Isaac Jenkins

A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life

RATIONALE Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline. OBJECTIVES We aimed to determine if there were individuals with a distinct, persistently low lung function trajectory in the CRS (Tucson Childrens Respiratory Study). METHODS The CRS, an ongoing birth cohort study, enrolled 1,246 participants between 1980 and 1984. Latent class linear mixed effects modeling of the ratio of FEV1 to FVC was used to identify distinct lung function trajectories among participants with two or more spirometry measurements between ages 11 and 32 years. MEASUREMENTS AND MAIN RESULTS Among 599 participants with 2,142 observations, a model with two distinct trajectories (a low trajectory [n = 56; 9.3%] and a normal trajectory) fit the data significantly better than a model with only one trajectory (P = 0.0007). As compared with those with a normal trajectory, participants with a persistently low trajectory were more likely to have a history of maternal asthma (20.0% vs. 9.9%; P = 0.02); early life lower respiratory illness caused by respiratory syncytial virus (41.2% vs. 21.4%; P = 0.001); and physician-diagnosed active asthma at age 32 years (43.9% vs. 16.2%; P < 0.001). Individuals with a persistently low trajectory also demonstrated lower lung function as measured by average maximal expiratory flow at functional residual capacity during infancy and at age 6 years. CONCLUSIONS A distinct group of individuals in a nonselected population demonstrates a persistently low lung function trajectory that may be partly established at birth and predisposes them to chronic obstructive pulmonary disease later in life.

Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma.

Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

A two-stage statistical procedure for feature selection and comparison in functional analysis of metagenomes

MOTIVATION With the advance of new sequencing technologies producing massive short reads data, metagenomics is rapidly growing, especially in the fields of environmental biology and medical science. The metagenomic data are not only high dimensional with large number of features and limited number of samples but also complex with a large number of zeros and skewed distribution. Efficient computational and statistical tools are needed to deal with these unique characteristics of metagenomic sequencing data. In metagenomic studies, one main objective is to assess whether and how multiple microbial communities differ under various environmental conditions. RESULTS We propose a two-stage statistical procedure for selecting informative features and identifying differentially abundant features between two or more groups of microbial communities. In the functional analysis of metagenomes, the features may refer to the pathways, subsystems, functional roles and so on. In the first stage of the proposed procedure, the informative features are selected using elastic net as reducing the dimension of metagenomic data. In the second stage, the differentially abundant features are detected using generalized linear models with a negative binomial distribution. Compared with other available methods, the proposed approach demonstrates better performance for most of the comprehensive simulation studies. The new method is also applied to two real metagenomic datasets related to human health. Our findings are consistent with those in previous reports. AVAILABILITY R code and two example datasets are available at http://cals.arizona.edu/∼anling/software.htm. SUPPLEMENTARY INFORMATION Supplementary file is available at Bioinformatics online.

Phase I/II Trial of Combined Pegylated Liposomal Doxorubicin and Cyclophosphamide in Metastatic Breast Cancer

Micro‐Abstract Conventional doxorubicin in combination with cyclophosphamide is active in breast cancer; however, use in metastatic disease is limited by significant toxicity and poor tolerability. This phase I/II trial (n = 30) demonstrated that pegylated liposomal doxorubicin with daily oral cyclophosphamide is an active and tolerable regimen with modest toxicity and reasonable efficacy. Introduction: Doxorubicin in combination with cyclophosphamide is active in breast cancer; however, its use in metastatic cancer is limited owing to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was formulated to decrease the toxicity of conventional doxorubicin. We evaluated the safety and efficacy of PLD with metronomic oral cyclophosphamide. Patients and Methods: We conducted a single‐arm open‐label phase I/II study of PLD and oral cyclophosphamide in patients with metastatic breast cancer. In phase I, 3 escalating doses of PLD were planned (30, 35, and 40 mg/m2) with cyclophosphamide (60 mg/m2 orally daily) to determine the maximum tolerated dose (MTD). In phase II, the MTD of PLD in combination of oral cyclophosphamide was used to assess the primary endpoint of overall clinical response rate and secondary endpoints of progression‐free survival, overall survival, and adverse events. Results: Thirty patients were enrolled in the study (n = 6 in phase I and n = 24 in phase II). The MTD of PLD from phase I was 30 mg/m2. The median progression‐free and overall survival for the entire cohort were 6.4 months (95% confidence interval, 3.9 months to N/A) and 18.7 months (95% confidence interval, 15.1‐31.5 months), respectively. A total of 21 (75%) patients had clinical benefit, including 6 (21%) patients with partial response and 15 (54%) patients with stable disease. The majority of toxicities were uncomplicated myelosuppression, and no infection or febrile neutropenia were noted in any patient. Conclusion: PLD in combination with daily oral cyclophosphamide is an active and tolerable regimen in metastatic breast cancer.

Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells

Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D+ cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states. NKG2D+ ovarian cancer cell populations harbor substantially greater capacities for self-renewing in vitro sphere formation and in vivo tumor initiation in immunodeficient (NOD scid gamma) mice than NKG2D− controls. Sphere formation and tumor initiation are impaired by NKG2D silencing or ligand blockade using antibodies or a newly designed pan ligand-masking NKG2D multimer. In further support of pathophysiological significance, a prospective study of 47 high-grade serous ovarian cancer cases revealed that the odds of disease recurrence were significantly greater and median progression-free survival rates higher among patients with above and below median NKG2D+ cancer cell frequencies, respectively. Collectively, our results define cancer cell NKG2D as an important regulator of tumor initiation in ovarian cancer and presumably other malignancies and thus challenge current efforts in immunotherapy aimed at enhancing NKG2D function.

Selective pulmonary vasodilation improves ventriculovascular coupling and gas exchange in a patient with unrepaired single-ventricle physiology

We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.

Prospective study of serial 18F-FDG PET and 18F-fluoride (18F-NaF) PET to predict time to skeletal related events, time-to-progression, and survival in patients with bone-dominant metastatic breast cancer

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18F-FDG PET was predictive of time to skeletal-related events (tSRE) and time to progression (TTP). 18F-NaF PET improves bone metastasis detection compared with bone scanning. We prospectively tested 18F-FDG PET and 18F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (MBC). Methods: Patients with bone-dominant MBC were imaged with 18F-FDG PET and 18F-NaF PET before starting new therapy (scan1) and again at a range of times centered around approximately 4 mo later (scan2). Maximum standardized uptake value (SUVmax) and lean body mass adjusted standardized uptake (SULpeak) were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18F-FDG PET and 18F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) were also applied. Survival curves for mPERCIST compared response categories of complete response+partial response+stable disease versus progressive disease for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher 18F-FDG SULpeak at scan2 predicted shorter time to tSRE (P = <0.001) and TTP (P = 0.044). Higher 18F-FDG SUVmax at scan2 predicted a shorter time to tSRE (P = <0.001). A multivariable model using 18F-FDG SUVmax of the index lesion at scan1 plus the difference in SUVmax of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18F-FDG PET mPERCIST, tSRE and TTP were longer in responders (complete response, partial response, or stable disease) than in nonresponders (progressive disease) (P = 0.007, 0.028, respectively), with a trend toward improved survival (P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18F-NaF PET was associated with longer OS (P = 0.027). Conclusion: Changes in 18F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18F-NaF PET was associated with OS but was not useful for predicting TTP or tSRE in bone-dominant MBC.

Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation

Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication after hematopoietic cell transplantation (HCT) and is difficult to diagnose. In 41 patients with IPS, we evaluated 6 candidate proteins in plasma samples at day 7 post-HCT and at onset of IPS to identify potential diagnostic or prognostic biomarkers for IPS. Samples at similar times from 162 HCT recipients without documented infections and 37 HCT recipients with respiratory viral pneumonia served as controls. In multivariable models, a combination of Stimulation-2 (ST2; odds ratio [OR], 2.8; P < .001) and IL-6 (OR, 1.4; P = .025) was the best panel for distinguishing IPS at diagnosis from unaffected controls, whereas tumor necrosis factor receptor 1 (TNFR1; OR, 2.9; P = .002) was the best marker when comparing patients with IPS and viral pneumonia. The areas under the curve of the receiver operating characteristic (ROC) curves for discriminating between IPS and unaffected controls at day 7 post-HCT were .8 for ST2, .75 for IL-6, and .68 for TNFR1. Using estimated sensitivity and specificity values from cutoffs determined with the ROC analysis (cutoff level: ST2, 21 ng/mL; IL-6, 61 pg/mL; TNFR1, 3421 pg/mL), we calculated positive predictive values (PPV) for a range of estimated population prevalence values of IPS. Among the 3 markers, ST2 showed the highest PPV for IPS occurrence. Based on an assumed prevalence of 8%, a positive ST2 test increased likelihood of IPS to 50%. We conclude that a prospective validation study is warranted to determine whether a plasma biomarker panel can aid the noninvasive diagnosis and prognosis of IPS.