Johns Hopkins University School of Medicine

About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.

Protein aggregation and neurodegenerative disease.

Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.

Neuronal Population Coding of Movement Direction

Abstract: Although individual neurons in the arm area of the primate motor cortex are only broadly tuned to a particular direction in three-dimensional space, the animal can very precisely control the movement of its arm. The direction of movement was found to be uniquely predicted by the action of a population of motor cortical neurons. When individual cells were represented as vectors that make weighted contributions along the axis of their preferred direction (according to changes in their activity during the movement under consideration) the resulting vector sum of all cell vectors (population vector) was in a direction congruent with the direction of movement. This population vector can be monitored during various tasks, and similar measures in other neuronal populations could be of heuristic value where there is a neural representation of variables with vectorial attributes.

Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy

Abstract: The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers

Abstract: Background: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Methods: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5‐9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPVpositive tumors was determined by proportional hazards regression analysis. Results: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%‐30%). Highrisk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2‐ 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1‐12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPVpositive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05‐0.61) and smokers (OR = 0.16; 95% CI = 0.02‐1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1‐167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01‐0.36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07‐0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4‐ 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4‐4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8‐2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20‐0.88). Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis. [J Natl Cancer Inst 2000; 92:709‐20]

Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage

Abstract: After DNA damage, many cells appear to enter a sustained arrest in the G 2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, γ radiated cells progressed into mitosis and exhibited a G 2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G 2 checkpoint in human cells.