AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines

The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells

MiR-21 is Required for the Epithelial–Mesenchymal Transition in MDA-MB-231 Breast Cancer Cells

Breast cancer (BCa) is one of the leading health problems among women. Although significant achievements have led to advanced therapeutic success with targeted therapy options, more efforts are required for different subtypes of tumors and according to genomic, transcriptomic, and proteomic alterations. This study underlines the role of microRNA-21 (miR-21) in metastatic MDA-MB-231 breast cancer cells. Following the knockout of miR-21 from MDA-MB-231 cells, which have the highest miR-21 expression levels compared to MCF-7 and SK-BR-3 BCa cells, a decrease in epithelial-mesenchymal transition (EMT) via downregulation of mesenchymal markers was observed. Wnt-11 was a critical target for miR-21, and the Wnt-11 related signaling axis was altered in the stable miR-21 knockout cells. miR-21 expression was associated with a significant increase in mesenchymal markers in MDA-MB-231 BCa cells. Furthermore, the release of extracellular vesicles (EVs) was significantly reduced in the miR-21 KO cells, alongside a significant reduction in relative miR-21 export in EV cargo, compared with control cells. We conclude that miR-21 is a leading factor involved in mesenchymal transition in MDA-MB-231 BCa. Future therapeutic strategies could focus on its role in the treatment of metastatic breast cancer

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

The in vivo genotoxic effects of carvacrol and thymol in rat bone marrow cells

PubMedID: 18361405The aim of this study was to investigate the in vivo genotoxic effects of carvacrol and thymol in bone marrow cells of rats. In the present study, both carvacrol (10, 30, 50, and 70 mg/kg b.w.) and thymol (40, 60, 80, and 100 mg/kg b.w.) significantly induced the structural and total chromosome abnormalities (CA) for all treatment periods (6, 12, and 24 h) when compared with control in bone marrow cells of rats intraperitonally administered. Both carvacrol and thymol showed similar effects with the positive control urethane on induction of the percentage of structural and total CA at the highest concentrations except the effects of carvacrol for 6 h treatment (70 mg/kg b.w. and 100 mg/kg b.w., respectively). In addition, carvacrol induced the numerical CA at all concentrations when compared to control and at two highest concentrations (50 and 70 mg/kg b.w.) when compared to solvent control. Thymol also induced the numerical CA especially at the highest concentration (100 mg/kg b.w.) for all treatment periods. It was shown that there was a dose-dependent effect on induction of structural, numerical and total CA for both carvacrol and thymol. Carvacrol and thymol decreased the mitotic index (MI) in all the concentrations and treatment times when compared with control. Carvacrol showed the similar effects with EC on decreasing the MI at 70 mg/ kg b.w. for 6 h, at 30 and 50 mg/kg b.w. for 12 h and at all concentrations for 24 h treatment periods. Thymol also showed a similar effect with urethane (ethyl carbamate, EC) on decreasing the MI at 60, 80, and 100 mg/kg b.w. for 6 h and at all concentrations for 24 h treatment periods. Test substances decreased the MI in a dose-dependent manner. © 2008 Wiley Periodicals, Inc

The effects of thymol on sister chromatid exchange, chromosome aberration and micronucleus in human lymphocytes

PubMedID: 19046601The genotoxic effects of thymol were investigated in human peripheral lymphocytes treated with 25, 50, 75, and 100 µg/ml concentrations of thymol for 24 and 48 h treatment periods by using sister chromatid exchange (SCE), chromosome aberration (CA), and micronucleus (MN) tests. Nuclear division index (NDI), replication index (RI), and mitotic index (MI) were also calculated in order to determine the cytotoxicity of thymol. Thymol significantly increased the SCE, especially at the lower concentrations. Thymol also increased the SCE at the highest concentrations without statistical significance. Thymol induced both the structural CA and frequency of MN at all concentrations. Thymol dose-dependently decreased the NDI for two treatment periods. Thymol decreased the RI for the 24 h treatment time without any statistical significance. However, thymol decreased the RI for the 48 h treatment time in a dose-dependent manner. Thymol also decreased the MI at the higher concentration without dose-dependent effect.FEF2006YL58This study was funded by Cukurova University Research Fund FEF2006YL58

The genotoxic and antigenotoxic effects of Salvia fruticosa leaf extract in human blood lymphocytes

PubMedID: 24224704The aim of this study was to investigate the genotoxic and antigenotoxic effects of Salvia fruticosa (Sf) leaf extract with the absence and presence of S9 mix using sister chromatid exchange (SCE), chromosome aberration (CA) and micronucleus (MN) formation test systems in human peripheral blood lymphocytes (HPBLs) that were treated with 1.5-, 3.0- and 6.0-µL/mL concentrations for 24- and 48-hour treatment periods. The cytotoxicity of Sf leaf extract was also investigated by calculating the mitotic index (MI), proliferation index (PI) and nuclear division index (NDI). In the absence of S9 mix, Sf leaf extract alone increased SCE frequency at the 48-hour treatment period; however, it induced the CA and MN at all concentrations and at all treatment periods. Sf plus MMC (mitomycin C) synergically induced SCE and CA, except the highest concentration of Sf leaf extract and MMC on induction of SCE. In addition, Sf leaf extract induced the effect of MMC on MN frequency for 24 hours, but it significantly decreased the effect of MMC on MN frequency for the 48-hour treatment period. Sf leaf extract showed a cytotoxic effect by decreasing the MI; however, it did not decrease the PI and NDI. In the presence of S9 mix, Sf leaf extract did not increase the SCE, when compared to solvent control, whereas it reduced the effect of cyclophosphamide (Cyp). Sf leaf extract induced the CA and MN, but could not increase the effect of Cyp on CA and MN formation. Sf leaf extract had no cytotoxic effect; however, it induced the cytotoxicity of Cyp. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.FEF2009YL44This study was supported by the Cukurova University Research Fund (grant no.: FEF2009YL44

The genotoxic and teratogenic effects of maltitol in rats

PubMedID: 22585934In the present study, the genotoxic and cytotoxic effects of the low-caloric artificial sweetener maltitol, which is a sugar alcohol (polyol), were investigated in the bone marrow cells of rats using the chromosome aberration (CA) test. In addition, the teratogenicity and embryotoxicity of maltitol was also investigated in rats. To reveal the genotoxicity and cytotoxicity of maltitol, rats were intraperitoneally administered 2.5, 5 and 10 g/kg body weight (bw) concentrations of maltitol for 6, 12 and 24 h treatment period. The pregnant females were intraperitoneally treated with 1, 2 and 4 g/kg bw/day concentrations of maltitol during the first 7 days of gestation (first trimester) to investigate the teratogenicity of maltitol. The embryos were collected after killing the dams by cervical dislocation under ether anaesthesia on gestation day 19. Maltitol did not induce the CA and did not decrease the mitotic index in bone marrow cells of rats at all concentrations and treatment periods. In addition, maltitol was not teratogenic; however, it decreased the foetuses weight and at the highest dose (4 g/kg bw) caused growth retardation. © 2012, SAGE Publications. All rights reserved

The genotoxic and anti-genotoxic effects of Stachys petrokosmos leaf extract in human lymphocytes using microsomal fractions

The genotoxic and anti-genotoxic effects of Stachys petrokosmos leaf extracts (Sp) were investigated in human lymphocytes. The cells were treated with 1.5, 3.0 and 6.0 µL/mL concentrations of Sp leaf extracts for 24 and 48 h treatment periods in the absence and presence of metabolic activator (S9mix). In the absence of S9mix, Sp alone did not induce chromosome aberrations and formation of micronucleus while inducing the mean sister chromatid exchange at the highest concentration. In addition, Sp decreased the mutagenic effect of mitomycin-c. Sp alone showed a cytotoxic effect determined by a decrease in the proliferation index, mitotic index and nuclear division index. On the other hand a mixture of Sp and mitomycin-c resulted in a higher cytotoxic effect especially for 48 h treatment period. In the presence of S9mix, Sp was not genotoxic and cytotoxic however, it showed an anti-genotoxic effect by decreasing the effects of cyclophosphamide. © 2011 Springer Science+Business Media B.V.This study was supported by C. U. Researc

The effects of boric acid on sister chromatid exchanges and chromosome aberrations in cultured human lymphocytes

The aim of this study was to determine the possible genotoxic effects of boric acid (BA) (E284), which is used as an antimicrobial agent in food, by using sister chromatid exchange (SCEs) and chromosome aberration (CAs) tests in human peripheral lymphocytes. The human lymphocytes were treated with 400, 600, 800, and 1000 µg/mL concentrations of BA dissolved in dimethyl sulfoxide (DMSO), for 24 h and 48 h treatment periods. BA did not increase the SCEs for all the concentrations and treatment periods when compared to control and solvent control (DMSO). BA induced structural and total CAs at all the tested concentrations for 24 and 48 h treatment periods. The induction of the total CAs was dose dependent for the 24 h treatment period. However, BA did not cause numerical CAs. BA showed a cytotoxic effect by decreasing the replication index (RI) and mitotic index (MI). BA decreased the MI in a dose-dependent manner for the 24 h treatment period. © 2007 Springer Science+Business Media B.V