RANTES Secretion by Gene-Modified Tumor Cells Results in Loss of Tumorigenicity In Vivo: Role of Immune Cell Subpopulations

Overview summary Members of the chemokine superfamily mediate potent and selective chemoattraction of a variety of immune cell subsets, which is concentration dependent. This important and novel biologic activity raises the possibility of using chemokines as adjuvants in cancer vaccine strategies. We describe here the in vitro chemotactic capacity of RANTES for murine CD8+ tumor-infiltrating lymphocytes (TIL). Moreover, murine fibrosarcoma cells transfected with the cDNA encoding RANTES and secreting high levels of this chemokine become nontumorigenic in immunocompetent mice. The antitumor effect of RANTES is dependent on inherent tumor immunogenicity and is mediated through the participation of host-derived T cells and macrophages. Thus, the general chemoattractant properties exhibited by RANTES in vitro appear to be relevant in an in vivo model. These data warrant further investigation of other distinct members of the chemokine superfamily for their potential use, either alone or in combination, in gene therapy approaches that employ tumor cells as immunogens.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63285/1/hum.1996.7.13-1545.pd

Global expression analysis of cancer/testis genes in uterine cancers reveals a high incidence of BORIS expression

Abstract Purpose: Cancer/testis (CT) genes predominantly expressed in the testis (germ cells) and generally not in other normal tissues are aberrantly expressed in human cancers. This highly restricted expression provides a unique opportunity to use these CTgenes for diagnostics, immunotherapeutic, or other targeted therapies. The purpose of this study was to identify those CT genes with the greatest incidence of expression in uterine cancers. Experimental Design: We queried the expression of known and putative CT gene transcripts (representing 79 gene loci) using whole genome gene expression arrays. Specifically, the global gene expressions of uterine cancers (n = 122) and normal uteri (n = 10) were determined using expression data from the Affymetrix HG-U133A and HG-U133B chips. Additionally, we also examined the brother of the regulator of imprinted sites (BORIS) transcript by reverse transcription-PCR and quantitative PCR because its transcript was not represented on the array. Results: Global microarray analysis detected many CT genes expressed in various uterine cancers; however, no individual CT gene was expressed in more than 25% of all cancers. The expression of the two most commonly expressed CT genes on the arrays, MAGEA9 (24 of 122 cancers and 0 of10 normal tissues) and Down syndrome critical region 8 (DSCR8)/MMA1 (16 if 122 cancers and 0 of 10 normal tissues), was confirmed by reverse transcription-PCR methods, validating the array screening approach. In contrast to the relatively low incidence of expression of the other CTgenes, BORIS expression was detected in 73 of 95 (77%) endometrial cancers and 24 of 31 (77%) uterine mixed mesodermal tumors. Conclusions: These data provide the first extensive survey of multiple CT genes in uterine cancers. Importantly, we detected a high frequency of BORIS expression in uterine cancers, suggesting its potential as an immunologic or diagnostic target for these cancers. Given the high incidence of BORIS expression and its possible regulatory role, an examination of BORIS function in the etiology of these cancers is warranted

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial

IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. OBJECTIVE To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. INTERVENTIONS Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200mg (n = 588), or placebo (n = 587). MAIN OUTCOMES AND MEASURES The primary outcomewas incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase–polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. RESULTS The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5%vs 15.2%; odds ratio, 0.43 [95%CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95%CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). CONCLUSIONS AND RELEVANCE Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Functional Analysis of the Cordon-bleu Protein in Mouse

<p>The actin cytoskeleton is a fundamental component of the cell and is involved in many processes, including cell division, cell migration, vesicle trafficking and cell polarity. The actin cytoskeleton has a very important role in embryogenesis as the cells within developing tissues proliferate, migrate, interpret extracellular cues, and shape complex tissues. The molecules that help the cell to interpret their environment and turn those cues into morphological changes are of great interest. One protein which may be involved in this manner is Cordon-bleu (Cobl). </p><p>In mouse embryos, <italic>Cobl's</italic> expression pattern resembles that of important developmental genes, is restricted to distinct domains, and changes dynamically throughout development as tissues are formed. While it is known that <italic>Cobl</italic> expression is regulated by developmental signaling pathways such as Shh and BMP, its molecular function at the cellular level remains elusive. In this study, we have identified molecular functions of Cobl. Cobl has C-terminal Wasp Homology-2 (WH2) domains which bind actin and nucleate new actin filaments in <italic>in vitro</italic> polymerization assays. Using cultured cells, we have determined that Cobl is involved in cytoskeletal remodeling during neurite branching and epithelial cell migration. We also demonstrate that Cobl interacts with the Syndapin family of adaptor proteins that link endocytosis and vesicle trafficking. Cobl colocalizes with Sdp2 in cultured epithelial cells and similarly localizes with Sdp1 and Sdp2 in developing mouse embryos. The localization of Cobl or Sdp2 in cultured epithelial cells is dependent on the other, as demonstrated using shRNA knockdown. </p><p>Previous studies demonstrated that a hypomorphic allele of <italic>Cobl</italic> interacts genetically with <italic>Looptail</italic>, in midbrain neurulation. <italic>Looptail</italic> mutants are deficient in the gene <italic>Vangl2</italic>, a member of the planar cell polarity pathway that coordinates the morphogenesis of a sheet of cells. To discover other roles for <italic>Cobl</italic> in the developing mouse, we have generated a conditionally null allele of <italic>Cobl</italic>. We find that outbred <italic>Cobl</italic> homozygous mutants are viable, but that they have inner ear defects. Together, our studies demonstrate that Cobl is a tissue-specific actin nucleator whose localization is regulated by its interaction with Syndapins and which functions in the development of sensory epithelia.</p>Dissertatio

The boy general : story of the life of Major-General George A. Custer, as told by Elizabeth B. Custer ... /

A condensed survey of the life of Custer after the close of the civil war, from Mrs. Custer's "Tenting on the plains," "Following the guidon," and "Boots and saddles."Mode of access: Internet