TGF-β family co-receptor function and signaling

Abstract

Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.

http://ift.tt/2DojtmB

A special issue on TGF-β signaling: regulation, crosstalk, and biology

http://ift.tt/2DSK63Z

Feedback regulation of TGF-β signaling

Abstract

Transforming growth factor beta (TGF-β) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-β ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-β/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-β signaling, and then discuss how each step of TGF-β signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs.

http://ift.tt/2DlHYAS

Molecular regulation of Nodal signaling during mesendoderm formation

Abstract

One of the most important events during vertebrate embryogenesis is the formation or specification of the three germ layers, endoderm, mesoderm, and ectoderm. After a series of rapid cleavages, embryos form the mesendoderm and ectoderm during late blastulation and early gastrulation. The mesendoderm then further differentiates into the mesoderm and endoderm. Nodal, a member of the transforming growth factor β (TGF-β) superfamily, plays a pivotal role in mesendoderm formation by regulating the expression of a number of critical transcription factors, including Mix-like, GATA, Sox, and Fox. Because the Nodal signal transduction pathway is well-characterized, increasing effort has been made to delineate the spatiotemporal modulation of Nodal signaling during embryonic development. In this review, we summarize the recent progress delineating molecular regulation of Nodal signal intensity and duration during mesendoderm formation.

http://ift.tt/2DSc9AQ

Quantitative single-molecule study of TGF-β/Smad signaling

Abstract

TGF-β/Smad signaling pathway triggers diverse cellular responses among different cell types and environmental conditions. Quantitative analysis of protein-protein interactions involved in TGF-β/Smad signaling is demanded for understanding the molecular mechanism of this signaling pathway. Live-cell single-molecule microcopy with high spatiotemporal resolution is a new tool to monitor key molecular events in a real-time manner. In this review, we mainly presented the recent work on the quantitative characterization of TGF-β/Smad signaling proteins by single-molecule method, and showed how it enabled us to obtain new insights about this canonical signaling process.

http://ift.tt/2DOBSd7

TGF-β signaling pathway in early mouse development and embryonic stem cells

Abstract

TGF-β superfamily signaling pathways essentially contribute to the broad spectrum of early developmental events including embryonic patterning, cell fate determination and dynamic movements. In this review, we first introduced some key developmental processes that require TGF-β signaling to show the fundamental importance of these pathways. Then we discuss how their activities are regulated, and new findings about how the TGF-β superfamily ligands bind to the chromatin to regulate transcription during embryo development.

http://ift.tt/2DR5bvC

Paradoxical roles of TGF-β signaling in suppressing and promoting squamous cell carcinoma

Abstract

Transforming growth factor β (TGF-β) signaling either promotes or inhibits tumor formation and/or progression of many cancer types including squamous cell carcinoma (SCC). Canonical TGF-β signaling is mediated by a number of downstream proteins including Smad family proteins. Alterations in either TGF-β or Smad signaling can impact cancer. For instance, defects in TGF-β type I and type II receptors (TGF-βRI and TGF-βRII) and in Smad2/3/4 could promote tumor development. Conversely, increased TGF-β1 and activated TGF-βRI and Smad3 have all been shown to have tumor-promoting effects in experimental systems of human and mouse SCCs. Among TGF-β/Smad signaling, only TGF-βRII or Smad4 deletion in mouse epithelium causes spontaneous SCC in the mouse model, highlighting the critical roles of TGF-βRII and Smad4 in tumor suppression. Herein, we review the dual roles of the TGF-β/Smad signaling pathway and related mechanisms in SCC, highlighting the potential benefits and challenges of TGF-β/Smad-targeted therapies.

http://ift.tt/2DhZiXh

The role of TGF-β superfamily signaling in neurological disorders

Abstract

The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

http://ift.tt/2DhZiGL

Crosstalk between TGF-β signaling and epigenome

Abstract

The transforming growth factor beta (TGF-β) family of ligands plays major roles in embryonic development, tissue homeostasis, adult immunity, and wound repair. Dysregulation of TGF-β signaling pathway leads to severe diseases. Its key components have been revealed over the past two decades. This family of cytokines acts by activating receptor activated SMAD (R-SMAD) transcription factors, which in turn modulate the expression of specific sets of target genes. Cells of a multicellular organism have the same genetic information, yet they show structural and functional differences owing to differential expression of their genes. Studies have demonstrated that epigenetic regulation, an integral part of the TGF-β signaling, enables cells to sense and respond to TGF-β signaling in a cell context-dependent manner. R-SMAD, as the central transcription factor of TGF-β signaling, can recruit various epigenetic regulators to shape the transcriptome. In this review, we focus on epigenetic regulatory mechanisms in the TGF-β signaling during mammalian development and diseases and discuss the central role of the interaction between R-SMAD and various epigenetic regulators in this epigenetic regulation. The crosstalk between TGF-β signaling and the epigenome could serve as a versatile fine-tuning mechanism for transcriptional regulation during embryonic development and progression of diseases, particularly cancer.

http://ift.tt/2DkttgE

TGF-β signaling in cancer metastasis

Abstract

The transforming growth factor (TGF)-β signaling events are well known to control diverse processes and numerous responses, such as cell proliferation, differentiation, apoptosis, and migration. TGF-β signaling plays context-dependent roles in cancer: in pre-malignant cells TGF-β primarily functions as a tumor suppressor, while in the later stages of cancer TGF-β signaling promotes invasion and metastasis. Recent studies have also suggested that the cross-talk between TGF-β signaling and other signaling pathways, such as Hippo, Wnt, EGFR/RAS, and PI3K/AKT pathways, may substantially contribute to our current understanding of TGF-β signaling and cancer. As a result of the wide-ranging effects of TGF-β, blockade of TGF-β and its downstream signaling components provides multiple therapeutic opportunities. Therefore, the outlook for anti-TGF-β signaling therapy for numerous diseases appears bright and will provide valuable information and thinking on the drug molecular design. In this review, we focus on recent insights into the regulation of TGF-β signaling in cancer metastasis which may contribute to the development of novel cancer-targeting therapies.

http://ift.tt/2DTe3Rx

Intracellular trafficking of transforming growth factor β receptors

Abstract

Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.

http://ift.tt/2DlHxGK

Smad3–STAT3 crosstalk in pathophysiological contexts

Abstract

Smad3 and STAT3 are intracellular molecules that transmit signals from plasma membrane receptors to the nucleus. Smad3 operates downstream of growth/differentiation factors that utilize activin receptor-like kinase (ALK)-4, 5, or 7, such as transforming growth factor-β (TGF-β), activin, and myostatin. STAT3 principally functions downstream of cytokines that exert their effects via gp130 and Janus family kinases, including interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M. Accumulating evidence indicates that Smad3 and STAT3 engage in crosstalk in a highly context-dependent fashion, cooperating in some conditions while acting antagonistically each other in others. Here, we review the crosstalk between Smad3 and STAT3 in various biological contexts, including early tumorigenesis, epithelial–mesenchymal transition, fibrosis, and T cell differentiation.

http://ift.tt/2DR5syD

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

Abstract

TGF-β's multipotent cellular effects and their relations are critical for TGF-β's pathophysiological functions. However, these effects may appear to be paradoxical in understanding TGF-β's functions. Apoptosis and epithelial–mesenchymal transition (EMT) are two fundamental events that are deeply linked to various physiological and disease-related processes. These two major cellular fates are subtly regulated and can be potently stimulated by TGF-β, which profoundly contribute to the biological roles of TGF-β. Moreover, these two events are also indirectly and directly correlated with TGF-β-mediated growth inhibition and are relevant to the current understanding of the roles of TGF-β in tumorigenesis and cancer progression. Although TGF-β-induced apoptosis and EMT can be singly independent cellular events, they can also be mutually exclusive but interrelated concomitant events in various cases. Thus, the modulation of apoptosis and EMT is essential for the seemingly paradoxical functions of TGF-β. However, the concomitant effect of TGF-β on apoptosis and EMT, the balance and regulated alterations of them are still been ignored or underestimated. This review focuses on the TGF-β-induced concomitant apoptosis and EMT. We aim to provide an insight in understanding their significance, balance, and modulation in TGF-β-mediated biological functions.

http://ift.tt/2DlHtqu

Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion

To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy.

http://ift.tt/2EXvFuM

Skin CanceR Brachytherapy vs External beam radiation therapy (SCRiBE) meta-analysis

To compare cosmesis and local recurrence (LR) of definitive external beam radiation therapy (EBRT) vs brachytherapy (BT) for indolent basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin.

http://ift.tt/2Du2mD1

Palliative radiotherapy for locally advanced non-metastatic head and neck cancer: A systematic review

Objectives: The objective of this systematic review was to identify and appraise the existing evidence of role of palliative radiotherapy for locally advanced non-metastatic head and neck cancer. Methods: A systematic search of the literature was conducted using Medline, Embase and Cochrane databases and relevant references were included. Results: Literature search revealed a wide variation in dose fractionation regimens. Reported outcomes showed high efficacy and low rate of significant side effects, except in studies utilising higher doses of radiotherapy where higher grade toxicities were seen.

http://ift.tt/2EZjs8O

Optimization of combined proton–photon treatments

Proton treatment slots are a limited resource. Therefore, we consider combined proton–photon treatments in which most fractions are delivered with photons and only a few with protons. We demonstrate how both modalities can be combined to optimally capitalize on the proton's ability to reduce normal tissue dose.

http://ift.tt/2Dt2GC9

From Foundation to Demolition: The Influence of Perioperative Tranexamic Acid

No abstract available

http://ift.tt/2DmXAUH

The Impact of Prehospital Tranexamic Acid on Blood Coagulation in Trauma Patients

BACKGROUND: There is limited data on prehospital administration of tranexamic acid (TXA) in civilian trauma. The aim of this study was to evaluate changes in coagulation after severe trauma from on-scene to the hospital after TXA application in comparison to a previous study without TXA. METHODS: The study protocol was registered at ClinicalTrials.gov (NCT02354885). A prospective, multicenter, observational study investigating coagulation status in 70 trauma patients receiving TXA (1 g intravenously) on-scene versus a control group of 38 patients previously published without TXA. To account for potential differences in patient and trauma epidemiology, crystalloid and colloidal resuscitation fluid, 2 propensity score matched groups (n = 24 per group) were created. Measurements included ROTEM, standard coagulation tests and blood gas analyses on-scene and emergency department admission. Presented values are mean and [standard deviation], and difference in means and 95% confidence intervals. RESULTS: Patient epidemiology was not different between groups. Coagulation assays on-scene were comparable between the TXA and C. Prehospital hyperfibrinolysis was blunted in all 4 patients in the TXA group. Viscoelastic FIBTEM maximum clot firmness (MCF), representing functional fibrinogen levels, did not change from on-scene to the emergency department in the TXA group, whereas MCF decreased −3.7 [1.8] mm in the control group. Decrease of MCF was significantly reduced in the TXA group in EXTEM by 9.2 (7.2–11.2) mm (P

http://ift.tt/2DjHdIC

A Tale of Two Solutions: High vs Low-Chloride Intravenous Fluids

No abstract available

http://ift.tt/2DQiOLv

Low- Versus High-Chloride Content Intravenous Solutions for Critically Ill and Perioperative Adult Patients: A Systematic Review and Meta-analysis

BACKGROUND: To assess whether use of low-chloride solutions in unselected critically ill or perioperative adult patients for maintenance or resuscitation reduces mortality and renal replacement therapy (RRT) use when compared to high-chloride fluids. METHODS: Systematic review and meta-analysis with random-effects inverse variance model. PubMed, Cochrane library, EMBASE, LILACS, and Web of Science were searched from inception to October 2016. Published and unpublished randomized controlled trials in any language that enrolled critically ill and/or perioperative adult patients and compared a low- to a highchloride solution for volume maintenance or resuscitation. The primary outcomes were mortality and RRT use. We conducted trial sequential analyses and assessed risk of bias of individual trials and the overall quality of evidence. Fifteen trials with 4067 patients, most at low risk of bias, were identified. Of those, only 11 and 10 trials had data on mortality and RRT use, respectively. A total of 3710 patients were included in the mortality analysis and 3724 in the RRT analysis. RESULTS: No statistically significant impact on mortality (odds ratio, 0.90; 95% confidence interval, 0.69–1.17; P = .44; I2 = 0%) or RRT use (odds ratio, 1.12; 95% confidence interval, 0.80–1.58; P = .52; I2 = 0%) was found. Overall quality of evidence was low for both primary outcomes. Trial sequential analyses highlighted that the sample size needed was much larger than that available for properly powered outcome assessment. CONCLUSIONS: The current evidence on low- versus high-chloride solutions for unselected critically ill or perioperative adult patients demonstrates no benefit, but suffers from considerable imprecision. We noted a limited exposure volume for study fluids and a relatively low risk of the populations in each study. Together with the relatively small pooled sample size, these data leave us underpowered to detect potentially important differences. Results from well-conducted, adequately powered randomized controlled trials examining sufficiently large fluid exposure are necessary.

http://ift.tt/2DPCjnD

Brain Monitoring and the Depth of Anesthesia: Another Goldilocks Dilemma

No abstract available

http://ift.tt/2mTqzIH

Multiple primary malignancies and prolonged survival in a patient with widespread metastatic cutaneous melanoma

No abstract available

http://ift.tt/2DS0MJ4

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea

Future Oncology, Ahead of Print.


http://ift.tt/2FZlPdp

Abiraterone acetate and its use in the treatment of metastatic prostate cancer: a review

Future Oncology, Ahead of Print.


http://ift.tt/2rtAsm7

Abiraterone acetate and its use in the treatment of metastatic prostate cancer: a review

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/2rtAsm7
via IFTTT

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea

Future Oncology, Ahead of Print.


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

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis

Abstract

Background

Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.

Methods

We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H₃-thymidine detected in a beta counter.

The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.

Results

Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells.

Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.

Conclusions

Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that—provided a normal distribution and count of lymphocyte subgroups—patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.

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

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis

Abstract

Background

Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.

Methods

We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H₃-thymidine detected in a beta counter.

The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.

Results

Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells.

Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.

Conclusions

Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that—provided a normal distribution and count of lymphocyte subgroups—patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.

http://ift.tt/2mVkQls

Fusion-Negative Rhabdomyosarcoma Can Arise from Endothelial Cells [Research Watch]

Aberrant myogenic activation in endothelial cells can drive fusion-negative rhabdomyosarcoma (FN-RMS).

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

REV-ERB Agonists Block Autophagy in Cancer Cells [Research Watch]

Disruption of the circadian clock components reduces cancer cell viability in vitro and in vivo.

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

Patients with Desmoplastic Melanoma May Respond to PD-1 Blockade [Research Watch]

PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.

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

LXR Agonism Depletes MDSCs to Promote Antitumor Immunity [Research Watch]

LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.

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

Personalized chemosensitivity assays for mesothelioma- is it worth the effort?

Cell-lines formed from an individual's tumor can be used to predict response to specific therapies and determine genomic predictors. For mesothelioma, where chemotherapy remains the backbone of current therapeutic paradigms, such assays could be used to treat patients with the most effective agents specific to their "chemical profile".

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

Pathways impacted by genomic alterations in pulmonary carcinoid tumors

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, typical and atypical carcinoid, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death and apoptosis and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1 and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-ĸB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

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

A novel method for rapid molecular subgrouping of medulloblastoma

Purpose: The classification of medulloblastoma into WNT, SHH, Group 3 and Group 4 subgroups has become of critical importance for patient risk-stratification and subgroup-tailored clinical trials. Here, we aimed to develop a simplified, clinically applicable classification approach that can be implemented in the majority of centers treating patients with medulloblastoma. Experimental Design: We analyzed 1,577 samples comprising previously published DNA methylation microarray data (913 medulloblastomas, 457 non-medulloblastoma tumors, 85 normal tissues), and 122 frozen and formalin-fixed paraffin-embedded medulloblastoma samples. Biomarkers were identified applying stringent selection filters and Linear Discriminant Analysis (LDA) method, and validated using DNA methylation microarray data, bisulfite pyrosequencing and direct-bisulfite sequencing. Results: Using a LDA-based approach, we developed and validated a prediction method (^EpiWNT-SHH classifier) based on six epigenetic biomarkers that allowed for rapid classification of medulloblastoma into the clinically relevant subgroups WNT, SHH and non-WNT/non-SHH with excellent concordance (>99%) with current gold-standard methods, DNA methylation microarray and gene-signature profiling analysis. The ^EpiWNT-SHH classifier showed high prediction capacity using both frozen and formalin-fixed material, as well as diverse DNA methylation detection methods. Similarly, we developed a classifier specific for Group 3 and Group 4 tumors, based on five biomarkers (^EpiG3-G4) with good discriminatory capacity, allowing for correct assignment of more than 92% of tumors. ^EpiWNT-SHH and ^EpiG3-G4 methylation profiles remained stable across tumor primary, metastasis and relapse samples. Conclusions: The ^EpiWNT-SHH and ^EpiG3-G4 classifiers represent a new simplified approach for accurate, rapid and cost-effective molecular classification of single medulloblastoma DNA samples, using clinically applicable DNA methylation detection methods.

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

High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole exome sequencing on a selected cohort of children with cancer. Experimental design: To identify mutations in known and novel cancer predisposing genes, we performed trio-based whole exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Results: Four patients carried causative mutations in a known cancer predisposing gene: TP53 and DICER1 (n=3). In another four patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition. Conclusion: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in eight patients and two possible novel cancer predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition.

from Cancer via ola Kala on Inoreader http://ift.tt/2FU2Wsh
via IFTTT

Exceptional response to pembrolizumab in a metastatic, chemotherapy/radiation resistant ovarian cancer patient harboring a CD274/PD-L1-genetic rearrangement

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. Experimental Design: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques. Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high grade ovarian carcinoma with clear cell features.  While progressing on any standard treatment modality she demonstrated a remarkable complete response to the anti-PD1 immune check-point inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (Tumor Mutation Load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-1L gene causing aberrant PD-L1 surface expression as confirmed by immunohistochemistry (IHC) and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T cell lymphocytes (ie, CD4+/CD8+ TIL), CD68+ macrophages and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side-effects reported to date. Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression.

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

Personalized chemosensitivity assays for mesothelioma- is it worth the effort?

Cell-lines formed from an individual's tumor can be used to predict response to specific therapies and determine genomic predictors. For mesothelioma, where chemotherapy remains the backbone of current therapeutic paradigms, such assays could be used to treat patients with the most effective agents specific to their "chemical profile".

http://ift.tt/2rjOBBW

Pathways impacted by genomic alterations in pulmonary carcinoid tumors

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, typical and atypical carcinoid, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death and apoptosis and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1 and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-ĸB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

http://ift.tt/2FVZgGi

A novel method for rapid molecular subgrouping of medulloblastoma

Purpose: The classification of medulloblastoma into WNT, SHH, Group 3 and Group 4 subgroups has become of critical importance for patient risk-stratification and subgroup-tailored clinical trials. Here, we aimed to develop a simplified, clinically applicable classification approach that can be implemented in the majority of centers treating patients with medulloblastoma. Experimental Design: We analyzed 1,577 samples comprising previously published DNA methylation microarray data (913 medulloblastomas, 457 non-medulloblastoma tumors, 85 normal tissues), and 122 frozen and formalin-fixed paraffin-embedded medulloblastoma samples. Biomarkers were identified applying stringent selection filters and Linear Discriminant Analysis (LDA) method, and validated using DNA methylation microarray data, bisulfite pyrosequencing and direct-bisulfite sequencing. Results: Using a LDA-based approach, we developed and validated a prediction method (^EpiWNT-SHH classifier) based on six epigenetic biomarkers that allowed for rapid classification of medulloblastoma into the clinically relevant subgroups WNT, SHH and non-WNT/non-SHH with excellent concordance (>99%) with current gold-standard methods, DNA methylation microarray and gene-signature profiling analysis. The ^EpiWNT-SHH classifier showed high prediction capacity using both frozen and formalin-fixed material, as well as diverse DNA methylation detection methods. Similarly, we developed a classifier specific for Group 3 and Group 4 tumors, based on five biomarkers (^EpiG3-G4) with good discriminatory capacity, allowing for correct assignment of more than 92% of tumors. ^EpiWNT-SHH and ^EpiG3-G4 methylation profiles remained stable across tumor primary, metastasis and relapse samples. Conclusions: The ^EpiWNT-SHH and ^EpiG3-G4 classifiers represent a new simplified approach for accurate, rapid and cost-effective molecular classification of single medulloblastoma DNA samples, using clinically applicable DNA methylation detection methods.

http://ift.tt/2rotkau

High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole exome sequencing on a selected cohort of children with cancer. Experimental design: To identify mutations in known and novel cancer predisposing genes, we performed trio-based whole exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Results: Four patients carried causative mutations in a known cancer predisposing gene: TP53 and DICER1 (n=3). In another four patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition. Conclusion: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in eight patients and two possible novel cancer predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition.

http://ift.tt/2FU2Wsh

Exceptional response to pembrolizumab in a metastatic, chemotherapy/radiation resistant ovarian cancer patient harboring a CD274/PD-L1-genetic rearrangement

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. Experimental Design: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques. Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high grade ovarian carcinoma with clear cell features.  While progressing on any standard treatment modality she demonstrated a remarkable complete response to the anti-PD1 immune check-point inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (Tumor Mutation Load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-1L gene causing aberrant PD-L1 surface expression as confirmed by immunohistochemistry (IHC) and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T cell lymphocytes (ie, CD4+/CD8+ TIL), CD68+ macrophages and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side-effects reported to date. Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression.

http://ift.tt/2rkjWVq

ER{alpha}-mediated nuclear sequestration of RSK2 is required for ER+ breast cancer tumorigenesis

Although ribosomal protein S6 kinase A3 (RSK) activation status positively correlates with patient responses to anti-estrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of ER+ breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N-terminus to activate a pro-neoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Anti-estrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to anti-estrogen therapies.

http://ift.tt/2FVCDlt

XIAP regulation by MNK links MAPK and NF{kappa}B signaling to determine an aggressive breast cancer phenotype

Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked epidermal growth factor receptor (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK-interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intra-vital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular crosstalk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.

http://ift.tt/2roMpct

Integrative genomic analysis predicts causative cis-regulatory mechanisms of the breast cancer-associated genetic variant rs4415084

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) that systematically utilizes haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1. We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2=0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3 binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.

http://ift.tt/2Bhx5OG

Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation and breast cancer metastasis

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) which mediates cancer pathogenesis. A high fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key pro-inflammatory cytokines, macrophage infiltration and tumor progression induced by obesity. S1P produced in the lung pre-metastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL-6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL-6, macrophage infiltration and S1P-mediated signaling pathways in the lung induced by a high fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches and breast cancer metastasis, with potential implications for prevention and treatment.

http://ift.tt/2mW8o5Q

ER{alpha}-mediated nuclear sequestration of RSK2 is required for ER+ breast cancer tumorigenesis

Although ribosomal protein S6 kinase A3 (RSK) activation status positively correlates with patient responses to anti-estrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of ER+ breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N-terminus to activate a pro-neoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Anti-estrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to anti-estrogen therapies.

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

XIAP regulation by MNK links MAPK and NF{kappa}B signaling to determine an aggressive breast cancer phenotype

Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked epidermal growth factor receptor (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK-interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intra-vital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular crosstalk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.

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

Integrative genomic analysis predicts causative cis-regulatory mechanisms of the breast cancer-associated genetic variant rs4415084

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) that systematically utilizes haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1. We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2=0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3 binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.

from Cancer via ola Kala on Inoreader http://ift.tt/2Bhx5OG
via IFTTT

Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation and breast cancer metastasis

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) which mediates cancer pathogenesis. A high fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key pro-inflammatory cytokines, macrophage infiltration and tumor progression induced by obesity. S1P produced in the lung pre-metastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL-6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL-6, macrophage infiltration and S1P-mediated signaling pathways in the lung induced by a high fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches and breast cancer metastasis, with potential implications for prevention and treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/2mW8o5Q
via IFTTT

Grantee Spotlight: Luis G. Carvajal-Carmona, PhD

Dr. Carvajal-Carmona is an Associate Professor and CRCHD R21 awardee researching cancer genetics, epidemiology, and cancer health disparities.

http://ift.tt/2FWbiQ8

Grantee Spotlight: Luis G. Carvajal-Carmona, PhD

Dr. Carvajal-Carmona is an Associate Professor and CRCHD R21 awardee researching cancer genetics, epidemiology, and cancer health disparities.

from Cancer via ola Kala on Inoreader http://ift.tt/2FWbiQ8
via IFTTT

Association of processed food, synergistic effect of alcohol and HBV with Hepatocellular Carcinoma in a high incidence region of India

