PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors,making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B-cell malignancies.We have previously reported on the discovery and preclinical characterization of PRT062607,a potent and highly selective inhibitor of SYK that exhibits robust anti-inflammatory activity in a variety of animal models.Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK),pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations.PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole-blood assays.The PD half-life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours.Selectivity for SYK was observed at all dose levels tested.Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B-cell antigen receptor-mediated B-cell activation and 205 nM for inhibition of FcRI-mediated basophil degranulation. PRT062607was safe and well tolerated acrossthe entire range ofdoses.Clinical PK/PDwas related to in vivo anti-inflammatoryactivity of PRT062607 in the rat collagen-induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease.PRT062607 has a desirable PK profile and is capable of safely,potently,and selectively suppressing SYK kinase function in humans following once-daily oral dosing

Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative

Background: Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question: Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods: Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results: Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation: Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA

In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180

COVID-19 and interstitial lung disease: Keep them separate

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Nonlinear associations between computed tomography‐measures of adiposity and long pentraxin‐3 in the Multi‐Ethnic Study of Atherosclerosis

Abstract Objective Long pentraxin‐3 (PTX‐3) is an acute phase protein associated with cardiovascular disease, lung injury, and mortality. We evaluated the association between computed tomography (CT)‐measurements of adipose tissue and plasma levels of PTX‐3. Methods We performed a cross‐sectional analysis of community‐dwelling adults enrolled in the multi‐center Multiethnic Study of Atherosclerosis who underwent cardiac or abdominal CT and had available PTX‐3 measurements. Results There was a U‐shaped association between pericardial adipose tissue volume (PAT), abdominal visceral adipose tissue area (VAT), hepatic attenuation, and PTX‐3 levels, with extremes of adiposity associated with greater PTX‐3 levels. Using multivariable‐adjusted piecewise regression models, among participants with low PAT, every 1% increase in PAT volume was associated with a 13.8% decrease in PTX‐3 (95% confidence interval [CI] −21.6 to −6.0); among participants with high PAT, every 1% increase in PAT volume was associated with a 6.0% increase in PTX‐3 (95% CI −0.4 to 12.5). Results were similar for abdominal VAT and hepatic attenuation. Conclusions In a cohort of community‐dwelling adults, we demonstrated a “U‐shaped” association between pericardial, abdominal visceral, and hepatic adiposity with PTX3 levels, suggesting that extreme adiposity is associated with greater circulating levels of PTX3. Further work is required to identify the mechanisms linking adiposity and PTX‐3