Doubly Penalized Buckley-James Method for Survival Data with High-Dimensional Covariates

Recent interest in cancer research focuses on predicting patients\u27 survival by investigating gene expression profiles based on microarray analysis. We propose a doubly penalized Buckley-James method for the semiparametric accelerated failure time model to relate high-dimensional genomic data to censored survival outcomes, which uses a mixture of L1-norm and L2-norm penalties. Similar to the elastic-net method for linear regression model with uncensored data, the proposed method performs automatic gene selection and parameter estimation, where highly correlated genes are able to be selected (or removed) together. The two-dimensional tuning parameter is determined by cross-validation and uniform design. The proposed method is evaluated by simulations and applied to the Michigan squamous cell lung carcinoma study

Executive Functioning Skills in Preschool-Age Children With Cochlear Implants

Purpose The purpose of this study was to determine whether deficits in executive functioning (EF) in children with cochlear implants (CIs) emerge as early as the preschool years. Method Two groups of children ages 3 to 6 years participated in this cross-sectional study: 24 preschoolers who had CIs prior to 36 months of age and 21 preschoolers with normal hearing (NH). All were tested on normed measures of working memory, inhibition-concentration, and organization-integration. Parents completed a normed rating scale of problem behaviors related to EF. Comparisons of EF skills of children with CIs were made to peers with NH and to published nationally representative norms. Results Preschoolers with CIs showed significantly poorer performance on inhibition-concentration and working memory compared with peers with NH and with national norms. No group differences were found in visual memory or organization-integration. When data were controlled for language, differences in performance measures of EF remained, whereas differences in parent-reported problems with EF were no longer significant. Hearing history was generally unrelated to EF. Conclusions This is the first study to demonstrate that EF deficits found in older children with CIs begin to emerge as early as preschool years. The ability to detect these deficits early has important implications for early intervention and habilitation after cochlear implantation

Neurocognitive Risk in Children With Cochlear Implants

IMPORTANCE Children who receive a cochlear implant (CI) for early severe to profound sensorineural hearing loss may achieve age-appropriate spoken language skills not possible before implantation. Despite these advances, reduced access to auditory experience may have downstream effects on fundamental neurocognitive processes for some children with CIs. OBJECTIVE To determine the relative risk (RR) of clinically significant executive functioning deficits in children with CIs compared with children with normal hearing (NH). DESIGN, SETTING, AND PARTICIPANTS In this prospective, cross-sectional study, 73 children at a hospital-based clinic who received their CIs before 7 years of age and 78 children with NH, with average to above average mean nonverbal IQ scores, were recruited in 2 age groups: preschool age (age range, 3–5 years) and school age (age range, 7–17 years). No children presented with other developmental, cognitive, or neurologic diagnoses. INTERVENTIONS Parent-reported checklist measures of executive functioning were completed during psychological testing sessions. MAIN OUTCOMES AND MEASURES Estimates of the RR of clinically significant deficits in executive functioning (≥ 1 SDs above the mean) for children with CIs compared with children with NH were obtained based on 2 parent-reported child behavior checklists of everyday problems with executive functioning. RESULTS In most domains of executive functioning, children with CIs were at 2 to 5 times greater risk of clinically significant deficits compared with children with NH. The RRs for preschoolers and school-aged children, respectively, were greatest in the areas of comprehension and conceptual learning (RR [95% CI], 3.56 [1.71–7.43] and 6.25 [2.64–14.77]), factual memory ( 4.88 [1.58–15.07] and 5.47 [2.03–14.77]), attention (3.38 [1.03–11.04] and 3.13 [1.56–6.26]), sequential processing (11.25 [1.55–81.54] and 2.44 [1.24–4.76]), working memory (4.13 [1.30–13.06] and 3.64 [1.61–8.25] for one checklist and 1.77 [0.82–3.83] and 2.78 [1.18–6.51] for another checklist), and novel problem-solving (3.93 [1.50–10.34] and 3.13 [1.46–6.67]). No difference between the CI and NH samples was found for visual-spatial organization (2.63 [0.76–9.03] and 1.04 [0.45–2.40] on one checklist and 2.86 [0.98–8.39] for school-aged children on the other checklist). CONCLUSIONS AND RELEVANCE A large proportion of children with CIs are at risk for clinically significant deficits across multiple domains of executive functioning, a rate averaging 2 to 5 times that of children with NH for most domains. Screening for risk of executive functioning deficits should be a routine part of the clinical evaluation of all children with deafness and CIs

Automated integration of monolith-based protein separation with on-plate digestion for mass spectrometric analysis of esophageal adenocarcinoma human epithelial samples

A unique approach of automating the integration of monolithic capillary HPLC-based protein separation and on-plate digestion for subsequent MALDI-MS analysis has been developed. All liquid-handling procedures were performed using a robotic module. This automated high-throughput method minimizes the amount of time and extensive labor required for traditional in-solution digestion followed by exhaustive sample cleanup and analysis. Also, precise positioning of the droplet from the capillary HPLC separation onto the MALDI plate allows for preconcentration effects of analytes for improved sensitivity. Proteins from primary esophageal Barrett's adenocarcinoma tissue were prefractionated by chromatofocusing and analyzed successfully by this automated configuration, obtaining rapid protein identifications through PMF and sequencing analyses with high sequence coverage. Additionally, intact protein molecular weight values were obtained as a means to further confirm protein identification and also to identify potential sequence modifications of proteins. This simple and rapid method is a highly versatile and robust approach for the analysis of complex proteomes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55811/1/3643_ftp.pd

