Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13 showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer

Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds

High sensitivity of ultrasound for the diagnosis of tuberculosis in adults in South Africa: A proof-of-concept study.

BACKGROUND: There are limited data on the performance characteristics of ultrasound for the diagnosis of pulmonary tuberculosis in both HIV-positive and HIV-negative persons. The objective of this proof-of-concept study was to determine the sensitivity and specificity of ultrasound for the diagnosis of tuberculosis in adults. METHODS: Comprehensive thoracic and focused abdominal ultrasound examinations were performed by trained radiologists and pulmonologists on adults recruited from a community multimorbidity survey and a primary healthcare clinic in KwaZulu-Natal Province, South Africa. Sputum samples were systematically collected from all participants. Sensitivity and specificity of ultrasound to detect tuberculosis were calculated compared to a reference standard of i) bacteriologically-confirmed tuberculosis, and ii) either bacteriologically-confirmed or radiologic tuberculosis. RESULTS: Among 92 patients (53 [58%] male, mean age 41.9 [standard deviation 13.7] years, 49 [53%] HIV positive), 34 (37%) had bacteriologically-confirmed tuberculosis, 8 (9%) had radiologic tuberculosis with negative bacteriologic studies, and 50 (54%) had no evidence of active tuberculosis. Ultrasound abnormalities on either thoracic or abdominal exams were detected in 31 (91%) participants with bacteriologic tuberculosis and 27 (54%) of those without tuberculosis. Sensitivity and specificity of any ultrasound abnormality for bacteriologically-confirmed tuberculosis were 91% (95% confidence interval [CI] 76%-98%) and 46% (95% CI 32%-61%). Sensitivity and specificity of any ultrasound abnormality for either bacteriologically-confirmed or radiologic tuberculosis were 86% (95% CI 71%-95%) and 46% (95% CI 32%-61%). Overall performance did not appear to differ markedly between participants with and without HIV. CONCLUSION: A comprehensive ultrasound scanning protocol in adults in a high TB burden setting had high sensitivity but low specificity to identify bacteriologically-confirmed tuberculosis

Renal Transplant Immunosuppression Impairs Natural Killer Cell Function In Vitro and In Vivo

Background: Despite an increasing awareness of the importance of innate immunity, the roles of natural killer (NK) cells in transplant rejection and antiviral and cancer immunity during immunosuppression have not been clearly defined. Methods: To address this issue we have developed a quantitative assay of NK cell function that can be used on clinical samples and have studied the influence of immunosuppression on NK cell function. NK cell degranulation and intracellular interferon (IFN)-c production were determined by flow cytometry of peripheral blood samples. Results: Overnight ex vivo treatment of peripheral blood cells from healthy controls with ciclosporin or tacrolimus inhibited NK cell degranulation and IFN-c production in a dose-dependent manner. A similar impairment of function was seen in NK cells from patients treated in vivo with calcineurin inhibitors. In the early post-transplant period, there was a variable reduction of NK cell counts after treatment with alemtuzumab and basiliximab. Conclusions: The functional inhibition of NK cells in early transplant patients coincides with the period of maximum susceptibility to viral infections. The ability to assay NK cell function in clinical samples allows assessment of the impact of immunosuppressio

Assessment of Radiologist Performance in the Detection of Lung Nodules

RATIONALE AND OBJECTIVES: Studies that evaluate the lung-nodule-detection performance of radiologists or computerized methods depend on an initial inventory of the nodules within the thoracic images (the “truth”). The purpose of this study was to analyze (1) variability in the “truth” defined by different combinations of experienced thoracic radiologists and (2) variability in the performance of other experienced thoracic radiologists based on these definitions of “truth” in the context of lung nodule detection on computed tomography (CT) scans. MATERIALS AND METHODS: Twenty-five thoracic CT scans were reviewed by four thoracic radiologists, who independently marked lesions they considered to be nodules ≥ 3 mm in maximum diameter. Panel “truth” sets of nodules then were derived from the nodules marked by different combinations of two and three of these four radiologists. The nodule-detection performance of the other radiologists was evaluated based on these panel “truth” sets. RESULTS: The number of “true” nodules in the different panel “truth” sets ranged from 15–89 (mean: 49.8±25.6). The mean radiologist nodule-detection sensitivities across radiologists and panel “truth” sets for different panel “truth” conditions ranged from 51.0–83.2%; mean false-positive rates ranged from 0.33–1.39 per case. CONCLUSION: Substantial variability exists across radiologists in the task of lung nodule identification in CT scans. The definition of “truth” on which lung nodule detection studies are based must be carefully considered, since even experienced thoracic radiologists may not perform well when measured against the “truth” established by other experienced thoracic radiologists

The influence of initial outlines on manual segmentation

Purpose: Initial outlines are often presented as an aid to reduce the time-cost associated with manual segmentation and measurement of structures in medical images. This study evaluated the influence of initial outlines on manual segmentation intraobserver and interobserver precision

Novel approach to the synthesis of aliphatic and aromatic alpha-keto acids

A new practical and efficient synthesis of alpha-keto acids was accomplished starting from the synthon 1,4-diacetylpiperazine-2,5-dione. The synthesis encompasses both aromatic and aliphatic substrates proving to be versatile and innovative with excellent carbon economy and recycling of the glycine by-product.Science Foundation IrelandHigher Education Authorit

Classification of ultrasound findings.

Classification of ultrasound findings.</p