Circulating tumor cells in pancreatic adenocarcinoma

Background: Circulating tumor cells (CTCs) have been identified in the blood of patients with pancreatic adenocarcinoma (PDAC), but little is known about the exact phenotype of these cells. We assessed expression of aldehyde dehydrogenase (ALDH), CD133, and CD44 as markers of CTCs with a tumor initiating cell (TIC) phenotype in PDAC patients and the relationship of this expression to patient outcomes. Methods: Peripheral blood from sixty consecutive PDAC patients undergoing surgical resection was obtained and processed using the Isolation by Size of Epithelial Tumor (ISET) method. Immunofluorescence was used to identify CTCs expressing cytokeratin, CD133, CD44 and ALDH. Results: Forty-seven patients (78%) had epithelial CTCs staining positive for pan-cytokeratin and at least one TIC marker. Forty-six patients (77%) had epithelial CTCs that labeled with antibodies to cytokeratin and ALDH. By separate analysis, 34 (57%) had cytokeratin-positive, CD133-positive, and CD44-positive (triple positive) CTCs while 40 (67%) had cytokeratin-positive, CD133-positive, CD44-negative CTCs. The remaining 13 patients did not have CTCs, as defined by cytokeratin expression. ALDH-positive CTCs and triple-positive CTCs were significantly associated with worse survival by univariate analysis, even when accounting for other significant prognostic factors (all, P<0.01). ALDH-positive CTCs, triple-positive CTCs, and dual cytokeratin- and CD133-positive CTCs were independent predictors of tumor recurrence by logistic regression analysis and associated with decreased disease free survival (all, P<0.03). Conclusion: CTCs labeling with one or more markers of TICs are found in a majority of PDAC patients and are independently predictive of decreased disease free and overall survival.

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eIF4F and cancer

The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers leading to the selective synthesis of proteins involved in tumour growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here we review the contribution of the eIF4F complex to tumourigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A.

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The role of FilGAP, a Rac-specific Rho-GTPase-activating protein, in tumor progression and behavior of astrocytomas

Abstract

FilGAP, a Rac-specific Rho-GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focused on the possible roles of FilGAP expression in astrocytomas. In clinical samples, FilGAP expression was significantly increased in grade (G) II astrocytomas as compared to normal astrocytes, but its expression strongly decreased in a grade-dependent manner, and was positively associated with isocitrate dehydrogenase 1 (IDH1) mutations and inversely to cytoplasmic Rac1. Patients with astrocytoma showing a high FilGAP score had favorable overall survival as compared to the low score patients. Multivariate Cox regression analysis also showed that a high FilGAP score was a significant and independent favorable prognostic factor. Moreover, patients with high FilGAP score and IDH1 mutant-type astrocytomas had significantly the best Overall survival (OS) and Progression-free survival (PFS), in contrast to the patients with low FilGAP score and wild-type IDH1 tumors who had the worst prognosis. In GIV tumors (GBM: glioblastomas), elongated tumor cells with low FilGAP expression were frequently observed in tumor core lesions, whereas the rounded cells with abundant expression were found in the peripheral areas adjacent to non-neoplastic brain tissues. In an astrocytoma cell line, suppression of endogenous FilGAP expression by siRNAs caused an increased proportion of mesenchymal elongated cells, probably through increased Rac1 activity. These findings suggest that FilGAP, as well as IDH1 status, may be useful for predicting the behavior of astrocytomas. In addition, the FilGAP/Rac1 axis may serve as an important regulator of tumor progression in GBMs, probably through alteration of cell morphology.

FilGAP, as well as isocitrate dehydrogenase 1 (IDH1) status, may be useful for predicting the behavior of astrocytomas. In addition, the FilGAP/Rac1 axis may serve as an important regulator of tumor progression in glioblastomas (GBMs), probably through alteration of cell morphology.

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Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia

Abstract

In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402-item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind–body therapy (17.2%), herbal supplements (13.5%), manipulative and body-based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

This study demonstrates that a large proportion (54.1%) of HSCT survivors is using one or more form of complementary and alternative medical (CAM) therapies. Given the potential benefits demonstrated by small studies of particular CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

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The role of FilGAP, a Rac-specific Rho-GTPase-activating protein, in tumor progression and behavior of astrocytomas

Abstract

FilGAP, a Rac-specific Rho-GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focused on the possible roles of FilGAP expression in astrocytomas. In clinical samples, FilGAP expression was significantly increased in grade (G) II astrocytomas as compared to normal astrocytes, but its expression strongly decreased in a grade-dependent manner, and was positively associated with isocitrate dehydrogenase 1 (IDH1) mutations and inversely to cytoplasmic Rac1. Patients with astrocytoma showing a high FilGAP score had favorable overall survival as compared to the low score patients. Multivariate Cox regression analysis also showed that a high FilGAP score was a significant and independent favorable prognostic factor. Moreover, patients with high FilGAP score and IDH1 mutant-type astrocytomas had significantly the best Overall survival (OS) and Progression-free survival (PFS), in contrast to the patients with low FilGAP score and wild-type IDH1 tumors who had the worst prognosis. In GIV tumors (GBM: glioblastomas), elongated tumor cells with low FilGAP expression were frequently observed in tumor core lesions, whereas the rounded cells with abundant expression were found in the peripheral areas adjacent to non-neoplastic brain tissues. In an astrocytoma cell line, suppression of endogenous FilGAP expression by siRNAs caused an increased proportion of mesenchymal elongated cells, probably through increased Rac1 activity. These findings suggest that FilGAP, as well as IDH1 status, may be useful for predicting the behavior of astrocytomas. In addition, the FilGAP/Rac1 axis may serve as an important regulator of tumor progression in GBMs, probably through alteration of cell morphology.

FilGAP, as well as isocitrate dehydrogenase 1 (IDH1) status, may be useful for predicting the behavior of astrocytomas. In addition, the FilGAP/Rac1 axis may serve as an important regulator of tumor progression in glioblastomas (GBMs), probably through alteration of cell morphology.

http://ift.tt/2fd05RP

Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia

Abstract

In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402-item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind–body therapy (17.2%), herbal supplements (13.5%), manipulative and body-based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

This study demonstrates that a large proportion (54.1%) of HSCT survivors is using one or more form of complementary and alternative medical (CAM) therapies. Given the potential benefits demonstrated by small studies of particular CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

http://ift.tt/2eWdxpm

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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

http://ift.tt/2fbwjwR

Adjuvant treatment combining cellular immunotherapy with chemotherapy improves the clinical outcome of patients with stage II/III gastric cancer

Abstract

Postsurgical relapse remains a common issue for resectable gastric cancer (GC). Here, we investigated the efficacy and safety of an adjuvant treatment combining chemotherapy with cellular immunotherapy (CIT) using autologous natural killer cells, γδT cells, and cytokine-induced killer cells in the treatment of stage II/III GC. A pilot prospective cohort study was conducted in 169 patients with stage II/III GC who had undergone gastrectomy with D2 lymph node dissection. Patients were assigned into two groups according to the patient choice of treatment, including chemotherapy alone (chemo) or chemotherapy combined with CIT (chemo/CIT). Disease-free survival (DFS), overall survival (OS), and adverse events were evaluated. Univariate and multivariate Cox models were used to analyze the impact of chemo/CIT on DFS and OS. Kaplan–Meier analysis with the log-rank test was used to compare the clinical outcome between two groups. Three-year DFS rate was 60.6% and 74.7% (P = 0.036) and 3-year OS rate was 64.9% and 83% (P = 0.051) for the chemo and chemo/CIT group, respectively. TNM stage and chemo/CIT were independent prognostic factors for both DFS (for TNM stage, P < 0.001, hazard ratio [HR]: 5.599, 95% confidence interval [CI]: 2.791–11.232; for chemo/CIT, P = 0.013, HR: 0.478, 95% CI: 0.266–0.858) and OS (for TNM stage, P < 0.001, HR: 6.559, 95% CI: 2.903–14.817; for chemo/CIT, P = 0.04, HR: 0.506, 95% CI: 0.264–0.970). In subgroup analysis, 3-year DFS and OS rates of patients with stage III GC in the chemo/CIT group were significantly higher than those in the chemo group (38.4% vs. 57.1%, P = 0.038; and 45.9% vs. 76%, P = 0.06, respectively), while there was no significant difference between the two groups in patients with stage II GC. Only 15.9% of patients (10/63) in the chemo/CIT group had mild and manageable fever (grades 1 and 2), while no other side effects were observed. The adjuvant treatment combining chemotherapy with cellular immunotherapy is well tolerated and significantly improves the clinical outcome of patients with stage II/III GC, when compared with chemotherapy alone, therefore warrants further attention in treatment for relapsed GC after tumor resection.

The adjuvant treatment combining chemotherapy with cellular immunotherapy is well tolerated and significantly improves the clinical outcome of patients with stage II/III gastric cancer (GC), when compared with chemotherapy alone, therefore warrants further attention in treatment for relapsed GC after tumor resection.

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Upregulation of LncRNA-HIT promotes migration and invasion of non-small cell lung cancer cells by association with ZEB1

Abstract

Lung cancer is the most common solid tumor and the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer cases. The main reason of lung cancer-related deaths is due to tumor metastasis. But, the mechanisms of NSCLC metastasis remains poorly understood. LncRNAs play pivotal roles in multiple biological processes. LncRNA-HIT (HOXA transcript induced by TGFβ) was recently identified. LncRNA-HIT promotes cell migration, invasion, tumor growth, and metastasis. However, the detailed role of lncRNA-HIT in NSCLC remains unknown. In this study, for the first time, we revealed a novel role of lncRNA-HIT in the migration and invasion of NSCLC cells. The expression of lncRNA-HIT was significantly upregulated in NSCLC tissues and cell lines, and the expression level of lncRNA-HIT correlates with advanced disease stage and predicts unfavorable prognosis of NSCLC patients. Functional assays demonstrated that lncRNA-HIT markedly increased the ability of NSCLC cells to migrate and invade. Furthermore, the molecular mechanism by which lncRNA-HIT affects NSCLC cells was associated with regulation of ZEB1 stability. LncRNA-HIT functions as a prometastasis oncogene by directly associating with ZEB1 to regulate NSCLC. The interaction of lncRNA-HIT and ZEB1 may be a potential target for NSCLC therapy.

The expression level of lncRNA-HIT correlates with advanced disease stage and predicts unfavorable prognosis of NSCLC patients. lncRNA-HIT affects the migration and invasion of NSCLC cells through association with regulation of ZEB1 stability.

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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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‘Unexpected’ Vulnerability Creates Treatment Opportunity in Aggressive Type of Lung Cancer

Researchers have identified a potentially critical weakness in lung cancers that have mutations in the KRAS gene, a cancer-promoting genetic alteration that has proven nearly impossible to target therapeutically. Moreover, the research team showed that a drug already being tested against other types of cancer could successfully exploit this vulnerability in KRAS mutant lung cancer cell lines and mouse models of lung cancer.

The weakness lies in the dependency of KRAS mutant lung cancer cells on a protein, called XPO1, that helps to shuttle molecules involved in important cellular functions from the cell nucleus into the surrounding cytoplasm. The XPO1 inhibitor shrank tumors in several different mouse models of non-small cell lung cancer (NSCLC)—the most common form of lung cancer—with KRAS mutations.

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‘Unexpected’ Vulnerability Creates Treatment Opportunity in Aggressive Type of Lung Cancer

Researchers have identified a potentially critical weakness in lung cancers that have mutations in the KRAS gene, a cancer-promoting genetic alteration that has proven nearly impossible to target therapeutically. Moreover, the research team showed that a drug already being tested against other types of cancer could successfully exploit this vulnerability in KRAS mutant lung cancer cell lines and mouse models of lung cancer.

The weakness lies in the dependency of KRAS mutant lung cancer cells on a protein, called XPO1, that helps to shuttle molecules involved in important cellular functions from the cell nucleus into the surrounding cytoplasm. The XPO1 inhibitor shrank tumors in several different mouse models of non-small cell lung cancer (NSCLC)—the most common form of lung cancer—with KRAS mutations.

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Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR)

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.

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The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy

Financial difficulties, measured by the EORTC C30 questionnaire, were associated with worse quality of life and shorter overall survival of cancer patients enrolled in 16 academic clinical trials performed within the Italian public health system. The pooled database included 3670 patients with lung, breast or ovarian cancer. This finding support further studies on financial toxicity in Europe.

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Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR)

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens.

http://ift.tt/2dR4jbT

The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy

Financial difficulties, measured by the EORTC C30 questionnaire, were associated with worse quality of life and shorter overall survival of cancer patients enrolled in 16 academic clinical trials performed within the Italian public health system. The pooled database included 3670 patients with lung, breast or ovarian cancer. This finding support further studies on financial toxicity in Europe.

http://ift.tt/2fla1Yz

A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development

Publication date: Available online 27 October 2016
Source:Cell Stem Cell
Author(s): Zizhen Yao, John K. Mich, Sherman Ku, Vilas Menon, Anne-Rachel Krostag, Refugio A. Martinez, Leon Furchtgott, Heather Mulholland, Susan Bort, Margaret A. Fuqua, Ben W. Gregor, Rebecca D. Hodge, Anu Jayabalu, Ryan C. May, Samuel Melton, Angelique M. Nelson, N. Kiet Ngo, Nadiya V. Shapovalova, Soraya I. Shehata, Michael W. Smith, Leah J. Tait, Carol L. Thompson, Elliot R. Thomsen, Chaoyang Ye, Ian A. Glass, Ajamete Kaykas, Shuyuan Yao, John W. Phillips, Joshua S. Grimley, Boaz P. Levi, Yanling Wang, Sharad Ramanathan
During human brain development, multiple signaling pathways generate diverse cell types with varied regional identities. Here, we integrate single-cell RNA sequencing and clonal analyses to reveal lineage trees and molecular signals underlying early forebrain and mid/hindbrain cell differentiation from human embryonic stem cells (hESCs). Clustering single-cell transcriptomic data identified 41 distinct populations of progenitor, neuronal, and non-neural cells across our differentiation time course. Comparisons with primary mouse and human gene expression data demonstrated rostral and caudal progenitor and neuronal identities from early brain development. Bayesian analyses inferred a unified cell-type lineage tree that bifurcates between cortical and mid/hindbrain cell types. Two methods of clonal analyses confirmed these findings and further revealed the importance of Wnt/β-catenin signaling in controlling this lineage decision. Together, these findings provide a rich transcriptome-based lineage map for studying human brain development and modeling developmental disorders.

Graphical abstract

Teaser

Yao et al. perform single-cell RNA-seq during neural differentiation of hESCs. They identify many classes of neural progenitors and neurons that map to early human brain cells, computationally infer and experimentally confirm lineage relationships between them, and show that Wnt signaling influences the bifurcation between forebrain and mid/hindbrain lineages in vitro.