Signatures of Drug Sensitivity in Nonsmall Cell Lung Cancer

We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways. A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the tumor cell growth. The HER1 pathway in HER1 mutant cell lines HCC827 and H1975 were found to be highly activated and sensitive to HER1 inhibition. H1993 is a c-MET amplified cell line showing c-MET and HER1 pathway activation and responsiveness to c-MET inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H1650 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not H358, A549 and H460. Hierarchical clustering of primary tumor samples with the corresponding tumor cell lines based on their pathway signatures revealed similar profiles for HER1, c-MET and IGF-1R pathway activation and predict potential treatment options for the primary tumors based on the tumor cell lines response to the panel of kinase inhibitors

Identification of intestinal-type Barrett's metaplasia by using the intestine-specific protein villin and esophageal brush cytology

Villin is an actin-binding cytoskeletal protein required for brush-border formation in the normal small intestinal and renal proximal tubule epithelium. Villin is a marker of cell differentiation in small intestinal and renal cell lineages, and recent studies have shown villin to be highly expressed in 100% of intestinal-type Barrett's metaplasias. This epithelium is the single greatest risk factor for developing esophageal adenocarcinoma and arises when the normal esophageal squamous epithelium is replaced by a small intestine–like columnar epithelium after damage by chronic gastroesophageal reflux. In intestinal-type Barrett's metaplasia, the villin protein exhibits a highly characteristic staining pattern in which strong apical, brush-border staining of columnar epithelial cells is observed. In this study, the ability to identify intestinal metaplastic cells by using this distinct villin staining pattern was examined in endoscopic esophageal brushings from patients with confirmed Barrett's metaplasia. Esophageal brushings from 81% (17 of 21) of patients with Barrett's metaplasia demonstrated individual columnar cells with the characteristic villin staining pattern, whereas all normal esophageal squamous cells, blood cells, and gastric columnar cells were negative for villin expression. Northern blot analysis demonstrated villin mRNA expression in Barrett's metaplasia but not in the normal squamous esophagus or gastric mucosa from the same patients. The combined use of villin immunohistochemical analysis and esophageal brush cytology may provide a simple and effective method of detecting intestinal-type Barrett's metaplasia in patients at higher risk for developing this epithelium, such as those experiencing chronic gastroesophageal reflux symptoms. Mol. Carcinog. 24:137–143, 1999. © 1999 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35059/1/8_ftp.pd

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly

Housing Affordability, Tenure and Mental Health in Australia and the United Kingdom: A Comparative Panel Analysis

The paper contributes insights into the role of tenure in modifying the relationship between housing affordability and health, using a cross-national comparison of similar post-industrial nations ? Australia and the United Kingdom ? with different tenure structures. The paper utilises longitudinal data from the Household, Income and Labour Dynamics in Australia Survey (HILDA) and British Household Panel Survey (BHPS) to examine change in the mental health of individuals associated with housing becoming unaffordable and considers modification by tenure. We present evidence that the role of tenure in the relationship between housing and health is context dependent and should not be unthinkingly generalised across nations. These findings suggest that the UK housing context offers a greater level of protection to tenants living in unaffordable housing when compared with Australia, and this finds expression in the mental health of the two populations. We conclude that Australian governments could improve the mental health of their economically vulnerable populations through more supportive housing policies

Using second harmonic generation to predict patient outcome in solid tumors

Abstract Background Over-treatment of estrogen receptor positive (ER+), lymph node-negative (LNN) breast cancer patients with chemotherapy is a pressing clinical problem that can be addressed by improving techniques to predict tumor metastatic potential. Here we demonstrate that analysis of second harmonic generation (SHG) emission direction in primary tumor biopsies can provide prognostic information about the metastatic outcome of ER+, LNN breast cancer, as well as stage 1 colorectal adenocarcinoma. Methods SHG is an optical signal produced by fibrillar collagen. The ratio of the forward-to-backward emitted SHG signals (F/B) is sensitive to changes in structure of individual collagen fibers. F/B from excised primary tumor tissue was measured in a retrospective study of LNN breast cancer patients who had received no adjuvant systemic therapy and related to metastasis-free survival (MFS) and overall survival (OS) rates. In addition, F/B was studied for its association with the length of progression-free survival (PFS) in a subgroup of ER+ patients who received tamoxifen as first-line treatment for recurrent disease, and for its relation with OS in stage I colorectal and stage 1 lung adenocarcinoma patients. Results In 125 ER+, but not in 96 ER-negative (ER-), LNN breast cancer patients an increased F/B was significantly associated with a favorable MFS and OS (log rank trend for MFS: p = 0.004 and for OS: p = 0.03). On the other hand, an increased F/B was associated with shorter PFS in 60 ER+ recurrent breast cancer patients treated with tamoxifen (log rank trend p = 0.02). In stage I colorectal adenocarcinoma, an increased F/B was significantly related to poor OS (log rank trend p = 0.03), however this relationship was not statistically significant in stage I lung adenocarcinoma. Conclusion Within ER+, LNN breast cancer specimens the F/B can stratify patients based upon their potential for tumor aggressiveness. This offers a “matrix-focused” method to predict metastatic outcome that is complementary to genomic “cell-focused” methods. In combination, this and other methods may contribute to improved metastatic prediction, and hence may help to reduce patient over-treatment.http://deepblue.lib.umich.edu/bitstream/2027.42/116036/1/12885_2015_Article_1911.pd

Blood Omega-3 Fatty Acids Are Inversely Associated With Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study).

Background: Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. Design and Methods: The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Results: Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m2 (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; p = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; p = 0.47). Conclusions: A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR