Clinical Trial of Oral Nelfinavir Before and During Radiation Therapy for Advanced Rectal Cancer

Purpose Nelfinavir, a PI3-kinase pathway inhibitor, is a radiosensitizer which increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. Patients and Methods Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pre-treatment, after 7 days of nelfinavir and prior to last fraction of RT. Biopsies taken pre-treatment and 7 days after the last fraction of RT were analysed for tumor cell density (TCD). Results There were 3 drug-related grade 3 adverse events: diarrhea, rash, lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P=0.01). Overall, 5/9 evaluable patients exhibited good tumor regression on MRI assessed by Tumor Regression Grade (mrTRG). Conclusions This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.

from Cancer via ola Kala on Inoreader http://ift.tt/1QUJfjv
via IFTTT

Olfactory receptor family receptor, family 7, subfamily C, member 1 is a novel marker of colon cancer-initiating cells and is a potent target of immunotherapy.

Purpose: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. Experimental Design: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CIC were analyzed by cDNA micro-array and RT-PCR. Protein expression of Olfactory receptor family receptor, family 7, subfamily C, member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene over-expression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by flowcytometer and analyzed. Cytotoxic T lymphocytes (CTLs) specific for OR7C1 peptide were generated, and the anti-tumor effect was addressed by mice adoptive transfer model. Results: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicty than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific cytotoxic T lymphocytes (CTLs) showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater anti-tumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. Conclusions: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1T6cTEC
via IFTTT

PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity

PURPOSE: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor vascular endothelial growth factor receptor-1 (VEGFR-1) have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN: We established diet-induced obese mouse models of wild type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null or PlGF null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS: We found that obesity increased TAM infiltration, tumor growth and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment towards an anti-tumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced anti-tumor immunity. CONCLUSIONS: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression.

from Cancer via ola Kala on Inoreader http://ift.tt/1QUJdbs
via IFTTT

A NOVEL CARCINOEMBRYONIC ANTIGEN T CELL BISPECIFIC ANTIBODY (CEA TCB) FOR THE TREATMENT OF SOLID TUMORS

Purpose: CEA TCB is a novel IgG-based T Cell Bispecific antibody for the treatment of CEA-expressing solid tumors currently in Phase 1 clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA and CD3e binding Fab domains and an engineered Fc region with completely abolished binding to FcRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB. Experimental design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human PBMCs. Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunological synapses, T cell activation, secretion of cytotoxic granules and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA binding sites/cell, which allows distinguishing between high- and low-CEA expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells and converts PD-L1 negative into PD-L1 positive tumors. Conclusion: CEA TCB is a novel generation TCB displaying potent anti-tumor activity; it is efficacious in poorly-infiltrated tumors where it increases T cell infiltration and generates a highly-inflamed tumor microenvironment.

from Cancer via ola Kala on Inoreader http://ift.tt/1T6cTEv
via IFTTT

Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma (ES) cells in the blood and bone marrow (BM). These techniques were used to evaluate the prognostic significance of micrometastatic disease in ES. Experimental Design: Newly diagnosed patients with ES were enrolled on two prospective multi-center studies. In the flow cytometry cohort, patients were defined as "positive" for BM micrometastatic disease if their CD99+/CD45- values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or BM samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Co-expression of IGF-1R on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total BM CD99+CD45- percent was 0.0012% (range 0-1.10%) in the flow cytometry cohort, with 14/109 (12.8%) of ES patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or BM. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" vs. "negative" by either method. CD99+CD45- cells had significantly higher IGF-1R expression compared to CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; p<0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with ES. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest.

from Cancer via ola Kala on Inoreader http://ift.tt/1QUJf35
via IFTTT

Translational and clinical research highlights from the 38th San Antonio Breast Cancer Symposium

Future Oncology Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/20KaKEE
via IFTTT

The genetic classification of prostate cancer: what’s on the horizon?

Future Oncology Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/1Wd25E1
via IFTTT

Matrix metalloproteinase-11 as a marker of metastasis and predictor of poor survival in urothelial carcinomas

Background and Objectives

Urothelial carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality. We looked for genes with metalloendopeptidase activity in a published UBUC transcriptomic database (GSE31684):MMP-11 was the most significant, showing stepwise up-regulation. We analyzed MMP-11 expression and association with clinicopathologic factors and survival in our well-characterized cohort of UCs.

Methods

We determined MMP-11 expression in 295 UBUCs and 340 UTUCs with immunohistochemistry, evaluated by H-score. In a retrospective study, MMP-11 expression was correlated with clinicopathologic features and with disease-specific survival (DSS) and metastasis-free survival (MeFS). The statistical significance was evaluated with univariate and multivariate analyses.

Results

High MMP-11 expression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular and perineural invasion, and frequent mitoses. In multivariate Cox regression analyses, which adjusted for standard clinicopathologic characteristics, MMP-11 expression was independently associated with cancer-specific mortality (hazard ratio [HR] in UTUC:3.027, P = 0.005; in UBUC: 2.631, P = 0.010) and with metastasis development (HR in UTUC:2.261, P = 0.018; in UBUC:1.801, P = 0.026).

