Aryeh Fischer

About 90 percent of human pancreatic carcinomas show allelic loss at chromosome 18q. To identify candidate tumor suppressor genes on 18q, a panel of pancreatic carcinomas were analyzed for convergent sites of homozygous deletion. Twenty-five of 84 tumors had homozygous deletions at 18q21.1, a site that excludes DCC (a candidate suppressor gene for colorectal cancer) and includes DPC4, a gene similar in sequence to a Drosophila melanogaster gene (Mad) implicated in a transforming growth factor-beta (TGF-beta)-like signaling pathway. Potentially inactivating mutations in DPC4 were identified in six of 27 pancreatic carcinomas that did not have homozygous deletions at 18q21.1. These results identify DPC4 as a candidate tumor suppressor gene whose inactivation may play a role in pancreatic and possibly other human cancers.

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.

Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin α(X) chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c(+) B cells, both from autoimmune-prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans.