Curcumin Enhances Chemosensitivity and Apoptosis in T24 Bladder Cancer Cells through Inhibition of the Ras/ MAPK Signaling Pathway: submitted: Feb 3, 2018 Accepted: Mar 10, 2018 Published online: Mar 15, 2018

Background. Curcumin (CUR), a natural phenolic compound, has been recently reported to exert antitumor actions in variety of cancers; however, the exact mechanism(s) is not clear. In this study we investigated whether CUR could inhibit Ras/MAPK pathway and enhance mitomycin C (MMC) cytotoxicity in T24 bladder cancer cells. Methods. T24 cells were cultured with different concentrations of CUR (5, 10, 20 μM) alone or combined with 10 μg/ml MMC. At the end of 72 h culture, cell viability was assessed by MTT assay; apoptosis by flow cytometry; total Ras and ERK1/2 by immunohistochemistry and western blotting. Results. In comparison to cells exposed to MMC alone, cells treated with combined MMC and either 10 or 20 μM CUR showed reduced cell proliferation, disrupted morphological appearance, and increased subG0/G1 apoptotic events. This inhibition was associated with marked reduction of Ras and ERK1/2 expression. Likewise, cells treated with 10 or 20 μM CUR alone showed significant inhibition, while the effect of 5 μM was less obvious. Conclusion. Resistance of T24 cells to cytotoxic effect of MMC is dependent, at least partially, on Ras/ERK activation. CUR at concentrations of 10 and 20 μM in combination with low dose MMC induced toxic synergism in T24 cells. Clinical translation of this experimental study may be reasonable in light of wide safety margin and availability of CUR

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Clinical and histopathological assessment of the combined therapeutic effect of Curcumin Nanoparticles and PRP on the cutaneous wound repair in rats.

Skin wound healing is a complex biological process in which the replacement of dead tissue by a vital one takes place. The aim of this study is to assess the clinical and histopathological modalities of Curcumin nanoparticles and (Platelet-rich plasma) application on excisional skin wound healing activity. Under complete aseptic conditions full-thickness (10 mm) artificial uniform skin wounds were created on the back of twenty anaesthetized male rats (divided into four groups; Control (Group A), Curcumin treatment (Group B), Platelet-rich plasma treatment (Group C), and Curcumin - Platelet-rich plasma treatment (Group D). Tissue sections were stained by hematoxylin and eosin, PAS, and Crossman trichrome for histopathological evaluation of the wound healing properties following the curcumin and PRP topical treatment. Significant skin regeneration including wound closure and histopathological healing was better in Curcumin nanoparticles and PRP treated groups compared to the control untreated one through better reepithelization and coaptation between the epidermis and dermal layers, more vascular angiogenesis, less inflammatory reactions, healthy granulation tissue and better collagen fibers density in the dermal layer. The obtained results proved an effective external therapeutic use of both Curcumin and PRP on cutaneous wound healing progression

Clinical and histopathological assessment of the combined therapeutic effect of Curcumin Nanoparticles and PRP on the cutaneous wound repair in rats.

Skin wound healing is a complex biological process in which the replacement of dead tissue by a vital one takes place. The aim of this study is to assess the clinical and histopathological modalities of Curcumin nanoparticles and (Platelet-rich plasma) application on excisional skin wound healing activity. Under complete aseptic conditions full-thickness (10 mm) artificial uniform skin wounds were created on the back of twenty anaesthetized male rats (divided into four groups; Control (Group A), Curcumin treatment (Group B), Platelet-rich plasma treatment (Group C), and Curcumin - Platelet-rich plasma treatment (Group D). Tissue sections were stained by hematoxylin and eosin, PAS, and Crossman trichrome for histopathological evaluation of the wound healing properties following the curcumin and PRP topical treatment. Significant skin regeneration including wound closure and histopathological healing was better in Curcumin nanoparticles and PRP treated groups compared to the control untreated one through better reepithelization and coaptation between the epidermis and dermal layers, more vascular angiogenesis, less inflammatory reactions, healthy granulation tissue and better collagen fibers density in the dermal layer. The obtained results proved an effective external therapeutic use of both Curcumin and PRP on cutaneous wound healing progression

Reduction of mitomycin C resistance in human bladder cancer T24 cells by knocking-down ras oncogene

Aim: Mitomycin C (MMC) is a commonly used as intravesical treatment for superficial bladder cancer. However, its role in combination with ras inhibition has not been investigated. The aim of this study was to explore the role of ras in MMC-induced apoptosis in T24 bladder cancer cells and to determine the efficacy of combination therapy in vitro.Methods: We measured the effects of various doses of MMC on apoptosis induction as well as on ras, ERK and Ki-67 protein expression by T24 cell line using immunocytochemistry, flow cytometry and Western blotting. We also tested the effect of siRNA on ras employed singly or in combination with MMC.Results: T24 cells expressed high level of ras protein. MMC treatment increased the level of ras and ERK protein expression after 24 h, and decreased these levels after 72 h. Ras siRNA (100 nmol/L) caused massive apoptosis associated with a marked decrease in ras expression in T24 cells. When combined with low doses of MMC, ras siRNA (50 nmol/L) sensitized T24 cells to apoptosis and decreased their expression of ras. The effect of combined therapy was higher than that of either compound used alone. Expression levels of ERK, a downstream target of ras, declined following combination therapy.Conclusion: Ras siRNA in combination with low dose MMC is a possible treatment strategy for patients with ras-positive bladder tumors