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Rup Kumar Phukan, Biswa Jyoti Borkakoty, Sanjib Kumar Phukan, Kumar Bhandari, Jagdish Mahanta, Sopai Tawsik, Sangita Bhandari, Ashish Rai, Kanwar Narain
BackgroundDietary factors, tobacco, and alcohol use have been identified as important factors of rising various cancer incidence in several northeastern states of India. However, little is known about the factors associated with hepatocellular carcinoma (HCC) in this region. The aim of the paper was to identify the factors associated with HCC in the northeast region.MethodsA case-control study was conducted in Arunachal Pradesh and Sikkim, two northeastern states of India, including 104 histologically-confirmed cases of HCC and same number (104) of age and sex matched control enrolled. Logistic regression analysis was performed to identify the factors associated with HCC.ResultsA statistically significant association was demonstrated between HCC and alcohol consumption, consumption of 'Sai-mod' (OR 2.77, CI 1.57–4.87) a homemade alcohol beverage, and with HBV (OR 7.97, CI 3.36–18.94). Positive synergism index (S = 3.04) was observed between HBV and alcohol consumption to risk of HCC. Higher intake of processed meat (OR 2.56, CI 1.09–6.03) and processed fish (OR 2.24, CI 1.02–4.95) were found associated with increased risk of HCC; and decreased risk of HCC with fresh fish, fruits, and milk.ConclusionsStrong relationship between different dietary factors, alcohol beverage with HCC suggests that control on dietary and drinking habit will be an important strategy to combat HCC in this region. Risk factors identified in this study will help to plan more effectively targeted risk reduction strategies and programs in this region.



from Cancer via ola Kala on Inoreader http://ift.tt/2FYDy4G
via IFTTT

Nilotinib Can Be Discontinued in Some Patients with Chronic Myelogenous Leukemia

On December 22, FDA approved an update to the label of nilotinib (Tasignia) that states that some patients with CML who are taking nilotinib and whose cancer has been in remission for an extended period can safely stop taking it.

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

Association of processed food, synergistic effect of alcohol and HBV with Hepatocellular Carcinoma in a high incidence region of India

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Rup Kumar Phukan, Biswa Jyoti Borkakoty, Sanjib Kumar Phukan, Kumar Bhandari, Jagdish Mahanta, Sopai Tawsik, Sangita Bhandari, Ashish Rai, Kanwar Narain
BackgroundDietary factors, tobacco, and alcohol use have been identified as important factors of rising various cancer incidence in several northeastern states of India. However, little is known about the factors associated with hepatocellular carcinoma (HCC) in this region. The aim of the paper was to identify the factors associated with HCC in the northeast region.MethodsA case-control study was conducted in Arunachal Pradesh and Sikkim, two northeastern states of India, including 104 histologically-confirmed cases of HCC and same number (104) of age and sex matched control enrolled. Logistic regression analysis was performed to identify the factors associated with HCC.ResultsA statistically significant association was demonstrated between HCC and alcohol consumption, consumption of 'Sai-mod' (OR 2.77, CI 1.57–4.87) a homemade alcohol beverage, and with HBV (OR 7.97, CI 3.36–18.94). Positive synergism index (S = 3.04) was observed between HBV and alcohol consumption to risk of HCC. Higher intake of processed meat (OR 2.56, CI 1.09–6.03) and processed fish (OR 2.24, CI 1.02–4.95) were found associated with increased risk of HCC; and decreased risk of HCC with fresh fish, fruits, and milk.ConclusionsStrong relationship between different dietary factors, alcohol beverage with HCC suggests that control on dietary and drinking habit will be an important strategy to combat HCC in this region. Risk factors identified in this study will help to plan more effectively targeted risk reduction strategies and programs in this region.



http://ift.tt/2FYDy4G

Nilotinib Can Be Discontinued in Some Patients with Chronic Myelogenous Leukemia

On December 22, FDA approved an update to the label of nilotinib (Tasignia) that states that some patients with CML who are taking nilotinib and whose cancer has been in remission for an extended period can safely stop taking it.

http://ift.tt/2EWRCKA

Benefit Finding and Diurnal Cortisol after Prostate Cancer: The Mediating Role of Positive Affect

Abstract

Objective

Benefit finding (BF) has exhibited a salutary effect on psychological adjustment to cancer. However, few studies have examined its relationship with physiology or have examined BF in men with cancer. This study investigated whether BF is associated with Hypothalamic-Pituitary-Adrenal (HPA) axis activity (i.e., diurnal salivary cortisol) in men treated for prostate cancer. Positive affect (PA) is proposed as a potential pathway linking BF to diurnal salivary cortisol.

Methods

A sample of 66 men treated for localized prostate cancer within the prior two years completed questionnaires and collected salivary cortisol three times per day over three consecutive days. Hierarchical linear modeling was used for estimating the effects of BF and PA on cortisol responses as measured by diurnal slope and area under the curve (AUCg). Confidence intervals for indirect effects were estimated using the Monte Carlo method for mediation testing.

Results

BF was significantly associated with diurnal cortisol slope, controlling for body mass index and age (B = -.12, p = .03), such that greater BF was associated with steeper cortisol slope. Analyses revealed that PA mediated the effect of BF on cortisol slope (Monte Carlo estimation 95% CI = -0.087, -0.001); negative affect did not mediate this relationship. BF was not significantly associated with AUCg.

Conclusions

Deriving more benefit from one's experience with prostate cancer is associated with a healthier diurnal cortisol rhythm. Through its potential to enhance PA, the relationship of BF and physiological processes underscores the health relevant value of BF in prostate cancer survivors.

http://ift.tt/2EWNM40

Benefit Finding and Diurnal Cortisol after Prostate Cancer: The Mediating Role of Positive Affect

Abstract

Objective

Benefit finding (BF) has exhibited a salutary effect on psychological adjustment to cancer. However, few studies have examined its relationship with physiology or have examined BF in men with cancer. This study investigated whether BF is associated with Hypothalamic-Pituitary-Adrenal (HPA) axis activity (i.e., diurnal salivary cortisol) in men treated for prostate cancer. Positive affect (PA) is proposed as a potential pathway linking BF to diurnal salivary cortisol.

Methods

A sample of 66 men treated for localized prostate cancer within the prior two years completed questionnaires and collected salivary cortisol three times per day over three consecutive days. Hierarchical linear modeling was used for estimating the effects of BF and PA on cortisol responses as measured by diurnal slope and area under the curve (AUCg). Confidence intervals for indirect effects were estimated using the Monte Carlo method for mediation testing.

Results

BF was significantly associated with diurnal cortisol slope, controlling for body mass index and age (B = -.12, p = .03), such that greater BF was associated with steeper cortisol slope. Analyses revealed that PA mediated the effect of BF on cortisol slope (Monte Carlo estimation 95% CI = -0.087, -0.001); negative affect did not mediate this relationship. BF was not significantly associated with AUCg.

Conclusions

Deriving more benefit from one's experience with prostate cancer is associated with a healthier diurnal cortisol rhythm. Through its potential to enhance PA, the relationship of BF and physiological processes underscores the health relevant value of BF in prostate cancer survivors.

from Cancer via ola Kala on Inoreader http://ift.tt/2EWNM40
via IFTTT

Accurate understanding of infertility risk among families of adolescent males newly diagnosed with cancer

Abstract

Objective

To examine patient and parent understanding of infertility risk (relative to oncologists' risk ratings) among adolescents newly diagnosed with cancer, and to identify background factors related to inaccurate reporting/estimating.

Methods

Male patients (N=137; aged 13-21) and their parents completed self-report questionnaires. Those who reported a fertility-related conversation with their provider (N=102 adolescents, N=74 parents), reported their infertility risk (i.e., what oncologist had communicated) and all participants estimated risk (i.e., personal belief). Reports/estimates were compared to oncologists' ratings to assess relative accuracy, and regression analyses assessed potentially related background factors.

Results

Participants' agreement of their risk reports with the oncologist was poor (kappa=.079/.122 for adolescents/parents), resulting in most adolescents (59.8%) and parents (58.7%) inaccurately reporting risk. Older adolescents were less likely to over-report risk (OR=0.69; 95%CI [0.49-0.97]) and parents of sons with the highest Tanner stage were less likely to under-report (OR=0.28; 95%CI [0.08-0.92]). Risk estimates were also in poor agreement with oncologists' ratings among adolescents (kappa=.040) and parents (kappa=.088). Accordingly, incongruent estimates occurred in most adolescents (63.7%) and parents (62.2%), although all reported fertility-related conversations with their providers.

Conclusions

Most adolescents and parents inaccurately reported infertility risk, and more poorly estimated risk. Research is needed to identify additional factors associated with accurate understanding of cancer-related infertility risk. Providers should be supported with user-friendly educational tools to promote awareness of infertility risk.

from Cancer via ola Kala on Inoreader http://ift.tt/2EW3BIg
via IFTTT

The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer

Abstract

Background

Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.

Methods

In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter.

Results

We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.

Conclusions

Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.

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

Accurate understanding of infertility risk among families of adolescent males newly diagnosed with cancer

Abstract

Objective

To examine patient and parent understanding of infertility risk (relative to oncologists' risk ratings) among adolescents newly diagnosed with cancer, and to identify background factors related to inaccurate reporting/estimating.

Methods

Male patients (N=137; aged 13-21) and their parents completed self-report questionnaires. Those who reported a fertility-related conversation with their provider (N=102 adolescents, N=74 parents), reported their infertility risk (i.e., what oncologist had communicated) and all participants estimated risk (i.e., personal belief). Reports/estimates were compared to oncologists' ratings to assess relative accuracy, and regression analyses assessed potentially related background factors.

Results

Participants' agreement of their risk reports with the oncologist was poor (kappa=.079/.122 for adolescents/parents), resulting in most adolescents (59.8%) and parents (58.7%) inaccurately reporting risk. Older adolescents were less likely to over-report risk (OR=0.69; 95%CI [0.49-0.97]) and parents of sons with the highest Tanner stage were less likely to under-report (OR=0.28; 95%CI [0.08-0.92]). Risk estimates were also in poor agreement with oncologists' ratings among adolescents (kappa=.040) and parents (kappa=.088). Accordingly, incongruent estimates occurred in most adolescents (63.7%) and parents (62.2%), although all reported fertility-related conversations with their providers.

Conclusions

Most adolescents and parents inaccurately reported infertility risk, and more poorly estimated risk. Research is needed to identify additional factors associated with accurate understanding of cancer-related infertility risk. Providers should be supported with user-friendly educational tools to promote awareness of infertility risk.

http://ift.tt/2EW3BIg

The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer

Abstract

Background

Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.

Methods

In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter.

Results

We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.

Conclusions

Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.

http://ift.tt/2DQLbJS

EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

Publication date: Available online 18 January 2018
Source:Cancer Cell
Author(s): Amanda Balboni Iniguez, Björn Stolte, Emily Jue Wang, Amy Saur Conway, Gabriela Alexe, Neekesh V. Dharia, Nicholas Kwiatkowski, Tinghu Zhang, Brian J. Abraham, Jaume Mora, Peter Kalev, Alan Leggett, Dipanjan Chowdhury, Cyril H. Benes, Richard A. Young, Nathanael S. Gray, Kimberly Stegmaier
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

Graphical abstract

Teaser

Iniguez et al. find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression. CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models.


http://ift.tt/2DiS19S

EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

Publication date: Available online 18 January 2018
Source:Cancer Cell
Author(s): Amanda Balboni Iniguez, Björn Stolte, Emily Jue Wang, Amy Saur Conway, Gabriela Alexe, Neekesh V. Dharia, Nicholas Kwiatkowski, Tinghu Zhang, Brian J. Abraham, Jaume Mora, Peter Kalev, Alan Leggett, Dipanjan Chowdhury, Cyril H. Benes, Richard A. Young, Nathanael S. Gray, Kimberly Stegmaier
Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

Graphical abstract

Teaser

Iniguez et al. find that inhibition of CDK12 is synthetic lethal with EWS/FLI expression. CDK12/13 inhibitors impair DNA damage repair in cells expressing EWS/FLI, and the combination of CDK12/13 and PARP inhibitors synergistically reduces tumor growth and extends survival in Ewing sarcoma mouse models.


from Cancer via ola Kala on Inoreader http://ift.tt/2DiS19S
via IFTTT

Hibernation of masses suspected to be remnant tumors after surgical resection of retroperitoneal liposarcoma is related to improved overall survival

Abstract

Background

Although complete surgical resection is considered the best treatment for retroperitoneal liposarcoma, it is related to a high local recurrence rate. This study analyzed patterns of recurrence of retroperitoneal liposarcoma.

Methods

Records of patients who experienced recurrence after surgery for retroperitoneal liposarcoma from January 2000 to May 2017 were analyzed. Site, number, and characteristics of recurrent mass on computed tomography were serially collected. If a mass did not change size, it was considered a hibernating mass. Potential prognostic factors for overall survival were calculated using Kaplan–Meier survival log-rank tests.

Results

A total of 74 patients, 28 within 6 months and 46 after 6 months, were detected as having a recurrence-suspected mass after surgery. Hibernation of a recurrence-suspected mass was found in 19 patients, 12 within 6 months and 7 after 6 months. While the presence of hibernation was not related to overall survival (P = 0.245), it was significantly related to improved survival in patients with a mass detected within 6 months (P = 0.022). Hibernation was not related to improved survival in patients with a mass detected after 6 months (P = 0.056).

Conclusions

Hibernation of a recurrence-suspected mass was related to improvement of overall survival in patients with a mass detected within 6 months. This specific patient group should be monitored with care to see if the size of the mass increases. When a mass seemed to be hibernating, a favorable prognosis could be expected.

http://ift.tt/2mQk8pL

Hibernation of masses suspected to be remnant tumors after surgical resection of retroperitoneal liposarcoma is related to improved overall survival

Abstract

Background

Although complete surgical resection is considered the best treatment for retroperitoneal liposarcoma, it is related to a high local recurrence rate. This study analyzed patterns of recurrence of retroperitoneal liposarcoma.

Methods

Records of patients who experienced recurrence after surgery for retroperitoneal liposarcoma from January 2000 to May 2017 were analyzed. Site, number, and characteristics of recurrent mass on computed tomography were serially collected. If a mass did not change size, it was considered a hibernating mass. Potential prognostic factors for overall survival were calculated using Kaplan–Meier survival log-rank tests.

Results

A total of 74 patients, 28 within 6 months and 46 after 6 months, were detected as having a recurrence-suspected mass after surgery. Hibernation of a recurrence-suspected mass was found in 19 patients, 12 within 6 months and 7 after 6 months. While the presence of hibernation was not related to overall survival (P = 0.245), it was significantly related to improved survival in patients with a mass detected within 6 months (P = 0.022). Hibernation was not related to improved survival in patients with a mass detected after 6 months (P = 0.056).

Conclusions

Hibernation of a recurrence-suspected mass was related to improvement of overall survival in patients with a mass detected within 6 months. This specific patient group should be monitored with care to see if the size of the mass increases. When a mass seemed to be hibernating, a favorable prognosis could be expected.

from Cancer via ola Kala on Inoreader http://ift.tt/2mQk8pL
via IFTTT

Baculovirus-based gene silencing of Humanin for the treatment of pituitary tumors

Abstract

Pituitary tumors are the most common primary intracranial neoplasms. Humanin (HN) and Rattin (HNr), a rat homolog of HN, are short peptides with a cytoprotective action. In the present study, we aimed to evaluate whether endogenous HNr plays an antiapoptotic role in pituitary tumor cells. Thus, we used RNA interference based on short-hairpin RNA (shRNA) targeted to HNr (shHNr). A plasmid including the coding sequences for shHNr and dTomato fluorescent reporter gene was developed (pUC-shHNr). Transfection of somatolactotrope GH3 cells with pUC-shHNr increased apoptosis, suggesting that endogenous HNr plays a cytoprotective role in pituitary tumor cells. In order to evaluate the effect of blockade of endogenous HNr expression in vivo, we constructed a recombinant baculovirus (BV) encoding shHNr (BV-shHNr). In vitro, BV-shRNA was capable of transducing more than 80% of GH3 cells and decreased HNr mRNA. Also, BV-shHNr increased apoptosis in transduced GH3 cells. Intratumor injection of BV-shHNr to nude mice bearing s.c. GH3 tumors increased the number of apoptotic cells, delayed tumor growth and enhanced survival rate, suggesting that endogenous HNr may be involved in pituitary tumor progression. These preclinical data suggests that the silencing of HN expression could have a therapeutic impact on the treatment of pituitary tumors.

http://ift.tt/2ripob8

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Abstract

Background

Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H⁺ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation.

Methods

Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription–PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues.

Results

Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3).

Conclusion

Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.

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

Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells

Abstract

Background

Autophagy is a dynamic physiological process that can generate energy and nutrients for cell survival during stress. Autophagy can regulate the migration and invasive ability in cancer cells. However, the connection between autophagy and metabolism is unclear. Monocarboxylate transporter 1 (MCT1) plays an important role in lactic acid transport and H⁺ clearance in cancer cells, and Wnt/β-catenin signaling can increase cancer cell glycolysis. We investigated whether autophagy promotes glycolysis in hepatocellular carcinoma (HCC) cells by activating the Wnt/β-catenin signaling pathway, accompanied by MCT1 upregulation.

Methods

Autophagic activity was evaluated using western blotting, immunoblotting, and transmission electron microscopy. The underlying mechanisms of autophagy activation on HCC cell glycolysis were studied via western blotting, and Transwell, lactate, and glucose assays. MCT1 expression was detected using quantitative reverse transcription–PCR (real-time PCR), western blotting, and immunostaining of HCC tissues and the paired adjacent tissues.

Results

Autophagy promoted HCC cell glycolysis accompanied by MCT1 upregulation. Wnt/β-catenin signaling pathway activation mediated the effect of autophagy on HCC cell glycolysis. β-Catenin downregulation inhibited the autophagy-induced glycolysis in HCC cells, and reduced MCT1 expression in the HCC cells. MCT1 was highly expressed in HCC tissues, and high MCT1 expression correlated positively with the expression of microtubule-associated protein light chain 3 (LC3).

Conclusion

Activation of autophagy can promote metastasis and glycolysis in HCC cells, and autophagy induces MCT1 expression by activating Wnt/β-catenin signaling. Our study describes the connection between autophagy and glucose metabolism in HCC cells and may provide a potential therapeutic target for HCC treatment.

http://ift.tt/2rnwWJO

Mechanisms Linking Obesity and Thyroid Cancer Development and Progression in Mouse Models

Abstract

Recent compelling epidemiological studies indicate a strong association of obesity with thyroid cancer. Obesity has been shown to promote thyroid cancer progression and exacerbate poor outcome in thyroid cancer patients. However, the molecular mechanisms by which obesity increases thyroid cancer risk and facilitates cancer progression are not completely understood. Obesity induces complex pathological changes including hyperglycemia, hyperinsulinemia, hyperlipidemia, oxidative stress, adipokines, and inflammatory responses. These changes can affect the development and progression of cancer through highly complex interactions in vivo. The deleterious effect of obesity may differ according to the different cancer types. In view of the increased incidence of thyroid cancer in parallel with the widespread occurrence of obesity in the past decades, it is imperative to clarify how obesity affects thyroid carcinogenesis. This review focuses on molecular mechanisms by which obesity aggravates thyroid carcinogenesis as elucidated by mouse models of thyroid cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2FVeco3
via IFTTT

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors

Abstract

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

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

Mechanisms Linking Obesity and Thyroid Cancer Development and Progression in Mouse Models

Abstract

Recent compelling epidemiological studies indicate a strong association of obesity with thyroid cancer. Obesity has been shown to promote thyroid cancer progression and exacerbate poor outcome in thyroid cancer patients. However, the molecular mechanisms by which obesity increases thyroid cancer risk and facilitates cancer progression are not completely understood. Obesity induces complex pathological changes including hyperglycemia, hyperinsulinemia, hyperlipidemia, oxidative stress, adipokines, and inflammatory responses. These changes can affect the development and progression of cancer through highly complex interactions in vivo. The deleterious effect of obesity may differ according to the different cancer types. In view of the increased incidence of thyroid cancer in parallel with the widespread occurrence of obesity in the past decades, it is imperative to clarify how obesity affects thyroid carcinogenesis. This review focuses on molecular mechanisms by which obesity aggravates thyroid carcinogenesis as elucidated by mouse models of thyroid cancer.

http://ift.tt/2FVeco3

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors

Abstract

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

http://ift.tt/2BeinYJ

HIV-associated Kaposi’s sarcoma in Maputo, Mozambique: outcomes in a specialized treatment center, 2010–2015

Abstract

Background

Kaposi's sarcoma (KS) is a common HIV-associated malignancy associated with disability, pain and poor outcomes. The cornerstone of its treatment is antiretroviral therapy, but advanced disease necessitates the addition of chemotherapy. In high-income settings, this often consists of liposomal anthracyclines, but in Mozambique, the first line includes conventional doxorubicin, bleomycin and vincristine, which is poorly-tolerated. Médecins Sans Frontières supports the Ministry of Health (MOH) in a specialized HIV and KS treatment center at the Centro de Referencia de Alto Maé in Maputo.

Methods

We performed a retrospective analysis of data collected on patients enrolled at the CRAM between 2010 and 2015, extracting routinely-collected clinical information from patient care databases. KS treatment followed national guidelines, and KS staging followed AIDS Clinical Trials Group and MOH criteria. Baseline description of the cohort and patient outcomes was performed. Risk factors for negative outcomes (death or loss to follow-up) were explored using Cox regression.

Results

Between 2010 and 2015, 1573 patients were enrolled, and 1210 began chemotherapy. A majority were young adult males. At enrollment, CD4 was < 200 cells/μl in 45% of patients. Among patients receiving chemotherapy, 78% received combination doxorubicin-bleomycin-vincristine. Among patients receiving chemotherapy, 43% were lost to follow-up and 8% were known to have died. In multivariate regression, the only risk factors identified with poor outcomes were CD4 < 100 cells/μl at enrollment (Risk ratio 1.5, 95%CI 1.1–2.1, p = 0.02 and having S1 disease (RR 1.7, 95%CI 1.2–2.3, p = 0.001).

Discussion

We describe a large cohort of patients receiving care for HIV-associated KS in a specialized clinic in an urban setting. Outcomes were nonetheless unsatisfactory. Efforts should be made to decrease late referrals and entry into care and to increase access to more effective and better-tolerated treatments like liposomal doxorubicin.

http://ift.tt/2Di4Wsp

HIV-associated Kaposi’s sarcoma in Maputo, Mozambique: outcomes in a specialized treatment center, 2010–2015

Abstract

Background

Kaposi's sarcoma (KS) is a common HIV-associated malignancy associated with disability, pain and poor outcomes. The cornerstone of its treatment is antiretroviral therapy, but advanced disease necessitates the addition of chemotherapy. In high-income settings, this often consists of liposomal anthracyclines, but in Mozambique, the first line includes conventional doxorubicin, bleomycin and vincristine, which is poorly-tolerated. Médecins Sans Frontières supports the Ministry of Health (MOH) in a specialized HIV and KS treatment center at the Centro de Referencia de Alto Maé in Maputo.

Methods

We performed a retrospective analysis of data collected on patients enrolled at the CRAM between 2010 and 2015, extracting routinely-collected clinical information from patient care databases. KS treatment followed national guidelines, and KS staging followed AIDS Clinical Trials Group and MOH criteria. Baseline description of the cohort and patient outcomes was performed. Risk factors for negative outcomes (death or loss to follow-up) were explored using Cox regression.

Results

Between 2010 and 2015, 1573 patients were enrolled, and 1210 began chemotherapy. A majority were young adult males. At enrollment, CD4 was < 200 cells/μl in 45% of patients. Among patients receiving chemotherapy, 78% received combination doxorubicin-bleomycin-vincristine. Among patients receiving chemotherapy, 43% were lost to follow-up and 8% were known to have died. In multivariate regression, the only risk factors identified with poor outcomes were CD4 < 100 cells/μl at enrollment (Risk ratio 1.5, 95%CI 1.1–2.1, p = 0.02 and having S1 disease (RR 1.7, 95%CI 1.2–2.3, p = 0.001).

Discussion

We describe a large cohort of patients receiving care for HIV-associated KS in a specialized clinic in an urban setting. Outcomes were nonetheless unsatisfactory. Efforts should be made to decrease late referrals and entry into care and to increase access to more effective and better-tolerated treatments like liposomal doxorubicin.

from Cancer via ola Kala on Inoreader http://ift.tt/2Di4Wsp
via IFTTT

A metastasized hepatocellular carcinoma in the capsule of an undescended testis in the right inguinal area: report of a rare case

Abstract

Background

Hepatocellular Carcinoma (HCC) is the most common primary carcinoma of the liver, which mainly metastasizes through the portal vein system.

Case presentation

Here, we report an extremely rare case in which HCC metastasized to the capsule of an undescended testis in the right inguinal area of the patient. A tumor approximately 8.8 × 7.0 cm in size was found in the patient's liver during a health check-up. Initially, it was considered a metastatic tumor because the patient was found to have cryptorchidism, which had been left untreated before he presented to our hospital. The patient underwent a radical orchiectomy via inguinal approach, and the resected testis in the right inguinal region was examined via microscopy. The cancer cells were arranged in nests and showed abundant red or clear cytoplasm and marked nuclear atypia. Immunohistochemical staining showed that the tumor cells were positive for CK, CK8/18, AFP, hepatocyte, GCP3, but negative for PLAP, CD10, CD30, CD34, and vimentin.

Conclusion

According to these findings, the tumor in the inguinal region was considered a metastatic HCC arising from the liver, rather than a seminoma that had originated in the undescended testis. We suggest that during the diagnosis of malignancies, metastatic tumors should always be considered in the differential diagnosis even if the original presentation is at rare metastatic sites or concurrent with other disease(s).

from Cancer via ola Kala on Inoreader http://ift.tt/2Dmn3O3
via IFTTT