Medulloblastoma: Clinical Challenges and Emerging Molecular Discoveries

Medulloblastoma is the most common type of malignant brain tumor in children, responsible for 25% of pediatric brain cancers. Conventional treatment methods, which include surgery, radiotherapy, and chemotherapy, have improved overall survival rates for patients with medulloblastoma to over 50%. A majority of survivors, however, suffer serious long-term side effects, including developmental, neurological, and psychosocial deficits. Now entering clinical trials for sonic hedgehog-driven medulloblastomas, Smoothened inhibitors have been FDA approved for the treatment of basal cell carcinomas. However, treatment efficacy endures only for a few months before lesion relapses and drug resistance occurs. Therefore, there is an urgent need for new therapies to reduce the significant problems associated with current drug-resistant treatments. In this chapter, we will illustrate the clinical presentation and current treatment methods for medulloblastoma and detail the molecular pathways within each of the four molecular subgroups of medulloblastoma, with an eye for possible candidates for novel combination therapies

Preschoolers’ Selfish Sharing Is Reduced by Prior Experience With Proportional Generosity

Young children make sophisticated social and normative inferences based on proportional reasoning. We explored the possibility that proportional cues also help children learn from and about their own generosity. Across two experiments, 3- to 4-year-olds had the opportunity to give either 1 of 4, 1 of 3, 1 of 2, or 1 of 1 of their resources to an individual in need. We then measured children’s subsequent prosociality by looking at sharing behavior with a new individual. The more proportionally generous the initial action, the less likely children were to share selfishly in the second phase. Our results suggest that children make sense of their own actions using proportional cues and that giving children experience with difficult, prosocial actions increases the likelihood of their recurrence

A Two Micron Coherent Differential Absorption Lidar Development

A pulsed, 2-micron coherent Differential Absorption Lidar (DIAL)/Integrated Path Differential Absorption (IPDA) transceiver, developed under the Laser Risk Reduction Program (LRRP) at NASA, is integrated into a fully functional lidar instrument. This instrument measures atmospheric CO2 profiles (by DIAL) from a ground platform. It allows the investigators to pursue subsequent in science-driven deployments, and provides a unique tool for Active Sensing of CO2 Emissions over Night, Days, and Seasons (ASCENDS) validation that was strongly advocated in the recent ASCENDS Workshop. Keywords: Differential Absorption Lidar, Near Infrared Laser

High-Level Expression of Various Apolipoprotein (a) Isoforms by "Transferrinfection". The Role of Kringle IV Sequences in the Extracellular Association with Low-Density Lipoprotein

Characterization of the assembly of lipoprotein(a) [Lp(a)] is of fundamental importance to understanding the biosynthesis and metabolism of this atherogenic lipoprotein. Since no established cell lines exist that express Lp(a) or apolipoprotein(a) [apo(a)], a "transferrinfection" system for apo(a) was developed utilizing adenovirus receptor- and transferrin receptor-mediated DNA uptake into cells. Using this method, different apo(a) cDNA constructions of variable length, due to the presence of 3, 5, 7, 9, 15, or 18 internal kringle IV sequences, were expressed in cos-7 cells or CHO cells. All constructions contained kringle IV-36, which includes the only unpaired cysteine residue (Cys-4057) in apo(a). r-Apo(a) was synthesized as a precursor and secreted as mature apolipoprotein into the medium. When medium containing r-apo(a) with 9, 15, or 18 kringle IV repeats was mixed with normal human plasma LDL, stable complexes formed that had a bouyant density typical of Lp(a). Association was substantially decreased if Cys-4057 on r-apo(a) was replaced by Arg by site-directed mutagenesis or if Cys-4057 was chemically modified. Lack of association was also observed with r-apo(a) containing only 3, 5, or 7 kringle IV repeats without "unique kringle IV sequences", although Cys-4057 was present in all of these constructions. Synthesis and secretion of r-apo(a) was not dependent on its sialic acid content. r-Apo(a) was expressed even more efficiently in sialylation-defective CHO cells than in wild-type CHO cells. In transfected CHO cells defective in the addition of N-acetylglucosamine, apo(a) secretion was found to be decreased by 50%. Extracellular association with LDL was not affected by the carbohydrate moiety of r-apo(a), indicating a protein-protein interaction between r-apo(a) and apoB. These results show that, besides kringle IV-36, other kringle IV sequences are necessary for the extracellular association of r-apo(a) with LDL. Changes in the carbohydrate moiety of apo(a), however, do not affect complex formation

