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth. Here we extended our analysis to the effects of this FGFR2c forced expression on human keratinocyte differentiation and stratification. Our findings demonstrated that, differently from cells overexpressing the epithelial splicing variant FGFR2b, keratinocytes ectopically expressing FGFR2c are not able to form a monolayer and display decreased expression of early differentiation markers. This impaired ability to enter the differentiation program is related to the up-modulation of the transcription factor ΔNp63. In addition, FGFR2c-expressing keratinocytes undergo defective stratification and invasion of the collagen matrix in 3D organotypic cultures, further suggesting their tumorigenic potential. Taken together, our results support the hypothesis that the receptor switching and the consequent appearance of the mesenchymal FGFR2c variant in the epithelial context would drive early steps of carcinogenesis, unbalancing the p63/FGFR interplay and altering the paracrine response to the microenvironment. This article is protected by copyright. All rights reserved

http://ift.tt/2yLqufJ

The PI3K/AKT Signaling Pathway: associations of miRNAs with dysregulated gene expression in colorectal cancer

Abstract

The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC).

We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons.

Of the 304 genes evaluated, 76 had a FC of <0.67 and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks.

Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner. This article is protected by copyright. All rights reserved

http://ift.tt/2yPxdam

MiR-489 suppresses tumor growth and invasion by targeting HDAC7 in colorectal cancer

Abstract

Purpose

The expression of miR-489 is linked to tumor development and progression; nevertheless, its role in tumor growth and invasion of colorectal cancer (CRC) and the underlying mechanism has not been clarified.

Experimental design

We used quantitative RT-PCR to measure the expression of mature miR-489 in human colorectal tissues and the corresponding CRCs. Targets of miR-489 were predicted with TargetScan and substantiated by dual-luciferase reporter assay. Furthermore, we did in vitro and in vivo analysis with expression vectors and small interfering RNAs, to elucidate the precise role of miR-489 and its target gene histone deacetylase 7 (HDAC7) on cell proliferation, survival, and invasion.

Results

Compared to the corresponding non-tumor tissues, miR-489 was frequently downregulated in CRC. By Kaplan–Meier analysis, we found that lower CRC recurrence free survival years in the group with elevated miR-489 expression than those with lower miR-489 expression. In addition, we examined that miR-489 obviously inhibited the migratory and invasive capability in CRC. In further study, we found that miR-489 targets the 3′-UTR of the HDAC7 transcript and downregulates its expression, and HDAC7 expression promoted tumor cell proliferation and invasion. We demonstrated that miR-489 suppresses tumor invasion and metastasis in CRC by targeting HDAC7.

Conclusions

We identified that MiR-489 suppresses tumor growth and invasion in CRC by targeting HDAC7. The expression of miR-489 suggests CRC recurrence and metastasis, which shed crucial light on how miR-489 functions in CRC pathogenesis.

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