Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma. Cancer Res; 76(5); 1–12. ©2016 AACR.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 12 Φεβρουαρίου 2016
Therapeutic Targeting in Multiple Myeloma
Basophil recruitment into tumor draining lymph nodes correlates with Th2 inflammation and reduced survival in pancreatic cancer patients
In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates comprised mainly of T helper 2 (Th2) cells predict a poor survival outcome in patients. IL-4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL-4 in PDAC is unclear. Here we show that basophils expressing IL-4 are enriched in tumor-draining lymph nodes (TDLNs) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. Recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell-derived IL-3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping illuminating a key element of the immune milieu of pancreatic cancer.
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Corrigendum
Future Oncology Ahead of Print.
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Novel small molecule inhibitors of the OLIG2 transcription factor: promising new therapeutics for glioblastoma
Future Oncology Ahead of Print.
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Acute pancreatitis as a complication of childhood cancer treatment
Abstract
Acute pancreatitis (AP) is now well recognized as a possible complication of childhood cancer treatment, interrupting the chemotherapy regimen, and requiring prolonged hospitalization, possibly with intensive care and surgical intervention, thereby compromising the effect of chemotherapy and the remission of the underlying malignant disease. This review summarizes the current literature and presents the various etiological factors for AP during chemotherapy as well as modern trends in the diagnosis and therapy of AP in children.
Acute pancreatitis (AP) is now well recognized as a possible complication of childhood cancer treatment. This review summarizes the current literature and presents the various etiological factors for AP during chemotherapy as well as modern trends in the diagnosis and therapy of AP in children.
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Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma
Purpose: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. Experimental Design: A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Results: Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Conclusions: Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC.
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Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Anti-tumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma
Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma. Patients and Methods: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity (DTH) was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5x106 GM-K562 cells or 1x107 GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation. Results: 11 patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4+ cells and PD-1 and 4-1BB by CD8+ cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4+ T-lymphocytes. Conclusion: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma.
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Corrigendum
Future Oncology Ahead of Print.
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Novel small molecule inhibitors of the OLIG2 transcription factor: promising new therapeutics for glioblastoma
Future Oncology Ahead of Print.
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Do Referral Patterns in Adolescents and Young Adults with Testicular Cancer Impact Oncologic Outcomes?
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Health Behavior Change Interventions for Teenage and Young Adult Cancer Survivors: A Systematic Review
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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68 Gallium-Arginine-Glycine-Aspartic Acid and 18 F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Chondroblastic Osteosarcoma of the Skull
Abstract
We report the case of a 32 year-old male with Chondroblastic Osteosarcoma of the skull, which was imaged with both 18[F]fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and 68Gallium-arginine-glycine-aspartic acid (68Ga-RGD) PET/CT. The 18F-FDG PET/CT did not demonstrate the tumour, whereas the 68Ga-RGD PET/CT clearly depicted a left-sided frontal tumour. 68Ga-RGD PET/CT may be a clinically useful imaging modality for early detection of recurrent osteosarcoma, considering the limitations of 18F-FDG PET in a setting of low glycolytic activity.
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An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer
Summary
Background Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. Methods A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5 %, H1 ≥ 20 %, α = 10 % and β = 20 %). Eligibility included failure of at least one platinum-based regimen. Results From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4 %) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4 %) had an ECOG-performance status 1–2. Two partial responses (PR, ORR: 9.1 %), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7–10.3), 6-month progression-free survival (PFS) was 13.6 % (95%CI: 4.8–39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1 %, 95%CI: 41.7–83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3–4 adverse events (AE) were: 40.9 % mucositis, 36.4 % fatigue, 18.2 % neutropenia (13.6 % febrile neutropenia). There were 2 treatment-related deaths. Conclusions The study did not meet the primary EP, yet sustained disease control was obtained in about 14 % of patients. The incidence of AE and the issue of patient selection are two major concerns.
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Targeted therapies in gastric cancer treatment: where we are and where we are going
Summary
Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.
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Is there a role of nab-paclitaxel in the treatment of advanced non-small cell lung cancer? The data suggest yes
Publication date: March 2016
Source:European Journal of Cancer, Volume 56
Author(s): Liza C. Villaruz, Mark A. Socinski
Nab-paclitaxel is a novel therapeutic agent, which was approved in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) regardless of histologic subtype in the United States of America by the Food and Drug Administration in 2012 and by the European Commission in 2015. This approval was based on the results of a phase III clinical trial showing superior response rates compared with solvent-based paclitaxel in combination with carboplatin. This review will focus on the early development and clinical data to date supporting the use of nab-paclitaxel in advanced NSCLC. The clinical question central to this review is whether nab-paclitaxel has a place in the current therapeutic landscape of advanced NSCLC.
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Quality of Life of Patients with Cancer: A Determinant of the Quality of Life of Their Family Caregivers
Abstract
Cancer disrupts the quality of life of both the patients and their family caregivers. This study attempted to explore the relationship between the quality of life of cancer patients and their family caregivers and to examine whether the quality of life, age, and gender of the patients contributed to the quality of life of their family caregivers. This correlational study involved 206 pairs of participants consisting of cancer patients and their corresponding family caregivers. The European Organization for the Treatment and Research of Quality of Life Questionnaire C-30 (version 3) was administered on the patients and the Caregiver Quality of Life-Cancer was administered on their family caregivers. The result revealed that social functioning, appetite loss, physical functioning, and gender of the patients contributed significantly to the quality of life of their family caregivers. Implications, shortcomings, and future directions were discussed.
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Loss of PPARα perpetuates sex differences in stroke reflected by peripheral immune mechanisms
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor transcription factor that plays a role in immune regulation. Because of its expression in cerebral tissue and immune cells, PPARα has been examined as an important regulator in immune-based neurological diseases. Many studies have indicated that pre-treatment of animals with PPARα agonists induces protection against stroke. However, our previous reports indicate that protection is only in males, not females, and can be attributed to different PPARα expression between the sexes. In the current study, we examine how loss of PPARα affects male and female mice in experimental stroke. Male and female PPARα knockout mice were subject to middle cerebral artery occlusion (MCAO) or sham surgery, and the ischemic (local) or spleen specific (peripheral) immune response was examined 96 h after reperfusion. We found that loss of PPARα perpetuated sex differences in stroke, and this was driven by the peripheral, not local, immune response. Specifically we observed an increase in peripheral pro-inflammatory and adhesion molecule gene expression in PPARα KO males after MCAO compared to females. Our data supports previous evidence that PPARα plays an important role in sex differences in the immune response to disease, including stroke.
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Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory
Abstract
We examined how serum cholesterol, an established risk factor for cerebrovascular disease (CVD), relates to cognitive function in healthy middle-older aged individuals with no neurologic or CVD history. A complete lipid panel was obtained from a cohort of one hundred twenty individuals, ages 43–85, who also underwent a comprehensive neuropsychological examination. In order to reduce the number of variables and empirically identify broad cognitive domains, scores from neuropsychological tests were submitted into a factor analysis. This analysis revealed three explainable factors: Memory, Executive Function and Memory/Language. Three separate hierarchical multiple regression analyses were conducted using individual cholesterol metrics (total cholesterol, low density lipoprotein; LDL, high density lipoprotein; HDL, and triglycerides), as well as age, education, medication status (lipid lowering agents), ApoE status, and additional risk factors for CVD to predict neuropsychological function. The Memory Factor was predicted by a combination of age, LDL, and triglyceride levels; both age and triglycerides were negatively associated with factor score, while LDL levels revealed a positive relationship. Both the Executive and Memory/Language factor were only explained by education, whereby more years were associated with better performance. These results provide evidence that individual cholesterol lipoproteins and triglycerides may differentially impact cognitive function, over and above other common CVD risk factors and ApoE status. Our findings demonstrate the importance of consideration of vascular risk factors, such as cholesterol, in studies of cognitive aging.
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Effects of receptor for advanced glycation endproducts on microvessel formation in endometrial cancer
Abstract
Background
The receptor for advanced glycation endproducts (RAGE) and microvascular status both play a critical role in cancer progression. However, the crosstalk between RAGE and microvascular formation in endometrial cancer remains largely unknown.
Methods
RAGE expression and microvessel density were examined in 20 cases of normal endometrial tissue, 37 cases of well-differentiated endometrial cancer tissue, and 35 cases of poorly-differentiated endometrial cancer tissue. Regression analysis was used to examine the relationship between RAGE and microvessel density. The knockdown of RAGE was achieved using a small interfering RNA in HEC-1A endometrial cancer cells. A xenografted tumour model was used to evaluate RAGE-mediated microvascular formation and proliferation of endometrial cancer cells.
