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Relapse following CD19 CAR-T cell (CAR-T) therapy has been linked to the upregulation of negative regulators of T cell function. Recent studies showed that inhibition of the negative T cell regulator PTPN2 using a small molecule inhibitor greatly improves T cell mediated tumor clearance in murine models. We now assessed the function, proliferation, persistence and toxicity of PTPN2 KO CAR-Ts in primary human CD19 CAR-Ts and in a clinical relevant model of Non-Human Primate (NHP) CD20 CAR-Ts.

Following allogeneic hematopoietic cell transplantation (alloHCT) donor T cells infiltrate and damage multiple target organs, resulting in acute GVHD (aGVHD). However, the critical biological mechanisms underpinning the tissue-specificity of aGVHD remains only partially understood. Deciphering the organ-specific alloimmune mechanisms responsible for target organ damage offers new prospects for precisely targeted treatments for acute GVHD, minimizing impact on protective immunity and reducing overall toxicity.

•Transcriptomic analysis of NHP and patient-derived T cells following CAR T-cell infusion identified activated CAR−bystander CD8+T cells.•Cytokine exposure–induced bystander-like CD8+T cells capable of T-cell receptor–independent cytotoxic killing of leukemia cells.

Background:Despite the success of CD19 CAR-T cells (CAR-Ts) in inducing remission, relapse remains a major issue. Previous studies have shown that upregulation of negative T cell regulators can contribute to CAR-T failure, and that deletion of these regulators can enhance CAR-T efficacy. A potent negative regulator is PTPN2, which inhibits T cell function by modulating T cell receptor and cytokine signaling pathways. While murine models have shown that PTPN2-knockout T cells improve tumor control, these models fail to reliably predict clinical efficacy or toxicity. To improve this predictability, we investigated PTPN2KO CAR-Ts in primary human cells and in a NHP model of B-cell directed CAR-T therapy.

Background: Chronic graft-versus-host disease (CGVHD) is the leading cause of long-term morbidity and mortality following hematopoietic stem cell transplant (HCT) and occurs in over 50% of patients undergoing unrelated donor HCT. Despite its frequency, the mechanisms driving this disease remain incompletely understood, making its prevention and successful treatment challenging. To address this issue, we have undertaken a transcriptomic analysis of T cell reconstitution after unrelated donor HCT, to dissect mechanisms driving CGVHD.

Production of effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by T cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific T cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on T cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory T cells in the red pulp. Thus, CXCR3 increases T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.

Introduction

Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 37370, 1, a related series of structures, exemplified by (±)-1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)piperazine, Sch 40338, 2, were prepared. Interestingly, the compounds exhibited a parallel structure–antiallergy activity relationship, suggesting that the two series may adopt a common conformation at the PAF receptor. Conformational analysis led to a proposal for this bioactive conformation accessible to both series. The synthesis of novel conformationally constrained analogues that might mimic the proposed bioactive conformation of these compounds, and the evaluation of their in vitro antiallergy activity form the subject matter of this report.

The synthesis of an homologous series of new water-soluble derivatives of pilocarpine is described. The new compounds, referred to as soft quaternary salts, are water soluble by virtue of a cationic ammonium head and their lipophilicity can be modulated by manipulating the size and the nature of the substituent in the inactive portion of the molecule. The miotic activity of the compounds was evaluated after administration to normotensive New Zealand White rabbits. Changes in pupil size indicated a substantial cholinergic effect on the iridal sphincter musculature. The best candidate, compound 20, which has a 16-carbon side chain, was evaluated for reduction of the intraocular pressure in genetically glaucomatous Beagles. Compound 20 is superior to pilocarpine in both tests, with a potency 10 to 20 times that of the parent compound and a longer duration of action. It is suggested that the new compounds are pro-drug forms of pilocarpine which greatly enhance the corneal bio-availability of the parent compound.

A series of N-acyl-4-(5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperazines is described that are dual antagonists of PAF and histamine. The structural requirements for activity in this series parallel those of their previously reported piperidinylidene counterparts. Whereas their global minimum energy conformations are different for both series of compounds, computer assisted molecular modeling suggests that a common bioactive conformation is possible.

The lone-pair ionization energies for N, O, and Cl heteroatoms in four derivatives of piperidine were measured from UV photoelectron spectra. The various lone-pair interactions in each piperidine were investigated. The hydrolytic stability and the antimicrobial activity for the N-chloropiperidines also were determined. The results suggest a correlation between the stability of the nitrogen lone pair, as determined from photoelectron spectroscopy, with the antibacterial activity of the corresponding N-chloramine.

Investigational drugs that either inhibit the metabolism of arachidonic acid to prostaglandins and leukotrienes, or antagonise leukotriene receptors, continue to be evaluated clinically. The encouraging clinical results observed with these agents provide the best opportunity to realise novel chemical entities, which operate by specific and unique mechanisms of action, that are also potentially useful therapeutics for the treatment of allergic and inflammatory disorders [1,2].Recently, a commentary on new drugs for asthma [3] and a report describing progress with investigational drugs for treating pulmonary and inflammatory diseases [4] have been published. In addition, the discovery of an inducible form of cyclooxygenase, COX-2, has also stimulated a resurgence of interest to discover selective inhibitors of this enzyme [5,6].The intent of this monthly update is to report the current status of investigational drugs that have been described previously [4], as well as to introduce novel chemical entities that have entered various stages of preclinical and clinical development.

The chlorination of α‐amino acids and their related derivatives was investigated. A kinetic study of the stability of these N‐chlorinated products led to an elucidation of the factors that significantly influence the stability and reactivity of the nitrogen‐chlorine bond in these N‐chloramines. From the kinetic investigations, a series of low chlorine potential, soft antimicrobial N‐chloramines was developed based on derivatives of α‐aminoisobutyric acid and related compounds.

Since the identification of the nonpeptide tachykinin antagonists CP96345 (Pfizer) and SR-48968 (Sanofi), interest in this area of research has increased markedly with several pharmaceutical companies actively patenting structures for a range of therapeutic applications. This review surveys the activity of several pharmaceutical companies in the patent literature during January through December 1995.

A sensitive and reproducible method for quantitative evaluation of the relative reactivities of alkylating agents was developed, based on competitve alkylation. The method is superior to the known colorimetric methods. The reactivities of the agents could also be correlated with the 13C chemical shifts of the α-methylene. The method was successfully applied for the ranking of "soft" alkylating agents of low reactivity.

Acronine was heated with tetraphosphorus decasulfide in benzene to give a mixture of products, the major component (A) being identified tentatively as an unstable product derived from four molecules of noracronine with one molecule of tetraphosphorus decasulfide. Treatment of Compound A with various solvents and heat converted it into a maroon solid (B), which was shown to be 7-thionoracronine.

Comparative antimicrobial activity studies for certain new classes of soft N-chloramines derived from α-aminoisobutyric acid and 2-amino-2-methyl-1-propanol were examined using the minimum inhibitory concentration (MIC) and/or the contact germicidal efficiency (CGE) procedures. Several factors significantly influence the antimicrobial activity of the soft N-chloramines: (a) the aliphatic chain length in a homologous series, (b) the degree of chlorination of the nitrogen atom, (c) the solution pH, (d) the presence of a denaturant, and (e) the nature of a positive charge.

Comparative antimicrobial activity of 3‐chloro‐2‐oxazolidinone (I), 3‐chloro‐4‐methyl‐2‐oxazolidinone (II), 3‐chloro‐4, 4‐dimethyl‐2‐oxazolidinone (III), and N‐chlorosuccinimide (IV) was evaluated in aqueous buffers in the absence and presence of 5% horse serum. All four compounds had similar bactericidal activity in the absence of horse serum, but I and III had superior activity relative to IV when serum was present. Compound III was considerably more stable with respect to loss of positive chlorine and bactericidal activity than I and II when stored in 0.1 Msodium dihydrogen phosphate buffered to pH 7.0 at 40°. Thus, III is potentially the most useful bactericidal agent of those evaluated. The chlorine potentials of I, II, and III, the rate constants for transfer of positive chlorine from I and III to morpholine in aqueous solutions, and the hydrolytic stabilities of I and III with respect to loss of positive chlorine were evaluated. These data, together with previously calculated data for IV, are used to rationalize the observed bactericidal activities.

A number of low chlorine potential, soft N‐chloramines containing nitrogen‐chlorine bonds of different polarity were prepared. These novel N‐chloramine systems were based on derivatization of 2‐amino‐2‐methyl‐1‐propanol.

Novel activated ester-type prodrugs of aspirin were designed and synthesized. The methylthiomethyl, methylsulfinylmethyl, and methylsulfinylmethyl esters of aspirin (acetylsalicylic acid) were cleaved in vitroin plasma to form aspirin rather than the corresponding salicylates. In vivostudies using dogs indicated that at least one aspirin derivative, methylsulfinylmethyl-2-acetoxybenzoate, is a true aspirin prodrug since aspirin was detected in the blood after prodrug administration.

Solid samples of 1, 3-dihydroxymethyluracil, 3-hydroxy-methyl-1-methyluracil, and 1-hydroxymethyl-3-methyluracil were prepared, and their structures were confirmed by spectroscopic analysis. The thermodynamics and kinetics of the formation of N-hydroxy-methylated uracils in aqueous formaldehyde solutions also were studied. The equilibrium constants for formation of N-1-hydroxymethyl derivatives were approximately twice those for formation of N-3-hydroxy-methyl derivatives, and they were formed more rapidly throughout the pH 3-8 range. Substituents at C-5 of uracil had little effect on the thermodynamics of N-hydroxymethylation. The potential usefulness of N-hydroxymethyl compounds as prodrugs is discussed.

Flow cytometric and transcriptomic analyses reveal coordinated tissue infiltration and tissue residence of donor T cells that drive gastrointestinal GVHD.

Reports on the upgrading of the Milwaukee Water Works treatment facilities with ozone filtration to provide safer drinking water. Milwaukee's past problems with the outbreak of illness caused by Cryptosporidium; Four barrier approach in designing ozonation facilities; Merits of ozonation; Ozone application. INSET: New ozone-injection methods..

7-Acetylacroninium perchlorate was hydrolyzed at 25° by both water enriched with 18O-labeled water and by unenriched water. The acronine obtained was examined by mass spectrometry, which indicated the unusual fact that hydrolysis of this ester proceeded by aryl oxygen cleavage to the extent of about 30% under those mild conditions.

The article offers information on Saint Barbara Roman Catholic Church located in Lackawanna, New York.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Details measures in Milwaukee, Wisconsin's downtown development plan aimed at improving parking in the area. Goals of the downtown plan; Availability of downtown public parking spaces; Parking concepts proposed under the plan.