Radiation is a significant treatment for patients with head and neck cancer. Despite advances to improve treatment, many tumors acquire radiation resistance resulting in poor survival. Radiation ...kills cancer cells by inducing DNA double-strand breaks. Therefore, radiation resistance is enhanced by efficient repair of damaged DNA. Head and neck cancers overexpress EGFR and have a high frequency of p53 mutations, both of which enhance DNA repair. This review discusses the clinical criteria for radiation resistance in patients with head and neck cancer and summarizes how cancer cells evade radiation-mediated apoptosis by p53- and epidermal growth factor receptor (EGFR)-mediated DNA repair. In addition, we explore the role of cancer stem cells in promoting radiation resistance, and how the abscopal effect provides rationale for combination strategies with immunotherapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune ...checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.
Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry.
Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 co-stimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice.
Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response.
We designed a head-mounted three-photon microscope for imaging deep cortical layer neuronal activity in a freely moving rat. Delivery of high-energy excitation pulses at 1,320 nm required both a ...hollow-core fiber whose transmission properties did not change with fiber movement and dispersion compensation. These developments enabled imaging at >1.1 mm below the cortical surface and stable imaging of layer 5 neuronal activity for >1 h in freely moving rats performing a range of behaviors.
Pre-eclampsia is a serious clinical gestational disorder occurring in 3%-5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of ...pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls.
Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay.
Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia.
This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies.
Advances in head-mounted microscopes have enabled imaging of neuronal activity using genetic tools in freely moving mice but these microscopes are restricted to recording in minimally lit arenas and ...imaging upper cortical layers. Here we built a 2-g, three-photon excitation-based microscope, containing a z-drive that enabled access to all cortical layers while mice freely behaved in a fully lit environment. The microscope had on-board photon detectors, robust to environmental light, and the arena lighting was timed to the end of each line-scan, enabling functional imaging of activity from cortical layer 4 and layer 6 neurons expressing jGCaMP7f in mice roaming a fully lit or dark arena. By comparing the neuronal activity measured from populations in these layers we show that activity in cortical layer 4 and layer 6 is differentially modulated by lit and dark conditions during free exploration.
Gallium chalcogenides are promising building blocks for novel van der Waals heterostructures. We report on the low-temperature micro-photoluminescence (PL) of GaTe and GaSe films with thicknesses ...ranging from 200 nm to a single unit cell. In both materials, PL shows a dramatic decrease by 104-105 when film thickness is reduced from 200 to 10 nm. Based on evidence from continuous-wave (cw) and time-resolved PL, we propose a model explaining the PL decrease as a result of non-radiative carrier escape via surface states. Our results emphasize the need for special passivation of two-dimensional films for optoelectronic applications.
1. The role of phenotypic plasticity in evolution has historically been a contentious issue because of debate over whether plasticity shields genotypes from selection or generates novel opportunities ...for selection to act. Because plasticity encompasses diverse adaptive and non-adaptive responses to environmental variation, no single conceptual framework adequately predicts the diverse roles of plasticity in evolutionary change. 2. Different types of phenotypic plasticity can uniquely contribute to adaptive evolution when populas are faced with new or altered environments. Adaptive plasticity should promote establishment and persistence in a new environment, but depending on how close the plastic response is to the new favoured phenotypic optimum dictates whether directional selection will cause adaptive divergence between populations. Further, non-adaptive plasticity in response to stressful environments can result in a mean phenotypic response being further away from the favoured optimum or alternatively increase the variance around the mean due to the expression of cryptic genetic variation. The expression of cryptic genetic variation can facilitate adaptive evolution if by chance it results in a fitter phenotype. 3. We conclude that adaptive plasticity that places populations close enough to a new phenotypic optimum for directional selection to act is the only plasticity that predictably enhances fitness and is most likely to facilitate adaptive evolution on ecological timescales in new environments. However, this type of plasticity is likely to be the product of past selection on variation that may have been initially non-adaptive. 4. We end with suggestions on how future empirical studies can be designed to better test the importance of different kinds of plasticity to adaptive evolution.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Highlights • BLA projections to the mPFC were targeted using optogenetic tools in mice. • Stimulation increased anxiety-like behavior and decreased social interaction. • Inhibition decreased ...anxiety-like behavior and increased social interaction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned ...the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.
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D’Silva and colleagues show that phosphorylation of TRIP13 by EGFR enhances DNA repair and treatment resistance in irradiated oral cancer. Remarkably, inhibiting EGFR-mediated phosphorylation with cetuximab, an FDA-approved targeted therapy, sensitizes tumors to radiation. Overall, their studies reveal a possible mechanism that could enhance response to radiation and cetuximab.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Approximately 10% to 20% of patients with joint arthroplasties are golfers. The aim of this study was to assess if being a golfer is associated with functional outcomes, satisfaction or ...improvement in quality of life (QoL) compared to non-golfers following total knee arthroplasty.
Methods
All patients undergoing primary total knee arthroplasty (TKA) over a one-year period at a single institution were included with one-year postoperative outcomes. Patients were retrospectively followed up to assess if they had been golfers at the time of their surgery. Multivariate linear regression analysis was performed to assess the independent association of preoperative golfing status on postoperative function and health-related outcomes.
Results
The study cohort consisted of a total of 514 patients undergoing TKA. This included 223 (43.3%) male patients and 291 (56.7%) female patients, with an overall mean age of 70 (SD 9.5) years. The preoperative Oxford Knee Score (OKS) was significantly higher in golfers when adjusting for confounders (Diff 3.4 95% CI 1 to 5.8,
p
= 0.006). There was no difference in postoperative outcomes between golfers and non-golfers. There was however a trend towards a higher Forgotten Joint Score (FJS) in the golfers (difference 9.3, 95% CI − 0.2 to 18.8,
p
= 0.056). Of the 48 patients who reported being golfers at the time of their surgery, 43 (89.6%) returned to golf and 88.4% of those were satisfied with their involvement in golf following surgery.
Conclusions
Golfers had better preoperative and equal postoperative knee specific function compared to non-golfers. The majority of golfers returned to golf by one year and were satisfied with their involvement in the game.
Level of evidence
III.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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