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Neuropilins are transmembrane glycoproteins that regulate developmental processes in the nervous system and other tissues. Overexpression of neuropilin-1 (NRP1) occurs in many solid tumor types and, in several instances, may predict patient outcome in terms of overall survival. Experimental inhibition of NRP1 activity can display antitumor effects in different cancer models. Here, we review NRP1 expression and function in adult and pediatric brain cancers, particularly glioblastomas (GBMs) and medulloblastomas, and present analyses of NRP1 transcript levels and their association with patient survival in GBMs. The case of NRP1 highlights the potential of regulators of neurodevelopment as biomarkers and therapeutic targets in brain cancer.

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OBJECTIVE: To evaluate impact of a multihospital collaborative quality improvement project implementing in situ simulation training for neonatal resuscitation on clinical outcomes for infants born preterm. STUDY DESIGN: Twelve neonatal intensive care units were divided into 4 cohorts; each completed a 15-month long program in a stepped wedge manner. Data from California Perinatal Quality Care Collaborative were used to evaluate clinical outcomes. Infants with very low birth weight between 22 through 31 weeks gestation were included. Primary outcome was survival without chronic lung disease (CLD); secondary outcomes included intubation in the delivery room, delivery room continuous positive airway pressure, hypothermia (<36°C) upon neonatal intensive care unit admission, severe intraventricular hemorrhage, and mortality before hospital discharge. A mixed effects multivariable regression model was used to assess the intervention effect. RESULTS: Between March 2017 and December 2020, a total of 2626 eligible very low birth weight births occurred at 12 collaborative participating sites. Rate of survival without CLD at participating sites was 74.1% in March to August 2017 and 76.0% in July to December 2020 (risk ratio 1.03; [0.94-1.12]); no significant improvement occurred during the study period for both participating and nonparticipating sites. The effect of in situ simulation on all secondary outcomes was stable. CONCLUSIONS: Implementation of a multihospital collaborative providing in situ training for neonatal resuscitation did not result in significant improvement in survival without CLD. Ongoing in situ simulations may have an impact on unit practice and unmeasured outcomes.

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During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.

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Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor. Neuropilin-1 (NRP1), encoded by the NRP1 gene, is a transmembrane glycoprotein overexpressed in several types of cancer. Previous studies indicate that NRP1 inhibition displays antitumor effects in MB models and higher NRP1 levels are associated with poorer prognosis in MB patients. Here, we used a large MB tumor dataset to examine NRP1 gene expression in different molecular subgroups and subtypes of MB. We found overall widespread NRP1 expression across MB samples. Tumors in the sonic hedgehog (SHH) subgroup showed significantly higher NRP1 transcript levels in comparison with Group 3 and Group 4 tumors, with SHH samples belonging to the α, ß, Δ, and γ subtypes. When all MB subgroups were combined, lower NRP1 expression was associated with significantly shorter patient overall survival (OS). Further analysis showed that low NRP1 was related to poorer OS, specifically in MB subgroups SHH and Group 3 MB. Our findings indicate that patients with SHH and Group 3 tumors that show lower expression of NRP1 in MB have a worse prognosis, which highlights the need for subgroup-specific investigation of the NRP1 role in MB.

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Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

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Paenibacillus elgii AC13 produces antimicrobial lipopeptides of agricultural and pharmaceutical importance. It secretes four cyclic lipopeptides named pelgipeptins, previously characterized in P. elgii B69. These lipopeptides result from the expression of a nonribosomal peptide gene cluster. P. elgii AC13 also produced two linear lipopeptides with ratios of [M + H] + 1105 and 1119 m/z. These compounds were previously observed in Paenibacillus sp. strain OSY-N, but due to purification difficulties, their characterization was executed using synthetically produced linear pelgipeptins. In the present study, purification was achieved from the supernatants of cultures from three complex media by high-performance liquid chromatography. The partial characterization of linear pelgipeptins revealed the similar antimicrobial activity and cytotoxicity of their synthetically produced counterparts, known as paenipeptins. Cyclic forms were highly stable to changes in pH, temperature, and organic extraction with n-butanol as shown by mass spectrometry (MALDI-TOF); therefore, these steps did not cause the hydrolysis of pelgipeptins. A low-activity thioesterase could also generate the linear isoforms observed; this enzyme catalyzes the cyclization process and is coded in the same gene cluster. Alternatively, the cyclic forms were hydrolyzed by an unknown protease produced during growth in the complex medium used in the present study. Although culture conditions are known to produce pelgipeptins with different yields and amino acid compositions, the occurrence of linear and cyclic forms simultaneously has not yet been reported. A mixture of cyclic and linear pelgipeptins presents a potential advantage of the higher antimicrobial activity of cyclic forms combined with the lower cytotoxicity of linear isoforms.