Conclusions

MMP-11 overexpression is associated with aggressive tumor phenotype and unfavorable clinical outcome in UTUC and UBUC, suggesting it may serve as a novel prognostic and therapeutic target. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1T6cTob
via IFTTT

Significance of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and prognostic nutrition index as preoperative predictors of early mortality after liver resection for huge (≥10 cm) hepatocellular carcinoma

Background

This study aimed to determine preoperative predictors of early (<1 year) mortality from disease recurrence after liver resection (LR) for huge (≥10 cm) HCC, with special emphasis on the importance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutrition index (PNI).

Methods

Between 2000 to 2013, 166 patients underwent LR for huge HCC. Optimal cut-offs for alpha fetoprotein (AFP), NLR, PLR, and PNI were determined by plotting the receiver operator curves (ROC) in predicting early mortality and utilizing the Youden index.

Results

The 30-day/in-hospital postoperative mortality rate was 4.2%. The 5-year overall survival (OS) and the 5-year recurrence-free survival (RFS) was 43% and 24%, respectively. Early mortality from disease recurrence occurred in 35 of 159 (22%) patients. Multivariate analyses demonstrated that tumor rupture and high AFP (>1,085 ng/ml) were independent preoperative predictors of early mortality after LR for HCC, and both a low PNI (<41) and high AFP were independent predictors of early mortality for non-ruptured HCC. In 51 patients who had none of these three factors, only four (7.8%) patients experienced early mortality from disease recurrence.

Conclusions

Spontaneous rupture, high AFP, and low PNI were predictors of early mortality from disease recurrence after LR for huge HCC. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1QUJdbq
via IFTTT

MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer. Prognostic markers are needed to guide patient management toward aggressive versus more conservative approaches, especially for small tumors ≤4 cm. miR-194 was reported to be downregulated in several cancers and is involved in epithelial to mesenchymal transition. We evaluated miR-194 as a prognostic marker in ccRCC. In a cohort of 234 patients with primary ccRCC, we correlated miR-194 expression level with multiple clinicopathological features including disease-free and overall survival, tumor size, clinical stage, and histological grade. Our results shows a stepwise decrease in miR-194 expression from normal kidney to primary ccRCC (P = 0.0032) and a subsequent decrease from primary to metastatic lesions. Additionally, patients with higher miR-194 expression has significantly longer disease-free survival (P = 0.041) and overall survival (P = 0.031) compared to those with lower expression. In multivariate analysis, miR-194-positive tumors retain significance in disease-free survival and overall survival, suggesting miR-194 is an independent marker for good prognosis in ccRCC. Moreover, miR-194 is a marker for good prognosis for patients with small renal masses (P = 0.014). These findings were validated on an independent data set from The Cancer Genome Atlas. We also compared miR-194 expression between RCC subtypes. ccRCC had the highest levels, whereas chromophobe RCC and oncocytoma had comparable lower levels. Target prediction coupled with pathway analysis show that miR-194 is predicted to target key molecules and pathways involved in RCC progression. miR-194 represents a prognostic biomarker in ccRCC.

Prognostic markers are needed to guide patient management in kidney cancer. We evaluated miR-194 expression by using qRT-PCR in 234 patients with primary renal cell carcinoma. High expression of miR-194 is associated with significantly longer disease-free survival and overall survival. We further validated our results on an independent data set from The Cancer Genome Atlas.

from Cancer via ola Kala on Inoreader http://ift.tt/1Q8c1QR
via IFTTT

Translational and clinical research highlights from the 38th San Antonio Breast Cancer Symposium

Future Oncology Ahead of Print.


from Cancer via ola Kala on Inoreader http://ift.tt/20KaKEE
via IFTTT

Sensitive methods for screening of the MEK1 gene mutations in patients with central nervous system metastases of non-small cell lung cancer

Abstract

Background

The mitogen-activated protein kinases 1 and 2 (MEK1, MEK2) are fundamental partners in the RAS–RAF–MEK–ERK pathway that is involved in regulation of cell proliferation, differentiation and survival. Downregulation of the MEK cascades has been implicated in acquiring of the malignant phenotype in various cancers. Somatic mutations in MEK1 gene (substitutions K57N, Q56P, D67N) were described in <1 % of non-small cell lung cancer (NSCLC) and they were more commonly reported in adenocarcinoma patients with current or former smoking status.

Materials and methods

In the following study, we assessed the MEK1 gene mutations in 145 FFPE tissue samples from central nervous system (CNS) metastases of NSCLC using HRM-PCR and ASP-qPCR techniques. The studied group was heterogeneous in terms of histopathology and smoking status. The prevalence of the MEK1 gene mutation was correlated with the occurrence of mutations in KRAS, EGFR, DDR2, PIK3CA, NRAS, HER2, AKT1 and PTEN genes.

Results

Using HRM and ASP-qPCR methods we identified one (0.7 %; 1/145) MEK1 substitution (Q56P) in CNS metastases of NSCLC. The mutation was identified in a single, 50-year-old, current smoking men with adenocarcinoma (1.25 %; 1/80 of all adenocarcinomas).

Conclusions

According to the current knowledge, the incidence of MEK1 gene mutation in CNS metastatic lesion of NSCLC is the first such report worldwide. The analysis of gene profile in cancer patients may extend the scope of molecularly targeted therapies used both in patients with primary and metastatic tumors of NSCLC.

from Cancer via ola Kala on Inoreader http://ift.tt/1QU2IRl
via IFTTT

An immunohistochemical study of cyclin-dependent kinase 5 (CDK5) expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): a possible prognostic biomarker

Abstract

Background

Cyclin-dependent kinase 5 (CDK5) is an atypical CDK which plays a vital role in several cancers via regulating migration and motility of cancer cells. However, the clinicopathological impact and function of CDK5 in lung cancer remain poorly understood. The present study was aimed at exploring expression and clinicopathological significance of CDK5 in lung cancer.

Methods

There were 395 samples of lung tissue including 365 lung tumors (339 non-small cell lung cancers and 26 small cell lung cancers) and 30 samples of normal lung. CDK5 expression was detected by immunohistochemistry on lung tissue microarrays.

Results

Over expression was detected in lung cancer compared with normal lung tissues (P = 0.001). Furthermore, area under curve (AUC) of receiver operating characteristic (ROC) of CDK5 was 0.685 (95 % CI 0.564~0.751, P = 0.004). In lung cancer, we also discovered close correlations between CDK5 and pathological grading (r = 0.310, P < 0.001), TNM stage (r = 0.155, P = 0.003), and lymph node metastasis (r = 0.279, P < 0.001) by using Spearman analysis. In two subgroups of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the expression of CDK5 was also higher than that of normal lung tissue, respectively (P = 0.001 and P = 0.004). Moreover, in NSCLCs, Spearman analysis revealed that expression of CDK5 was correlated with TNM stages (r = 0.129, P = 0.017), lymph node metastasis (r = 0.365, P < 0.001), and pathological grading (r = 0.307, P < 0.001), respectively. The significant correlation was also found between CDK5 expression and TNM stages (r = 0.415, P = 0.049) and lymphatic metastasis (r = 0.469, P = 0.024) in SCLCs.

Conclusions

The results of this present study suggest that the CDK5 expression is associated with several clinicopathological factors linked with poorer prognosis.

from Cancer via ola Kala on Inoreader http://ift.tt/1PMR3VF
via IFTTT

Incidental findings in population imaging revisited

from Cancer via ola Kala on Inoreader http://ift.tt/1SGRnYM
via IFTTT

Reported associations between asthma and acute lymphoblastic leukemia: insights from a hybrid simulation study

Abstract

Numerous studies have reported a protective association between asthma and acute lymphoblastic leukemia (ALL), but the causal structure of this association remains unclear. We present a hybrid simulation to examine the compatibility of this association with uncontrolled confounding by infection or another unmeasured factor. We generated a synthetic cohort using inputs on the interrelations of asthma, ALL, infections, and other suggested risk factors from the literature and the Danish National Birth Cohort. We computed odds ratios (ORs) between asthma and ALL in the synthetic cohort with and without adjustment for infections and other (including unmeasured) confounders. Only if infection was an extremely strong risk factor for asthma (OR of 10) and an extremely strong protective factor against ALL (OR of 0.1) was the asthma-ALL association compatible with the literature (OR of 0.78). Similarly, strong uncontrolled confounding by an unmeasured factor could downwardly bias the asthma-ALL association, but not enough to replicate findings in the literature. This investigation illustrates that the reported protective association between asthma and ALL is unlikely to be entirely due to uncontrolled confounding by infections or an unmeasured confounder alone. Simulation can be used to advance our understanding of risk factors for rare outcomes as demonstrated by this study.

from Cancer via ola Kala on Inoreader http://ift.tt/20nfAlH
via IFTTT

Role of NADPH oxidases in inducing a selective increase of oxidant stress and cyclin D1 and checkpoint 1 over-expression during progression to human gastric adenocarcinoma

Publication date: April 2016
Source:European Journal of Cancer, Volume 57
Author(s): Eduardo E. Montalvo-Javé, Marisela Olguín-Martínez, Diego R. Hernández-Espinosa, Lourdes Sánchez-Sevilla, Edgar Mendieta-Condado, Martha L. Contreras-Zentella, Luis F. Oñate-Ocaña, Tomás Escalante-Tatersfield, Agustín Echegaray-Donde, Juan M. Ruiz-Molina, Miguel F. Herrera, Julio Morán, Rolando Hernández-Muñoz
BackgroundGastric cancer is one of the main causes of global mortality. Here, reactive oxygen species (ROS) could largely contribute to gastric carcinogenesis. Hence, the present work was aimed to assess the role of ROS, oxidant status, NADPH oxidases (NOXs) expression, during human gastric adenocarcinoma.MethodsWe obtained subcellular fraction from samples of gastric mucosa taken from control subjects (n = 20), and from 40 patients with gastric adenocarcinoma, as well as samples of distant areas (tumour-free gastric mucosa).ResultsParameters indicative of lipid peroxidation and cell proliferation were selectively increased in both tumour-free and in cancerous gastric mucosa, despite of glutathione (GSH) content, glutathione reductase (GR) and superoxide dismutase (SOD) activities were increased in the adenocarcinoma. These high levels of antioxidant defences inversely correlated with down-regulated expression for NOX2 and 4; however, over-expression of NOX1 occurred with increased caspase-3 activity and overexpressed checkpoint 1 (MDC1) and cyclin D1 proteins. In the tumour-free mucosa an oxidant stress took place, without changing total GSH but with decreased activities for GR and mitochondrial SOD; moreover, over-expression of checkpoint 1 (MDC1) correlated with lower NOX2 and 4 expression in this mucosa.ConclusionsChronically injured gastric mucosa increases lipoperoxidative events and cell proliferation. In the adenocarcinoma, cell proliferation was further enhanced, oxidant stress decreased which seemed to be linked to NOX1, MDC1 and cyclin D1 over-expression, but with a lower NOXs activity leading a 'low tone' of ROS formation. Therefore, our results could be useful for early detection and treatment of gastric adenocarcinoma.



