BCOR Internal Tandem Duplications in Clear Cell Sarcoma of the Kidney

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Roles of N-Myc and STAT Interactor in Cancer: From Initiation to Dissemination

Abstract

N-myc & STAT Interactor, NMI, is a protein that has mostly been studied for its physical interactions with transcription factors that play critical roles in tumor growth, progression, and metastasis. NMI is an inducible protein, thus its intracellular levels and location can vary dramatically, influencing a diverse array of cellular functions in a context-dependent manner. The physical interactions of NMI with its binding partners have been linked to many aspects of tumor biology including DNA damage response, cell death, epithelial-to-mesenchymal transition, and stemness. Thus, discovering more details about the function(s) of NMI could reveal key insights into how transcription factors like c-Myc, STATs, and BRCA1 are contextually regulated. Although a normal, physiological function of NMI has not yet been discovered, it has potential roles in pathologies ranging from viral infection to cancer. This review provides a timely perspective of the unfolding roles of NMI with specific focus on cancer progression and metastasis. This article is protected by copyright. All rights reserved.

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The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer

Abstract

Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer (CRC). Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined. In this study, we investigated the relationships between the serum levels of thirteen cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in a prospectively recruited group of 147 CRC patients. There were strong positive correlations between the serum concentrations of different cytokines, as well as between the different types of tumor infiltrating immune cells, whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak. High serum IL-12 levels associated with increased densities of peritumoral CD8⁺ T cells, intraepithelial CD3⁺ T cells, and intratumoral neutrophils, while high serum CCL4 levels associated with increased densities of peritumoral CD68⁺ cells. In multivariate survival models, increased infiltration of intraepithelial CD3⁺ T cells and increased serum CCL4 associated with improved DFS, whereas higher intratumoral CD83⁺ dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS. Also high density of peritumoral CD3⁺ T cells associated with improved CSS. In conclusion, serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intra-group correlations but relatively weak inter-group correlations. The results suggest that tumor infiltrating CD3⁺ T cells, CD83⁺ dendritic cells, serum CCL4, and serum interferon gamma represent relevant markers of disease outcome. This article is protected by copyright. All rights reserved.

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TERT promoter mutations in melanoma survival

Abstract

Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at risk primary melanoma patients. In this study we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. DNA from 300 patients with stage I/II melanoma was sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression free and melanoma specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease free and melanoma specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease free survival was 2.25 (95%CI 1.2-4.4) and for melanoma specific survival 5.8 (95%CI 1.8-18.1). The effect of the mutations on melanoma-specific survival in non-carriers of variant allele of the polymorphism was significant (HR 4.4, 95%CI 1.3-14.9) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.4, 95%CI 0.1-0.9). The data in this study provides preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter. This article is protected by copyright. All rights reserved.

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PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells

ABSTRACT

The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma . Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G, and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway. This article is protected by copyright. All rights reserved.

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Prospective Study Links HPV Detection in the Mouth to Head and Neck Cancer

In a new study, researchers have confirmed that infection with human papillomavirus (HPV) 16 precedes the development of head and neck cancer. Previous studies have established an association between HPV-16 infection and oropharyngeal cancer, a type of head and neck cancer. The new study is the first to do so using samples collected from participants prior to their cancer diagnosis.

The study also reported, for the first time, an association between head and neck cancer risk and infection with HPV types other than HPV 16.

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Brain tumour differentiation: rapid stratified serum diagnostics via attenuated total reflection Fourier-transform infrared spectroscopy

Abstract

The ability to diagnose cancer rapidly with high sensitivity and specificity is essential to exploit advances in new treatments to lead significant reductions in mortality and morbidity. Current cancer diagnostic tests observing tissue architecture and specific protein expression for specific cancers suffer from inter-observer variability, poor detection rates and occur when the patient is symptomatic. A new method for the detection of cancer using 1 μl of human serum, attenuated total reflection—Fourier transform infrared spectroscopy and pattern recognition algorithms is reported using a 433 patient dataset (3897 spectra). To the best of our knowledge, we present the largest study on serum mid-infrared spectroscopy for cancer research. We achieve optimum sensitivities and specificities using a Radial Basis Function Support Vector Machine of between 80.0 and 100 % for all strata and identify the major spectral features, hence biochemical components, responsible for the discrimination within each stratum. We assess feature fed-SVM analysis for our cancer versus non-cancer model and achieve 91.5 and 83.0 % sensitivity and specificity respectively. We demonstrate the use of infrared light to provide a spectral signature from human serum to detect, for the first time, cancer versus non-cancer, metastatic cancer versus organ confined, brain cancer severity and the organ of origin of metastatic disease from the same sample enabling stratified diagnostics depending upon the clinical question asked.

