Citations

Loss of BMP (bone morphogenic protein) signaling induces a phenotype switch of pulmonary arterial smooth muscle cells (PASMCs), which is the pathological basis of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Here, we identified FGF12 (fibroblast growth factor 12) as a novel regulator of the BMP-induced phenotype change in PASMCs and elucidated its role in pulmonary vascular remodeling during PAH development. Using murine models of PAH and lung specimens of patients with PAH, we observed that FGF12 expression was significantly reduced in PASMCs. In human PASMCs, FGF12 expression was increased by canonical BMP signaling. FGF12 knockdown blocked the antiproliferative and prodifferentiation effect of BMP on human PASMCs, suggesting that FGF12 is required for the BMP-mediated acquisition of the quiescent and differentiated PASMC phenotype. Mechanistically, FGF12 regulated the BMP-induced phenotype change by inducing MEF2a (myocyte enhancer factor 2a) phosphorylation via p38MAPK signaling, thereby modulating the expression of MEF2a target genes involved in cell proliferation and differentiation. Furthermore, we observed that TG (transgenic) mice with smooth muscle cell–specific FGF12 overexpression were protected from chronic hypoxia–induced PAH development, pulmonary vascular remodeling, and right ventricular hypertrophy. Consistent with the in vitro data using human PASMCs, FGF12 TG mice showed increased MEF2a phosphorylation and a substantial change in MEF2a target gene expression, compared with the WT (wild type) controls. Overall, our findings demonstrate a novel BMP/FGF12/MEF2a pathway regulating the PASMC phenotype switch and suggest FGF12 as a potential target for the development of therapeutics for ameliorating pulmonary vascular remodeling in PAH.

AbstractFirst‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42,p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23,p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and health care apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.

ObjectiveDeficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease‐causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA).MethodsPatients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA‐2 enzyme activity was assessed in selected serum samples.ResultsNine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA‐2 enzyme activity. ADA‐2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA‐2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2.ConclusionA subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA‐2 testing should strongly be considered in patients with hepatitis B virus–negative idiopathic PAN.

Abstract Aim Female urethral stricture disease is rare and has several surgical approaches including endoscopic dilations (ENDO), urethroplasty with local vaginal tissue flap (ULT) or urethroplasty with free graft (UFG). This study aims to describe the contemporary management of female urethral stricture disease and to evaluate the outcomes of these three surgical approaches. Methods This is a multi‐institutional, retrospective cohort study evaluating operative treatment for female urethral stricture. Surgeries were grouped into three categories: ENDO, ULT, and UFG. Time from surgery to stricture recurrence by surgery type was analyzed using a Kaplan–Meier time to event analysis. To adjust for confounders, a Cox proportional hazard model was fit for time to stricture recurrence. Results Two‐hundred and ten patients met the inclusion criteria across 23 sites. Overall, 64% ( n = 115/180) of women remained recurrence free at median follow‐up of 14.6 months (IQR, 3–37). In unadjusted analysis, recurrence‐free rates differed between surgery categories with 68% ENDO, 77% UFG and 83% ULT patients being recurrence free at 12 months. In the Cox model, recurrence rates also differed between surgery categories; women undergoing ULT and UFG having had 66% and 49% less risk of recurrence, respectively, compared to those undergoing ENDO. When comparing ULT to UFG directly, there was no significant difference of recurrence. Conclusion This retrospective multi‐institutional study of female urethral stricture demonstrates that patients undergoing endoscopic management have a higher risk of recurrence compared to those undergoing either urethroplasty with local flap or free graft.

Abstract Background: Early detection decreases patient mortality for many cancers, but prevailing paradigms focus on distinct screening modalities for each cancer type. A minimally invasive test that detects multiple tumor types could substantially reduce cancer mortality and improve screening efficiency. In preliminary studies, we showed that a targeted methylation cell-free DNA (cfDNA) test can detect cancer and determine the tissue of origin (TOO) of abnormally methylated cfDNA with high sensitivity and specificity; however, blood was collected at the time of diagnosis and results were not disclosed to inform care. The current study includes disclosure of results to the study investigator to understand the care pathways prompted by a “signal detected” test result, and the benefits, harms, and burdens associated with a multi-cancer detection test. Methods: PATHFINDER (NCT04241796) is a prospective, longitudinal, multi-center clinical study. Approximately 6,200 participants with varying levels of cancer risk will be enrolled at 5-10 clinical sites in the United States. Participants must be ≥50 years of age. If participants have at least 1 of the following–a smoking history of ≥100 cigarettes, a genetic cancer predisposition, or a history of invasive or hematologic malignancy with definitive treatment completed >3 years prior to enrollment–they are eligible for the Elevated Risk Cohort (n = 4340); otherwise, they are eligible for the Non-Elevated Risk Cohort (n = 1860). Individuals being evaluated for cancer or who have a history of invasive or hematologic malignancy within 3 years of enrollment will be excluded. Blood drawn at study sites will be analyzed at GRAIL, Inc. (Menlo Park, CA). Participants and study investigators will be informed of the test results. Participants with “signal not detected” results will be advised to continue routine clinical care, including age- and risk-based cancer screening. Those with “signal detected” test results will be informed of the predicted origin and undergo diagnostic evaluation. The primary study objective is to determine the extent of diagnostic testing required to achieve diagnostic resolution following a “signal detected” test result, defined as the date when the study investigator determines to end diagnostic evaluation triggered by a “signal detected” test result. Health resource utilization, the number and types of tests and time required to reach this point, is the primary endpoint. Secondary objectives include evaluation of test performance (specificity, positive predictive value, and TOO accuracy), and assessment of participants' perceptions about the test and changes in anxiety and health-related quality of life. Exploratory aims include assessment of the number and types of invasive cancer diagnoses among participants with “signal not detected” test results and changes in attitude toward adherence to guideline-recommended screening. Citation Format: Lincoln Nadauld, Charles H. McDonnell III, Minetta C. Liu, Eric Klein, Tomasz M. Beer, Deborah Schrag, Andrew G. Hudnut, Richard Whittington, Bruce Taylor, Joanna Tierney, Catherine Marinac, Jafi Lipson, Margarita Lopatin, Karen C. Chung, Eric Fung, Anne-Renee Hartman, Geoffrey R. Oxnard. The PATHFINDER Study: Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT291.

Abstract Purpose: Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme over-expressed by tumor cells. Our group and others have shown that QSOX1 is involved in invasion and metastasis. We previously reported that a small molecule, SBI-183, inhibited the enzymatic activity of QSOX1 and suppressed tumor cell invasion in vitro and metastasis of MDA-MB-231 breast tumor cells in vivo. In our current work we tested SPX-009, an analog of SBI-183 with increased potency, to suppress invasion and metastasis in vitro and in vivo. Methods: Commercially available analogs for SBI-183 were screened in a cell-free fluorescent screening assay for the ability to inhibit QSOX1. Analog compounds that inhibited QSOX1 in a concentration-dependent manner were then tested for the ability to inhibit growth and invasion of triple negative breast cancer (TNBC) cells (MDA-MB-231), sarcomatoid kidney cancer cells (RCJ-41T2) and pancreatic adenocarcinoma cells (MIAPaCa2). MTT assays were used to measure the effect of the compounds on tumor growth. 2D invasion assays and 3D tumor spheroid assays were employed to measure the effect of the analogs on invasion. One potent analog (SPX-009) was evaluated for the ability to suppress tumor growth and metastasis in mice bearing MDA-MB-231-luc breast cancer orthotopic xenografts. Results: Three of 53 analogs inhibited the enzymatic activity of QSOX1 at levels similar to the parent compound. However, one of those compounds, SPX-009, suppressed invasion of breast, kidney and pancreas tumor cells in 2D and 3D invasion assays at >10-fold lower concentrations than the parent compound (SBI-183). In a non-metastatic xenograft of kidney cancer SBI-183 suppressed primary kidney tumor growth by 51%, but in a metastatic xenograft breast cancer model (MDA-MB-231-luc TNBC), SBI-183 reduced lung metastasis by 76% compared to control. Human-mouse xenograft studies are ongoing with the more potent analog (SPX-009) and will also be presented. Conclusions: Chemical inhibitors of QSOX1 have a minor effect on tumor cell viability, but a major effect on tumor cell invasion in vitro and metastasis in vivo. This finding suggests that combining a QSOX1 inhibitor with a cytotoxic agent might provide a means to inhibit metastasis of cells that are resistant to cytotoxic agents. Citation Format: Amber Fifield, Thai H. Ho, Douglas O. Faigel, Sergei Svarovsky, Eduard Sergienko, Thomas C. Chung, Douglas F. Lake. Chemical inhibitors of quiescin sulfhydryl oxidase (QSOX1) suppress tumor invasion and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5323.

Objective The aim of the study was to compare the prevalence of diffuse pulmonary ossification (DPO) in idiopathic pulmonary fibrosis (IPF), systemic sclerosis (SSc)-related interstitial lung disease (ILD), and chronic hypersensitivity pneumonitis (HP). Methods High-resolution computed tomography (HRCT) from 71 IPF, 67 SSc-ILD, and 75 HP cases were independently evaluated by 2 thoracic radiologists blinded to patient data. Studies were assessed for the presence of DPO, HRCT scanning pattern, stigmata of granulomatous infection, and honeycombing. Results The prevalence of DPO was significantly higher in cases of IPF and SSc compared with HP, although there was no significant difference in prevalence between the IPF and SSc groups, even when accounting for the presence of prior granulomatous infection. Interobserver agreement for the presence of DPO was substantial. Conclusions Although prevalence DPO on HRCT varies between some forms of ILD, the use of DPO to influence characterization of ILD should be considered with caution.