from Cancer via ola Kala on Inoreader http://ift.tt/1PjNTag
via IFTTT

Incidental findings in population imaging revisited

from Cancer via ola Kala on Inoreader http://ift.tt/1SGRnYM
via IFTTT

Reported associations between asthma and acute lymphoblastic leukemia: insights from a hybrid simulation study

Abstract

Numerous studies have reported a protective association between asthma and acute lymphoblastic leukemia (ALL), but the causal structure of this association remains unclear. We present a hybrid simulation to examine the compatibility of this association with uncontrolled confounding by infection or another unmeasured factor. We generated a synthetic cohort using inputs on the interrelations of asthma, ALL, infections, and other suggested risk factors from the literature and the Danish National Birth Cohort. We computed odds ratios (ORs) between asthma and ALL in the synthetic cohort with and without adjustment for infections and other (including unmeasured) confounders. Only if infection was an extremely strong risk factor for asthma (OR of 10) and an extremely strong protective factor against ALL (OR of 0.1) was the asthma-ALL association compatible with the literature (OR of 0.78). Similarly, strong uncontrolled confounding by an unmeasured factor could downwardly bias the asthma-ALL association, but not enough to replicate findings in the literature. This investigation illustrates that the reported protective association between asthma and ALL is unlikely to be entirely due to uncontrolled confounding by infections or an unmeasured confounder alone. Simulation can be used to advance our understanding of risk factors for rare outcomes as demonstrated by this study.

from Cancer via ola Kala on Inoreader http://ift.tt/20nfAlH
via IFTTT

Immunotherapy in Chronic Lymphocytic Leukaemia (CLL)

Abstract

Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies—past and present—demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future.

from Cancer via ola Kala on Inoreader http://ift.tt/1T5hNla
via IFTTT

Attitudes, Beliefs, and Trends Regarding Adolescent Oncofertility Discussions: A Systematic Literature Review

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


from Cancer via ola Kala on Inoreader http://ift.tt/1Q65DTT
via IFTTT

Health Literacy in Adolescents and Young Adults: An Updated Review

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


from Cancer via ola Kala on Inoreader http://ift.tt/1Q65Fv0
via IFTTT

Erratum to: Knockdown of clusterin sensitizes pancreatic cancer cells to gemcitabine chemotherapy by ERK1/2 inactivation

from Cancer via ola Kala on Inoreader http://ift.tt/1Q7OCij
via IFTTT

Erratum to: A study of association between expression of hOGG1, VDAC1, HK-2 and cervical carcinoma

from Cancer via ola Kala on Inoreader http://ift.tt/1Q65FeD
via IFTTT

Erratum to Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrectomy

from Cancer via ola Kala on Inoreader http://ift.tt/1Q7OAa8
via IFTTT

Retraction Note: siRNA directed against c-Myc inhibits proliferation and downregulates human telomerase reverse transcriptase in human colon cancer Colo 320 cells

from Cancer via ola Kala on Inoreader http://ift.tt/1Q65Fes
via IFTTT

A new era for Journal of Experimental & Clinical Cancer Research

from Cancer via ola Kala on Inoreader http://ift.tt/1Q7OzTN
via IFTTT

Deregulated expression of the HSP40 family members Auxilin-1 and -2 is indicative of proteostasis imbalance and predicts patient outcome in Ph + leukemia

Abstract

Background

Proteostasis is defined by the orchestrated control of anabolic and catabolic protein pathways. Disruption of proteostasis results in cell stress and adaptation to proteostasis imbalance is mediated by adaptive pathways such as the Heat Shock Response (including heat-shock proteins) or the unfolded protein response (UPR). The BCR-ABL1 kinase (Philadelphia chromosome) is the hallmark of chronic myeloid leukemia (CML) and defines a historically poor subset in acute lymphoblastic leukemia (Ph⁺ ALL). We previously demonstrated the importance of the UPR and particularly of the IRE1/XBP1 signaling axis in Ph⁺ ALL, while others demonstrated the therapeutic relevance of HSP70 in ALL. In this regard, HSP70 is regulated by smaller HSP40 s, whose function is so far poorly characterized.