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In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.

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AIM: To quantify the expression of angiogenic growth factors (ANG2, VEGFA, TGFß1) and their corresponding receptors (VEGFR1, VGFR2, NRP1 and TGFßR1) in human dental pulps from extracted third molars with complete and incomplete root development. METHODOLOGY: Fifty-six dental pulp samples obtained from freshly extracted human third molars were divided equally into two groups according to their stage of root development; 28 third molars with complete root development and 28 third molars with incomplete root development. All samples were processed and total RNA was extracted, cDNA was then synthetized for each sample and the target genes expression profiles for ANG2, VEGFA, VEGFR1, VEGFR2, NRP1, TGFß1 and TGFßR1 were obtained by RT2-PCR. The data was analysed with a Student's t-test to compare the replicate ∆∆Ct values for each gene. RESULTS: Teeth with incomplete root development were associated with a significantly greater gene expression of TGFßR1 (P = 0.03), whereas in teeth with complete root development the genes that had significantly greater expression were VEGFA (P = 0.04). CONCLUSION: The angiogenic growth factors (ANG2, VEGFA, TGFß1) and their receptors (NRP1, VEGFR1, VEGFR2 and TGFßR1) were expressed in pulps of teeth with complete and incomplete root development measured by RT2-PCR, with TGFBR1 genes being significantly different in teeth with incomplete root development and VEGFA genes in teeth with complete root development.

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The typical characteristics of mesenchymal stem cells (MSCs) can be affected by inflammatory microenvironment; however, the exact contribution of HTLV-1 to MSC dysfunction remains to be elucidated. In this study, we demonstrated that MSC cell surface molecules VCAM-1 and ICAM-1 are upregulated by contact with HTLV-1, and HLA-DR was most highly expressed in MSCs co-cultured with MT2 cells. The expression levels of VCAM-1 and HLA-DR were increased in MSCs cultured in the presence of PBMCs isolated from HTLV-1-infected symptomatic individuals compared with those cultured with cells from asymptomatic infected individuals or healthy subjects. HTLV-1 does not impair the MSC differentiation process into osteocytes and adipocytes. In addition, MSCs were efficiently infected with HTLV-1 in vitro through direct contact with HTLV-1-infected cells; however, cell-free virus particles were not capable of causing infection. In summary, HTLV-1 can alter MSC function, and this mechanism may contribute to the pathogenesis of this viral infection.

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OBJECTIVE: To determine whether resuscitation teams can better maintain newborn transitional oxygen saturation (SpO2) values within a prespecified target range using a graphical display of the targets and real-time SpO2 data compared with using only numerical oximeter values. STUDY DESIGN: Preterm neonates were enrolled in this prospective cohort evaluation of a change in practice. The Transitional Oxygen Targeting System (TOTS) plots real-time SpO2 values in relation to 10th and 50th percentile SpO2 curves, which provides a visual target. After introduction of the TOTS, the resuscitation team adjusted the fraction of inspired oxygen to maintain the SpO2 within the target range, and before its use neonates were resuscitated in attempt to target normal transitional SpO2 values without using the TOTS monitor. Duration of time within 10th-50th percentile values was compared between 2 cohorts, children evaluated with the TOTS and those not evaluated with the TOTS (controls). RESULTS: A total of 40 infants were enrolled, including 20 prospectively evaluated with the TOTS and 20 controls. Mean gestational age, birth weight, total resuscitation time, duration of supplemental oxygen administration, changes in oxygen concentration, and respiratory support provided were similar in the 2 groups. The TOTS cohort spent 52% of time within the target range; the control cohort, 37% (P = .03). CONCLUSION: SpO2 values were maintained within a specified target range for significantly longer in preterm neonates resuscitated using the TOTS display compared with those resuscitated without TOTS.