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Non-oncology physician visits after diagnosis of cancer in adolescents and young adults

Abstract

Purpose

Health care needs of adolescents and young adults (AYAs) with cancer are probably different from other age groups. Studying their non-oncology physician visits in the first years after diagnosis may provide insight into the specific health problems AYA patients experience and thereby help to improve care for these patients.

Methods

Seven hundred seventy-four AYAs identified from a Canadian provincial registry diagnosed with cancer between ages 15 and 24 years in 1991/2001 were included, matched by birth year and sex to ten controls. Based on provincial health insurance plan records, we determined the number of family physician and non-cancer specialist visits in the 5 years after diagnosis (for patients) or inclusion (for controls).

Results

The percentage of patients visiting a non-cancer specialist decreased from 96 to 49 % over the 5-year period. The percentage visiting a family physician decreased from 96 to 84 %. Visits in all years were significantly higher than among controls. In the first year after diagnosis, many patients visited a non-cancer specialist or a family physician for neoplasm-related health problems (77 and 55 %, respectively). In addition, family physicians were also consulted for general age-specific problems, such as genitourinary symptoms

Conclusions

In the first years after diagnosis of cancer in AYAs, both non-cancer specialist and family physician visits are common, although non-cancer specialist visits are less common and decline considerably faster than in younger children.

Implications for Cancer Survivors

The specific pattern of physician visits of this age group calls for care that is tailored to their specific needs.

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Computational prediction of Mycoplasma hominis proteins targeting in nucleus of host cell and their implication in prostate cancer etiology

Abstract

Cancer has long been assumed to be a genetic disease. However, recent evidence supports the enigmatic connection of bacterial infection with the growth and development of various types of cancers. The cause and mechanism of the growth and development of prostate cancer due to Mycoplasma hominis remain unclear. Prostate cancer cells are infected and colonized by enteroinvasive M. hominis, which controls several factors that can affect prostate cancer growth in susceptible persons. We investigated M. hominis proteins targeting the nucleus of host cells and their implications in prostate cancer etiology. Many vital processes are controlled in the nucleus, where the proteins targeting M. hominis may have various potential implications. A total of 29/563 M. hominis proteins were predicted to target the nucleus of host cells. These include numerous proteins with the capability to alter normal growth activities. In conclusion, our results emphasize that various proteins of M. hominis targeted the nucleus of host cells and were involved in prostate cancer etiology through different mechanisms and strategies.

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Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review

Publication date: April 2016
Source:European Journal of Cancer, Volume 57
Author(s): Shlomit Strulov Shachar, Grant R. Williams, Hyman B. Muss, Tomohiro F. Nishijima
BackgroundBody composition plays an important role in predicting treatment outcomes in adults with cancer. Using existing computed tomographic (CT) cross-sectional imaging and readily available software, the assessment of skeletal muscle mass to evaluate sarcopenia has become simplified. We performed a systematic review and meta-analysis to quantify the prognostic value of skeletal muscle index (SMI) obtained from cross-sectional CT imaging on clinical outcomes in non-haematologic solid tumours.MethodsWe searched PubMed and the American Society Clinical Oncology online database of meeting abstracts up to October 2015 for relevant studies. We included studies assessing the prognostic impact of pre-treatment SMI on clinical outcomes in patients with non-haematologic solid tumours. The primary outcome was overall survival (OS) and the secondary outcomes included cancer-specific survival (CSS), disease-free survival (DFS), and progression-free survival (PFS). The summary hazard ratio (HR) and 95% confidence interval (CI) were calculated.ResultsA total of 7843 patients from 38 studies were included. SMI lower than the cut-off was associated with poor OS (HR = 1.44, 95% CI = 1.32–1.56, p < 0.001). The effect of SMI on OS was observed among various tumour types and across disease stages. Worse CSS was also associated with low SMI (HR = 1.93, 95% CI = 1.38–2.70, p < 0.001) as well as DFS (HR = 1.16, 95% CI = 1.00–1.30, p = 0.014), but not PFS (HR = 1.54, 95% CI = 0.90–2.64, p = 0.117).ConclusionsThis meta-analysis demonstrates that low SMI at cancer diagnosis is associated with worse survival in patients with solid tumours. Further research into understanding and mitigating the negative effects of sarcopenia in adults with cancer is needed.



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Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial

Publication date: Available online 13 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ling-Wei Wang, Yi-Wei Chen, Ching-Yin Ho, Yen-Wan Hsueh Liu, Fong-In Chou, Yuan-Hao Liu, Hong-Ming Liu, Jinn-Jer Peir, Shiang-Huei Jiang, Chi-Wei Chang, Ching-Sheng Liu, Ko-Han Lin, Shyh-Jen Wang, Pen-Yuan Chu, Lo-Wen Liang, Shou-Yen Kao, Sang-Hue Yen
Purpose/ObjectivesTo investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H & N) cancer following photon radiotherapy.MethodsIn this prospective phase I/II trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue (T/N) ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively.ResultsSeventeen patients with a previous cumulative radiation dose of 63–165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median T/N ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range = 5.2–52 mo), 6 participants exhibited a complete response (CR) and 6 exhibited a partial response. Regarding the acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding the late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67 %) receiving total D80 >40 Gy-Eq procured a CR. Two-year overall survival was 47%. Two-year locoregional control was 28 %.ConclusionsOur results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H & N cancer. Modifications to our protocol may yield more satisfactory results in the future.

Teaser

To investigate the efficacy and safety of boron neutron capture therapy (BNCT), we treated 17 patients with recurrent head and neck (H & N) cancer following photon radiotherapy in a prospective phase I/II trial started in 2010. Two-fraction BNCT with intravenous L-boronophenylalanine at a 28-day interval was conducted. The total response rate was 71%, including 6 complete responses. Toxicity was acceptable. BNCT may be a treatment choice for locally recurrent H & N cancer.


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An assessment of intrafraction breathing motion on left anterior descending artery dose during left-sided breast radiation therapy

Publication date: Available online 13 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Omar El-Sherif, Edward Yu, Ilma Xhaferllari, Stewart Gaede

Teaser

Using four-dimensional computed tomography and deformable dose accumulation, we assessed the variation caused by breathing motion in the estimated dose to the heart, left-ventricle, and left anterior descending artery (LAD) of left-sided breast cancer patients. The LAD showed substantial variation (± 8.7 Gy) in dose due to breathing. In light of this, we suggest the use of 4D-CT and dose accumulation for future clinical studies looking at the relationship between LAD dose and cardiac toxicity.


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A Randomized Clinical Trial Comparing Proton Beam Radiotherapy to Transarterial Chemoembolization for Hepatocellular Carcinoma - Results of an Interim Analysis

Publication date: Available online 13 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): David A. Bush, Jason C. Smith, Jerry D. Slater, Michael L. Volk, Mark E. Reeves, Jason Cheng, Roger Grove, Michael E. de Vera
ObjectiveThis prospective randomized clinical trial was developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma (HCC). This report describes results of a planned interim analysis.MethodsEligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria. Patients were randomly assigned to transarterial chemoembolization (TACE) or to proton beam radiotherapy. Patients randomized to TACE received at least one TACE with additional TACE for persistent disease. Proton beam radiotherapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks. Primary endpoint was progression-free survival, with secondary endpoints of overall survival, local tumor control and treatment-related toxicities as represented by post-treatment days of hospitalization.ResultsAt the time of this analysis 69 subjects were available for analysis. 36 were randomized to TACE and 33 to proton. Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days respectively (p<0.001). Ten TACE and 12 proton patients underwent liver transplantation following treatment. Viable tumor identified in the explanted livers following TACE/proton averaged 2.4 and 0.9 cm respectively. Pathologic complete response following TACE/ proton was 10%/25% (p=o.38). The 2-year overall survival for all patients was 59% with no difference between treatment groups. Median survival time was 30 months (95%CI - 20.7-39.3 months). There was a trend toward improved 2-year local tumor control (88% vs. 45%, p=0.06) and progression-free survival (48% vs. 31%, p=0.06) favoring the proton beam treatment group.ConclusionThis interim analysis indicates similar overall survival rates for proton beam radiotherapy and TACE. There is a trend toward improved local tumor control and progression-free survival with proton beam. There are significantly fewer hospitalization days following proton treatment that may indicate reduced toxicity with proton beam therapy.

Teaser

Proton therapy and TACE were compared in a randomized clinical trial for patients with HCC. An interim analysis revealed a trend toward improved LC and PFS while significantly reducing number of days patients were hospitalized within 30 days of treatment. There was no difference in OS between groups with a median survival of 30 months. Proton therapy showed tumor down-staging at transplant. This early reports suggests that proton therapy may be effective therapy for HCC.


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Acute toxicity and quality of life in patients with prostate cancer treated with protons or carbon ions in a prospective randomized phase II study – the IPI trial

Publication date: Available online 12 February 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gregor Habl, Matthias Uhl, Sonja Katayama, Kerstin A. Kessel, Gencay Hatiboglu, Boris Hadaschik, L. Edler, Diana Tichy, Malte Ellerbrock, Thomas Haberer, Maja B. Wolf, Heinz-Peter Schlemmer, Jürgen Debus, Klaus Herfarth
BackgroundTo evaluate safety and feasibility of primary hypofractionated raster-scanned irradiation of the prostate with protons and carbon ions in a prospective randomized phase II trial.Methods and MaterialsIn this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized either to protons (arm A) or carbon ions (arm B) and treated with a total dose of 66 Gy(RBE) administered in 20 fractions (single dose of 3.3 Gy(RBE). Patients were stratified by the use of antihormonal therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, PSA-progression free survival (PSA-PFS), overall survival (OS) and quality-of-life (QoL).Results91 patients completed therapy with a median follow-up of 22.3 months. Among acute genitourinary toxicities, cystitis rates were 34.1% (A: 39.1%, B: 28.9%) grade 1 and 17.6% (A: 21.7%, B: 13.3%) grade 2. Seven patients (8%) required urinary catheterization during treatment due to urinary retention, of whom five were in arm A. Regarding acute gastrointestinal toxicities, two patients treated with protons developed a rectum fistula of grade 3. Radiation proctitis occurred in 12.1% (A: 13.0%, B: 11.1%) as grade 1 and in 5.5% (A: 8.7%, B: 2.2%) as grade 2. No statistically significant differences in the toxicity profiles regarding both arms were found. QoL was mainly reduced regarding fatigue, pain and urinary symptoms during therapy and six weeks thereafter. All EORTC QLQ-C30 and -PR25 scores improved during follow-up.ConclusionHypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and might be safe. Due to the occurrence of gel in the rectum wall and the consecutive occurrence of two rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS.

Teaser

To gain data for hypofractionated irradiation of the prostate with protons and carbon ions in an active raster scan technique the IPI trial (n = 92) was initiated. Primary endpoint was the assessment of safety and feasibility. Secondary endpoints were PSA-progression free survival (PSA-PFS), overall survival (OS) and quality-of-life (QoL). We could show that treatment with protons and carbon ions was safe and feasible with comparable acute toxicities and QoL parameters


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Killer-cell immunoglobulin-like receptor genes and ligands and their role in hematologic malignancies

Abstract

Natural killer (NK) cells are considered crucial for the elimination of emerging tumor cells. Effector NK-cell functions are controlled by interactions of inhibitory and activating killer-cell immunoglobulin-like receptors (KIRs) on NK cells with human leukocyte antigen (HLA) class I ligands on target cells. KIR and HLA are highly polymorphic genetic systems segregating independently, creating a great diversity in KIR/HLA gene profiles in different individuals. There is an increasing evidence supporting the relevance of KIR and HLA ligand gene background for the occurrence and outcome of certain cancers. However, the data are still controversial and the mechanisms of receptor-ligand mediated NK-cell action remain unclear. Here, the main characteristics and functions of KIRs and their HLA class I ligands are reviewed. In addition, we review the HLA and KIR correlations with different hematological malignancies and discuss our current understanding of the biological significance and mechanisms underlying these associations.

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Attitudes towards the Faecal Occult Blood Test (FOBT) versus the Faecal Immunochemical Test (FIT) for colorectal cancer screening: perceived ease of completion and disgust

Abstract

Background

Colorectal cancer screening is key to early detection and thus to early treatment, but uptake is often sub-optimal, particularly amongst lower income groups. It is proposed that the imminent introduction of the single-sample Faecal Immunochemical Test (FIT) in Scotland may lead to increased uptake as compared to the current Faecal Occult Blood Test (FOBT), but underlying reasons are yet to be determined. The aim was to evaluate attitudes and intentions towards completing the FIT compared to the current FOBT for colorectal cancer screening.

Methods

A convenience sample of 200 adults (mean age 56.5, range 40–89; 59 % female) living in Scotland rated both the FOBT and the FIT with regard to ease of completion, perceived disgust and intention to complete and return (all measured on Likert-type 1–7 scale). Participants were randomised to be presented (via a face-to-face contact) with either the FIT or FOBT first.

Results

Participants reported higher intention to complete and return the FIT versus the FOBT (mean difference 0.62, 95 % CI (0.44, 0.79)). Overall, 85.0 % (n = 170) of participants agreed or strongly agreed that they would intend to complete and return the FIT compared to 65.5 % (n = 131) for the FOBT (χ² = 20.4, p < .001). The FIT was also perceived to be easier to complete (mean difference 0.85, 95 % CI (0.70, 1.01) and much less disgusting (mean difference 1.11, 95 % CI (0.94, 1.27)). Lower perceived disgust, higher socio-economic status and previous participation in any cancer screening were significant predictors of intention to complete the FOBT, whilst only higher perceived ease of completion predicted intention to complete the FIT.

Conclusions

People reported higher intentions to complete and return a FIT than a FOBT test for colorectal cancer screening, largely due to a perception that it is easier and less disgusting to complete. The findings suggest that the introduction of the FIT as standard in the UK could result in a notable increase in screening uptake.

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LJNK, an indoline-2,3-dione-based aminopeptidase N inhibitor with promising antitumor potency.

In our previous study, we found that LJNK showed potent aminopeptidase N (APN)-inhibitory activity. In the current study, we further evaluated the antitumor effects of LJNK both in vitro and in vivo. Enzyme experiments showed that LJNK showed better inhibitory activity than bestatin against APN both from human carcinoma cells' surface and from porcine kidney microsomes. In addition, LJNK could suppress rat aortic ring microvessel growth and HUVEC tubular structure formation, which showed its stronger antiangiogenesis effects than bestatin. [(3-[4,5-Dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide)] assay and clonogenic assay showed that LJNK suppressed cancer cell growth both in the short and the long term. Mice bearing H22 transplantation tumor proved its antitumor effects in vivo. Annexin V-fluorescein isothiocyanate/propidium iodide assay showed that LJNK could induce 28.1% PLC/PRF/5 cell apoptosis and the apoptotic pathway was probably identified by western blot. The above-mentioned results suggested that LJNK inhibited cell proliferation and angiogenesis, and induced apoptosis by decreasing APN activity. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Liver X receptor as a drug target for the treatment of breast cancer.

Liver X receptor (LXR) has been exploited widely as a drug target in breast cancer treatment, and various mechanisms underlying the effects of LXR in this area are well studied. The activated LXR plays important roles in estrogen receptor [alpha] (ER[alpha])- breast cancer cells, such as reducing cell proliferation and arresting cell cycle progression. Different LXR ligands have diverse effects on the development of breast cancer, such as the inhibitory effect of oxysterol, which can return cells to normocholesterol conditions and target other metabolic genes. Moreover, 27-hydroxycholesterol, a locally produced cholesterol metabolite, reportedly promotes the proliferation of ER[alpha]+ breast cancer cells in vitro and facilitates tumor metastasis with other LXR ligands. Moreover, the expression of LXR also exerts potential effects on immune surveillance, tumor immunity, and tumor microenvironment. These advances in breast cancer research indicate that LXR may be a new therapeutic target to treat the refractory or drug-resistant subtypes of breast cancer. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Ultraviolet-A triggers photoaging in model nematode Caenorhabditis elegans in a DAF-16 dependent pathway

Abstract

Ultraviolet radiations (UV) are the primary causative agent for skin aging (photoaging) and cancer, especially UV-A. The mode of action and the molecular mechanism behind the damages caused by UV-A is not well studied, in vivo. The current study was employed to investigate the impact of UV-A exposure using the model organism, Caenorhabditis elegans. Analysis of lifespan, healthspan, and other cognitive behaviors were done which was supported by the molecular mechanism. UV-A exposure on collagen damages the synthesis and functioning which has been monitored kinetically using engineered strain, col-19:: GFP. The study results suggested that UV-A accelerated the aging process in an insulin-like signaling pathway dependent manner. Mutant (daf-2)-based analysis concrete the observations of the current study. The UV-A exposure affected the usual behavior of the worms like pharyngeal movements and brood size. Quantitative PCR profile of the candidate genes during UV-A exposure suggested that continuous exposure has damaged the neural network of the worms, but the mitochondrial signaling and dietary restriction pathway remain unaffected. Western blot analysis of HSF-1 evidenced the alteration in protein homeostasis in UV-A exposed worms. Outcome of the current study supports our view that C. elegans can be used as a model to study photoaging, and the mode of action of UV-A-mediated damages can be elucidated which will pave the way for drug developments against photoaging.

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Does VEGF facilitate local tumor growth and spread into the abdominal cavity by suppressing endothelial cell adhesion, thus increasing vascular peritoneal permeability followed by ascites production in ovarian cancer?

Abstract

Background

Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types.

Methods

Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition.

Results

VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5.

Conclusions

Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology may be associated with early dysregulation of vascular permeability leading to ascites. These patients may benefit from therapeutic VEGF inhibition.

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