Results

Herein, we characterize the expression of HSP40 s in Ph⁺ ALL and CML. We show that these genes are not regulated in a pan-class manner and identify a homologous gene pair, namely Auxilin-1 (DNAJC6) and Auxilin-2 (GAK) with a unique expression profile. Overexpression of Auxilin-2, the ubiquitously expressed homologue of Auxilin-1 correlated with superior clinical outcome in ALL and was tightly linked to both IRE1 RNase and BCR-ABL1 kinase activities.

Conclusions

Our findings suggest that HSP40 gens are uniquely regulated and provide a rationale for further studies between BCR-ABL1/IRE1-based therapies in combination with HSP40 inhibitors, thus opening potentially novel therapeutic avenues.

from Cancer via ola Kala on Inoreader http://ift.tt/1T5bpug
via IFTTT

Sensitive methods for screening of the MEK1 gene mutations in patients with central nervous system metastases of non-small cell lung cancer

Abstract

Background

The mitogen-activated protein kinases 1 and 2 (MEK1, MEK2) are fundamental partners in the RAS–RAF–MEK–ERK pathway that is involved in regulation of cell proliferation, differentiation and survival. Downregulation of the MEK cascades has been implicated in acquiring of the malignant phenotype in various cancers. Somatic mutations in MEK1 gene (substitutions K57N, Q56P, D67N) were described in <1 % of non-small cell lung cancer (NSCLC) and they were more commonly reported in adenocarcinoma patients with current or former smoking status.

Materials and methods

In the following study, we assessed the MEK1 gene mutations in 145 FFPE tissue samples from central nervous system (CNS) metastases of NSCLC using HRM-PCR and ASP-qPCR techniques. The studied group was heterogeneous in terms of histopathology and smoking status. The prevalence of the MEK1 gene mutation was correlated with the occurrence of mutations in KRAS, EGFR, DDR2, PIK3CA, NRAS, HER2, AKT1 and PTEN genes.

Results

Using HRM and ASP-qPCR methods we identified one (0.7 %; 1/145) MEK1 substitution (Q56P) in CNS metastases of NSCLC. The mutation was identified in a single, 50-year-old, current smoking men with adenocarcinoma (1.25 %; 1/80 of all adenocarcinomas).

Conclusions

According to the current knowledge, the incidence of MEK1 gene mutation in CNS metastatic lesion of NSCLC is the first such report worldwide. The analysis of gene profile in cancer patients may extend the scope of molecularly targeted therapies used both in patients with primary and metastatic tumors of NSCLC.

from Cancer via ola Kala on Inoreader http://ift.tt/1QU2IRl
via IFTTT

Differential expression of PDGFRB and EGFR in microvascular proliferation in glioblastoma

Abstract

Glioblastoma (GBM) is the highly malignant glioma and exhibits microvascular proliferation. PCR mRNA arrays and immunohistochemical stains on tissue microarray demonstrated that the expression level of PDGFRB in GBM microvascular proliferation was significantly higher than that in GBM tumor cells while the expression level of EGFR was lower in microvascular proliferation than in GBM tumor cells. PDGFRB protein was selectively expressed in pericytes in GBM microvascular proliferation. By analyzing The Cancer Genome Atlas (TCGA) datasets for GBM, it was found that genomic DNA alterations were the main reason for the high expression of EGFR in GBM tumor cells. Our miRNA microarray data showed that microRNAs (miRNAs) (miR-193b-3p, miR-518b, miR-520f-3p, and miR-506-5p) targeting PDGFRB were downregulated in microvascular proliferation, which might be the most likely reason for the high expression of PDGFRB in GBM microvascular proliferation. The increase of several miRNAs (miR-133b, miR-30b-3p, miR-145-5p, and miR-146a-5p) targeting EGFR in GBM microvascular proliferation was one of the reasons for the lack of expression of EGFR in GBM microvascular proliferation. These findings implicated that miRNAs, such as miR-506, miR-133b, miR-145, and miR-146a, that target PDGFRB or EGFR, might be potential therapeutic agents for GBM. A new generation of targeted therapeutic agents against both EGFR and PDGFRB might be developed in the future.

from Cancer via ola Kala on Inoreader http://ift.tt/1ooAKEh
via IFTTT

Clinical impact of circulating microRNAs as blood-based marker in childhood acute lymphoblastic leukemia

Abstract

Aberrant microRNA (miRNA) expression participates in childhood acute lymphoblastic leukemia (ALL). This study aimed to investigate the expression of miRNA-100, miRNA-196a, and miRNA-146a among childhood ALL and study their correlation with other hematological parameters and different phenotypes. Peripheral blood mononuclear cells (PMNCs) were obtained from 85 childhood ALL and 25 healthy children for the detection of miRNA expression using quantitative real-time PCR. Significant higher median levels were reported for ALL compared to control children. The diagnostic efficacy for miRNA-146a was superior as both sensitivity and specificity were absolute. A significant correlation was observed between higher expression of miRNA-100 and lower platelet and lymphocyte counts; high expression of miRNA-146a showed significant correlation with low total leukocyte count (TLC) and lymphocyte counts. Significant relation was reported between studied miRNAs and different phenotyping. miRNA-100, miRNA-196a, and miRNA-146a have significant role in childhood ALL leukemogenesis, and they may be useful as biological diagnostic molecular markers.

from Cancer via ola Kala on Inoreader http://ift.tt/1TQdzP0
via IFTTT

β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases

Abstract

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01–0.56) and high Ki67 (HR 3.68, 95 % CI 1.12–12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11–5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02–4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.

from Cancer via ola Kala on Inoreader http://ift.tt/1Rn6Ew2
via IFTTT

Prediction of anticancer molecules using hybrid model developed on molecules screened against NCI-60 cancer cell lines

Abstract

Background

In past, numerous quantitative structure-activity relationship (QSAR) based models have been developed for predicting anticancer activity for a specific class of molecules against different cancer drug targets. In contrast, limited attempt have been made to predict the anticancer activity of a diverse class of chemicals against a wide variety of cancer cell lines. In this study, we described a hybrid method developed on thousands of anticancer and non-anticancer molecules tested against National Cancer Institute (NCI) 60 cancer cell lines.

Results

Our analysis of anticancer molecules revealed that majority of anticancer molecules contains 18–24 carbon atoms and are dominated by functional groups like R₂NH, R₃N, ROH, RCOR, and ROR. It was also observed that certain substructures (e.g., 1-methoxy-4-methylbenzene, 1-methoxy benzene, Nitrobenzene, Indole, Propenyl benzene) are more abundant in anticancer molecules. Next, we developed anticancer molecule prediction models using various machine-learning techniques and achieved maximum matthews correlation coefficient (MCC) of 0.81 with 90.40 % accuracy using support vector machine (SVM) based models. In another approach, a novel similarity or potency score based method has been developed using selected fragments/fingerprints and achieved maximum MCC of 0.82 with 90.65 % accuracy. Finally, we combined the strength of above methods and developed a hybrid method with maximum MCC of 0.85 with 92.47 % accuracy.

Conclusions

We developed a hybrid method utilizing the best of machine learning and potency score based method. The highly accurate hybrid method can be used for classification of anticancer and non-anticancer molecules. In order to facilitate scientific community working in the field of anticancer drug discovery, we integrate hybrid and potency method in a web server CancerIN. This server provides various facilities that includes; virtual screening of anticancer molecules, analog based drug design, and similarity with known anticancer molecules (http://ift.tt/1Rn6DbA).

from Cancer via ola Kala on Inoreader http://ift.tt/1V1Iczj
via IFTTT

Tumor slice culture system to assess drug response of primary breast cancer

Abstract

Background

The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary treatment that would mainly result in the unwanted side effects of the therapy. This selection can be facilitated by characterization of individual tumors using robust and specific functional assays, which requires development of powerful ex vivo culture systems and procedures to analyze the response to treatment.

Methods

We optimized culture methods for primary breast tumor samples that allowed propagation of tissue ex vivo. We combined several tissue culture strategies, including defined tissue slicing technology, growth medium optimization and use of a rotating platform to increase nutrient exchange.

Results

We could maintain tissue cultures for at least 7 days without losing tissue morphology, viability or cell proliferation. We also developed methods to determine the cytotoxic response of individual tumors to the chemotherapeutic treatment FAC (5-FU, Adriamycin [Doxorubicin] and Cyclophosphamide). Using this tool we designated tumors as sensitive or resistant and distinguished a clinically proven resistant tumor from other tumors.

Conclusion

This method defines conditions that allow ex vivo testing of individual tumor responses to anti-cancer drugs and therefore might improve personalization of breast cancer treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/1Rn6Dbs
via IFTTT

Using gene expression from urine sediment to diagnose prostate cancer: development of a new multiplex mRNA urine test and validation of current biomarkers

Abstract

Background

Additional accurate non-invasive biomarkers are needed in the clinical setting to improve prostate cancer (PCa) diagnosis. Here we have developed a new and improved multiplex mRNA urine test to detect prostate cancer (PCa). Furthermore, we have validated the PCA3 urinary transcript and some panels of urinary transcripts previously reported as useful diagnostic biomarkers for PCa in our cohort.

Methods

Post-prostatic massage urine samples were prospectively collected from PCa patients and controls. Expression levels of 42 target genes selected from our previous studies and from the literature were studied in 224 post-prostatic massage urine sediments by quantitative PCR. Univariate logistic regression was used to identify individual PCa predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination was measured by ROC curve AUC for both, our model and the previously published biomarkers.

Results

Seven of the 42 genes evaluated (PCA3, ELF3, HIST1H2BG, MYO6, GALNT3, PHF12 and GDF15) were found to be independent predictors for discriminating patients with PCa from controls. We developed a four-gene expression signature (HIST1H2BG, SPP1, ELF3 and PCA3) with a sensitivity of 77 % and a specificity of 67 % (AUC = 0.763) for discriminating between tumor and control urines. The accuracy of PCA3 and previously reported panels of biomarkers is roughly maintained in our cohort.

Conclusions

Our four-gene expression signature outperforms PCA3 as well as previously reported panels of biomarkers to predict PCa risk. This study suggests that a urinary biomarker panel could improve PCa detection. However, the accuracy of the panels of urinary transcripts developed to date, including our signature, is not high enough to warrant using them routinely in a clinical setting.

from Cancer via ola Kala on Inoreader http://ift.tt/1V1IaaU
via IFTTT

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia – can findings from animal models be translated to humans?

Abstract

Background

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research.

Discussion

A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically.

Summary

More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

from Cancer via ola Kala on Inoreader http://ift.tt/1Rn6AN5
via IFTTT

A pharmacogenetic pilot study reveals MTHFR , DRD3 , and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

Abstract

Background

The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes.

Methods

A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay.

Results

Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype.

Conclusion

Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers.

Trial registration

Australian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.

from Cancer via ola Kala on Inoreader http://ift.tt/1V1Ibvh
via IFTTT

Distress experienced during pediatric VCUGs – a granular, prospective assessment using the brief behavioral distress scale

Abstract

Background

In spite of decades of experience with the procedure, controversy persists as to the overall distress experienced by children and the routine need for sedation in children undergoing voiding cystourethrograms (VCUG). Many studies have attempted to address these issues, often divided into one camp that champions routine sedation while another group believes that pretest preparation is often all that is needed. At the root of these issues are some of the limitations of previous studies as most incorporate inherently subjective parental questionnaires to determine distress levels rather than using an objective, unbiased observer.

Objective

The objective of this study is to use a validated and reliable tool (the brief behavioral distress scale) to objectively evaluate the distress experienced during VCUGs.

Materials and methods

A prospective study of 26 children (ages 3-7 years old) was performed by the pediatric radiology department at a large urban academic medical center. Patients were evaluated for distress during 12 separate VCUG steps beginning with the patient entering the room and ending with the clothing being replaced at study completion.

Results

Using a general linear model (repeated measures analysis of variance (ANOVA)), significant distress was identified during two phases of the examination, catheter insertion (P-values ranging <0.001-0.19) and the full bladder phase (P-values ranging 0.005-0.043). The mean distress score for catheter insertion (mean: 1.38, standard deviation [SD]: 1.098) was nearly three times higher than the next most distressful step, i.e. full bladder (mean: 0.65, SD: 0.745). Additionally, entering the room was perceived as significantly more distressing than the catheter out (P = 0.016) and clothing replacement phase (P = 0.006).

Conclusion

We find that despite there being significantly increased distress during the catheter insertion and full bladder phases, the distress levels during VCUGs are markedly less than in previous reports. Even the most distressful stage, catheterization, was less stressful than previously reported with levels closer to that of minor distress evinced by comfort-seeking behavior from a parent rather than more significant distress resulting in screaming. Our findings corroborate and expand on the conclusion of the effectiveness of pretest preparation and child life specialist involvement.

from Cancer via ola Kala on Inoreader http://ift.tt/1RmZSqa
via IFTTT

Imaging assessment of patellar instability and its treatment in children and adolescents

Abstract

Transient patellar dislocation is a common entity in children and adolescents, characterized by lateral dislocation of the patella, usually with spontaneous reduction. Many predisposing conditions have been described, including trochlear dysplasia, excessive lateral patellar tilt, patella alta and lateralization of the tibial tuberosity. Associated injuries are bone bruises of the patella and lateral femoral condyle, tears of the medial retinaculum that include the medial patellofemoral ligament (MPFL), tears of the vastus medialis obliquus muscle, injuries of articular cartilage, and intra-articular bodies. Children who are refractory to conservative management, have a large cartilage defect, or are at substantial risk for recurrent dislocations are candidates for surgical procedures to prevent future dislocations. Procedures can include MPFL repair or reconstruction, tibial tubercle repositioning and lateral retinacular release. The purpose of this review is to illustrate the imaging findings of transient patellar dislocation in the acute setting, the normal imaging appearance after surgical intervention, and post-surgical complications.

from Cancer via ola Kala on Inoreader http://ift.tt/1PjkIEm
via IFTTT

High dose rate brachytherapy for prostate cancer: Standard of care and future direction

Publication date: Available online 8 February 2016
Source:Cancer/Radiothérapie
Author(s): N. Thiruthaneeswaran, P.J. Hoskin




from Cancer via ola Kala on Inoreader http://ift.tt/1QpVUsa
via IFTTT

Méningite carcinomateuse : le point de vue de l’oncologue radiothérapeute

Publication date: Available online 8 February 2016
Source:Cancer/Radiothérapie
Author(s): S. Espenel, A. Vallard, J. Langrand-Escure, M. Ben Mrad, B. Méry, R. Rivoirard, G. Moriceau, J.-B. Guy, J.-C. Trone, C. Moncharmont, G. Wang, P. Diao, É. Bernichon, É. Chanal, P. Fournel, N. Magné




from Cancer via ola Kala on Inoreader http://ift.tt/23VnHun
via IFTTT

Radiothérapie des chloromes ou sarcomes granulocytiques : revue de la littérature

Publication date: Available online 8 February 2016
Source:Cancer/Radiothérapie
Author(s): S. Yossi, S. de Talhouet, S. Ducastelle-Leprêtre, A. Hassouni, G. Pigné, I. Selmaji, H. Samlali, M. Ginoux, I. Caraivan, A. d'Hombres




from Cancer via ola Kala on Inoreader http://ift.tt/1QpVS3e
via IFTTT

Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget’s disease

Summary

Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.

