Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10+ advanced non-small cell lung cancer

BACKGROUND: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10 METHODS: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×10 RESULTS: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m CONCLUSIONS: ADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing

GENTAMICIN POPULATION PHARMACOKINETICS IN INDIAN PEDIATRIC PATIENTS

Objective: The objective of this study was to characterize gentamicin population pharmacokinetics (PKs) in Indian pediatric patients.Methods: Population PK analysis was performed with nonlinear mixed-effect model software. The data set was inspected using both first order (FO)and FO conditional estimate (FOCE) methods by the inclusion of both patient and pathological conditions.Results: A total of 26 patients were involved in this study with 54 observations. The patient covariates, including body weight, gender, age, andcreatinine clearance (CLCR), were analyzed in a stepwise fashion to identify their potential influences on gentamicin PKs. The final modelgives the clearance (CL) and volume of distribution (V) by FO method as CL=θ1*(CLCR/35.14)+θ3*(WT/14.25)+θ5*(AGE/6.14)*EXP(θ1),V=θ2*(WT/14.25)+θ4*(CLCR/35.14)+θ6*(AGE/6.14)*EXP(θ2) and by FOCE method as CL=θ1*(CLCR/35.14+)θ3*(AGE/6.14)*EXP(θ1),V=θ2*(WT/14.25)+θ4*(CLCR/35.14)+θ6*(AGE/6.14)*EXP(θ2).Conclusion: The final model estimates of CL and V were 0.0014 L/hr/kg and 0.646 L/kg, respectively, and by FOCE method were 0.0014E-06 L/hr/kgand 0.774 L/kg, respectively. These parameters will be helpful in individualizing the loading and maintenance doses in pediatric patients.Keywords: Population pharmacokinetics, Gentamicin, Nonlinear mixed-effect model, Pediatrics

SuperDRUG2: a one stop resource for approved/marketed drugs

Regular monitoring of drug regulatory agency web sites and similar resources for information on new drug approvals and changes to legal status of marketed drugs is impractical. It requires navigation through several resources to find complete information about a drug as none of the publicly accessible drug databases provide all features essential to complement in silico drug discovery. Here, we propose SuperDRUG2 (http://cheminfo.charite.de/superdrug2) as a comprehensive knowledge-base of approved and marketed drugs. We provide the largest collection of drugs (containing 4587 active pharmaceutical ingredients) which include small molecules, biological products and other drugs. The database is intended to serve as a one-stop resource providing data on: chemical structures, regulatory details, indications, drug targets, side-effects, physicochemical properties, pharmacokinetics and drug-drug interactions. We provide a 3D-superposition feature that facilitates estimation of the fit of a drug in the active site of a target with a known ligand bound to it. Apart from multiple other search options, we introduced pharmacokinetics simulation as a unique feature that allows users to visualise the 'plasma concentration versus time' profile for a given dose of drug with few other adjustable parameters to simulate the kinetics in a healthy individual and poor or extensive metabolisers

In vitro cytotoxicity of carbon nanoparticles against Hep G 32 cells

The aim of the present study was to evaluate the in vitro toxicity of two multi wall carbon nanotubes (MWCNT) on human hepatocytes (Hep G 32 cell lines). The toxic effects of carbon nanoparticles were analyzed after 48 h of incubation with Hep G 32 cells using MTT assay and also estimated the levels of LDH (that is leakage into the media). The results of the LDH estimation demonstrated that exposure of multi wall carbon nanotubes to hepatocytes (Hep G 32) for 48 h resulted in concentration-dependent increase in LDH leakage and exhibited a significant (p 50 or IC50 values (toxic concentration 50 i.e. concentration of particles inducing 50 %cell mortality) of two nanoparticles were found in the range of 36.99-37.15 μg/ml, which were less than that of quartz (known toxic agent, 39.85 μg/ml), indicating the toxic nature of carbon nanoparticlesColegio de Farmacéuticos de la Provincia de Buenos Aire

RH-TRU Waste Inventory Characterization by AK and Proposed WIPP RH-TRU Waste Characterization Objectives

The U.S. Department of Energy (DOE)-Carlsbad Field Office (CBFO) has developed draft documentation to present the proposed Waste Isolation Pilot Plant (WIPP) remote-handled (RH-) transuranic (TRU) waste characterization program to its regulators, the U.S. Environmental Protection Agency and the New Mexico Environment Department. Compliance with Title 40, Code of Federal Regulations, Parts 191 and 194; the WIPP Land Withdrawal Act (PL 102-579); and the WIPP Hazardous Waste Facility Permit, as well as the Certificates of Compliance for the 72-B and 10-160B Casks, requires that specific waste parameter limits be imposed on DOE sites disposing of TRU waste at WIPP. The DOE-CBFO must control the sites' compliance with the limits by specifying allowable characterization methods. As with the established WIPP contact handled TRU waste characterization program, the DOE-CBFO has proposed a Remote-Handled TRU Waste Acceptance Criteria (RH-WAC) document consolidating the requirements from various regulatory drivers and proposed allowable characterization methods. These criteria are consistent with the recommendation of a recent National Academy Sciences/National Research Council to develop an RH-TRU waste characterization approach that removes current self imposed requirements that lack a legal or safety basis. As proposed in the draft RH-WAC and other preliminary documents, the DOE-CBFO RH-TRU waste characterization program proposes the use of acceptable knowledge (AK) as the primary method for obtaining required characterization information. The use of AK involves applying knowledge of the waste in light of the materials or processes used to generate the waste. Documentation, records, or processes providing information about various attributes of a waste stream, such as chemical, physical, and radiological properties, may be used as AK and may be applied to individual waste containers either independently or in conjunction with radiography, visual examination, assay, and other sampling and analytical data. RH-TRU waste cannot be shipped to WIPP on the basis of AK alone if documentation demonstrating that all of the prescribed limits in the RH-WAC are met is not available, discrepancies exist among AK source documents describing the same waste stream and the most conservative assumptions regarding those documents indicates that a limit will not be met, or all required data are not available for a given waste stream