The management of tetanus in adults in an intensive care unit in Southern Vietnam

Background: Tetanus remains common in many low- and middle-income countries (LMICs) yet the evidence base guiding management of this disease is extremely limited, particularly with respect to contemporary management options. Sharing knowledge about practice may facilitate improvement in outcomes elsewhere. Methods: We describe clinical interventions and outcomes of 180 adult patients ≥16 years-old with tetanus enrolled in prospective observational studies at a specialist infectious diseases hospital in Southern Vietnam. Patients were treated according to a holistic management protocol encompassing wound-care, antitoxin, antibiotics, symptom control, airway management, nutrition and de-escalation criteria. Results: Mortality rate in our cohort was 2.8%, with 90 (50%) patients requiring mechanical ventilation for a median 16 [IQR 12-24] days. Median [IQR] duration of ICU stay was 15 [8-23] days. Autonomic nervous system dysfunction occurred in 45 (25%) patients. Hospital acquired infections occurred in 77 (43%) of patients. Conclusion: We report favourable outcomes for patients with tetanus in a single centre LMIC ICU, treated according to a holistic protocol. Nevertheless, many patients required prolonged intensive care support and hospital acquired infections were common

Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia

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Genome-wide essential gene identification in Streptococcus sanguinis

A clear perception of gene essentiality in bacterial pathogens is pivotal for identifying drug targets to combat emergence of new pathogens and antibiotic-resistant bacteria, for synthetic biology, and for understanding the origins of life. We have constructed a comprehensive set of deletion mutants and systematically identified a clearly defined set of essential genes for Streptococcus sanguinis. Our results were confirmed by growing S. sanguinis in minimal medium and by double-knockout of paralogous or isozyme genes. Careful examination revealed that these essential genes were associated with only three basic categories of biological functions: maintenance of the cell envelope, energy production, and processing of genetic information. Our finding was subsequently validated in two other pathogenic streptococcal species, Streptococcus pneumoniae and Streptococcus mutans and in two other gram-positive pathogens, Bacillus subtilis and Staphylococcus aureus. Our analysis has thus led to a simplified model that permits reliable prediction of gene essentiality

Agrobacterium-mediated transformation systems of Primula vulgaris

Background: Genetic transformation is a valuable tool and an important procedure in plant functional genomics contributing to gene discovery, allowing powerful insights into gene function and genetically controlled characteristics. Primulaceae species provide one of the best-known examples of heteromorphic flower development, a breeding system which has attracted considerable attention, including that of Charles Darwin. Molecular approaches, including plant transformation give the best opportunity to define and understand the role of genes involved in floral heteromorphy in the common primrose, Primula vulgaris, along with other Primula species. Results: Two transformation systems have been developed in P. vulgaris. The first system, Agrobacterium-mediated vacuum infiltration of seedlings, enables the rapid testing of transgenes, transiently in planta. GUS expression was observed in the cotyledons, true leaves, and roots of Primula seedlings. The second system is based on Agrobacterium tumefaciens infection of pedicel explants with an average transformation efficiency of 4.6%. This transformation system, based on regeneration and selection of transformants within in vitro culture, demonstrates stable transgene integration and transmission to the next generation. Conclusion: The two transformation systems reported here will aid fundamental research into important traits in Primula. Although, stable integration of transgenes is the ultimate goal for such analyses, transient gene expression via Agrobacterium-mediated DNA transfer, offers a simple and fast method to analyse transgene functions. The second system describes, for the first time, stable Agrobacterium-mediated transformation of Primula vulgaris, which will be key to characterising the genes responsible for the control of floral heteromorphy

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma

Background: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. Methods: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. Results: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. Conclusions and interpretations: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

Background: Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer. Methods The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined. Results: Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13). Conclusions: This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results