Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM‐85

Objectives Incomplete maturation of immune regulatory functions at birth is antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the microbial-derived immune training agent OM-85 during pregnancy promotes accelerated postnatal maturation of mechanisms that regulate inflammatory processes in the offspring airways. Here, we aimed to provide proof of concept for a novel solution to reduce the burden and potential long-term sequelae of severe early-life respiratory viral infection through maternal oral treatment during pregnancy with OM-85, already in widespread human clinical use. Methods In this study, we performed flow cytometry and targeted gene expression (RT-qPCR) analysis on lungs from neonatal offspring whose mothers received oral OM-85 treatment during pregnancy. We next determined whether neonatal offspring from OM-85 treated mothers demonstrate enhanced protection against lethal lower respiratory infection with mouse-adapted rhinovirus (vMC0), and associated lung immune changes. Results Offspring from mothers treated with OM-85 during pregnancy display accelerated postnatal seeding of lung myeloid populations demonstrating upregulation of function-associated markers. Offspring from OM-85 mothers additionally exhibit enhanced expression of TLR4/7 and the IL-1β/NLRP3 inflammasome complex within the lung. These treatment effects were associated with enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with concomitant regulation of viral-induced IFN response intensity. Conclusion These results demonstrate that maternal OM-85 treatment protects offspring against lethal neonatal respiratory viral infection by accelerating development of innate immune mechanisms crucial for maintenance of local immune homeostasis in the face of pathogen challenge

Ergonomic assessment of posture risk factors among Iranian workers: An alternative to conventional methods

Objectives: Work-related musculoskeletal disorders are a global problem which evolves at different workplaces such as industries, administrative, and agriculture sectors. In various studies, such disorders were assessed through multiple methods. It is necessary to evaluate different tools to use them in diverse communities. The aim of this study was to assess the validity of the new ergonomic evaluating method of Novel Ergonomic Postural Assessment (NERPA) method in Iran. Methods: The employees (n=455) of operational units of four companies (drug producers, printing and publishing houses, dairy, and drinks producers) were assessed in 2014. It was a cross-sectional and descriptive-analytical study. One of the researchers developed a questionnaire that was applied to collect demographic data. The NERPA, Rapid Upper Limb Assessment (RULA), and Rapid Entire Body Assessment (REBA) methods were utilized to analyze posture risk factors. Spearman correlation and Kappa agreement were used to analyze the collected data through SPSS V22. Results: Findings indicated that printing company had the best and pharmaceutical industries had the worst state regarding RULA's results. The risk levels between NERPA and REBA were not statistically significant (P > 0.05), however, that was significant with RULA's outcome. Also, the results of NERPA and other two methods were correlated significantly (P < 0.05). Pain in the lumbar area was implied to be the most prevalent problem (35.1). Discussion: Data of the present study suggest that NERPA method was a valid tool compared to RULA. The NERPA method could be used to evaluate standing tasks among industrial workers. However, the concurrent validity of NERPA method compared with results of REBA, as a widely used method, were not verified

Ergonomic assessment of posture risk factors among Iranian workers: An alternative to conventional methods

Objectives: Work-related musculoskeletal disorders are a global problem which evolves at different workplaces such as industries, administrative, and agriculture sectors. In various studies, such disorders were assessed through multiple methods. It is necessary to evaluate different tools to use them in diverse communities. The aim of this study was to assess the validity of the new ergonomic evaluating method of Novel Ergonomic Postural Assessment (NERPA) method in Iran. Methods: The employees (n=455) of operational units of four companies (drug producers, printing and publishing houses, dairy, and drinks producers) were assessed in 2014. It was a cross-sectional and descriptive-analytical study. One of the researchers developed a questionnaire that was applied to collect demographic data. The NERPA, Rapid Upper Limb Assessment (RULA), and Rapid Entire Body Assessment (REBA) methods were utilized to analyze posture risk factors. Spearman correlation and Kappa agreement were used to analyze the collected data through SPSS V22. Results: Findings indicated that printing company had the best and pharmaceutical industries had the worst state regarding RULA's results. The risk levels between NERPA and REBA were not statistically significant (P > 0.05), however, that was significant with RULA's outcome. Also, the results of NERPA and other two methods were correlated significantly (P < 0.05). Pain in the lumbar area was implied to be the most prevalent problem (35.1). Discussion: Data of the present study suggest that NERPA method was a valid tool compared to RULA. The NERPA method could be used to evaluate standing tasks among industrial workers. However, the concurrent validity of NERPA method compared with results of REBA, as a widely used method, were not verified

