ALMA Observations of Asymmetric Molecular Gas Emission from a Protoplanetary Disk in the Orion Nebula

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of molecular line emission from d216-0939, one of the largest and most massive protoplanetary disks in the Orion Nebula Cluster (ONC). We model the spectrally resolved HCO$^+$ (4--3), CO (3--2), and HCN (4--3) lines observed at 0\farcs5 resolution to fit the temperature and density structure of the disk. We also weakly detect and spectrally resolve the CS (7--6) line but do not model it. The abundances we derive for CO and HCO$^+$ are generally consistent with expected values from chemical modeling of protoplanetary disks, while the HCN abundance is higher than expected. We dynamically measure the mass of the central star to be $2.17\pm0.07\,M_\odot$ which is inconsistent with the previously determined spectral type of K5. We also report the detection of a spatially unresolved high-velocity blue-shifted excess emission feature with a measurable positional offset from the central star, consistent with a Keplerian orbit at $60\pm20\,\mathrm{au}$. Using the integrated flux of the feature in HCO$^+$ (4--3), we estimate the total H$_2$ gas mass of this feature to be at least $1.8-8\,M_\mathrm{Jupiter}$, depending on the assumed temperature. The feature is due to a local temperature and/or density enhancement consistent with either a hydrodynamic vortex or the expected signature of the envelope of a forming protoplanet within the disk.Comment: 19 pages, 12 figures, accepted for publication in A

Gender influences health-related Quality of Life in IPF

Disclosure statements Dr. Han has received research support from the NIH. Dr. Bartholmai has received research support from the NIH and GlaxoSmithKline. Dr. Murray has received research support from the NIH. Dr. Giardino has received research support from the VAHS. Dr. Flaherty has received research support from Intermune and the NIH, consulting honorarium from GlaxoSmithKline and is a member of advisory boards for Boehringer Ingelheim and Gilead. Dr. Thompson has received research support from the NIH. Dr. Frederick has received research support from the NIH. Ms. Li has received research support from the NIH. Dr. Schwarz has received research support from the NIH. Dr. Limper received consulting fees and a research grant from Novartis and has received research support from the NIH. Dr. Martinez is a member of a steering committee for Actelion, Gilead, Centocor, and Genzyme and has received research support from Actelion and the NIH.Background HRQL in IPF patients is impaired. Data from other respiratory diseases led us to hypothesize that significant gender differences in HRQL in IPF also exist. Methods Data were drawn from the NIH-sponsored Lung Tissue Research Consortium (LTRC). Demographic and pulmonary physiology data along with MMRC, SF-12, and SGRQ scores from women vs. men were compared with two-sample t-tests. Multivariate linear regression was used to examine the association between SF-12 component scores and gender while adjusting for other relevant variables. Results The study sample consisted of 147 men and 74 women. Among several baseline variables, only DLCO% predicted differed between women and men, (43.7 vs. 38.0, p = 0.03). In general, men exhibited lower (better) MMRC scores (1.7 vs. 2.4, p = 0.02), particularly those with milder disease as measured by DLCO% predicted. In an adjusted analysis, SF-12 PCS scores in men were lower (worse) than women (p = 0.01), an effect that was more pronounced in men with greater dyspnea scores. In a similar analysis, SF-12 MCS scores in women were lower than men (worse) (48.3 vs. 54.4, p = 0.0004), an effect that was more pronounced in women with greater dyspnea scores. Conclusions Significant gender differences in HRQL exist in IPF. As compared to women, men reported less severe dyspnea, had worse SF-12 PCS scores, but better SF-12 MCS scores. Dyspnea appears to have a greater impact on the physical HRQL of men and the emotional HRQL of women. An improved understanding of the mechanism behind these differences is needed to better target interventions.This work is supported by the Lung Tissue Research Consortium (N01 HR46158 (Bartholmai), N01 HR46160 (Schwarz), N01 HR46161 (Limper), N01 HR46162 (Han, Martinez), N01 HR46164 (Li, Frederick, Thompson), KL2 RR024987 (Han), K24 HL04212 (Martinez).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91956/1/2010 Respiratory Medicine - Gender Influences health-related Quality of Life in IPF.pd

