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Calcium electroporation and electrochemotherapy for cancer treatment: Importance of cell membrane composition investigated by lipidomics, calorimetry and in vitro efficacy.
Hoejholt, KL, Mužić, T, Jensen, SD, Dalgaard, LT, Bilgin, M, Nylandsted, J, Heimburg, T, Frandsen, SK, Gehl, J
Scientific reports. 2019;(1):4758
Abstract
Calcium electroporation is a novel anti-cancer treatment investigated in clinical trials. We explored cell sensitivity to calcium electroporation and electroporation with bleomycin, using viability assays at different time and temperature points, as well as heat calorimetry, lipidomics, and flow cytometry. Three cell lines: HT29 (colon cancer), MDA-MB231 (breast cancer), and HDF-n (normal fibroblasts) were investigated for; (a) cell survival dependent on time of addition of drug relative to electroporation (1.2 kV/cm, 8 pulses, 99 µs, 1 Hz), at different temperatures (37 °C, 27 °C, 17 °C); (b) heat capacity profiles obtained by differential scanning calorimetry without added calcium; (c) lipid composition by mass spectrometry; (d) phosphatidylserine in the plasma membrane outer leaflet using flow cytometry. Temperature as well as time of drug administration affected treatment efficacy in HT29 and HDF-n cells, but not MDA-MB231 cells. Interestingly the HT29 cell line displayed a higher phase transition temperature (approximately 20 °C) versus 14 °C (HDF-n) and 15 °C (MDA-MB231). Furthermore the HT29 cell membranes had a higher ratio of ethers to esters, and a higher expression of phosphatidylserine in the outer leaflet. In conclusion, lipid composition and heat capacity of the membrane might influence permeabilisation of cells and thereby the effect of calcium electroporation and electrochemotherapy.
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An overview of deep learning algorithms and water exchange in colonoscopy in improving adenoma detection.
Hsieh, YH, Leung, FW
Expert review of gastroenterology & hepatology. 2019;(12):1153-1160
Abstract
Introduction: Among the Gastrointestinal (GI) Endoscopy Editorial Board top 10 topics in advances in endoscopy in 2018, water exchange colonoscopy and artificial intelligence were both considered important advances. Artificial intelligence holds the potential to increase and water exchange significantly increases adenoma detection.Areas covered: The authors searched MEDLINE (1998-2019) using the following medical subject terms: water-aided, water-assisted and water exchange colonoscopy, adenoma, artificial intelligence, deep learning, computer-assisted detection, and neural networks. Additional related studies were manually searched from the reference lists of publications. Only fully published journal articles in English were reviewed. The latest date of the search was Aug10, 2019. Artificial intelligence, machine learning, and deep learning contribute to the promise of real-time computer-aided detection diagnosis. By emphasizing near-complete suction of infused water during insertion, water exchange provides salvage cleaning and decreases cleaning-related multi-tasking distractions during withdrawal, increasing adenoma detection. The review will address how artificial intelligence and water exchange can complement each other in improving adenoma detection during colonoscopy.Expert opinion: In 5 years, research on artificial intelligence will likely achieve real-time application and evaluation of factors contributing to quality colonoscopy. Better understanding and more widespread use of water exchange will be possible.
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An FP's guide to AI-enabled clinical decision support.
Halamka, J, Cerrato, P
The Journal of family practice. 2019;(9):486;488;490;492
Abstract
To better understand the capabilities and challenges of artificial intelligence and machine learning, we look at the role they can play in screening for retinopathy and colon cancer.
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Clinical Impact of Highly Purified, Whey Proteins in Patients Affected With Colorectal Cancer Undergoing Chemotherapy: Preliminary Results of a Placebo-Controlled Study.
Mazzuca, F, Roberto, M, Arrivi, G, Sarfati, E, Schipilliti, FM, Crimini, E, Botticelli, A, Di Girolamo, M, Muscaritoli, M, Marchetti, P
Integrative cancer therapies. 2019;:1534735419866920
Abstract
Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfere in cancer patients outcome. As investigated, whey proteins could prevent the onset of sarcopenia. We have conducted a study to evaluate the effects of whey protein in colorectal cancer patients, undergoing 5-fluorouracil-based chemotherapy. Methods: After written informed consent, patients were blind randomized 1:1 to whey protein (ProLYOtin; arm A) versus placebo (arm B). The patients were assessed both physically and nutritionally before chemotherapy and after 3 (T2) and 6 months (T3) by body impedance assessment, L3-computed tomography scan, Mini Nutritional Assessment (MNA), and Malnutrition Universal Screening Tool (MUST) tests. Results: Forty-seven patients were included in this preliminary analysis. Baseline characteristics were well balanced between the 2 arms. During chemotherapy, 33 patients were reevaluated: anthropometric parameters (lean body mass from 68.5% to 71.2% vs 68.7% to 66.3%, and sarcopenia from 84% to 54% and 83% to 77% from baseline to T2 evaluation in arms A and B, respectively), nutritional status (MNA >24 = 100% [A] vs 73.7% [B]), and toxicity (no adverse effects in 86% [A] vs 29% [B] and 94% [A] vs 29% [B] for hematological and gastrointestinal toxicities, respectively) resulted to be significantly different. At univariate analysis, a condition of malnutrition risk according to MUST (relative risk [RR] = 7.5, P = .02) or MNA (RR = 1.45, P = .02) and ProLYOtin intake (RR = 0.12, P = .01) were found to be significantly predictive of chemotherapy toxicity. Conclusions: At present, our study shows how whey protein could be an important therapeutic option to improve nutritional status, and particularly to prevent severe toxicity during chemotherapy.
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Glycation affects differently the main soybean Bowman-Birk isoinhibitors, IBB1 and IBBD2, altering their antiproliferative properties against HT29 colon cancer cells.
Olías, R, Becerra-Rodríguez, C, Soliz-Rueda, JR, Moreno, FJ, Delgado-Andrade, C, Clemente, A
Food & function. 2019;(9):6193-6202
Abstract
Naturally-occurring serine protease inhibitors of the Bowman-Birk family, particularly abundant in legume seeds, exert their potential chemopreventive and/or therapeutic properties via protease inhibition. Processing of legume seeds, including soybeans, has been proposed as a major cause for their loss of bioactivity due to glycation. In order to assess how glycation affected the protease inhibitory activities of major soybean Bowman-Birk isoinhibitors (BBI) and their antiproliferative properties, IBB1 and IBBD2 were purified and subjected to glycation under controlled conditions using glucose at high temperature. Both soybean isoinhibitors showed remarkable heat stability. In the presence of glucose, IBBD2 lost most of its trypsin inhibitory activity while IBB1 maintains similar trypsin and chymotrypsin inhibitory activities as in the absence of sugar. Glycation patterns of both BBI proteins were assessed by MALDI-TOF spectrometry. Our results show that the glycation process affects IBBD2, losing partially its antiproliferative activity against HT29 colon cancer cells, while glycated-IBB1 was unaffected.
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Optimal Management of Malignant Polyps, From Endoscopic Assessment and Resection to Decisions About Surgery.
Rex, DK, Shaukat, A, Wallace, MB
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(8):1428-1437
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Abstract
Colorectal cancer is defined clinically as invasion of dysplastic cells into the submucosa. Lesions with submucosal invasion but without invasion into the muscularis propria are generally called malignant polyps. A stepwise approach produces optimal management of malignant polyps (including polypoid and flat/depressed lesions). The first step is to avoid endoscopic resection of non-pedunculated lesions with endoscopic features that predict deep submucosal invasion. Lesions without such features are candidates for endoscopic resection. The second step is to assess candidates for endoscopic resection for features that predict an increased risk of superficial submucosal invasion. Such lesions should be considered for en bloc endoscopic excision if feasible. The third step is giving patients with endoscopically resected malignant polyps good advice regarding whether to undergo adjuvant therapy, usually surgery. We review the endoscopic and histologic criteria that guide clinicians through these steps.
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Video-Based Assessments of Colonoscopy Inspection Quality Correlate With Quality Metrics and Highlight Areas for Improvement.
Duloy, A, Yadlapati, RH, Benson, M, Gawron, AJ, Kahi, CJ, Kaltenbach, TR, McClure, J, Gregory, DL, Keswani, RN
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(4):691-700
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Abstract
BACKGROUND & AIMS Adenoma detection rate (ADR) and serrated polyp detection rate (SDR) vary significantly among colonoscopists. Colonoscopy inspection quality (CIQ) is the quality with which a colonoscopist inspects for polyps and may explain some of this variation. We aimed to determine the relationship between CIQ and historical ADRs and SDRs in a cohort of colonoscopists and assess whether there is variation in CIQ components (fold examination, cleaning, and luminal distension) among colonoscopists with similar ADRs and SDRs. METHODS We conducted a prospective observational study to assess CIQ among 17 high-volume colonoscopists at an academic medical center. Over 6 weeks, we video-recorded >28 colonoscopies per colonoscopist and randomly selected 7 colonoscopies per colonoscopist for evaluation. Six raters graded CIQ using an established scale, with a maximum whole colon score of 75. RESULTS We evaluated 119 colonoscopies. The median whole-colon CIQ score was 50.1/75. Whole-colon CIQ score (r=0.71; P<.01) and component scores (fold examination r=0.74; cleaning r=0.67; distension r=0.77; all P<.01) correlated with ADR. Proximal colon CIQ score (r=0.67; P<.01) and component scores (fold examination r=0.71; cleaning r=0.62; distension r=0.65; all P<.05) correlated with SDR. CIQ component scores differed significantly between colonoscopists with similar ADRs and SDRs for most of the CIQ skills. CONCLUSION In a prospective observational study, we found CIQ and CIQ components to correlate with ADR and SDR. Colonoscopists with similar ADRs and SDRs differ in their performance of the 3 CIQ components-specific, actionable feedback might improve colonoscopy technique.
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A systematic review of the use of the alkaline comet assay for genotoxicity studies in human colon-derived cells.
Bankoglu, EE, Kodandaraman, G, Stopper, H
Mutation research. Genetic toxicology and environmental mutagenesis. 2019;:402976
Abstract
This review describes the use of the comet assay for assessment of DNA damage in human colon cells. We screened 98 papers, which employed human colon -derived cells to analyse DNA damage induced by different insults with the comet assay. In most cases tumour cell lines were used, and only a few studies were performed with primary colon cells. The comet assay was mostly applied to test chemotherapeutics and natural products. We could not find a clear difference between the susceptibility of cell lines to genotoxic insults and they were all suitable for comet assay experiments. Further comparisons between cell lines, and with primary cells and stem cells would be desirable to understand the relevance of the established cell lines as model for the human target tissue better.
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Tumor-associated redox state in metastatic colorectal cancer.
Burlaka, AP, Ganusevich, II, Virko, SV, Burlaka, AA, Kolesnik, OO
Experimental oncology. 2019;(2):148-152
Abstract
UNLABELLED The high incidence of recurrence and metastasizing in colorectal cancer (CRC) poses the challenge for the improvement in long-term treatment outcome. AIM: To determine the major indicators of redox-formative molecules in the tissue of metastatic CRC (mCRC), stages Т2-4N0-2M0G2-3, namely the rate of superoxide radical (SR) generation, nitric oxide (NO) content, the activity of matrix metalloproteinases (MMP), lactoferrin (LF) content, and "free" iron and their association with some clinical and pathological characteristics of the patients. MATERIALS AND METHODS mCRC samples from 51 patients were analyzed (stage II, 31 patients; stage III, 20 patients). The LF and "free" iron were assessed by electron paramagnetic resonance (EPR) at the temperature of 77 °K. The rate of SR and NO generation was determined with spin traps (ТЕМРО-Н, diethyl dithiocarbamate). The activity of MMP-2 and -9 was measured by gelatin zymography using SDS-polyacrylamide gel electrophoresis. Ki-67 expression was analyzed by immunofluorescence technique. RESULTS In tumors with metastases into the regional lymph nodes (N1-2 category), SR generation rate was 2.2-fold higher than in the tumors categorized as N0. In G3 mCRC, SR generation rate was 1.7-fold higher than in G2-tumors (p < 0.05). The rate of SR generation correlated inversely with differentiation grade of the tumor (r=-0.61; p < 0.05). MMP-2 and -9 activities in mCRC tissue correlated with SR generation rate and NO level (r = 0.44 ÷ 0.53, p < 0.05). The direct correlation between LF content and the stage of the disease (r = 0.42) and "free" iron content (r = 0.61) was demonstrated while the correlation between LF content and tumor differentiation grade was inverse (r = -0.57; p < 0.05). CONCLUSIONS The altered tumor-associated redox state in mCRC tissue contributes to the increased cell proliferation and formation of aggressive phenotype of the tumor. The assays for the content of redox-formative components in mCRC may be used as additional prognostic markers of the course of the disease in CRC patients.
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Primary Outcomes of a Randomized Controlled Crossover Trial to Explore the Effects of a High Chlorophyll Dietary Intervention to Reduce Colon Cancer Risk in Adults: The Meat and Three Greens (M3G) Feasibility Trial.
Frugé, AD, Smith, KS, Riviere, AJ, Demark-Wahnefried, W, Arthur, AE, Murrah, WM, Morrow, CD, Arnold, RD, Braxton-Lloyd, K
Nutrients. 2019;(10)
Abstract
Preclinical and observational research suggests green leafy vegetables (GLVs) may reduce the risk of red meat (RM)-induced colonic DNA damage and colon cancer (CC). We sought to determine the feasibility of a high GLV dietary intervention in adults with an increased risk of CC (NCT03582306) via a 12-week randomized controlled crossover trial. Participants were randomized to immediate or delayed (post-4-week washout) intervention groups. During the 4-week intervention period, participants were given frozen GLVs and counseled to consume one cooked cup equivalent daily. The primary outcomes were: accrual-recruiting 50 adults in 9 months; retention-retaining 80% of participants at completion; and adherence-meeting GLV intake goals on 90% of days. Adherence data were collected twice weekly and 24-h dietary recalls at each time point provided nutrient and food group measures. The Food Acceptability Questionnaire (FAQ) was completed to determine acceptability. On each of the four study visits, anthropometrics, stool, saliva, and blood were obtained. Fifty adults were recruited in 44 days. Participants were 48 ± 13 years of age, 62% female, and 80% Caucasian, with an average BMI at screening of 35.9 ± 5.1. Forty-eight (96%) participants were retained and completed the study. During the intervention phase, participants consumed GLVs on 88.8% of days; the adherence goal of one cup was met on 73.2% of days. Dietary recall-derived Vitamin K and GLVs significantly increased for all participants during the intervention periods. Overall satisfaction did not differ between intervention and control periods (p = 0.214). This feasibility trial achieved accrual, retention and acceptability goals, but fell slightly short of the benchmark for adherence. The analysis of biological specimens will determine the effects of GLVs on gut microbiota, oxidative DNA damage, and inflammatory cytokines.