from Cancer via ola Kala on Inoreader http://ift.tt/1QTiOuv
via IFTTT

Correction: Image guided dose escalated prostate radiotherapy: still room to improve

We regret to report that a proofreading error caused an incorrect legend and description of the contents of table 6 to appear in our original publication of this work. The correct description of table 6 is: Un...

from Cancer via ola Kala on Inoreader http://ift.tt/20mOCKP
via IFTTT

Extraneural metastases from cranial meningioma: a case report

Extracranial metastases from brain meningiomas is a rare, but well-documented entity. Metastases occur mostly in the lungs, pleura and liver, but may also affect lymph nodes and bones. We report here on a pati...

from Cancer via ola Kala on Inoreader http://ift.tt/20mOACE
via IFTTT

Peripheral blood complete remission after splenic irradiation in Mantle-Cell Lymphoma with 11q22-23 deletion and ATM inactivation

Mantle Cell Lymphoma (MCL) is a well-known histological and clinical subtype of B-cell non-Hodgkin's Lymphomas. It is usually characterized by an aggressive disease course, presenting with advanced stage disea...

from Cancer via ola Kala on Inoreader http://ift.tt/1Rn06hc
via IFTTT

A prospective study of differences in duodenum compared to remaining small bowel motion between radiation treatments: Implications for radiation dose escalation in carcinoma of the pancreas

As a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/20mOAmq
via IFTTT

Why "Radiation Oncology"

Radiotherapy continues to be a major treatment for solid tumours and is a cornerstone of modern oncology. The term 'radiation oncology' describes the integration of radiation therapy into the complexity of mul...

from Cancer via ola Kala on Inoreader http://ift.tt/1Rn03Sr
via IFTTT

Icariside II inhibits the EMT of NSCLC cells in inflammatory microenvironment via down-regulation of Akt/NF-κB signaling pathway

Inflammatory microenvironment created by immune cells is favorable for tumor metastasis. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in inflammatory microenvironment. In this study, we sought to investigate the effects of Icariside II, a flavonol glycoside isolated from Epimedium koreanum Nakai, on A549 and H1299 cells migration in inflammatory microenvironment. At non-cytotoxic concentrations, Icariside II could inhibit invasion and EMT of A549 and H1299 cells induced by LPS-stimulated-THP-1 medium or by pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Exposure to Icariside II resulted in the increment of E-cadherin, accompanied with decrement of N-cadherin, vimentin, Slug, and Snail in A549 and H1299 cells stimulated by TNF1α. Furthermore, Icariside II suppressed TNF-α-triggered nuclear translocation of NF-κB and phosphorylation of IκBα, and repressed the DNA-binding activity of NF-κB. Further data demonstrated that Akt/GSK-3β, other than MAPK signaling pathway was taking a part in the inhibitory potential of Icariside II on NF-κB activation. Importantly, Icariside II also impeded lung metastasis of A549 cells and EMT in nude mice. In conclusion, Icariside II might prohibit invasion through inactivating Akt/NF-κB pathway. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1RmKudn
via IFTTT

Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin

Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12-myristate 13-acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1nVY4Zw
via IFTTT

First trimester human placenta prevents breast cancer cell attachment to the matrix: The role of extracellular matrix

The extracellular matrix (ECM) affects cancer cell characteristics. Its detachment from the ECM induces cell apoptosis, termed anoikis. Cancer cells can develop anoikis resistance, a necessary step for metastasis, by switching integrins, over-expressing growth factor receptors, and inducing epithelial mesenchymal transition (EMT). The placenta is a non-supportive microenvironment for cancer cells. We showed that breast cancer cells (BCCL) were eliminated from placental implantation sites. During implantation, the placenta manipulates its surrounding matrix, which may induce BCCL elimination. Here, we explored the effect of placenta-induced ECM manipulations on BCCL. During experiments, BCCL (MCF-7/T47D) were cultured on placenta/BCCL-conditioned ECM (Matrigel used for first trimester placenta/BCCL culture and cleared by NH₄OH). After culturing the cells, we analyzed cancer cell phenotype (death, count, aggregation, MMP) and signaling (microarray analysis and pathway validation). We found that the BCCL did not attach to previous placental implantation sites and instead, similarly to anoikis-resistant cells, migrated away, displayed increased MMP levels/activity, and formed aggregates in distant areas. T47D were less affected than the MCF-7 cells, since MCF-7 also showed modest increases in cell death, EMT, and increased proliferation. Microarray analysis of the MCF-7 highlighted changes in the integrin, estrogen, EGFR, and TGFβ pathways. Indeed, placental ECM reduced ERα, induced Smad3/JNK phosphorylation and increased integrin-α5 expression (RGD-dependent integrin) in the BCCL. Addition of RGD or TGFβR/JNK inhibitors reversed the phenotypic changes. This study helps explain the absence of metastases to the placenta and why advanced cancer is found in pregnancy, and provides possible therapeutic targets for anoikis-resistant cells. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1Xgy8E1
via IFTTT