172 research outputs found

    Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment

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    Introduction: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. Methods: Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunofluorescent determination of phosphorylated histone H2AX (γ\gammaH2AX) foci, β\beta-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model. Results: Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of γ\gammaH2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions. Conclusions: Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects

    Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

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    IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

    Genetic and cytological studies of maize

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    Mechanisms that rapidly reorganize the genome : (genome reorganizations, transposable gene control systems, restriction enzymes, stabilizing mechanisms)

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    Extensive reorganization of components of the genome is initiated in maize by the breakage-fusion-bridge (BFB) cycle. Displacements include chromosomes other than those undergoing the cycle. Restructuring ranges from those rearrangements that are readily viewed with the light microscope, such as reciprocal translocations, inversions, duplications, etc., to apparently short DNA segments that include components of transposable gene control systems. Much of the restructuring appears to be nonrandom. Some examples of this are conspicuous, such as centromere to centromere, knob to knob, or centromere to knob attachments. Others are exhibited by attachment of a segment of some chromo some to a newly broken end o f a chromosome, or the placement of a piece of one chromosome onto the end of another chromosome that had not undergone the BFB cycle. These modifications suggest participation of "restriction enzyme" systems in their formation. One system responsible for special types of chromosomal modifications was extensively examined. The chromosome location of its principal genetic element was determined. This genetic element has never given evidence of serving as a component in a gene-control system. Instead, it serves to cut chromosomes. The locations of these cuts do not appear to be random. The BFB cycles exposed the presence in the maize genome of transposable elements that can serve to control the type and time of gene action. Previous to undergoing the cycle, these elements were quiescent in the genome. One component of a gene control system produces a product that is responsible for trans position of the elements of a system. In this regard, each system operates quite independently of the other. The product can induce modifications in chromosome organizations that are by-products of the transposition mechanism. It also can cause receptive elements located in different regions of the genome to respond by inducing DNA modifications in situ and without altering their subsequent receptivity to the product. Or, the product may cause an element to modify the organization of chromatin to one or the other side of it. Some responses of a receptive element that is located within a gene locus result in removal of sensitivity to the inducing product. Stable, new alleles are so produced. In such instances, the gene product may be altered and the patter n of its expression may also be altered during development of plant and kernel. It is suspected that the BFB cycle initiates stress within the genome and that the stress calls up reserves to counteract it. In some instances, coping with stress may involve a simple solution, such as gene amplification. Coping with drastic types of stress may initiate seemingly disorderly types of response. It is conceivable that, in some instances, stabilization may follow such disorder. This could provide newly organized genomes with orderly operating gene-control systems while still retaining those components that again can respond to stress.BARBARA McCLINTOCK Carnegie Institution of Washington, Cold Spring Harbor Laboratory, Cold Spring Harbor, N .Y

    A 2n-1 chromosomal chimera in maize

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    The fusion of broken ends of sister half-chromatids following chromatid breakage at meiotic anaphases

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    Publication authorized July 12, 1938.Digitized 2007 AES.Includes bibliographical references (page 48)
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