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A Atenção Farmacêutica tem se constituído numa nova prática clínica para o farmacêutico. O estudo tem por objetivo apresentar os indicadores do Serviço de Atenção Farmacêutica da Universidade do Sul de Santa Catarina. Foi realizada a análise documental dos prontuários farmacêuticos de 58 pacientes entre setembro de 2007 a março de 2008. A maioria dos pacientes eram mulheres (77,6 por cento) com idade média de 54 anos. Identificou-se no primeiro encontro a média de 4,6 problemas de saúde por paciente e no último 4,3. As classes farmacológicas mais prevalentes foram a cardiovascular (30,2 por cento) e no sistema nervoso (27,5 por cento). Detectou-se média de 2,7 problemas relacionados com medicamentos por paciente, sendo os mais comuns aqueles relacionados à efetividade e à segurança. Dos problemas identificados 82,2 por cento foram classificados como evitáveis e 63,7 por cento como manifestados. Das intervenções farmacêuticas registradas soube-se da aceitação de 79,0 por cento com 78,9 por cento de resultados positivos. Encontrou-se média de 2,6 necessidades relacionadas ao paciente sendo, principalmente, dúvidas quanto à terapia farmacológica (30,4 por cento) sendo em 84,8 por cento dos casos supridas.

Pharmaceutical Care has represented a new clinical practice for pharmacists. This study aims to show the indicators of the Pharmaceutical Care Service at the University of Southern Santa Catarina. Documentary analysis of pharmaceutical records of 58 patients was conducted between September 2007 and March 2008 to identify the indicators. Most patients were women (77.6 percent), with a mean age of 54 years. Average number of health problems per patient was 4.6 in the first visit and 4.3 in the last one. The most widely used drug classes were cardiovascular (30.2 percent) and nervous system (27.5 percent). On average, 2.7 drug-related problems per patient were detected, the most common being those related to effectiveness and safety. Of the problems identified, 82.2 percent were classified as preventable and 63.7 percent as manifested. Pharmaceutical interventions registered 79.0 percent of acceptance, of which 78.9 percent had positive results. On average, there were 2.6 patient-related needs, especially regarding questions about drug therapy (30.4 percent), which were positively answered in 84.8 percent of cases. These indicators show that the pharmaceutical care service is very active in promoting health education.

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Several quantitative trait loci (QTL) for important reproductive traits (ovulation rate) have been identified on the porcine chromosome 15 (SSC15). To assist in the selection of positional candidate swine genes for these QTL on SSC15, twenty-one genes had already been assigned to SSC15 in a previous study in our lab, by using the radiation hybrid panel IMpRH. Further polymorphism studies were carried out on these positional candidate genes with four breeds of pigs (Duroc, Erhualian, Dahuabai and Landrace) harboring significant differences in reproduction traits. A total of nineteen polymorphisms were found in 21 genes. Among these, seven in six genes were used for association studies, whereby NRP2 polymorphism was found to be significantly (p < 0.05) associated with litter-size traits. NRP2 might be a candidate gene for pig-litter size based on its chromosome location (Du et al., 2006), significant association with litter-size traits and relationships with Sema and the VEGF super families.

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Several quantitative trait loci (QTL) for important reproductive traits (ovulation rate) have been identified on the porcine chromosome 15 (SSC15). To assist in the selection of positional candidate swine genes for these QTL on SSC15, twenty-one genes had already been assigned to SSC15 in a previous study in our lab, by using the radiation hybrid panel IMpRH. Further polymorphism studies were carried out on these positional candidate genes with four breeds of pigs (Duroc, Erhualian, Dahuabai and Landrace) harboring significant differences in reproduction traits. A total of nineteen polymorphisms were found in 21 genes. Among these, seven in six genes were used for association studies, whereby NRP2 polymorphism was found to be significantly (p < 0.05) associated with litter-size traits. NRP2 might be a candidate gene for pig-litter size based on its chromosome location (Du et al., 2006), significant association with litter-size traits and relationships with Sema and the VEGF super families.

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