Clinical Pharmacology of MS-275, A Histone Deacetylase Inhibitor

The goal of this escalating single-dose phase I research study was to determine the safety, tolerability, pharmacokinetics, pharmacodynamics as well as in vitro metabolism and plasma protein binding of MS-275, a novel histone deacetylase inhibitor, in patients with solid tumors and lymphomas. A validated LC/MS assay was developed to quantitate MS-275 in plasma, human liver microsomes and urine. The pharmacokinetic (PK) evaluation was done using a non-compartmental approach. In-vitro plasma protein binding profile of MS-275 was characterized by a validated micro-equilibrium dialysis method. In vitro phase I and phase II hepatic metabolism of MS-275 were evaluated using human liver microsomes. A correlative covariate analysis was performed in an effort to explain the wide inter-individual variability among patients.Results from the study demonstrate that the validated LC-MS assay is specific, accurate, precise and sensitive. MS-275 demonstrates a substantial inter-individual PK variability in systemic exposure and clearance; exposures increase in near-proportion, while peak concentrations increase more than-proportionally with an increase in dose. Mean apparent oral clearance (CL/F) is independent of dose and exhibits apparent dose-independent PK behavior over the studied dose range. Oral absorption is highly variable. MS-275 has a 50-fold longer half-life in humans compared to pre-clinical species. PK/PD analysis showed significant correlation between occurrence of DLT and higher systemic exposures. Although there was an increase in the acetylation of histone H3 and H4 over time, preliminary analysis showed no significant correlation between PK parameters and change in % histone acetylation after 24 hours. MS-275 is moderately bound to plasma proteins. Hepatic phase I and II metabolic pathways are only minor routes of elimination, and MS-275 is neither a substrate for liver-specific organic anion transporting proteins, OATP1B1 and OATP1B3, nor a substrate for gastrointestinal efflux transporters ABCB1 (P-gp) or ABCG2. No significant correlation was found between CL/F and demographic, body measures and other clinical covariates, and inter-patient variability in CL/F remained similar in magnitude even after correcting dose for body surface area (BSA) or other body measures. BSA is not a significant predictor of MS-275 PK, and flat-fixed dosing can be used in the future

MSCT coronary angiography in non-invasive assessment of coronary artery bypass grafts patency

Background: Coronary artery disease (CAD) is one of the leading cause of the morbidity and mortality in India and worldwide and last decade has seen a steep rise in incidence of CAD in India and its treatment as bypass surgery. Direct visualization of the grafts and native coronary arteries by invasive catheterization is now being replaced by non-invasive CT coronary angiography with higher slice machines and newer technology as it has good temporal resolution, high scanning speed as well as low radiation dose. We share our experience of graft imaging on 128 slice CT machine.Methods: This is a retrospective, single-center, observational study. We included 500 symptomatic patients who have undergone CT study between the year 2014 to 2018 post bypass surgery.Results: Arterial grafts have a better patency rate than venous grafts. (88% vs. 64.1%). Amongst the individual arterial grafts RIMA had the best patency rate (100%) followed by LIMA (90.8%), RA (68.7%). LAD was the most commonly involved artery (91%).Conclusions: Significant absolute concordance between CT and catheter angiographic findings have been documented for all arterial and venous grafts patency in the literature. The MSCT with retrospective gating permits an accurate and non-invasive evaluation of patent and diseased arterial and vein grafts and could replace conventional angiography for the follow-up of symptomatic, stable patients. Moreover, an optimal diagnostic accuracy was also documented in the appraisal of native vessels distal to the graft anastomoses

Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures

<p>Abstract</p> <p>Background</p> <p>Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by β-amyloid (Aβ) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aβ42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia.</p> <p>Methods</p> <p>Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aβ neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 were assessed by ELISA. Levels of P_T451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of P_T451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test</p> <p>Results</p> <p>In these co-cultures, PKR inhibition prevented Aβ42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1β, and limited apoptosis.</p> <p>Conclusion</p> <p>In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.</p

Alternative Solutions to a Language Design Problem: The Role of Adjectives and Gender Marking in Efficient Communication

A central goal of typological research is to characterize linguistic features in terms of both their functional role and their fit to social and cognitive systems. One long-standing puzzle concerns why certain languages employ grammatical gender. In an information theoretic analysis of German noun classification, Dye, Milin, Futrell, and Ramscar (2017) enumerated a number of important processing advantages gender confers. Yet this raises a further puzzle: If gender systems are so beneficial to processing, what does this mean for languages that make do without them? Here, we compare the communicative function of gender marking in German (a deterministic system) to that of prenominal adjectives in English (a probabilistic one), finding that despite their differences, both systems act to efficiently smooth information over discourse, making nouns more equally predictable in context. We examine why evolutionary pressures may favor one system over another and discuss the implications for compositional accounts of meaning and Gricean principles of communication

Double outlet of right ventricle: imaging spectrum on multi-slice computed tomography

Background: Multi-slice computed tomography (MSCT) is the main stay of pre-operative assessment of many complex congenital heart diseases (CHD) in current clinical practice, one of them is double outlet of right ventricle (DORV). DORV is one of the conotruncal anomalies that encompasses a wide spectrum of anatomic malformations in which both the aorta and pulmonary arterial trunk arise entirely or predominantly from the morphologically right ventricle (RV). Purpose of this article is to understand spectrum of DORV and associated types of ventricular septal defect (VSD) on MSCT imaging with special emphasis of usefulness of 3-D volume rendered (VR) images in pre surgical evaluation.Methods: A total of 500 paediatric patients (<18 years old), who had undergone MSCT were studied during the period 2014 to 2019 at the tertiary cardiac care centre.Results: 500 patients having primary/suspicious diagnosis of DORV on echocardiography during the said period were enrolled in the study. All the patients who underwent MSCT scan, were studied in detail for: DORV spectrum, associated types of VSD and its relationship to the semilunar valves. Out of 500 total subjects, subaortic VSD was the most common type of VSD observed (53%), followed by subpulmonic VSD (22%), non-committed VSD (18%) and doubly committed VSD (7%). Associations of pulmonary stenosis, subaortic stenosis and aortic co-arctation with various types of VSDs were addressed. Associated other anomalies were also analysed.Conclusions: Advances in MSCT technology has revolutionized pre-surgical diagnosis, management approach and post-operative follow-up of DORV patients. Excellent image qualities along with 3D volume rendered images help surgeon understand complex morphology of DORV variants and associated types of VSD. Significant reduction in intra and post-operative mortality in DORV patients in current era is result of MSCT technology

Towards cognitively plausible data science in language research

Over the past 10 years, Cognitive Linguistics has taken a Quantitative Turn. Yet, concerns have been raised that this preoccupation with quantification and modelling may not bring us any closer to understanding how language works. We show that this objection is unfounded, especially if we rely on modelling techniques based on biologically and psychologically plausible learning algorithms. These make it possible to take a quantitative approach, while generating and testing specific hypotheses that will advance our understanding of how knowledge of language emerges from exposure to usage

10Be i molekulska stanja

The 10Be excitation energy spectra have been obtained from the inclusive and coincident measurements of the reactions: 7Li +7Li at E0 = 8 and 30 MeV and 9Be +7Li at E0 = 52 MeV. Contributions of the 10Be states below 12 MeV in excitation have been observed. Decays of the states at 9.6, 10.2 and 11.8 into a +6He and, for the first time, into a +6He* have been found. The results are discussed in addition to the other experimental data and recent theoretical predictions. Proposals for future measurements to search for exotic structures in carbon nuclei are also made.Proučavamo ekscitacijske energijske spektre 10Be iz inkluzivnih i koincidentnih mjerenja reakcija 7Li +7Li na E0 = 8 i 30 MeV, te 9Be +7Li na E0 = 52 MeV. Opaženi su doprinosi stanja 10Be u energiji uzbude do 12 MeV. Nađeni su raspadi stanja na 9.6, 10.2 i 11.8 MeV na α +6He te, po prvi put, na α +6He∗. Ovi se rezultati razmatraju zajedno s ostalim eksperimentalnim podacima i novijim teorijskim predviđanjima. Predlažu se buduća mjerenja u kojima bi se tražila stanja lakih jezgara egzotične građe