Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions.

The L1 cell adhesion molecule plays an essential role in neural development and repair. It is not only a 'lock and key' recognition molecule, but an important signal transducer that stimulates regenerative-beneficial cellular functions such as neurite outgrowth, neuronal cell migration, survival, myelination, and synapse formation. Triggering L1 functions after neurotrauma improves functional recovery. In addition, loss-of-function mutations in the L1 gene lead to the L1 syndrome, a rare, X-linked neurodevelopmental disorder with an incidence of approximately 1:30,000 in newborn males. To use L1 for beneficial functions, we screened small compound libraries for L1 agonistic mimetics that trigger L1 functions and improve conditions in animal models of neurotrauma and the L1 syndrome. To understand the mechanisms underlying these functions, it is important to gain a better understanding of L1-dependent cellular signaling that is triggered by the L1 agonistic mimetics. We tested the cell signaling features of L1 agonistic mimetics that contribute to neurite outgrowth and neuronal migration. Our findings indicates that L1 agonistic mimetics trigger the same cell signaling pathways underlying neurite outgrowth, but only the L1 mimetics tacrine, polydatin, trimebutine and honokiol trigger neuronal migration. In contrast, the mimetics crotamiton and duloxetine did not affect neuronal migration, thus limiting their use in increasing neuronal migration, leaving open the question of whether this is a desired or not desired feature in the adult.

A Single Centric Quantitative Assessment of Male Breast Cancer Knowledge, Perception, and Awareness: Breaking the Stigma in Indian Population.

Most people throughout the world are still uninformed of the problem of breast cancer in men. Despite increasing awareness programs targeting women, most people are unaware that breast cancer can also affect men. Our purpose is to assess the knowledge, perception, and awareness of male breast cancer among the adult male population. A descriptive cross-sectional survey included 128 male employees who agreed to participate in our study. We distributed pre-validated questionnaires to participants and gathered data following the one-on-one interview. The mean age of the participants was 37.71 years with a standard deviation of 7.65. About 55.5% of the participants were unaware that changes in the nipple position could be a sign of breast cancer. Majority of the participants, i.e., 60.9% believe positive family history will not increase the risk of breast cancer and 93% of participants have no idea about self-breast examination to detect lumps. On the other hand, 33.6% of participants stated that diagnosis and treatment of male breast cancer is embarrassing. Majority of the participants have no idea about the screening methods, 59.4% of participants have not heard about mammography, which is considered a modality of choice for early detection of breast cancer. The male university staff were lacking in knowledge and awareness about male breast cancer. In Indian community, because of shyness, they feel very embarrassed when it comes to openly discussing breast cancer. Because of this, it needs to receive more attention and to educate the male population about male breast cancer.

Application of Antibodies to Neuronally Expressed Nogo-A Increases Neuronal Survival and Neurite Outgrowth.

Nogo-A, a glycoprotein expressed in oligodendrocytes and central nervous system myelin, inhibits regeneration after injury. Antibodies against Nogo-A neutralize this inhibitory activity, improve locomotor recovery in spinal cord-injured adult mammals, and promote regrowth/sprouting/saving of damaged axons beyond the lesion site. Nogo-A is also expressed by neurons. Complete ablation of Nogo-A in all cell types expressing it has been found to lead to recovery in some studies but not in others. Neuronal ablation of Nogo-A reduces axonal regrowth after injury. In view of these findings, we hypothesized that, in addition to neutralizing Nogo-A in oligodendrocytes and myelin, Nogo-A antibodies may act directly on neuronal Nogo-A to trigger neurite outgrowth and neuronal survival. Here, we show that polyclonal and monoclonal antibodies against Nogo-A enhance neurite growth and survival of cultured cerebellar granule neurons and increase expression of the neurite outgrowth-promoting L1 cell adhesion molecule and polysialic acid. Application of inhibitors of signal transducing molecules, such as c-src, c-fyn, protein kinase A, and casein kinase II reduce antibody-triggered neurite outgrowth. These observations indicate that the recovery-promoting functions of antibodies against Nogo-A may not only be due to neutralizing Nogo-A in oligodendrocytes and myelin, but also to their interactions with Nogo-A on neurons.

ERRATUM TO: Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis.

The authors would like to make the following corrections to their manuscript, Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis (doi: 10.12788/jhm.2961), published online first April 25, 2018 (all corrections in bold): The last sentence of the results section in the abstract should read: The pooled likelihood ratios (LRs) for all-cause mortality were positive LR 2.04 [95% CI, 1.53 to 2.72] and negative LR 0.72 [95% CI, 0.37 to 1.40]. In the "All studies pooled" of the last row of Table 2, Tn+ is corrected to 463. On page E5, the first paragraph in the "Outcomes of Studies with Corresponding Troponin+ and Troponin-" section beginning with the fifth sentence should read as follows): "In the pooled data, 463 (67%) patients tested negative for troponin and 228 (33%) tested positive. The overall mortality (from sensitivity analysis) including in-hospital, 30-day, and 90-day mortalities was 1.2%. The NPVs for all individual studies and the overall NPV are 1 or approximately 1. The overall PPVs and by study were low, ranging from 0 to 0.60. The PLRs and NLRs were not estimated for an outcome within an individual study if none of the patients experienced the outcome. When outcomes were only observed among troponin-negative patients, such as in the study of Moore (2009) who used 30-day all-cause mortality, the PLR had a value of zero. When outcomes were only observed among troponin-positive patients, as for 30-day all-cause mortality in the Hakemi9(2015), Lauque10 (2014), and Lankeit16 (2011) studies, the NLR had a value of zero. For zero cells, a continuity correction of 0.5 was applied. The pooled likelihood ratios (LRs) for all-cause mortality were positive LR 2.04 [95% CI, 1.53 to 2.72] and negative LR 0.72 [95% CI, 0.37 to 1.40]. The OR for all-cause mortality was 4.79 [95% CI 1.11 to 20.68, P = .0357].

Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with low-risk pulmonary embolism (PE) should be considered as per current scoring systems for ambulatory treatment. However, there is uncertainty whether patients with low scores and positive troponins should require hospitalization. METHODS: We searched MEDLINE, SCOPUS, and Cochrane Library databases from inception to December 2016 and collected longitudinal studies that evaluated the prognostic value of troponins in patients with low-risk PE. The primary outcome measure was 30-day all-cause mortality. We calculated odds ratio (OR), likelihood ratios (LRs), and 95% confidence intervals (CI) by using randomeffects models. RESULTS: The literature search identified 117 candidate articles, of which 16 met the criteria for review. Based on pulmonary embolism severity index (PESI) or simplified PESI score, 1.2% was the all-cause mortality rate across 2,662 participants identified as low-risk. A positive troponin status in patients with low-risk PE was associated with an increased risk of 30-day all-cause mortality (odds ratio [OR]: 4.79; 95% confidence interval [CI]: 1.11 to 20.68). The pooled likelihood ratios (LRs) for all-cause mortality were positive LR 2.04 (95% CI, 1.53 to 2.72) and negative LR 0.072 (95% CI, 0.37 to 1.40). CONCLUSIONS: The use of positive troponin status as a predictor of increased mortality in low-risk PE patients exhibited relatively poor performance given the crossed negative LR CI (1.0) and modest positive LR. Larger prospective trials must be conducted to elucidate if patients with low-risk PE and positive troponin status can avoid hospitalization.

DNAVaxDB: the first web-based DNA vaccine database and its data analysis.

Since the first DNA vaccine studies were done in the 1990s, thousands more studies have followed. Here we report the development and analysis of DNAVaxDB (http://www.violinet.org/dnavaxdb), the first publically available web-based DNA vaccine database that curates, stores, and analyzes experimentally verified DNA vaccines, DNA vaccine plasmid vectors, and protective antigens used in DNA vaccines. All data in DNAVaxDB are annotated from reliable resources, particularly peer-reviewed articles. Among over 140 DNA vaccine plasmids, some plasmids were more frequently used in one type of pathogen than others; for example, pCMVi-UB for G- bacterial DNA vaccines, and pCAGGS for viral DNA vaccines. Presently, over 400 DNA vaccines containing over 370 protective antigens from over 90 infectious and non-infectious diseases have been curated in DNAVaxDB. While extracellular and bacterial cell surface proteins and adhesin proteins were frequently used for DNA vaccine development, the majority of protective antigens used in Chlamydophila DNA vaccines are localized to the inner portion of the cell. The DNA vaccine priming, other vaccine boosting vaccination regimen has been widely used to induce protection against infection of different pathogens such as HIV. Parasitic and cancer DNA vaccines were also systematically analyzed. User-friendly web query and visualization interfaces are available in DNAVaxDB for interactive data search. To support data exchange, the information of DNA vaccines, plasmids, and protective antigens is stored in the Vaccine Ontology (VO). DNAVaxDB is targeted to become a timely and vital source of DNA vaccines and related data and facilitate advanced DNA vaccine research and development.

Updates on the web-based VIOLIN vaccine database and analysis system.

The integrative Vaccine Investigation and Online Information Network (VIOLIN) vaccine research database and analysis system (http://www.violinet.org) curates, stores, analyses and integrates various vaccine-associated research data. Since its first publication in NAR in 2008, significant updates have been made. Starting from 211 vaccines annotated at the end of 2007, VIOLIN now includes over 3240 vaccines for 192 infectious diseases and eight noninfectious diseases (e.g. cancers and allergies). Under the umbrella of VIOLIN, >10 relatively independent programs are developed. For example, Protegen stores over 800 protective antigens experimentally proven valid for vaccine development. VirmugenDB annotated over 200 'virmugens', a term coined by us to represent those virulence factor genes that can be mutated to generate successful live attenuated vaccines. Specific patterns were identified from the genes collected in Protegen and VirmugenDB. VIOLIN also includes Vaxign, the first web-based vaccine candidate prediction program based on reverse vaccinology. VIOLIN collects and analyzes different vaccine components including vaccine adjuvants (Vaxjo) and DNA vaccine plasmids (DNAVaxDB). VIOLIN includes licensed human vaccines (Huvax) and veterinary vaccines (Vevax). The Vaccine Ontology is applied to standardize and integrate various data in VIOLIN. VIOLIN also hosts the Ontology of Vaccine Adverse Events (OVAE) that logically represents adverse events associated with licensed human vaccines.