Sex differences in physiological progression of idiopathic pulmonary fibrosis

In idiopathic pulmonary fibrosis, incidence is higher in males, and females may have better survival. The aim of the present study was to determine whether the rate of increase in desaturation during serial 6-min walk testing would be greater, and survival worse, for males versus females. Serial changes in the percentage of maximum desaturation area (DA) over 1 yr were estimated using mixed models in 215 patients. DA was defined as the total area above the curve created using desaturation percentage values observed during each minute of the 6-min walk test. Multivariate Cox regression assessed survival differences. Adjusting for baseline DA, 6-min walk distance, change in 6-min walk distance over time and smoking history, the percentage of maximum DA increased by an average of 2.83 and 1.37% per month for males and females, respectively. Females demonstrated better survival overall, which was more pronounced in patients who did not desaturate below 88% on ambulation at baseline and after additionally adjusting for 6-month relative changes in DA and forced vital capacity. These data suggest that differences in disease progression contribute to, but do not completely explain, better survival of females with idiopathic pulmonary fibrosis.This work was supported by National Institutes of Health grants 5P50HL56402, U10HL080371, 2K24HL04212, K12RR024987 and K23HL68713, and the Alberta Heritage Medical Foundation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91966/1/2008 ERJ - Sex Differences in Physiologic Progression of Idiopathic Pulmonary Fibrosis.pd

Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6–17 years (≥30; including ≥20 adolescents aged 12–17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects

Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema

The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (DLCO) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n=321), 6 months (n=211) and 12 months (n=144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p=0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in DLCO or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV1 predicted mortality (HR 3.7, p=0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in DLCO. For CPFE patients, change in FEV1 was the best predictor of mortality.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91949/1/2011 ERJ - Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema.pd

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective

Background. When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a “pre-test” probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods. The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into “high” (70-100%), “intermediate” (30-70%), or “low” (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into “definite” (90-100%), “high confidence” (70-89%), “low confidence” (51-69%), or “low” (0-50%) probability of IPF. Findings. A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF (“pre-test probability of IPF”) with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior into a “post-test probability of IPF”. The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation. The present approach will help incorporate the clinical judgement into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques

BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

The Peripheral Blood Transcriptome Identifies the Presence and Extent of Disease in Idiopathic Pulmonary Fibrosis

<div><h3>Rationale</h3><p>Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. We hypothesize that peripheral blood biomarkers will identify disease in its early stages, and facilitate monitoring for disease progression.</p> <h3>Methods</h3><p>Gene expression profiles of peripheral blood RNA from 130 IPF patients were collected on Agilent microarrays. Significance analysis of microarrays (SAM) with a false discovery rate (FDR) of 1% was utilized to identify genes that were differentially-expressed in samples categorized based on percent predicted D_LCO and FVC.</p> <h3>Main Measurements and Results</h3><p>At 1% FDR, 1428 genes were differentially-expressed in mild IPF (D_LCO >65%) compared to controls and 2790 transcripts were differentially- expressed in severe IPF (D_LCO >35%) compared to controls. When categorized by percent predicted D_LCO, SAM demonstrated 13 differentially-expressed transcripts between mild and severe IPF (< 5% FDR). These include CAMP, CEACAM6, CTSG, DEFA3 and A4, OLFM4, HLTF, PACSIN1, GABBR1, IGHM, and 3 unknown genes. Principal component analysis (PCA) was performed to determine outliers based on severity of disease, and demonstrated 1 mild case to be clinically misclassified as a severe case of IPF. No differentially-expressed transcripts were identified between mild and severe IPF when categorized by percent predicted FVC.</p> <h3>Conclusions</h3><p>These results demonstrate that the peripheral blood transcriptome has the potential to distinguish normal individuals from patients with IPF, as well as extent of disease when samples were classified by percent predicted D_LCO, but not FVC.</p> </div

A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. METHODOLOGY AND PRINCIPAL FINDINGS: miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. CONCLUSION: These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing