Co-culture with NK-92MI cells enhanced the anti-cancer effect of bee venom on NSCLC cells by inactivation of NF-κB

In the present study we experimented on a multimodal therapeutic approach, such as combining chemotherapy agent (Bee venom) with cellular (NK-92MI) immunotherapy. Previously bee venom has been found to show anti-cancer effect in various cancer cell lines. In lung cancer cells bee venom showed an IC⁵⁰ value of 3 μg/ml in both cell lines. The co-culture of NK-92MI cell lines with lung cancer cells also show a decrease in viability upto 50 % at 48 h time point. Hence we used bee venom treated NK-92MI cells to co-culture with NSCLC cells and found that there is a further decrease in cell viability upto 70 and 75 % in A549 and NCI-H460 cell lines respectively. We further investigated the expression of various apoptotic and anti-apoptotic proteins and found that Bax, cleaved caspase-3 and -8 were increasing where as Bcl-2 and cIAP-2 was decreasing. The expression of various death receptor proteins like DR3, DR6 and Fas was also increasing. Concomitantly the expression of various death receptor ligands (TNFalpha, Apo3L and FasL) was also increasing of NK-92MI cells after co-culture. Further the DNA binding activity and luciferase activity of NF-κB was also inhibited after co-culture with bee venom treated NK-92MI cell lines. The knock down of death receptors with si-RNA has reversed the decrease in cell viability and NF-κB activity after co-culture with bee venom treated NK-92MI cells. Thus this new approach can enhance the anti-cancer effect of bee venom at a much lower concentration.     

Prediction of ARA/PPI Drug-Drug Interactions at the Drug Discovery and Development Interface

Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus? with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented.     

Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; C_max, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E     

Anatomic feature-based registration for patient set-up in head and neck cancer radiotherapy

Modern radiotherapy equipment is capable of delivering high precision conformal dose distributions relative to isocentre. One of the barriers to precise treatments is accurate patient re-positioning before each fraction of treatment. At Massachusetts General Hospital, we perform daily patient alignment using radiographs, which are captured by flat panel imaging devices and sent to an analysis program. A trained therapist manually selects anatomically significant features in the skeleton, and couch movement is computed based on the image coordinates of the features. The current procedure takes about 5 to 10 min and significantly affects the efficiency requirement in a busy clinic. This work presents our effort to develop an improved, semi-automatic procedure that uses the manually selected features from the first treatment fraction to automatically locate the same features on the second and subsequent fractions. An implementation of this semi-automatic procedure is currently in clinical use for head and neck tumour sites. Radiographs collected from 510 patient set-ups were used to test this algorithm. A mean difference of 1.5 mm between manual and automatic localization of individual features and a mean difference of 0.8 mm for overall set-up were seen.     

Financing vaccinations - The South African experience

South Africa provides a useful country case study for financing vaccinations. It has been an early adopter of new vaccinations and has financed these almost exclusively from domestic resources, largely through general taxation. National vaccination policy is determined by the Department of Health, based on advice from a national advisory group on immunisation. Standard health economic criteria of effectiveness, cost-effectiveness, affordability and burden of disease are used to assess whether new vaccinations should be introduced. Global guidelines and the advice of local and international experts are also helpful in making the determination to introduce new vaccines. In terms of recent decisions to introduce new vaccines against pneumococcal disease and rotavirus diarrhoea in children, the evidence has proved unequivocal. Universal rollout has been implemented even though this has led to a fivefold increase in national spending on vaccines. The total cost to government remains below 1-1.5% of public expenditures for health, which is viewed by the South African authorities as affordable and necessary given the number of lives saved and morbidity averted. To manage the rapid increase in domestic spending, efforts have been made to scale up coverage over several years, give greater attention to negotiating price reductions and, in some cases, obtain initial donations or frontloaded deliveries to facilitate earlier universal rollout. There has been strong support from a wide range of stakeholders for the early introduction of new generation vaccines.     

Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes

SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents.     

High-sodium food choices by southern, urban African Americans with heart failure

BackgroundSodium restriction is important in the management of heart failure (HF). Although many low-sodium educational resources are available, few are directed specifically at urban African Americans.Methods and ResultsA registered dietitian prospectively interviewed 50 African-American and 25 white patients in an urban public hospital (derivation cohort) in Dallas, TX, using a food-frequency instrument that listed 146 food choices. Foods >300 mg sodium/serving consumed at least weekly by 50% of an ethnic group were classified as being a high-sodium core food for that group. Classification of foods (core or not core) was validated in a second African-American cohort (n = 144). Five high-sodium food choices were classified as core food in both the derivation and validation African-American cohorts (salt in cooking, canned vegetables, cheese, processed meats, and cold cereal) and another 3 when the derivation and validation cohorts were combined (fast food, fried chicken, and corn bread). Four of these 8 foods were not classified as core foods in whites.ConclusionEight high-sodium foods were frequently consumed by southern, urban African Americans with heart failure. Several of these foods were not commonly consumed by whites, emphasizing the need to be sensitive to ethnic differences in dietary habits when educating patients about sodium intake.