Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in ...DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.
Synopsis
This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients.
Physiological conditions of chronic oxidative stress, mediated by the loss of JunD or Nrf2 transcription factors, are associated with a reduced protein level of the histone variant H2AX.
Under conditions of chronic stress due to junD or Nrf2 deficiency, H2AX protein is targeted for degradation by the proteasome.
ROS‐dependent H2AX degradation is mediated by enhanced interaction of H2AX protein with the E3 ubiquitin ligase RNF168.
H2AX decrease by chronic oxidative stress increases tumour cell genomic instability and death.
Chemosensitivity and survival of triple‐negative breast cancer patients are improved by stress‐mediated H2AX degradation following successive cycles of chemotherapy.
This work gives new insights into the regulation of H2AX protein turnover under chronic oxidative stress that affects DNA damage response. H2AX degradation upon chronic stress sensitizes tumour cells to chemotherapy and is indicative of better survival in triple‐negative breast cancer patients.
Anti‐cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in ...DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD‐/Nrf2‐antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly‐ubiquitination and promotes its degradation by the proteasome. ROS‐mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple‐Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2‐antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS‐mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.
Telomeres define the ends of eukaryotic chromosomes and comprise multiprotein complexes bound to terminal DNA sequence repeats. An intrinsic role of telomeres is to protect chromosomal termini from ...being processed as damaged-induced DNA breaks; this role is critical for maintaining genomic integrity. The fission yeast Taz1 protein regulates telomere functions throughout the mitotic and meiotic cell cycles. In this study, we employed biochemical, molecular and genetic analysis to dissect the regulation and role that taz1+ and other telomere proteins play in promoting genomic stability. We find during growth at low temperatures, loss of taz1+ results in decreased viability, chromosome missegregation and DNA damage checkpoint activation. Strikingly, these cells exhibit entangled chromosomes and a pronounced de novo accumulation of DNA double strand breaks (DSBs). These defects are suppressed by altered topoisomerase II function, implicating unprotected telomeres as substrates for Top2p. Furthermore, taz1δ cells are sensitive to treatments that induce DSBs suggesting a role for Taz1p in general DSB repair. Recent data obtained from 2-D DNA gel electrophoresis suggests that Taz1 is specifically required for telomere replication and that loss of Taz1 results in perturbed fork progression through both telomere and telomere associated sequences. These data suggest a model whereby aberrant replication in taz1δ cells results in entangled chromosomes, leading to a requirement for altered Top2 activity and homologous recombination. These phenotypes are specific to taz1δ cells and not other telomere mutants suggesting that Taz1 plays a central role in promoting genomic stability that is separable from its interacting partners.
Telomeres define the ends of eukaryotic chromosomes and comprise multiprotein complexes bound to terminal DNA sequence repeats. An intrinsic role of telomeres is to protect chromosomal termini from ...being processed as damaged-induced DNA breaks; this role is critical for maintaining genomic integrity. The fission yeast Taz1 protein regulates telomere functions throughout the mitotic and meiotic cell cycles. In this study, we employed biochemical, molecular and genetic analysis to dissect the regulation and role that taz1+ and other telomere proteins play in promoting genomic stability. We find during growth at low temperatures, loss of taz1+ results in decreased viability, chromosome missegregation and DNA damage checkpoint activation. Strikingly, these cells exhibit entangled chromosomes and a pronounced de novo accumulation of DNA double strand breaks (DSBs). These defects are suppressed by altered topoisomerase II function, implicating unprotected telomeres as substrates for Top2p. Furthermore, taz1δ cells are sensitive to treatments that induce DSBs suggesting a role for Taz1p in general DSB repair. Recent data obtained from 2-D DNA gel electrophoresis suggests that Taz1 is specifically required for telomere replication and that loss of Taz1 results in perturbed fork progression through both telomere and telomere associated sequences. These data suggest a model whereby aberrant replication in taz1δ cells results in entangled chromosomes, leading to a requirement for altered Top2 activity and homologous recombination. These phenotypes are specific to taz1δ cells and not other telomere mutants suggesting that Taz1 plays a central role in promoting genomic stability that is separable from its interacting partners.
