Muscle catabolism in cancer and its attenuation by eicosapentaenic acid

This work examines skeletal muscle catabolism in cancer and its attenuation by Eicosapentaenoic Acid (EPA). In vivo studies in mice bearing a cachexia inducing murine colon adenocarcinoma - MAC16, demonstrated an elevation in the gastrocnemius muscle in the activity and expression of regulatory components of the ubiquitin-proteasome proteolytic pathway. This was accompanied by an accelerated loss of muscle tissue correlating with an increase in overall weight loss, all of which were attenuated by prior daily dosing with EPA. Recently a proteolysis inducing factor (PIF) has been isolated from the MAC16 tumour, and from the serum and urine of cachectic cancer patients. Previous studies have shown that PIF induces protein degradation in vitro, and that this is possibly mediated through 15-hydroxyeicosatetraenoic acid (15-HETE), a metabolite of the n-6 polyunsaturated fatty acid- arachidonate. Employing the murine myoblast cell line C2C12, it was shown that both PIF and 15-HETE increased protein degradation and expression of proteasome subunits, processes which were again attenuated by prior incubation in EPA. Similarly, in NMRI mice which had been fasted for 24hours, EPA and the lipoxygenase inhibitor CV-6504 (but not structurally related fatty acids) inhibited skeletal muscle proteolysis and expression of various proteasome subunits, showing that firstly, EPA may be anti-cachexic partly through its ability to influence 15-HETE production; and secondly that the effect is specific for EPA as other fatty acids had no effect. Previous studies have suggested the involvement of the signal transduction family NFKB in response to PIF in the liver. It has been demonstrated here that both PIF and 15-HETE increased nuclear translocation of NFKB in the skeletal muscle of tumour bearing mice and that EPA inhibited this process by its ability to prevent the degradation of the NFKB inhibitor protein IKB. When an NFKB inhibitor was added to C2C12 myotubes, prior to the addition of PIF, proteasome activity and protein degradation was inhibited, showing that NFKB is responsible for the increased proteasome activity and muscle catabolism induced by PIF. Taken together this work suggests that 15-hydroxyeicosatetraenoic acid is the intracellular mediator for PIF induced protein degradation in skeletal muscle and that elevated muscle catabolism is accomplished through an increased functioning of the ubiquitin-proteasome pathway, a process possibly mediated through an NFKB dependent mechanism. The anticachectic (and possibly the anti-tumourigenic) effects of EPA appear to be achieved in part by its ability to inhibit the degradation of IKB and possibly by its ability to interfere with 15-HETE production.

Studies of skin antisepsis and enhanced penetration of chlorhexidine

Current evidence-based guidelines recommend that 2% (w/v) chlorhexidine digluconate (CHG), preferentially in 70% (v/v) isopropyl alcohol (IIPA), is used for skin antisepsis prior to incision of the skin. In this current study, the antimicrobial efficacy of CHG, six essential oils [tea tree oil (TTO), thymol, eucalyptus oil (EO), juniper oil, lavender oil and citronella] and novel benzylidenecarboxamidrazone and thiosemicarbazone compounds were determined against a panel of microorganisms commonly associated with skin infection (Staphylococcus epidermidis, S. aureus, meticillin-resistant S. aureus, Propionibacterium acnes, Acinetobacter spp., Pseudomonas aeruginosa and Candida albicans) The results demonstrated synergistic activity of CHG in combination with EO against biofilm cultures of S. epidermidis, with significantly reduced concentrations of CHG and EO required to inhibit biofilm growth compared to CHG or EO alone. Skin permeation of CHG was subsequently investigated using an in vitro human skin model (Franz cell) and the penetration profile was determined by serial sectioning of the full thickness human skin. Two percent (w/v) CHG in aqueous solution and in 70% (v/v) IPA demonstrated poor skin permeation; however, the skin permeation was significantly enhanced in combination with 5% - 50% (v/v) EO. Detectable levels of CHG did not permeate through full thickness skin in 24 h. Skin permeation of 2% (w/v) CHG in 70% (v/v) IPA in the presence of 10% (v/v) EO was subsequently studied. The results demonstrated a significantly enhanced skin penetration of CHG after a 2 min application, with CHG detected at significant levels to a depth of 600 m with CHG in combination with EO and IPA compared to 100 m with IPA alone. Combination antisepsis comprising CHG and EO may be beneficial for skin antisepsis prior to invasive procedures to reduce the number of microorganisms on and within the skin due to enhanced skin penetration of CHG and improved efficacy against S. epidermidis in a biofilm mode of growth.

Renegotiating sexual intimacy in the context of altered embodiment:the experiences of women with breast cancer and their male partners following mastectomy and reconstruction

OBJECTIVE: Breast cancer diagnosis and treatments can have a profound impact upon women's well-being, body image, and sexual functioning, but less is known about the relational context of their coping and the impact upon their intimate partners. Our study focuses upon couples' experiences of breast cancer surgery, and its impact on body image and sexual intimacy. METHOD: Utilizing a dyadic design, we conducted 8 semistructured individual interviews, with 4 long-term heterosexual couples, after the women had undergone mastectomy with reconstruction. Interviews explored both partners' experiences of diagnosis, decision-making, and experiences of body image and sexual intimacy. Interpretative phenomenological analysis (IPA) was adopted; this is a qualitative research approach characterized by in-depth analysis of the personal meaning of experiences. RESULTS: Findings illustrate the positive acceptance that partners may express toward their wives' postsurgical bodies. They illuminate ways in which gendered coping styles and normative sexual scripts may shape couples' negotiations of intimacy around "altered embodiment." Reciprocal communication styles were important for couples' coping. The management of expectations regarding breast reconstruction may also be helpful. CONCLUSIONS: The insights from the dyadic, multiple perspective design suggest that psychologists must situate the meaning of supportive relationships and other protective factors in the context of complex life events and histories, in order to understand and support people's developing responses to distress. (PsycINFO Database Record

Development of micro immunosensors to study genomic and proteomic biomarkers related to cancer and Alzheimer's disease

A report from the National Institutes of Health defines a disease biomarker as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” Early diagnosis is a crucial factor for incurable disease such as cancer and Alzheimer’s disease (AD). During the last decade researchers have discovered that biochemical changes caused by a disease can be detected considerably earlier as compared to physical manifestations/symptoms. In this dissertation electrochemical detection was utilized as the detection strategy as it offers high sensitivity/specificity, ease of operation, and capability of miniaturization and multiplexed detection. Electrochemical detection of biological analytes is an established field, and has matured at a rapid pace during the last 50 years and adapted itself to advances in micro/nanofabrication procedures. Carbon fiber microelectrodes were utilized as the platform sensor due to their high signal to noise ratio, ease and low-cost of fabrication, biocompatibility, and active carbon surface which allows conjugation with biorecognition moieties. This dissertation specifically focuses on the detection of 3 extensively validated biomarkers for cancer and AD. Firstly, vascular endothelial growth factor (VEGF) a cancer biomarker was detected using a one-step, reagentless immunosensing strategy. The immunosensing strategy allowed a rapid and sensitive means of VEGF detection with a detection limit of about 38 pg/mL with a linear dynamic range of 0–100 pg/mL. Direct detection of AD-related biomarker amyloid beta (Aβ) was achieved by exploiting its inherent electroactivity. The quantification of the ratio of Aβ1-40/42 (or Aβ ratio) has been established as a reliable test to diagnose AD through human clinical trials. Triple barrel carbon fiber microelectrodes were used to simultaneously detect Aβ1-40 and Aβ1-42 in cerebrospinal fluid from rats within a detection range of 100nM to 1.2μM and 400nM to 1μM respectively. In addition, the release of DNA damage/repair biomarker 8-hydroxydeoxyguanine (8-OHdG) under the influence of reactive oxidative stress from single lung endothelial cell was monitored using an activated carbon fiber microelectrode. The sensor was used to test the influence of nicotine, which is one of the most biologically active chemicals present in cigarette smoke and smokeless tobacco.

Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:
Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.
METHODS:
A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.
RESULTS:
Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.
CONCLUSIONS:
In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis.

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.

PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.

RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.

CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Pleiotropic Analysis of Lung Cancer and Blood Triglycerides

Epidemiologically related traits may share genetic risk factors, and pleiotropic analysis could identify individual loci associated with these traits. Because of their shared epidemiological associations, we conducted pleiotropic analysis of genome-wide association studies of lung cancer (12 160 lung cancer case patients and 16 838 control subjects) and cardiovascular disease risk factors (blood lipids from 188 577 subjects, type 2 diabetes from 148 821 subjects, body mass index from 123 865 subjects, and smoking phenotypes from 74 053 subjects). We found that 6p22.1 (rs6904596, ZNF184) was associated with both lung cancer (P = 5.50x10(-6)) and blood triglycerides (P = 1.39x10(-5)). We replicated the association in 6097 lung cancer case patients and 204 657 control subjects (P = 2.40 × 10(-4)) and in 71 113 subjects with triglycerides data (P = .01). rs6904596 reached genome-wide significance in lung cancer meta-analysis (odds ratio = 1.15, 95% confidence interval = 1.10 to 1.21 ,: Pcombined = 5.20x10(-9)). The large sample size provided by the lipid GWAS data and the shared genetic risk factors between the two traits contributed to the uncovering of a hitherto unidentified genetic locus for lung cancer.

Comparison of Objectively and Subjectively Measured Sedentary Behavior in Men with Prostate Cancer and a History of Androgen-Deprivation Therapy Use

Thesis (Master's)--University of Washington, 2016-08

Easy preoperative planning of deeply located brain lesions using external skin reference and 3-Dimensional surface MRI

Open skull surgery of deeply located intracerebral lesions requires precise determination of the treatment area in 3-dimensional (3-D) space. 3-D MRI can give important additional information in presurgical determination of the surgical approach to the target, taking into account highly functional brain areas and important vascular structures. The day before surgery, a grid composed of 9 tubings intersecting at 90° at 1 cm intervals and filled with a Q1SO4 solution is firmly attached to the skin of the patient’s head in the presumed region of the craniotomy. A 3-D turbo-FLASH sequence is then performed in the sagittal plane after intravenous Gd-DOTA injection on a IT Magnetom. 3-D surface reconstruction of the cortical gyri and sulci is performed. Once the gyri are identified, the 3-D program is then implemented in order to perform a color display of the cortical veins and of the tumor boundaries. The surgical access is then chosen by the surgeon, taking into account highly functional areas. Finally, the boundaries of the tumor are projected on the cortex reconstruction and on the external reference placed on the skin. The entry place for surgery as well as the size of craniotomy are drawn on the skin and the tubed grid is removed. The accuracy of this method tested in 9 patients with deeply located brain tumors or arteriovenous malformations was very satisfactory. In daily practice, this method is a valuable technique providing important clinical information in determining the shortest and safest way through the brain tissue, decreasing possible functional deficit and reducing craniotomy size in cases of difficult to access deep brain areas. Our method does not require a stereotactic frame permanently fixed to the head of the patient during surgery. © 1994 S. Karger AG, Basel.

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians. In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of "cancer and fertility preservation". A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation. Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations.

Connections between Modern and Postmodern art and fashion.

This paper undertakes to construe the affinities and divergences in the genres of art and fashion throughout the 20th century through the use of particular visual and theoretical examples, examined at greater length in a more extensive study of ‘The relationship between the artist and the fashion designer in the twentieth century’ (Vettese, 2005). Examination of the 20th century has revealed two particular periods – ‘Modernism’ and ‘Postmodernism’ – that were evident and fitting to this analysis. The research is a summation of these findings, where the differences and affinities in the mechanisms of 20th century art and fashion, including imposing messages and innovation in Modernism and the mixed messages, recycling and commercial aspects of Postmodernism, are disseminated.

A visual and contextual comparative study of the work of Picasso and Chanel towards an understanding of the overlaps between Modern Art and Fashion.

From the beginning of the twentieth century, ``Modernism`` impacted and transformed art and clothing. Pablo Picasso and Gabrielle ``Coco`` Chanel were two of the most central characters in Modernism working simultaneously in their disciplines. Picasso`s innovations, particularly in abstract art and Chanel`s fashion designs, that dramatically departed from the previous corseted and highly deco-rative styles, were so significant that they have left an influence on contemporary art and fashion. This study will compare their visual works and documented evidence of their motivations, within the context of their cultural backgrounds, to reveal meaning in the occurrences of overlaps. This approach has ex-amined the historical, cultural background of the artist and designer`s environment from different per-spectives, adding to previous research in this area. Through this research, outcomes of the analysis have shown similarities and divergences in the wider genres of art and fashion and the practice of the artist and fashion designer. The reference list to this text, used in the survey, gives a comprehensive overview of pertinent publications disseminating Picasso and Chanel`s visual works, oral perspectives and cultural impact.

Anti-cancer and antioxidant properties of phenolics isolated from Toona sinensis A Juss acetone leaf extract

Purpose: To investigate the antioxidant and anticancer activities of phenolics from the leaf extract of Toona sinensis (TS). Methods: Acetone leaf extract of TS was screened for total phenolic and flavanoid contents, and the flanonoids were subjected to high performance liquid chromatographic (HPLC) analysis. Antioxidant properties were assessed via oxygen radical absorbance capacity (ORAC), peroxyl radical scavenging capacity (PSC) and cellular antioxidant activity (CAA), while anti-proliferative activity ins HepG2 cell line was assessed using methylene blue assay. Results: The extract contained 36.02 ± 0.24 mg of gallic acid equiv/g dry weight (DW) and 20.24 ± 1.73 mg of catechin equiv/g DW of total phenolic and total flavonoid, respectively. The levels of rutin and quercitrin were 0.51 and 19.55 mg/g, respectively. Epicatechin, gallic acid, quercitin, isoquercetin were not detected. The extract showed significant antioxidant potential and high anti-proliferation capacity with low cytotoxicity against HepG2 cell in vitro. The underlying mechanism of anti-proliferative effect was induction of apoptosis. Conclusion: TS leaf extract possesses significant in vitro antioxidant properties and anti-proliferative effect against HepG2 cells, which make it a potential anticancer drug source.

Clinical efficacy of paclitaxel in the treatment of mid-stage and advanced malignant gastric cancer, and effect of nursing interventions

Purpose: To investigate the clinical efficacy of paclitaxel combined with additional chemotherapy for mid-stage and advanced malignant tumors, and the benefits afforded by scientific nursing. Methods: Patients with mid-stage and advanced gastric cancer were randomly divided into test and control groups. Control group was given intravenous chemotherapy (400 mg/m2 fluorouracil and 2500 mg/m2 cisplatin) and nursed conventionally, while the test group was additionally treated with 80 mg/m2 paclitaxel and underwent special scientific nursing. Clinical effects and changes in the rates of apoptosis and cell proliferation were recorded. The effect of applying scientific nursing on therapeutic outcomes was also evaluated. Results: The overall rate of treatment effectiveness, clinical control rate, mean apoptosis and proliferation rates in the test group were 56.40, 92.30, (7.10 ± 3.17 and 28.70 ± 3.22 %, respectively, while, in the control group, the values were 38.50, 64.10, 25.40 ± 2.67 and 32.60 ± 2.93 %, respectively. The differences were all statistically significant (p < 0.05). In terms of nursing efficacy, the test group had a lower pain score and higher quality-of-life scores (Karnofsky performance status score) than control group. There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). Conclusion: Paclitaxel has a significant effect when used to treat mid-stage and advanced gastric cancer. Moreover, additional nursing not only enhances the therapeutic effect but also improves prognosis and quality-of-life.

Global methylation of bovine cells derived from amniotic fluid, adipose tissue and skin fibroblastos and its use in nuclear transfer in the presence or absence of Trichostatin A.

2016