Despite the increasing knowledge of the molecular events that induce the glycolysis pathway in effector T cells, very little is known about the transcriptional mechanisms that dampen the glycolysis ...program in quiescent cell populations such as memory T cells. Here we found that the transcription factor Bcl-6 directly repressed genes encoding molecules involved in the glycolysis pathway, including Slc2a1, Slc2a3, Pkm and Hk2, in type 1 helper T cells (TH1 cells) exposed to low concentrations of interleukin 2 (IL-2). Thus, Bcl-6 had a role opposing the IL-2-sensitive glycolytic transcriptional program that the transcription factors c-Myc and HIF-1α promote in effector T cells. Additionally, the TH1 lineage-specifying factor T-bet functionally antagonized the Bcl-6-dependent repression of genes encoding molecules in the glycolysis pathway, which links the molecular balance of these two factors to regulation of the metabolic gene program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In developing follicles, cellular coupling within cumulus–oocyte complexes (COCs) creates a functional syncytium allowing for the passage of small molecules. In many species, intercellular coupling ...between granulosa cells results from the expression of connexin 43 (CX43 or Gja1) and the formation of gap junctional plaques. Previously, our lab has shown that oocytes with a higher developmental potential had higher CX43 expression in their cumulus cells compared with developmentally incompetent oocytes. All‐trans retinoic acid (ATRA) has been shown to increase CX43 expression in several different cell types. In this study we investigated the effect of ATRA treatment, during maturation, on CX43 expression and localization in cumulus cells and the developmental competence of bovine oocytes. COCs and granulosa cells exposed to ATRA during maturation had significantly higher CX43 expression and increased gap junctional coupling, respectively. In addition, there was a significant increase in the maturation, cleavage, and blastocyst rates in ATRA treated COCs. Data from these studies suggest that not only can CX43 be used as a biomarker for oocyte health, it can also potentially be manipulated using ATRA to increase the number of oocytes achieving developmental competence.
Exposure of bovine cumulus–oocyte complexes to all‐trans retinoic acid, during maturation, increases cellular communication and improves in vitro developmental outcomes.
The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ...ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.
Objectives
We aim to propose a modified surveillance strategy using a novel blood assay that detects plasma circulating tumor‐specific HPV DNA with reported 100% NPV and 94% PPV as the main method of ...detection to understand the cost implications of potentially avoiding routine imaging and surveillance visits at our institution.
Methods
We performed a retrospective chart review focusing on recurrences in p16+ patients with OPSCC and defined two surveillance strategies: “Strategy A", follow‐up visits with flexible laryngoscopy (FL) plus regular imaging studies; “Strategy B", follow‐up visits with FL plus regular NavDx assays and imaging used at the discretion of the physician(s) in cases of high clinical suspicion.
Results
Of the p16+ OPSCC patients (n = 214), 23 had confirmed recurrence (11%). Standard work‐flow model determined 72 imaging studies and 2198 physical examinations with FL were needed to detect one recurrence. Potential individual patient cost reduction during surveillance was 42%.
Conclusion
Implementing NavDx for HPV + OPSCC surveillance would benefit patients by reducing costs and unnecessary diagnostic testing.
Level of Evidence
Step/Level 3 Laryngoscope, 133:3006–3012, 2023
We performed a retrospective analysis of patients at our institution with HPV associated squamous cell oropharyngeal carcinoma to determine how to integrate a DNA assay with high positive and negative predictive values called NavDx into a new surveillance strategy. Calculations of health care costs were compared, showing reduced costs using NavDx versus the standard surveillance strategy and other benefits of adopting the new surveillance strategy were also examined.
In contrast to the situation in plants inhabiting most of the world’s ecosystems, mycorrhizal fungi are usually absent from roots of the only two native vascular plant species of maritime Antarctica, ...Deschampsia antarctica and Colobanthus quitensis. Instead, a range of ascomycete fungi, termed dark septate endophytes (DSEs), frequently colonise the roots of these plant species. We demonstrate that colonisation of Antarctic vascular plants by DSEs facilitates not only the acquisition of organic nitrogen as early protein breakdown products, but also as non‐proteinaceous d‐amino acids and their short peptides, accumulated in slowly‐decomposing organic matter, such as moss peat. Our findings suggest that, in a warming maritime Antarctic, this symbiosis has a key role in accelerating the replacement of formerly dominant moss communities by vascular plants, and in increasing the rate at which ancient carbon stores laid down as moss peat over centuries or millennia are returned to the atmosphere as CO2.
Cytokines represent a class of environmental factors that are critical drivers of immune cell development. Cytokines of the common gamma-chain family, including interleukin (IL)-2, IL-7, and IL-15, ...have been the subject of intense experimental scrutiny and have well-defined roles as regulators of diverse immune cell types including CD4+ T helper cells. Because of their pleiotropic effects on T-cell development and function, researchers and clinicians have attempted to harness the capabilities of these cytokines for therapeutic benefit. In this review, we summarize the recent progress in our understanding of the molecular mechanisms underlying the effects of these cytokines on CD4+ T cell development and briefly discuss how these immunomodulatory cytokines are being used in efforts to treat human disease.
Voluntary deep inhalation breath hold (VDIBH) reduces heart dose during left breast irradiation. We present results of the first study performed to quantify reproducibility of breath hold using bony ...anatomy, heart position, and heart dose for VDIBH patients at treatment table.
Data from 10 left breast cancer patients undergoing VDIBH whole-breast irradiation were analyzed. Two computed tomography (CT) scans, free breathing (FB) and VDIBH, were acquired to compare dose to critical structures. Pretreatment weekly kV orthogonal images and tangential ports were acquired. The displacement difference from spinal cord to sternum across the isocenter between coregistered planning Digitally Reconstructed Radiographs (DRRs) and kV imaging of bony thorax is a measure of breath hold reproducibility. The difference between bony coregistration and heart coregistration was the measured heart shift if the patient is aligned to bony anatomy.
Percentage of dose reductions from FB to VDIBH: mean heart dose (48%, SD 19%, p = 0.002), mean LAD dose (43%, SD 19%, p = 0.008), and maximum left anterior descending (LAD) dose (60%, SD 22%, p = 0.008). Average breath hold reproducibility using bony anatomy across the isocenter along the anteroposterior (AP) plane from planning to treatment is 1 (range, 0-3; SD, 1) mm. Average heart shifts with respect to bony anatomy between different breath holds are 2 ± 3 mm inferior, 1 ± 2 mm right, and 1 ± 3 mm posterior. Percentage dose changes from planning to delivery: mean heart dose (7%, SD 6%); mean LAD dose, ((9%, SD 7%)S, and maximum LAD dose, (11%, SD 11%) SD 11%, p = 0.008).
We observed excellent three-dimensional bony registration between planning and pretreatment imaging. Reduced delivered dose to heart and LAD is maintained throughout VDIBH treatment.
Gap junctional coupling between cumulus cells is required for oocytes to reach developmental competence. Multiple connexins, which form these gap junctions, have been found within the ovarian ...follicles of several species including bovine. The aim of this study was to determine the role of connexin 43 (CX43) and its relationship to embryo development, after in vitro fertilization (IVF). Cumulus−oocyte complexes (COCs) were obtained from abattoir sourced, mixed breed, bovine ovaries. COCs were isolated from follicles ranging from 2 to 5 mm in size, representing the preselected follicle pool. Immediately after isolation, two cumulus cell biopsies were collected and stored for analysis pending determination of developmental outcomes. Using in vitro procedures, COCs were individually matured, fertilized, and cultured to the blastocyst stage. Biopsies were grouped as originating from COCs that arrested at the two‐cell stage (low developmental competence LDC) or having developed to the late morula/blastocyst stage (high developmental competence HDC), after IVF and embryo culture. The expression level of CX43 was found to be significantly higher in cumulus cells from COCs that had an HDC when compared with those that had an LDC. Moreover, the gap junctional intercellular coupling rate was significantly higher in cumulus from COCs deemed to have an HDC. Significantly higher expression of the cumulus health markers luteinizing hormone receptor and cytochrome p450 19A1 was found in the cumulus originating from oocytes with HDC, suggesting that this system may provide a mechanism for noninvasively testing for oocyte health in preselected bovine follicles.
In this randomized trial, patients who had unresectable stage III or IV squamous-cell head and neck cancer with no distant metastases were assigned to receive induction treatment with docetaxel plus ...cisplatin and fluorouracil (TPF) or cisplatin and fluorouracil (PF) before receiving chemoradiotherapy. Patients who received TPF induction chemotherapy had significantly longer survival than did patients who received PF induction chemotherapy.
Patients who received TPF induction chemotherapy had significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy.
Squamous-cell carcinoma of the head and neck accounts for 5% of newly diagnosed cancers in adults in the United States and 8% of cancers worldwide.
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The disease is potentially curable at an early stage, but most patients present with locally advanced disease. After standard therapy (surgery and irradiation), only 30 to 50% of patients with locally advanced disease live for 3 years, and locoregional recurrences or distant metastases develop in 40 to 60% of them.
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Various strategies to improve outcomes by coordinating chemotherapy with surgery and radiotherapy have been tried, but the optimal schedule for integrating chemotherapy into the . . .
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