The simultaneous, concerted transfer of electrons and protons--electron-proton transfer (EPT)--is an important mechanism utilized in chemistry and biology to avoid high energy intermediates. There ...are many examples of thermally activated EPT in ground-state reactions and in excited states following photoexcitation and thermal relaxation. Here we report application of ultrafast excitation with absorption and Raman monitoring to detect a photochemically driven EPT process (photo-EPT). In this process, both electrons and protons are transferred during the absorption of a photon. Photo-EPT is induced by intramolecular charge-transfer (ICT) excitation of hydrogen-bonded-base adducts with either a coumarin dye or 4-nitro-4'-biphenylphenol. Femtosecond transient absorption spectral measurements following ICT excitation reveal the appearance of two spectroscopically distinct states having different dynamical signatures. One of these states corresponds to a conventional ICT excited state in which the transferring H⺠is initially associated with the proton donor. Proton transfer to the base (B) then occurs on the picosecond time scale. The other state is an ICT-EPT photoproduct. Upon excitation it forms initially in the nuclear configuration of the ground state by application of the Franck-Condon principle. However, due to the change in electronic configuration induced by the transition, excitation is accompanied by proton transfer with the protonated base formed with a highly elongated âºHhorizontal lineB bond. Coherent Raman spectroscopy confirms the presence of a vibrational mode corresponding to the protonated base in the optically prepared state.
Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management ...strategy after open-globe injury (OGI) remains controversial.
This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat.
Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR).
Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval CI, 0.00%-0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%-0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%-0.33%). The ARR using a random effects model was -0.0010 (in favour of eye removal; 95% CI, -0.0031 in favor of eye removal to 0.0011 in favor of primary repair). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data.
Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management ...strategy after open-globe injury (OGI) remains controversial.
This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat.
Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR).
Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval CI, 0.00%–0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%–0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%–0.33%). The ARR using a random effects model was −0.0010 (in favour of eye removal; 95% CI, −0.0031 in favor of eye removal to 0.0011 in favor of primary repair). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data.
Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
There is growing interest in using machine learning approaches to priority rank studies and reduce human burden in screening literature when conducting systematic reviews. In addition, identifying ...addressable questions during the problem formulation phase of systematic review can be challenging, especially for topics having a large literature base. Here, we assess the performance of the SWIFT-Review priority ranking algorithm for identifying studies relevant to a given research question. We also explore the use of SWIFT-Review during problem formulation to identify, categorize, and visualize research areas that are data rich/data poor within a large literature corpus.
Twenty case studies, including 15 public data sets, representing a range of complexity and size, were used to assess the priority ranking performance of SWIFT-Review. For each study, seed sets of manually annotated included and excluded titles and abstracts were used for machine training. The remaining references were then ranked for relevance using an algorithm that considers term frequency and latent Dirichlet allocation (LDA) topic modeling. This ranking was evaluated with respect to (1) the number of studies screened in order to identify 95 % of known relevant studies and (2) the "Work Saved over Sampling" (WSS) performance metric. To assess SWIFT-Review for use in problem formulation, PubMed literature search results for 171 chemicals implicated as EDCs were uploaded into SWIFT-Review (264,588 studies) and categorized based on evidence stream and health outcome. Patterns of search results were surveyed and visualized using a variety of interactive graphics.
Compared with the reported performance of other tools using the same datasets, the SWIFT-Review ranking procedure obtained the highest scores on 11 out of 15 of the public datasets. Overall, these results suggest that using machine learning to triage documents for screening has the potential to save, on average, more than 50 % of the screening effort ordinarily required when using un-ordered document lists. In addition, the tagging and annotation capabilities of SWIFT-Review can be useful during the activities of scoping and problem formulation.
Text-mining and machine learning software such as SWIFT-Review can be valuable tools to reduce the human screening burden and assist in problem formulation.
Abstract
Climate change models often assume similar responses to temperatures across the range of a species, but local adaptation or phenotypic plasticity can lead plants and animals to respond ...differently to temperature in different parts of their range. To date, there have been few tests of this assumption at the scale of continents, so it is unclear if this is a large‐scale problem. Here, we examined the assumption that insect taxa show similar responses to temperature at 96 sites in grassy habitats across North America. We sampled insects with Malaise traps during 2019–2021 (
N
= 1041 samples) and examined the biomass of insects in relation to temperature and time of season. Our samples mostly contained Diptera (33%), Lepidoptera (19%), Hymenoptera (18%), and Coleoptera (10%). We found strong regional differences in the phenology of insects and their response to temperature, even within the same taxonomic group, habitat type, and time of season. For example, the biomass of nematoceran flies increased across the season in the central part of the continent, but it only showed a small increase in the Northeast and a seasonal decline in the Southeast and West. At a smaller scale, insect biomass at different traps operating on the same days was correlated up to ~75 km apart. Large‐scale geographic and phenological variation in insect biomass and abundance has not been studied well, and it is a major source of controversy in previous analyses of insect declines that have aggregated studies from different locations and time periods. Our study illustrates that large‐scale predictions about changes in insect populations, and their causes, will need to incorporate regional and taxonomic differences in the response to temperature.
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