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Single-Cell Analysis Reveals a Close Relationship between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages

Publication date: Available online 27 October 2016
Source:Cell Stem Cell
Author(s): Nigel Kee, Nikolaos Volakakis, Agnete Kirkeby, Lina Dahl, Helena Storvall, Sara Nolbrant, Laura Lahti, Åsa K. Björklund, Linda Gillberg, Eliza Joodmardi, Rickard Sandberg, Malin Parmar, Thomas Perlmann
Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons is a promising strategy for brain repair in Parkinson's disease (PD). Refinement of differentiation protocols to optimize this approach will require deeper understanding of mesDA neuron development. Here, we studied this process using transcriptome-wide single-cell RNA sequencing of mouse neural progenitors expressing the mesDA neuron determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons, while also highlighting a distinct transcription factor set that can distinguish between them. While previous hESC mesDA differentiation protocols have relied on markers that are shared between the two lineages, we found that application of these highlighted markers can help to refine current stem cell engineering protocols, increasing the proportion of appropriately patterned mesDA progenitors. Our results, therefore, have important implications for cell replacement therapy in PD.

Graphical abstract

Teaser

Kee et al. use single-cell RNA-seq to reconstruct Lmx1a+ differentiation in silico, revealing an unexpectedly close relationship between mesDA and STN neuronal lineages during differentiation. Application of markers that distinguish the two can help optimize mesDA differentiation of hESCs with a view to improving therapeutic translation.


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Predictive Markers Guide Differentiation to Improve Graft Outcome in Clinical Translation of hESC-Based Therapy for Parkinson’s Disease

Publication date: Available online 27 October 2016
Source:Cell Stem Cell
Author(s): Agnete Kirkeby, Sara Nolbrant, Katarina Tiklova, Andreas Heuer, Nigel Kee, Tiago Cardoso, Daniella Rylander Ottosson, Mariah J. Lelos, Pedro Rifes, Stephen B. Dunnett, Shane Grealish, Thomas Perlmann, Malin Parmar
Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors. We found that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs.

Graphical abstract

Teaser

Kirkeby et al. show that identification and application of a set of predictive markers can help refine differentiation protocols and improve transplant outcome in a preclinical model for hESC-based treatment of Parkinson's disease.


http://ift.tt/2e2aPzR

CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

Publication date: Available online 27 October 2016
Source:Cancer Cell
Author(s): Jeevisha Bajaj, Takaaki Konuma, Nikki K. Lytle, Hyog Young Kwon, Jailal N. Ablack, Joseph M. Cantor, David Rizzieri, Charles Chuah, Vivian G. Oehler, Elizabeth H. Broome, Edward D. Ball, Edward H. van der Horst, Mark H. Ginsberg, Tannishtha Reya
Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.

Graphical abstract

Teaser

Bajaj et al. demonstrate the importance of CD98-mediated adhesion for survival of acute myelogenous leukemia (AML) and show that genetic deletion of CD98 in mice or use of a therapeutic CD98 antibody in patient-derived xenografts blocks AML growth.


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UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis

Publication date: Available online 27 October 2016
Source:Cancer Cell
Author(s): Laurence Wurth, Panagiotis Papasaikas, David Olmeda, Nadine Bley, Guadalupe T. Calvo, Santiago Guerrero, Daniela Cerezo-Wallis, Javier Martinez-Useros, María García-Fernández, Stefan Hüttelmaier, Maria S. Soengas, Fátima Gebauer
RNA binding proteins (RBPs) modulate cancer progression through poorly understood mechanisms. Here we show that the RBP UNR/CSDE1 is overexpressed in melanoma tumors and promotes invasion and metastasis. iCLIP sequencing, RNA sequencing, and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady-state levels, UNR was found to control many of its targets at the level of translation elongation/termination. Key pro-oncogenic targets of UNR included VIM and RAC1, as validated by loss- and gain-of-function studies. Our results identify UNR as an oncogenic modulator of melanoma progression, unravel the underlying molecular mechanisms, and identify potential targets for this therapeutically challenging malignancy.

Graphical abstract

Teaser

Wurth et al. find that the RNA binding protein UNR is often overexpressed in melanoma and promotes invasion and metastasis. Using iCLIP-seq, RNA-seq, and ribosome profiling, the authors identify potentially oncogenic RNA regulons, one of which includes RAC1 and VIM, whose translation is regulated by UNR.


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CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia

Publication date: Available online 27 October 2016
Source:Cancer Cell
Author(s): Jeevisha Bajaj, Takaaki Konuma, Nikki K. Lytle, Hyog Young Kwon, Jailal N. Ablack, Joseph M. Cantor, David Rizzieri, Charles Chuah, Vivian G. Oehler, Elizabeth H. Broome, Edward D. Ball, Edward H. van der Horst, Mark H. Ginsberg, Tannishtha Reya
Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.

Graphical abstract

Teaser

Bajaj et al. demonstrate the importance of CD98-mediated adhesion for survival of acute myelogenous leukemia (AML) and show that genetic deletion of CD98 in mice or use of a therapeutic CD98 antibody in patient-derived xenografts blocks AML growth.


http://ift.tt/2eS64Iz

UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis

Publication date: Available online 27 October 2016
Source:Cancer Cell
Author(s): Laurence Wurth, Panagiotis Papasaikas, David Olmeda, Nadine Bley, Guadalupe T. Calvo, Santiago Guerrero, Daniela Cerezo-Wallis, Javier Martinez-Useros, María García-Fernández, Stefan Hüttelmaier, Maria S. Soengas, Fátima Gebauer
RNA binding proteins (RBPs) modulate cancer progression through poorly understood mechanisms. Here we show that the RBP UNR/CSDE1 is overexpressed in melanoma tumors and promotes invasion and metastasis. iCLIP sequencing, RNA sequencing, and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady-state levels, UNR was found to control many of its targets at the level of translation elongation/termination. Key pro-oncogenic targets of UNR included VIM and RAC1, as validated by loss- and gain-of-function studies. Our results identify UNR as an oncogenic modulator of melanoma progression, unravel the underlying molecular mechanisms, and identify potential targets for this therapeutically challenging malignancy.

Graphical abstract

Teaser

Wurth et al. find that the RNA binding protein UNR is often overexpressed in melanoma and promotes invasion and metastasis. Using iCLIP-seq, RNA-seq, and ribosome profiling, the authors identify potentially oncogenic RNA regulons, one of which includes RAC1 and VIM, whose translation is regulated by UNR.


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Inhibition of Mnk–eIF4E pathway sensitizes the efficacy to chemotherapy in anaplastic thyroid cancer

Future Oncology Ahead of Print.


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Imaging on nodal staging of prostate cancer

Future Oncology Ahead of Print.


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Momelotinib in myelofibrosis: JAK1/2 inhibitor with a role in treating and understanding the anemia

Future Oncology Ahead of Print.


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Cardiac safety of systemic therapy in breast cancer patients with high risk of atherosclerosis complications

Future Oncology Ahead of Print.


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Basal body temperature as a biomarker of healthy aging

Abstract

Scattered evidence indicates that a lower basal body temperature may be associated with prolonged health span, yet few studies have directly evaluated this relationship. We examined cross-sectional and longitudinal associations between early morning oral temperature (95.0–98.6 °F) and usual gait speed, endurance walk performance, fatigability, and grip strength in 762 non-frail men (52 %) and women aged 65–89 years participating in the Baltimore Longitudinal Study of Aging. Since excessive adiposity (body mass index ≥35 kg/m² or waist-to-height ratio ≥0.62) may alter temperature set point, associations were also examined within adiposity strata. Overall, controlling for age, race, sex, height, exercise, and adiposity, lower temperature was associated with faster gait speed, less time to walk 400 m quickly, and lower perceived exertion following 5-min of walking at 0.67 m/s (all p ≤ 0.02). In the non-adipose (N = 662), these associations were more robust (all p ≤ 0.006). Direction of association was reversed in the adipose (N = 100), but none attained significance (all p > 0.22). Over 2.2 years, basal temperature was not associated with functional change in the overall population or non-adipose. Among the adipose, lower baseline temperature was associated with greater decline in endurance walking performance (p = 0.006). In longitudinal analyses predicting future functional performance, low temperature in the non-adipose was associated with faster gait speed (p = 0.021) and less time to walk 400 m quickly (p = 0.003), whereas in the adipose, lower temperature was associated with slower gait speed (p = 0.05) and more time to walk 400 m (p = 0.008). In older adults, lower basal body temperature appears to be associated with healthy aging in the absence of excessive adiposity.

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Growing Teratoma Syndrome

Abstract

Growing teratoma syndrome, a disease characterized by presence of benign metastasis increasing in size and number after chemotherapy, is infrequent occurrence. Being unfamiliar with the disease entity, many oncologists misinterpret it as disease progression. Though the exact etio-pathognesis of the disease is still unidentified, but clinical characteristics are well defined. Being a chemo and radio-resistant disease, surgery offers only cure. We present a case of ovarian immature teratoma, who after chemotherapy presented with increased tumor size. Resected specimen confirms the diagnosis of mature teratoma leading to recognition of GTS. Surgery resulted in cure.

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The UCA1/miR-204/Sirt1 axis modulates docetaxel sensitivity of prostate cancer cells

Abstract

Purpose

In this study, we firstly investigated the regulative effect of miR-204 on Sirt1 expression in prostate cancer cells. Then, we examined whether miR-204 downregulation in the cells is a result of UCA1 upregulation. In addition, the regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was studied.

Methods

QRT-PCR was performed to detect UCA1, miR-204 and Sirt1 mRNA expression. Western blot assay was performed to assess Sirt1, P-gp and caspase-3 expression. The regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was examined by measurement of docetaxel IC50, dictation of cleaved caspase-3 and flow cytometric analysis of cell apoptosis.

