AAV8 capsid variable regions at the two-fold symmetry axis contribute to high liver transduction by mediating nuclear entry and capsid uncoating

AbstractAdeno-associated virus serotype 8 (AAV8) is a promising vector for liver-directed gene therapy. Although efficient uncoating of viral capsids has been implicated in AAV8׳s robust liver transduction, much about the biology of AAV8 hepatotropism remains unclear. Our study investigated the structural basis of AAV8 liver transduction efficiency by constructing chimeric vector capsids containing sequences derived from AAV8 and AAV2 – a highly homologous yet poorly hepatotropic serotype. Engineered vectors containing capsid variable regions (VR) VII & IX from AAV8 in an AAV2 backbone mediated near AAV8-like transduction in mouse liver, with higher numbers of chimeric genomes detected in whole liver cells and isolated nuclei. Interestingly, chimeric capsids within liver nuclei also uncoated similarly to AAV8 by 6 weeks after administration, in contrast with AAV2, of which a significantly smaller proportion were uncoated. This study links specific AAV capsid regions to the transduction ability of a clinically relevant AAV serotype

LLM Comparator: Visual Analytics for Side-by-Side Evaluation of Large Language Models

Automatic side-by-side evaluation has emerged as a promising approach to evaluating the quality of responses from large language models (LLMs). However, analyzing the results from this evaluation approach raises scalability and interpretability challenges. In this paper, we present LLM Comparator, a novel visual analytics tool for interactively analyzing results from automatic side-by-side evaluation. The tool supports interactive workflows for users to understand when and why a model performs better or worse than a baseline model, and how the responses from two models are qualitatively different. We iteratively designed and developed the tool by closely working with researchers and engineers at a large technology company. This paper details the user challenges we identified, the design and development of the tool, and an observational study with participants who regularly evaluate their models

Structural Framework for Flight II: NASAs Role in Development of Advanced Composite Materials for Aircraft and Space Structures

This monograph is organized to highlight the successful application of light alloys on aircraft and space launch vehicles, the role of NASA in enabling these applications for each different class of flight vehicles, and a discussion of the major advancements made in discipline areas of research. In each section, key personnel and selected references are included. These references are intended to provide additional information for technical specialists and others who desire a more in-depth discussion of the contributions. Also in each section, lessons learned and future challenges are highlighted to help guide technical personnel either in the conduct or management of current and future research projects related to light-weighting advanced air and space vehicles

Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma (CheckMate 915)

PURPOSE Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma. PATIENTS AND METHODS In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for <= 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup. RESULTS At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients. CONCLUSION Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment

MISAME

Recording of James Tenney's Dialogu

The public services of Joseph Draper Sayers

Histor

American Indian and Alaska Native Cancer Data Issues

INTRODUCTION TO CANCER AS AN ISSUE AMONG AMERICAN INDIANS AND ALASKA NATIVES Cancer is a growing problem among American Indians and Alaska Natives. Unfortunately, both non-Native and First Nations peoples are less aware of the growing cancer dilemma than they are of alcohol, violence, diabetes, and other well-promoted and widely dispersed conditions within Native communities. In the second half of the twentieth century, cancer has become the leading cause of death for Alaska Native women and is the second leading cause of death among Alaska Native men. In fact, cancer is currently the third leading cause of death for all North American Natives5 and is the second leading cause of death among American Indians (both sexes) over age 45. The disease is the third most cited reason for hospital stays among Indian Health Service beneficiaries served by the Alaska Area Native Indian Health Service. Cancer rates, previously reported as less frequent in American Indian and Alaska Natives, have been increasing throughout the last twenty years. Incidence rates among Alaska Natives have exceeded “U.S. All Races” rates for most cancer sites. Rates are increasing similarly for Canadian bands. Within Native American communities, health programs continue to focus on alcoholism and diabetes, although cancer is responsible for more deaths than either of these conditions. Because the word cancer is not indigenous, it translates into some Native languages as “the disease for which there is no cure” or “the disease that eats the body.” Many tribes regard cancer as a white man’s disease because of its rarity before European contact. For many Native cancer patients, the disease is not discussed and is considered a form of punishment, shame, and guilt. A few tribes consider the patient’s suffering necessary in order to ensure the health of the other tribal members (they wear the pain so that their community will be spared). Some tribal members living with cancer—infected with the cancer spirit—are considered contagious and are ostracized by their communities. Other tribal members refuse cancer treatment surgery for fear that their body and spirit will be incomplete, leaving them incapable of finding their ancestors when they move to the other side (death)