Results
It was shown that (i) RAGE expression gradually increased in normal endometrium, well-differentiated endometrial cancer, and poorly-differentiated endometrial cancer, respectively; (ii) a positive correlation existed between RAGE and microvessel density in human endometrial cancer samples; (iii) RAGE knockdown was effective in decreasing microvessel formation in xenografted tumour models; and (iv) RAGE knockdown can significantly inhibit the proliferation of endometrial cancer cells in vivo.
Conclusions
These results indicate that RAGE may be a potential trigger in microvascular formation and proliferation in the development of endometrial cancer.
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A nomogram for predicting the likelihood of lymph node metastasis in early gastric patients
Abstract
Background
Early gastric cancer is defined as a lesion confined to the mucosa or submucosa, regardless of the size or lymph node metastasis. Treatment methods include endoscopic mucosal resection or endoscopic submucosal dissection, wedge resection, laparoscopically assisted gastrectomy and open gastrectomy. Lymph node metastasis is strong related with survival and recurrence. Therefore, the likelihood of lymph node metastasis is one of the most important factors when determining the most appropriate treatment.
Methods
We retrospectively analyzed 597 patients who underwent D2 gastrectomy for early gastric cancer. The relationship between lymph node metastasis and clinicopathological features was analyzed. Using multivariate logistic regression analyses, we created a nomogram to predict the lymph node metastasis probability for early gastric cancer. Receiver operating characteristic analyses was performed to assess the predictive value of the model.
Results
In the present study, 58 (9.7 %) early gastric cancer patients were histologically shown to have lymph node metastasis. The multivariate logistic regression analysis demonstrated that the age at diagnosis, differentiation status, the presence of ulcers, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in early gastric cancer. Additionally, the tumor macroscopic type, size and histology type significantly correlated with these important independent factors. We constructed a predictive nomogram with these factors for lymph node metastasis in early gastric cancer patients, and the discrimination was good with the AUC of 0.860 (95 % CI: 0.809–0.912).
Conclusions
We developed an effective nomogram to predict the incidence of lymph node metastasis for early gastric cancer patients.
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The prognostic value of stromal and epithelial periostin expression in human breast cancer: correlation with clinical pathological features and mortality outcome
Abstract
Background
PN is a secreted cell adhesion protein critical for carcinogenesis. In breast cancer, it is overexpressed compared to normal breast, and a few reports suggest that it has a potential role as a prognostic marker.
Methods
Tumour samples obtained at the time of mastectomy from 200 women followed for a median time of 18.7 years (range 0.5–29.5 years) were investigated through IHC with a polyclonal anti-PN antibody using tissue microarrays. Epithelial and stromal PN expression were scored independently according to the percentage of coloured cells; the 60th percentile of PN epithelial expression, corresponding to 1 %, and the median value of PN stromal expression, corresponding to 90 %, were used as arbitrary cut-offs. The relationships between epithelial and stromal PN expression and clinical-pathological features, tumour phenotype and the risk of mortality following surgery were analysed. Appropriate statistics, including the Fine and Gray competing risk proportional hazard regression model, were used.
Results
The expression of PN in tumour epithelial cells was significantly lower than that which was observed in stromal cells (p < 0.000). No specific association between epithelial or stromal PN expression and any of the clinical-pathological parameters analysed was found as it was observed in respect to mortality when these variables were analysed individually. However, when both variables were considered as a function of the other one, the expression of PN in the stromal cells maintained a statistically significant predictive value with respect to both all causes and cancer-specific mortality only in the presence of high epithelial expression levels. No significant differences in either all causes or BCa-specific mortality rates were shown according to epithelial expression for tumours displaying higher stromal PN expression rates. However, the trends were opposite for the higher stromal values and the patients with high epithelial expression levels denoted the group with the worst prognosis, while higher epithelial values in patients with lower stromal expression levels denoted the group with the best prognosis, suggesting that PN epithelial/stromal interactions play a crucial role in breast carcinogenesis, most likely due to functional cross-talk between the two compartments. On the basis of PN expression in both compartments, we defined 4 subgroups of patients with different mortality rates with the group of patients characterized by positive epithelial and low stromal PN expression cells showing the lowest mortality risk as opposed to the groups of patients identified by a high PN expression in both cell compartments or those identified by a low or absent PN expression in both cell compartments showing the worst mortality rates. The differences were highly statistically significant and were also retained after multiparametric analysis. Competing risk analysis demonstrated that PN expression patterns characterizing each of previous groups are specifically associated with cancer-specific mortality.
Conclusions
Although they require further validation through larger studies, our findings suggest that the patterns of expression of PN in both compartments can allow for the development of IHC "signatures" that maintain a strong independent predictive value of both all causes and, namely, of cancer-specific mortality.
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Organic Cation Transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment
Abstract
Background
The polyspecific organ cation transporter 1 (OCT1) is one of the most important active influx pumps for drugs like the kinase inhibitor sorafenib. The aim of this retrospective study was the definition of the role of intratumoral OCT1 mRNA expression in hepatocellular carcinoma (HCC) as a biomarker in systemic treatment with sorafenib.
Methods
OCT1 mRNA expression levels were determined in biopsies from 60 primary human HCC by real time PCR. The data was retrospectively correlated with clinical parameters.
Results
Intratumoral OCT1 mRNA expression is a significant positive prognostic factor for patients treated with sorafenib according to Cox regression analysis (HR 0.653, 95 %-CI 0.430-0.992; p = 0.046). Under treatment with sorafenib, a survival benefit could be shown using the lower quartile of intratumoral OCT1 expression as a cut-off. Macrovascular invasion (MVI) was slightly more frequent in patients with low OCT1 mRNA expression (p = 0.037). Treatment-induced AFP response was not associated with intratumoral OCT1 mRNA expression levels (p = 0.633).
Conclusions
This study indicates a promising role for intratumoral OCT1 mRNA expression as a prognostic biomarker in therapeutic algorithms in HCC. Further prospective studies are warranted on this topic.
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Downregulated Expression of E-cadherin and TP53 in Patients with Gastric Diseases: the Involvement of H. pylori Infection and Its Virulence Markers
Abstract
Purpose
Gastritis caused by infection with Helicobacter pylori is characterized by chronic inflammation and damage in gastric tissue, which is a main risk factor for gastric cancer. Associated with H. pylori, the TP53 gene tumor suppressor and the cell adhesion glycoprotein epithelial cadherin develop a relevant role in the integrity and carcinogenesis of the epithelium. We aimed to detection of H. pylori and its main virulence markers and measured the messenger RNA (mRNA) expression levels of E-cadherin and TP53 genes.
Methods
The detection of H. pylori and its virulence markers, as well as the mRNA expression levels of E-cadherin and TP53 genes, were obtained for 161 samples of gastric biopsies including 37 with normal gastric tissue, 70 with gastritis, 24 from neoplastic tissue, and 27 from adjacent non-neoplastic by means of a quantitative real-time polymerase chain reaction.
Results
The mRNA expression levels of E-cadherin and TP53 were found to be decreased in patients with gastritis, independently of H. pylori infection. In samples from gastric patients, the neoplastic tissue showed an accentuated decrease of expression; on the other hand, the expression of E-cadherin was normal in adjacent non-neoplastic.
Conclusions
No evidence was found of the involvement of the cagA and vacA genes in the decreased expression of E-cadherin and TP53. The process of carcinogenesis is complex, and the decrease of the E-cadherin gene expression and TP53 gene expression appears to contribute significantly.
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Examining Mediators and Moderators of Yoga for Women With Breast Cancer Undergoing Radiotherapy
Hypothesis. This study examines moderators and mediators of a yoga intervention targeting quality-of-life (QOL) outcomes in women with breast cancer receiving radiotherapy.Methods. Women undergoing 6 weeks of radiotherapy were randomized to a yoga (YG; n = 53) or stretching (ST; n = 56) intervention or a waitlist control group (WL; n = 54). Depressive symptoms and sleep disturbances were measured at baseline. Mediator (posttraumatic stress symptoms, benefit finding, and cortisol slope) and outcome (36-item Short Form [SF]-36 mental and physical component scales [MCS and PCS]) variables were assessed at baseline, end-of-treatment, and 1-, 3-, and 6-months posttreatment. Results. Baseline depressive symptoms (P = .03) and sleep disturbances (P < .01) moderated the Group x Time effect on MCS, but not PCS. Women with high baseline depressive symptoms in YG reported marginally higher 3-month MCS than their counterparts in WL (P = .11). Women with high baseline sleep disturbances in YG reported higher 3-months MCS than their counterparts in WL (P < .01) and higher 6-month MCS than their counterparts in ST (P = .01). YG led to greater benefit finding than ST and WL across the follow-up (P = .01). Three-month benefit finding partially mediated the effect of YG on 6-month PCS. Posttraumatic stress symptoms and cortisol slope did not mediate treatment effect on QOL. Conclusion. Yoga may provide the greatest mental-health–related QOL benefits for those experiencing pre-radiotherapy sleep disturbance and depressive symptoms. Yoga may improve physical-health–related QOL by increasing ability to find benefit in the cancer experience.
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Mechanisms of vascularization in murine models of primary and metastatic tumor growth
Abstract
Directed capillary ingrowth has long been considered synonymous with tumor vascularization. However, the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting; instead, malignant tumors can acquire blood vessels via alternative vascularization mechanisms, such as intussusceptive microvascular growth, vessel co-option, and glomeruloid angiogenesis. Importantly, in response to anti-angiogenic therapies, malignant tumors can switch from one vascularization mechanism to another. In this article, we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology.
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Why some tumours trigger neovascularisation and others don’t: the story thus far
Abstract
Background
Angiogenesis is not essential for tumours to develop and expand, as cancer can also grow in a non-angiogenic fashion, but why this type of growth occurs is unknown. Surprisingly, our data from mRNA transcription profiling did not show any differences in the classical angiogenic pathways, but differences were observed in mitochondrial metabolic pathways, suggesting a key role for metabolic reprogramming. We then validated these results with mRNA profiling by investigating differential protein expression via immunohistochemistry in angiogenic and non-angiogenic non-small cell lung cancers (NSCLCs).
Methods
Immunohistochemical staining for 35 angiogenesis- and hypoxia-related biomarkers were performed on a collection of 194 angiogenic and 73 non-angiogenic NSCLCs arranged on tissue microarrays. Sequencing of P53 was performed with frozen tissue samples of NSCLC.
Results
The non-angiogenic tumours were distinguished from the angiogenic ones by having higher levels of proteins associated with ephrin pathways, mitochondria, cell biogenesis, and hypoxia-inducible factor 1 (HIF1) regulation by oxygen and transcription of HIF-controlled genes but lower levels of proteins involved in the stroma, cell–cell signaling and adhesion, integrins, and Delta-Notch and epidermal growth factor (EGF)-related signaling. However, proteins classically associated with angiogenesis were present in both types of tumours at very comparable levels. Cytoplasmic expression of P53 was strongly associated with non-angiogenic tumours. A pilot investigation showed that P53 mutations were observed in 32.0% of angiogenic cases but in 71.4% of non-angiogenic tumours.
Conclusions
Our observations thus far indicate that both angiogenic and non-angiogenic tumours experience hypoxia/HIF and vascular endothelial growth factor (VEGF) pathway protein expression in a comparable fashion. However, angiogenesis does not ensue in the non-angiogenic tumours. Surprisingly, metabolic reprogramming seems to distinguish these two types of neoplastic growth. On the basis of these results, we raise the hypothesis that in some, but not in all cases, initial tissue remodeling and/or inflammation could be one of the secondary steps necessary to trigger angiogenesis. In the non-angiogenic tumours, in which neovascularisation fails to occur, HIF pathway activation could be the driving force toward metabolic reprogramming.
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Sonidegib: A Review in Locally Advanced Basal Cell Carcinoma
Abstract
Sonidegib (Odomzo®), an oral smoothened (SMO) antagonist, is indicated for the treatment of adults with locally advanced basal cell carcinoma (laBCC) who are not candidates for surgery or radiation therapy, or adults with recurrent laBCC following surgery or radiation therapy. In the multicentre BOLT trial, the primary endpoint (i.e., an objective tumour response rate point estimate of ≥30 % and a 95 % confidence interval lower bound of >20 % in patients with fully assessable laBCC and all patients with metastatic BCC) was met at the primary analysis cut-off date (median follow-up 13.9 months) in the sonidegib 200 mg (36 % [95 % CI 24–50]) and 800 mg (34 % [95 % CI 25–43]) once-daily groups. Sonidegib 200 mg once daily (recommended dosage) had a better benefit-risk profile than the 800 mg dosage. Central review of the patients with laBCC in this population showed that 43 % achieved an objective response with sonidegib 200 mg once daily at the primary analysis date. Clinically meaningful responses were sustained in the sonidegib 200 mg group, based on an 18-month analysis. The majority of treatment-emergent adverse events were of mild to moderate severity and manageable with dosage adjustments, concomitant medications and/or non-drug therapies (e.g., adequate hydration). The acceptable benefit-risk profile of sonidegib, along with a paucity of treatment options and the seriousness of the condition, makes sonidegib an emerging option for the treatment of adults with laBCC that has recurred following surgery or radiation therapy, or in those who are not candidates for surgery or radiation therapy
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Lenvatinib: A Review in Refractory Thyroid Cancer
Abstract
Lenvatinib (Lenvima®) is an oral, multi-targeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor alpha, and RET and KIT signalling networks, which are implicated in tumour growth and maintenance. In the EU and USA, lenvatinib is indicated for the treatment of locally recurrent or metastatic progressive, radioiodine-refractory differentiated thyroid cancer (RR-DTC). This approval was based on the results of the randomized, double-blind, multinational, phase 3 SELECT study, in which lenvatinib significantly improved median progression-free survival (PFS) and overall response rate compared with placebo in patients with RR-DTC. The PFS benefit with lenvatinib was seen in all pre-specified subgroups, including patients who had received either one or no prior VEGF-targeted therapy. Moreover, the PFS benefit with lenvatinib was maintained regardless of BRAF or RAS mutation status. The safety and tolerability profile of lenvatinib in SELECT was consistent with that of other VEGF/VEGF receptor-targeted therapies and was mostly manageable. Hypertension was the most common treatment-related adverse event in lenvatinib-treated patients, but only infrequently led to discontinuation of the drug. Although not collected in SELECT, information on quality of life would be useful in assessing the overall impact of therapy on the patient. This notwithstanding, the data which are available indicate that lenvatinib is an effective and generally well-tolerated treatment option for patients with RR-DTC. Lenvatinib, therefore, offers an acceptable alternative to sorafenib — currently, the only other TKI approved for this indication.
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In vitro evaluation of antitumoral efficacy of catalase in combination with traditional chemotherapeutic drugs against human lung adenocarcinoma cells
Abstract
Lung cancer is the most lethal cancer-related disease worldwide. Since survival rates remain poor, there is an urgent need for more effective therapies that could increase the overall survival of lung cancer patients. Lung tumors exhibit increased levels of oxidative markers with altered levels of antioxidant defenses, and previous studies demonstrated that the overexpression of the antioxidant enzyme catalase (CAT) might control tumor proliferation and aggressiveness. Herein, we evaluated the effect of CAT treatment on the sensitivity of A549 human lung adenocarcinoma cells toward various anticancer treatments, aiming to establish the best drug combination for further therapeutic management of this disease. Exponentially growing A549 cells were treated with CAT alone or in combination with chemotherapeutic drugs (cisplatin, 5-fluorouracil, paclitaxel, daunorubicin, and hydroxyurea). CalcuSyn® software was used to assess CAT/drug interactions (synergism or antagonism). Growth inhibition, NFκB activation status, and redox parameters were also evaluated in CAT-treated A549 cells. CAT treatment caused a cytostatic effect, decreased NFκB activation, and modulated the redox parameters evaluated. CAT treatment exhibited a synergistic effect among most of the anticancer drugs tested, which is significantly correlated with an increased H2O2 production. Moreover, CAT combination caused an antagonism in paclitaxel anticancer effect. These data suggest that combining CAT (or CAT analogs) with traditional chemotherapeutic drugs, especially cisplatin, is a promising therapeutic strategy for the treatment of lung cancer.
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Transforming growth factor (TGF) β1 acted through miR-130b to increase integrin α5 to promote migration of colorectal cancer cells
Abstract
Transforming growth factor (TGF)-β1 is a significant stimulator of tumor invasion and metastasis. More recently, it has been found that TGF-β1 acts through microRNAs to regulate their target genes to promote cancer progresses. However, such similar regulation is rarely reported in colorectal cancer (CRC). Here, we observed a decrease in TGF-β1 expression in CRC specimens, compared with matched adjacent normal tissues. In parallel, there was an increase in miR-130b characterized in the same samples by microarray assay. Further, treatment of CRC cells with TGF-β1 caused a significant decrease in the expression of miR-130b and an increased CRC cell migration. Luciferase reporter assay revealed that miR-130b directly targeted the 3′ untranslated region (3′UTR) region of integrin α5 gene, which encodes a key molecule involved in cell motility. Subsequently, in the overexpression of miR-130b CRC cells, we observed a decreased level of integrin α5 protein. The regulation of integrin α5 by miR-130b was further shown using the miR-130b mimics and inhibitor of miR-130b. And, knockdown miR-130b with inhibitor in the overexpression of miR-130b CRC cells recovered integrin α5 expression and integrin α5-mediated cell motility. Moreover, the inverse relevance between miR-130b and integrin α5 was also observed in CRC specimens. At last, the enhancement of integrin α5 in TGF-β1-treated cells can be reversed partly when rescuing miR-130b expression. Together, our findings suggested that TGF-β1 acted through miR-130b to promote integrin α5 expression, resulting in the enhanced migration of CRC cells.
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Chromogranin A is preferentially cleaved into pro-angiogenic peptides in the bone marrow of multiple myeloma patients
Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma (MM), a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an anti-angiogenic protein, can activate latent anti- and pro-angiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in MM patients and the subsequent implications for disease progression. We show that the ratio of pro-/anti-angiogenic forms of CgA is altered in MM patients compared with healthy subjects, and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of MM, we further demonstrate that exogenously administered CgA was cleaved in favor of the pro-angiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that MM and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter-balance the pro-/anti-angiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of MM patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target.
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New Strategies in Breast Cancer: Immunotherapy
More than 70% of breast cancers contain lymphocytic infiltration in the stroma and preclinical studies suggest that immune-editing and partial control of cancer progression by the local immune microenvironment operates in most breast cancers. Consistent with this hypothesis, a large number of studies demonstrated a favorable prognostic and chemotherapy response predictive role for immune infiltration in breast cancer. The evidence is particularly strong for triple negative and HER2 positive cancers. The development of clinically effective immune checkpoint inhibitors now provides an opportunity to test the therapeutic potential of augmenting the local anti-tumor immune response. Several Phase I clinical trials using single agent anti-PD1 and anti-PDL1 antibodies demonstrated objective tumor response rates, with remarkably durable responses, in heavily pretreated, metastatic, triple negative cancers and somewhat lower responses in estrogen-receptor positive cancers. Currently, close to 50 ongoing, or soon to open, clinical trials evaluate the role of this new treatment modality in breast cancer.
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Melanoma associated antigen (MAGE)-A3 promotes cell proliferation and chemotherapeutic drug resistance in gastric cancer
Abstract
Background
Melanoma-associated antigen (MAGE)-A3 is a member of the family of cancer-testis antigens and has been found to be epigenetically regulated and aberrantly expressed in various cancer types. It has also been found that MAGE-A3 expression may correlate with an aggressive clinical course and with chemo-resistance. The objectives of this study were to assess the relationship between MAGE-A3 promoter methylation and expression and (1) gastric cancer patient survival and (2) its functional consequences in gastric cancer-derived cells.
Methods
Samples from two independent gastric cancer cohorts (including matched non-malignant gastric samples) were included in this study. MAGE-A3 methylation and mRNA expression levels were determined by methylation-specific PCR (MSP) and quantitative real-time PCR (qPCR), respectively. MAGE-A3 expression was knocked down in MKN1 gastric cancer-derived cells using miRNAs. In addition, in vitro cell proliferation, colony formation, apoptosis, cell cycle, drug treatment, immunohistochemistry and Western blot assays were performed.
Results
Clinical analysis of 223 primary patient-derived samples (ntumor = 161, nnormal = 62) showed a significant inverse correlation between MAGE-A3 promoter methylation and expression in the cancer samples (R = −0.63, p = 5.99e–19). A lower MAGE-A3 methylation level was found to be associated with a worse patient survival (HR: 1.5, 95 % CI: 1.02–2.37, p = 0.04). In addition, we found that miRNA-mediated knockdown of MAGE-A3 expression in MKN1 cells caused a reduction in its proliferation and colony forming capacities, respectively. Under stress conditions MAGE-A3 was found to regulate the expression of Bax and p21. MAGE-A3 knock down also led to an increase in Puma and Noxa expression, thus contributing to an enhanced docetaxel sensitivity in the gastric cancer-derived cells.
Conclusions
From our results we conclude that MAGE-A3 expression is regulated epigenetically by promoter methylation, and that its expression contributes to gastric cell proliferation and drug sensitivity. This study underscores the potential implications of MAGE-A3 as a therapeutic target and prognostic marker in gastric cancer patients.
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