LMW-E/CDK2 Deregulates Acinar Morphogenesis, Induces Tumorigenesis, and Associates with the Activated b-Raf-ERK1/2-mTOR Pathway in Breast Cancer Patients

Elastase-mediated cleavage of cyclin E generates low molecular weight cyclin E (LMW-E) isoforms exhibiting enhanced CDK2–associated kinase activity and resistance to inhibition by CDK inhibitors p21 and p27. Approximately 27% of breast cancers express high LMW-E protein levels, which significantly correlates with poor survival. The objective of this study was to identify the signaling pathway(s) deregulated by LMW-E expression in breast cancer patients and to identify pharmaceutical agents to effectively target this pathway. Ectopic LMW-E expression in nontumorigenic human mammary epithelial cells (hMECs) was sufficient to generate xenografts with greater tumorigenic potential than full-length cyclin E, and the tumorigenicity was augmented by in vivo passaging. However, cyclin E mutants unable to interact with CDK2 protected hMECs from tumor development. When hMECs were cultured on Matrigel, LMW-E mediated aberrant acinar morphogenesis, including enlargement of acinar structures and formation of multi-acinar complexes, as denoted by reduced BIM and elevated Ki67 expression. Similarly, inducible expression of LMW-E in transgenic mice generated hyper-proliferative terminal end buds resulting in enhanced mammary tumor development. Reverse-phase protein array assay of 276 breast tumor patient samples and cells cultured on monolayer and in three-dimensional Matrigel demonstrated that, in terms of protein expression profile, hMECs cultured in Matrigel more closely resembled patient tissues than did cells cultured on monolayer. Additionally, the b-Raf-ERK1/2-mTOR pathway was activated in LMW-E–expressing patient samples, and activation of this pathway was associated with poor disease-specific survival. Combination treatment using roscovitine (CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (a pan kinase inhibitor targeting b-Raf) effectively prevented aberrant acinar formation in LMW-E–expressing cells by inducing G1/S cell cycle arrest. LMW-E requires CDK2–associated kinase activity to induce mammary tumor formation by disrupting acinar development. The b-Raf-ERK1/2-mTOR signaling pathway is aberrantly activated in breast cancer and can be suppressed by combination treatment with roscovitine plus either rapamycin or sorafenib

DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer

Ann Killary and colleagues describe a new gene that is genetically altered in breast tumors, and that may provide a new breast cancer prognostic marker

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8\u2009mg/kg loading dose, then 6\u2009mg/kg every 3\u2009weeks (q3w)] and pertuzumab (840\u2009mg loading dose, then 420\u2009mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54\u2009years; 29% had received prior trastuzumab. Median treatment duration was 16\u2009months for pertuzumab and trastuzumab and 4\u2009months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1\u2009months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design

Mothers' Experiences of Maze Path of Type 1 Diabetes Diagnosis in Children

BACKGROUND: Incidence of diabetes Type 1 in children with non-classic symptoms is one of the reasons for the delay in their follow-up. Failure in its diagnosis by the health professional exposes the mothers tomany challenges. This study was conducted to exploremothers’ experiences in the diagnosis pathway of diabetes Type 1 in children.METHODS: Semi-structured qualitative interviews were conducted with fifteen mothers of children with Type 1 diabetes.theywere selected by the purposefull sampling method.Their child had a medical file in diabetes centers in Kerman, Iran, at least one year has passed of diabetes diagnosis in their child and the maximum age of the child is 14 years. Data were analyzed using content analysis.Three themes and nine sub-themes emerged during dataanalysis.RESULTS: The extracted themes included “presence in the maze path to the child's disease”, “facing the reality of the child's disease”, and “to grin and bear with new conditions”.CONCLUSIONS: According to the finding, these mothers experienced various challenges. Therefore, identification of thesechallenges by health professionals to prevent and decrease of Them, is necessary.