Uniaxial plasmon polaritons via\textit{via} charge transfer at the graphene/CrSBr interface

Graphene is a privileged 2D platform for hosting confined light-matter excitations known as surface plasmon-polaritons (SPPs), as it possesses low intrinsic losses with a high degree of optical confinement. However, the inherently isotropic optical properties of graphene limit its ability to guide and focus SPPs, making it less suitable than anisotropic elliptical and hyperbolic materials as a platform for polaritonic lensing and canalization. Here, we present the graphene/CrSBr heterostructure as an engineered 2D interface that hosts highly anisotropic SPP propagation over a wide range of frequencies in the mid-infrared and terahertz. Using a combination of scanning tunneling microscopy (STM), scattering-type scanning near-field optical microscopy (s-SNOM), and first-principles calculations, we demonstrate mutual doping in excess of 10$^{13}$ cm$^{-2}$ holes/electrons between the interfacial layers of graphene/CrSBr heterostructures. SPPs in graphene activated by charge transfer interact with charge-induced anisotropic intra- and interband transitions in the interfacial doped CrSBr, leading to preferential SPP propagation along the quasi-1D chains that compose each CrSBr layer. This multifaceted proximity effect both creates SPPs and endows them with anisotropic transport and propagation lengths that differ by an order-of-magnitude between the two in-plane crystallographic axes of CrSBr

Exploring the Relationship Between Sleep Apnea, Myocardial Infarct Size, and Coronary Collaterals in Acute Myocardial Infarction: A Multidisciplinary Study

Vaishnavi Kundel,1 Kavya Devarakonda,1 Samira Khan,1 Mayte Suarez-Farinas,1 Oren Cohen,1 Carlos Santos-Gallego,1 Mark A Menegus,2 Annapoorna Kini,1 Yuliya Vengrenyuk,1 Naotaka Okamoto,1 Hiroshi Ueda,1 Umesh Gidwani,1 Jorge R Kizer,3 Susan Redline,4 Robert Kaplan,2,5 Neomi Shah1 1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Albert Einstein College of Medicine, Bronx, NY, USA; 3Cardiology Section, San Francisco Veterans Affairs Health Care System and Departments of Medicine, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA; 4Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 5Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USACorrespondence: Vaishnavi Kundel, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1232, New York, NY, 10029, USA, Tel +1-212-241-1967, Email [email protected]: We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation.Methods: We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0– 3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher’s Exact test as appropriate, with a significance threshold set at p 0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08).Conclusion: Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.Keywords: sleep apnea, MI, myocardial infarction, cardiac MRI, Rentrop, ischemic preconditionin

The Hobby–Eberly Telescope Dark Energy Experiment (HETDEX) Survey Design, Reductions, and Detections

We describe the survey design, calibration, commissioning, and emission-line detection algorithms for the Hobby–Eberly Telescope Dark Energy Experiment (HETDEX). The goal of HETDEX is to measure the redshifts of over a million Lyα emitting galaxies between 1.88 < z < 3.52, in a 540 deg2 area encompassing a comoving volume of 10.9 Gpc3. No preselection of targets is involved; instead the HETDEX measurements are accomplished via a spectroscopic survey using a suite of wide-field integral field units distributed over the focal plane of the telescope. This survey measures the Hubble expansion parameter and angular diameter distance, with a final expected accuracy of better than 1%. We detail the project’s observational strategy, reduction pipeline, source detection, and catalog generation, and present initial results for science verification in the Cosmological Evolution Survey, Extended Groth Strip, and Great Observatories Origins Deep Survey North fields. We demonstrate that our data reach the required specifications in throughput, astrometric accuracy, flux limit, and object detection, with the end products being a catalog of emission-line sources, their object classifications, and flux-calibrated spectra

Nitric oxide releasing-dendrimers: an overview

Platforms able to storage, release or scavenge NO in a controlled and specific manner is interesting for biological applications. Among the possible matrices for these purposes, dendrimers are excellent candidates for that. These molecules have been used as drug delivery systems and exhibit interesting properties, like the possibility to perform chemical modifications on dendrimers surface, the capacity of storage high concentrations of compounds of interest in the same molecule and the ability to improve the solubility and the biocompatibility of the compounds bonded to it. This review emphasizes the recent progress in the development and in the biological applications of different NO-releasing dendrimers and the nitric oxide release pathways in these compounds