The modulatory effect of septilin on cytotoxicity of cisplatin in a human breast adenocarcinoma cell line

435-441Cisplatin (Csp) is a recurrently used chemotherapeutic drug but its use is inadequate due to undesirable adverse effects. In search of alternative medicine more attention has been given to phytochemicals. Septilin (Spt), a polyherbal drug and its therapeutic potential is huge but there is a scarcity of studies on its cytotoxic potential on cancer cells. The current study was designed to examine the effects of Spt in combination with Csp on human breast adenocarcinoma (MCF-7) and normal human breast epithelial (MCF-10A) cell lines. Cell viability for Spt treated cells was studied using MTT assay. IC50 value of Csp on MCF-7 cells was found to be 10 µg/mL at 24 h. This dose was further used to study the combined effects of Csp with Spt on MCF-7 and MCF-10A cell lines. Maximum cytotoxicity of Spt on MCF-7 cells was observed at Spt 5 µg/mL. The mechanism of Spt induced cytotoxicity was studied using apoptosis assay. Spt did not show any cytotoxic effects on MCF-10 A normal human breast epithelial cells, indicating Spt has no effect on normal cells. Our findings suggest that Spt can be used in combination with an anticancer drug Csp to increase its efficacy and/or to minimize its side effects on normal cells

Correlation of serum fructosamine, erythrocyte Na+-K+ ATPase and glutathione peroxidase with HbA1c levels

Glycated hemoglobin is the frequently used test in the diagnosis of diabetes mellitus. However, because this test is affected by various factors and may not be accurate for patients of certain health conditions, the present study aims to explore the association between potential and cost-effective markers like serum Fructosamine, Erythrocyte Na+-K+ ATPase, and Glutathione peroxidase with altering levels of established marker HbA1c (Glycated haemoglobin). The study showed that serum Fructosamine has a statistically significant (P = <0.0001) association with increasing levels of HbA1c as well as blood glucose. There was a 100% sensitivity and specificity for serum fructosamine test against HbA1c in ROC analysis, however, the erythrocyte glutathione peroxidase and erythrocyte membrane Na+-K+ ATPase activity was not affected by increasing HbA1c levels

Correlation of serum fructosamine, erythrocyte Na+-K+ ATPase and glutathione peroxidase with HbA1c levels

334-338Glycated hemoglobin is the frequently used test in the diagnosis of diabetes mellitus. However, because this test is affected by various factors and may not be accurate for patients of certain health conditions, the present study aims to explore the association between potential and cost-effective markers like serum Fructosamine, Erythrocyte Na+-K+ ATPase, and Glutathione peroxidase with altering levels of established marker HbA1c (Glycated haemoglobin). The study showed that serum Fructosamine has a statistically significant (P = <0.0001) association with increasing levels of HbA1c as well as blood glucose. There was a 100% sensitivity and specificity for serum fructosamine test against HbA1c in ROC analysis, however, the erythrocyte glutathione peroxidase and erythrocyte membrane Na+-K+ ATPase activity was not affected by increasing HbA1c levels

The modulatory effect of septilin on cytotoxicity of cisplatin in a human breast adenocarcinoma cell line

Cisplatin (Csp) is a recurrently used chemotherapeutic drug but its use is inadequate due to undesirable adverse effects. In search of alternative medicine more attention has been given to phytochemicals. Septilin (Spt), a polyherbal drug and its therapeutic potential is huge but there is a scarcity of studies on its cytotoxic potential on cancer cells. The current study was designed to examine the effects of Spt in combination with Csp on human breast adenocarcinoma (MCF-7) and normal human breast epithelial (MCF-10A) cell lines. Cell viability for Spt treated cells was studied using MTT assay. IC50 value of Csp on MCF-7 cells was found to be 10 μg/mL at 24 h. This dose was further used to study the combined effects of Csp with Spt on MCF-7 and MCF-10A cell lines. Maximum cytotoxicity of Spt on MCF-7 cells was observed at Spt 5 μg/mL. The mechanism of Spt induced cytotoxicity was studied using apoptosis assay. Spt did not show any cytotoxic effects on MCF-10 A normal human breast epithelial cells, indicating Spt has no effect on normal cells. Our findings suggest that Spt can be used in combination with an anticancer drug Csp to increase its efficacy and/or to minimize its side effects on normal cells

Strain engineering and one-dimensional organization of metal-insulator domains in single-crystal VO2 beams

Spatial phase inhomogeneity at the nano- to microscale is widely observed in strongly-correlated electron materials. The underlying mechanism and possibility of artificially controlling the phase inhomogeneity are still open questions of critical importance for both the phase transition physics and device applications. Lattice strain has been shown to cause the coexistence of metallic and insulating phases in the Mott insulator VO2. By continuously tuning strain over a wide range in single-crystal VO2 micro- and nanobeams, here we demonstrate the nucleation and manipulation of one-dimensionally ordered metal-insulator domain arrays along the beams. Mott transition is achieved in these beams at room temperature by active control of strain. The ability to engineer phase inhomogeneity with strain lends insight into correlated electron materials in general, and opens opportunities for designing and controlling the phase inhomogeneity of correlated electron materials for micro- and nanoscale device applications.Comment: 14 pages, 4 figures, with supplementary informatio

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Quantitative Modeling of GRK-Mediated β2AR Regulation

We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved

HIV-1 Neutralization Profile and Plant-Based Recombinant Expression of Actinohivin, an Env Glycan-Specific Lectin Devoid of T-Cell Mitogenic Activity

The development of a topical microbicide blocking the sexual transmission of HIV-1 is urgently needed to control the global HIV/AIDS pandemic. The actinomycete-derived lectin actinohivin (AH) is highly specific to a cluster of high-mannose-type glycans uniquely found on the viral envelope (Env). Here, we evaluated AH's candidacy toward a microbicide in terms of in vitro anti-HIV-1 activity, potential side effects, and recombinant producibility. Two validated assay systems based on human peripheral blood mononuclear cell (hPBMC) infection with primary isolates and TZM-bl cell infection with Env-pseudotyped viruses were employed to characterize AH's anti-HIV-1 activity. In hPMBCs, AH exhibited nanomolar neutralizing activity against primary viruses with diverse cellular tropisms, but did not cause mitogenicity or cytotoxicity that are often associated with other anti-HIV lectins. In the TZM-bl-based assay, AH showed broad anti-HIV-1 activity against clinically-relevant, mucosally transmitting strains of clades B and C. By contrast, clade A viruses showed strong resistance to AH. Correlation analysis suggested that HIV-1′s AH susceptibility is significantly linked to the N-glycans at the Env C2 and V4 regions. For recombinant (r)AH expression, we evaluated a tobacco mosaic virus-based system in Nicotiana benthamiana plants as a means to facilitate molecular engineering and cost-effective mass production. Biochemical analysis and an Env-mediated syncytium formation assay demonstrated high-level expression of functional rAH within six days. Taken together, our study revealed AH's cross-clade anti-HIV-1 activity, apparent lack of side effects common to lectins, and robust producibility using plant biotechnology. These findings justify further efforts to develop rAH toward a candidate HIV-1 microbicide

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700