Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis.

Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebrospinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease. We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.

High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury.

We analyzed retrospective data from toxicology studies involving administration of high doses of adeno-associated virus expressing different therapeutic transgenes to 21 cynomolgus and 15 rhesus macaques. We also conducted prospective studies to investigate acute toxicity following high-dose systemic administration of enhanced green fluorescent protein-expressing adeno-associated virus to 10 rhesus macaques. Toxicity was characterized by transaminitis, thrombocytopenia, and alternative complement pathway activation that peaked on post-administration day 3.

Integrated vector genomes may contribute to long-term expression in primate liver after AAV administration.

The development of liver-based adeno-associated virus (AAV) gene therapies is facing concerns about limited efficiency and durability of transgene expression. We evaluated nonhuman primates following intravenous dosing of AAV8 and AAVrh10 vectors for over 2 years to better define the mechanism(s) of transduction that affect performance. High transduction of non-immunogenic transgenes was achieved, although expression declined over the first 90 days to reach a lower but stable steady state.

Prevention of musculoskeletal disorders among animal research technicians: Understanding difficulties and their determinants through a work activity analysis.

This study aimed at understanding animal research technicians (ART) work activity to identify difficulties encountered by workers and their determinants which may increase musculoskeletal disorders (MSD) risks. The methods for the work activity analysis combined interviews, observations, events and operations chronicles as well as inclinometry. From the work activity analysis of the three main tasks (changing mouse cages, preparation of water bottles and unloading dirty material), difficulties such as awkward postures, heavy load handling, repetitiveness, high workload, supplementary tasks, interruptions and difficult social interactions emerged.

EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes.

Viruses suppress immune recognition through diverse mechanisms. Epstein-Barr Virus (EBV) establishes latent infection in memory B-lymphocytes and B-cell malignancies where it impacts B-cell immune function. We show here that EBV primary infection of naïve B-cells results in a robust down-regulation of HLA genes.

Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes.

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14).

Biofabrication of a three dimensional human-based personalized neurofibroma model.

Neurofibromas are the most characteristic feature of neurofibromatosis type 1 (NF1), a multisystemic disorder caused by aberrations in the neurofibromin gene (NF1). Despite significant progress over the last several years in understanding this disease, a suitable in vitro model to better mimic neurofibroma formation and growth has yet to be described. There is therefore a need to establish an in vitro, three dimensional model that allows the incorporation of multicellular lineages and the modulation of the cellular microenvironment-known to be important for cellular crosstalk and distribution of soluble factors-to study neurofibroma biology and morphogenesis.

A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism.

Epstein-Barr virus (EBV) immortalizes resting B-lymphocytes through a highly orchestrated reprogramming of host chromatin structure, transcription and metabolism. Here, we use a multi-omics-based approach to investigate these underlying mechanisms. ATAC-seq analysis of cellular chromatin showed that EBV alters over a third of accessible chromatin during the infection time course, with many of these sites overlapping transcription factors such as PU.

A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways.

Objective: As the leading risk factor for the development of liver cancer, chronic infection with hepatitis B virus (HBV) represents a significant global health concern. Although an effective HBV vaccine exists, at least 240 million people are chronically infected with HBV worldwide. Therapeutic options for the treatment of chronic HBV remain limited, and none achieve an absolute cure.

Hepatitis B virus modulates store-operated calcium entry to enhance viral replication in primary hepatocytes.

Many viruses modulate calcium (Ca2+) signaling to create a cellular environment that is more permissive to viral replication, but for most viruses that regulate Ca2+ signaling, the mechanism underlying this regulation is not well understood. The hepatitis B virus (HBV) HBx protein modulates cytosolic Ca2+ levels to stimulate HBV replication in some liver cell lines. A chronic HBV infection is associated with life-threatening liver diseases, including hepatocellular carcinoma (HCC), and HBx modulation of cytosolic Ca2+ levels could have an important role in HBV pathogenesis.

Hepatitis B virus molecular biology and pathogenesis.

As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression.

Getting at the source of distinctive encoding effects in the DRM paradigm: evidence from signal-detection measures and source judgments.

Studying Deese-Roediger-McDermott (DRM) lists using a distinctive encoding task can reduce the DRM false memory illusion. Reductions for both distinctively encoded lists and non-distinctively encoded lists in a within-group design have been ascribed to use of a distinctiveness heuristic by which participants monitor their memories at test for distinctive-task details. Alternatively, participants might simply set a more conservative response criterion, which would be exceeded by distinctive list items more often than all other test items, including the critical non-studied items.

Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients.

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord progressively leading to paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms. The clinical manifestations observed in ALS appear relatively late in the disease course after degeneration of a significant number of motor neurons.

Randomized trial of a smoking cessation intervention in hospitalized patients.

A hospitalization is a time when perceived vulnerability to dangers from smoking and quitting motivation may be at their peak. Aim was to determine whether a smoking cessation intervention of moderate intensity would increase the smoking cessation rate in hospitalized smokers. Design was randomized trial, conducted in a university-affiliated cardio-pulmonary tertiary care center.

Development of a fiber-optic sensor for trace metal detection in aqueous environments.

The availability and speciation of a number of metals widely dispersed in the aquatic environment intimately affect the biogeochemistry of the ocean and its inhabitants. Much research has been focused on the development of analytical methodologies to elucidate better the background concentrations, variability, and contaminant effects of metal species. The purpose of this research is to investigate the viability of a fiber-optic sensor that will be a sensitive and selective probe for trace metals in natural waters.

L'ABC de la supervision clinique par discussion de cas.

Beginning with a review of the literature and a survey of instructors in family medicine, the authors show that supervision through case discussions is one of the least studied teaching tools in medicine, even though it is one of the most frequently used. On the basis of individual and collective consideration, they suggest the basic elements that seem to be requisite to this type of teaching activity: clarification of the aims of the supervisor and the resident by means of a verbal contract; a method of practice based on a clinical approach; provision of several examples of problems and various strategies for raising or solving problems.

Risks of discontinuing anticoagulant therapy in a selected group of patients with atherosclerotic heart disease: a prospective study.

In 134 patients with coronary artery disease, long-term oral anticoagulant therapy (mean duration, 56 months) for acute myocardial infarction (98 patients), acute coronary insufficiency (25 patients) or severe chronic angina (11 patients) was terminated abruptly in 50 patients (group 1) and gradually in 84 (group 2). The 134 patients represented a homogeneous population of patients with coronary artery disease since most patients older than 75 years and those with conditions known to increase the risks of thromboembolic complications were excluded. The two groups were comparable in terms of sex, age, presence of risk factors, duration of anticoagulant therapy, and presence of angina and abnormal resting electrocardiograms during therapy.

Trichlorofluoromethane in the Troposphere, Distribution and Increase, 1971 to 1974.

Trichlorofluoromethane (CCl3F) measurements in the troposphere over the Atlantic in 1971 and over the Pacific in 1972 and 1974 were compared. A rapid increase of CCl3F in the troposphere is evident. The observed increase of CCl3F between 1971 and 1974 is proportional to the increase of industrially produced amounts of CCl3F in the same time period.

Carbon monoxide in rainwater.

Concentrations of carbon monoxide in rainwater collected at widely diverse locations show up to a 200-fold supersaturation relative to the partial pressure of the gas in the atmosphere. These results indicate the existence of an additional natural source of carbon monoxide not heretofore considered. Production of carbon monoxide in clouds is tentatively attributed to the photochemical oxidation of organic matter or the slight dissociation of carbon dioxide induced by electrical discharges, or both.