Results

MiR-204 negatively modulated Sirt1 expression in prostate cancer cells. UCA1 upregulation directly resulted in decreased miR-204 expression. UCA1 overexpression resulted in increased Sirt1 expression in PNT2 cells, while knockdown of endogenous UCA1 led to decreased Sirt1 in LNCaP and 22RV1 cells. UCA1 siRNA, Sirt1 siRNA and miR-204 mimics could enhance docetaxel-induced activation of caspase-3 and cell apoptosis in 22RV1/DR cells.

Conclusions

There is a UCA1/miR-204/Sirt1 axis in LNCaP and 22RV1 cells. The UCA1/miR-204/Sirt1 axis plays an important role in modulating in vitro docetaxel sensitivity of the prostate cancer cells.

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Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors

Abstract

Purpose

A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.

Methods

In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.

Results

A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUC_last, 0.95 (90 % CI 0.88–1.01); C _max, 0.98 (90 % CI 0.91–1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.

Conclusions

Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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Status of oncologic specialties: global survey of physicians treating cancer

Abstract

Background

In the United States, medical oncologists play a central role in the management of systemic therapy for cancer patients. Medical oncology as a specialty is not as established in Japan and several other European nations according to recent surveys, and little is known about this specialty in developing nations. We aimed to identify global differences in the roles of physicians treating cancer; specifically, how the management of advanced disease differs among nations.

Methods

In March 2016, a self-administered internet survey was conducted with degreed physicians who prescribed systemic agents for adult cancer treatment within the past 5 years. Physicians were identified from the American Society of Clinical Oncology active member online directory.

Results

Among 3907 members in 55 nations, 376 (9.6%) responded to the survey. The 310 respondents who provided an answer to the recognition of medical oncology were dominated by male MDs that have practiced for more than 5 years at academic centers, and ~60% were medical oncologists. A majority of the respondents in all four regions reported that medical oncology was established in their corresponding nations. However, there are several outlying nations where oncologic specialties play a minimal role in the management of systemic therapy.

Conclusion

Despite general recognition of medical oncology, the role is not globally established as the primary point of care for delivery of systemic therapy. Nations lacking this specialty should be assisted by the international community to develop medical oncology.

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Capsaicin reactivates hMOF in gastric cancer cells and induces cell growth inhibition

.


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Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy

.


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Alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 can support immune responses toward tumors overexpressing ganglioside D3 in mice

Abstract

An immunotherapeutic strategy is discussed supporting anti-tumor activity toward malignancies overexpressing ganglioside D3. GD3 can be targeted by NKT cells when derived moieties are presented in the context of CD1d. NKT cells can support anti-tumor responses by secreting inflammatory cytokines and through cytotoxicity toward CD1d⁺GD3⁺ tumors. To overexpress GD3, we generated expression vector DNA and an adenoviral vector encoding the enzyme responsible for generating GD3 from its ubiquitous precursor GM3. We show that DNA encoding α-N-acetyl-neuraminide α-2,8-sialyltransferase 1 (SIAT8) introduced by gene gun vaccination in vivo leads to overexpression of GD3 and delays tumor growth. Delayed tumor growth is dependent on CD1d expression by host immune cells, as shown in experiments engaging CD1d knockout mice. A trend toward greater NKT cell populations among tumor-infiltrating lymphocytes is associated with SIAT8 vaccination. A single adenoviral vaccination introduces anti-tumor activity similarly to repeated vaccination with naked DNA. Here, greater NKT tumor infiltrates were accompanied by marked overexpression of IL-17 in the tumor, later switching to IL-4. Our results suggest that a single intramuscular adenoviral vaccination introduces overexpression of GD3 by antigen-presenting cells at the injection site, recruiting NKT cells that provide an inflammatory anti-tumor environment. We propose adenoviral SIAT8 (AdV-SIAT8) can slow the growth of GD3 expressing tumors in patients.

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Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors

Abstract

Purpose

A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.

Methods

In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.

Results

A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUC_last, 0.95 (90 % CI 0.88–1.01); C _max, 0.98 (90 % CI 0.91–1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.

Conclusions

Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

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The UCA1/miR-204/Sirt1 axis modulates docetaxel sensitivity of prostate cancer cells

Abstract

Purpose

In this study, we firstly investigated the regulative effect of miR-204 on Sirt1 expression in prostate cancer cells. Then, we examined whether miR-204 downregulation in the cells is a result of UCA1 upregulation. In addition, the regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was studied.

Methods

QRT-PCR was performed to detect UCA1, miR-204 and Sirt1 mRNA expression. Western blot assay was performed to assess Sirt1, P-gp and caspase-3 expression. The regulative effect of UCA1/miR-204/Sirt1 axis on docetaxel sensitivity of prostate cancer cells was examined by measurement of docetaxel IC50, dictation of cleaved caspase-3 and flow cytometric analysis of cell apoptosis.

Results

MiR-204 negatively modulated Sirt1 expression in prostate cancer cells. UCA1 upregulation directly resulted in decreased miR-204 expression. UCA1 overexpression resulted in increased Sirt1 expression in PNT2 cells, while knockdown of endogenous UCA1 led to decreased Sirt1 in LNCaP and 22RV1 cells. UCA1 siRNA, Sirt1 siRNA and miR-204 mimics could enhance docetaxel-induced activation of caspase-3 and cell apoptosis in 22RV1/DR cells.

Conclusions

There is a UCA1/miR-204/Sirt1 axis in LNCaP and 22RV1 cells. The UCA1/miR-204/Sirt1 axis plays an important role in modulating in vitro docetaxel sensitivity of the prostate cancer cells.

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Oligometastatic Prostate Cancer

Opinion statement

The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

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Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy

ABSTRACT

Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. This article is protected by copyright. All rights reserved

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Stromal contributions to the carcinogenic process

Abstract

Tumor-associated stromal cells are dynamic characters that endorse the carcinogenic process in a multitude of ways. The tumor microenvironment plays a crucial role throughout the tumor progression, which includes initiation, growth, invasion, and metastasis. The tumor microenvironment consists of cellular and non-cellular components. Tumor-associated stromal cell types include the microbiome, immune cells including macrophages, dendritic and T-cells, cells associated with blood and lymphatic vessels including pericytes and endothelial cells, fibroblasts, neuronal cells, and adipocytes. The non-cellular components of the microenvironment include matrix proteins and secreted factors. The development of therapies that target the mechanisms by which stromal cells contribute to successful tumorigenesis is major goal of upcoming cancer research. The purpose of this review is to present a comprehensive discussion of the role of each of the tumor-associated stromal cell types in the carcinogenic process with a special focus on target development and therapeutic intervention. This article is protected by copyright. All rights reserved

http://ift.tt/2ezHPju

Oligometastatic Prostate Cancer

Opinion statement

The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

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Resveratrol inhibits IL-6-induced ovarian cancer cell migration through epigenetic up-regulation of autophagy

ABSTRACT

Interleukin-6 (IL-6), a pro-inflammatory cytokine released by cancer associated fibroblasts, has been linked to the invasive and metastatic behavior of ovarian cancer cells. Resveratrol is a naturally occurring polyphenol with the potential to inhibit cancer cell migration. Here we show that Resveratrol and IL-6 affect in an opposite manner the expression of RNA messengers and of microRNAs involved in cell locomotion and extracellular matrix remodeling associated with the invasive properties of ovarian cancer cells. Among the several potential candidates responsible for the anti-invasive effect promoted by Resveratrol, here we focused our attention on ARH-I (DIRAS3), that encodes a Ras homolog GTPase of 26-kDa. This protein is known to inhibit cell motility, and it has been shown to regulate autophagy by interacting with BECLIN 1. IL-6 down-regulated the expression of ARH-I and inhibited the formation of LC3-positive autophagic vacuoles, while promoting cell migration. On opposite, Resveratrol could counteract the IL-6 induction of cell migration in ovarian cancer cells through induction of autophagy in the cells at the migration front, which was paralleled by up-regulation of ARH-I and down-regulation of STAT3 expression. Spautin 1-mediated disruption of BECLIN 1-dependent autophagy abrogated the effects of Resveratrol, while promoting cell migration. The present data indicate that Resveratrol elicits its anti-tumor effect through epigenetic mechanisms and support its inclusion in the chemotherapy regimen for highly aggressive ovarian cancers. This article is protected by copyright. All rights reserved

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Stromal contributions to the carcinogenic process

Abstract

Tumor-associated stromal cells are dynamic characters that endorse the carcinogenic process in a multitude of ways. The tumor microenvironment plays a crucial role throughout the tumor progression, which includes initiation, growth, invasion, and metastasis. The tumor microenvironment consists of cellular and non-cellular components. Tumor-associated stromal cell types include the microbiome, immune cells including macrophages, dendritic and T-cells, cells associated with blood and lymphatic vessels including pericytes and endothelial cells, fibroblasts, neuronal cells, and adipocytes. The non-cellular components of the microenvironment include matrix proteins and secreted factors. The development of therapies that target the mechanisms by which stromal cells contribute to successful tumorigenesis is major goal of upcoming cancer research. The purpose of this review is to present a comprehensive discussion of the role of each of the tumor-associated stromal cell types in the carcinogenic process with a special focus on target development and therapeutic intervention. This article is protected by copyright. All rights reserved

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Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710

BACKGROUND

Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil-to-lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC).

METHODS

This study is an unplanned secondary analysis of SWOG 8710, a randomized phase 3 trial that assessed cystectomy with or without NAC in 317 patients with muscle-invasive BC. NLR was calculated from prospectively collected complete blood counts. For the prognostic analysis, 230 patients were identified; for the predictive analysis, 263 were identified. NLR was evaluated with proportional hazards models including prespecified factors (age, sex, T-stage, lymphovascular invasion, and treatment arm).

RESULTS

With a median follow-up of 18.6 years, there were 172 and 205 deaths in the prognostic and predictive cohorts, respectively. In a multivariable analysis, NLR was not prognostic for OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.98-1.11; P = .24). Furthermore, NLR did not predict for the OS benefit from NAC (HR, 1.01; 95% CI, 0.90-1.14; P = .86). Factors associated with worse OS were older age (HR, 1.05; 95% CI, 1.04-1.07; P < .001) and surgery without NAC (HR, 1.39; 95% CI, 1.03-1.88; P = .03).

CONCLUSIONS

This is the first analysis of NLR in BC to use prospectively collected clinical trial data. In contrast to previous studies, it suggests that NLR is neither a prognostic nor predictive biomarker for OS in muscle-invasive BC. Cancer 2016. © 2016 American Cancer Society.

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Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1

Abstract

Small cell lung cancer (SCLC) is one of the most malignant neoplasms in common human cancers. The tumor is composed of small immature-looking cells with a round or fusiform shape, which possesses weak adhesion features among them, suggesting that SCLC shows the morphological characteristics of epithelial to mesenchymal transition (EMT). SCLC is characterized by high metastatic and recurrent rates, sensitivity to the initial chemotherapy, and easy acquirement of chemoresistance afterwards. These characters may be related to the EMT phenotype of SCLC. Notch signaling is an important signaling pathway, and could have roles in regulating neuroendocrine differentiation, proliferation, cell adhesion, EMT, and chemoresistance. Notch1 is usually absent in SCLC in vivo, but could appear after chemotherapy. Notch1 can enhance cell adhesion by induction of E-cadherin in SCLC, which indicates mesenchymal to epithelial transition. On the other hand, achaete-scute complex homologue 1 (ASCL1), negatively regulated by Notch signaling, is a lineage-specific gene of SCLC, and functions to promote neuroendocrine differentiation as well as EMT. ASCL1-transfected adenocarcinoma cell lines induced neuroendocrine phenotypes and lost epithelial cell features. SCLC is characterized by neuroendocrine differentiation and EMT-like features, which could be produced by inactive Notch signaling and ASCL1 expression. In addition, chemical and radiation treatments can activate Notch signaling, which suppress neuroendocrine differentiation and induces chemoradioresistance, accompanied by secession from EMT. Thus, the status of Notch signaling and ASCL1 expression may determine the cell behaviors of SCLC partly through modifying EMT phenotypes.

http://ift.tt/2falknf

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710

BACKGROUND

Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil-to-lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC).

METHODS

This study is an unplanned secondary analysis of SWOG 8710, a randomized phase 3 trial that assessed cystectomy with or without NAC in 317 patients with muscle-invasive BC. NLR was calculated from prospectively collected complete blood counts. For the prognostic analysis, 230 patients were identified; for the predictive analysis, 263 were identified. NLR was evaluated with proportional hazards models including prespecified factors (age, sex, T-stage, lymphovascular invasion, and treatment arm).

RESULTS

With a median follow-up of 18.6 years, there were 172 and 205 deaths in the prognostic and predictive cohorts, respectively. In a multivariable analysis, NLR was not prognostic for OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.98-1.11; P = .24). Furthermore, NLR did not predict for the OS benefit from NAC (HR, 1.01; 95% CI, 0.90-1.14; P = .86). Factors associated with worse OS were older age (HR, 1.05; 95% CI, 1.04-1.07; P < .001) and surgery without NAC (HR, 1.39; 95% CI, 1.03-1.88; P = .03).

CONCLUSIONS

This is the first analysis of NLR in BC to use prospectively collected clinical trial data. In contrast to previous studies, it suggests that NLR is neither a prognostic nor predictive biomarker for OS in muscle-invasive BC. Cancer 2016. © 2016 American Cancer Society.

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Small cell lung cancer, an epithelial to mesenchymal transition (EMT)-like cancer: significance of inactive Notch signaling and expression of achaete-scute complex homologue 1

Abstract

Small cell lung cancer (SCLC) is one of the most malignant neoplasms in common human cancers. The tumor is composed of small immature-looking cells with a round or fusiform shape, which possesses weak adhesion features among them, suggesting that SCLC shows the morphological characteristics of epithelial to mesenchymal transition (EMT). SCLC is characterized by high metastatic and recurrent rates, sensitivity to the initial chemotherapy, and easy acquirement of chemoresistance afterwards. These characters may be related to the EMT phenotype of SCLC. Notch signaling is an important signaling pathway, and could have roles in regulating neuroendocrine differentiation, proliferation, cell adhesion, EMT, and chemoresistance. Notch1 is usually absent in SCLC in vivo, but could appear after chemotherapy. Notch1 can enhance cell adhesion by induction of E-cadherin in SCLC, which indicates mesenchymal to epithelial transition. On the other hand, achaete-scute complex homologue 1 (ASCL1), negatively regulated by Notch signaling, is a lineage-specific gene of SCLC, and functions to promote neuroendocrine differentiation as well as EMT. ASCL1-transfected adenocarcinoma cell lines induced neuroendocrine phenotypes and lost epithelial cell features. SCLC is characterized by neuroendocrine differentiation and EMT-like features, which could be produced by inactive Notch signaling and ASCL1 expression. In addition, chemical and radiation treatments can activate Notch signaling, which suppress neuroendocrine differentiation and induces chemoradioresistance, accompanied by secession from EMT. Thus, the status of Notch signaling and ASCL1 expression may determine the cell behaviors of SCLC partly through modifying EMT phenotypes.

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