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Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies. DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

The seismic velocity structure beneath East Africa suggests interconnected corridors of hot mantle are upwelling beneath the continent. However, the geochemical evidence for deep mantle in Ethiopia‐Kenya‐Tanzania volcanism is sparse questioning the existence of superplume. The development of new geothermal fields in the region offers the opportunity to access high temperature magmatic‐hydrothermal fluids. Well gases from the geothermal field in the Menengai caldera in the central Kenya Rift have C‐He isotope systematics that are dominated by magmatic volatiles. High precision Ne isotope data confirm a primordial deep mantle that has experienced long‐term convective isolation like that beneath Hawaii is present beneath the Kenyan rift. The Ne isotope composition of the gases is indistinguishable from volatiles in basalts from the Afar plume and Western Rift (and significantly more precise) providing the first geochemical evidence for a common deep mantle beneath the entirety of the East African Rift System.

The relationship between Sn–Ag mineralization and mantle magmatism is a topic of high interest in current ore deposit research. Here, we investigate porphyry-, skarn-, and cassiterite-sulfide type Sn-polymetallic deposits associated with granitoids and vein-type Ag–Pb–Zn deposits hosted in sub-volcanic rocks in the southern Great Xing’an Range (SGXR), northeast China, as a case example. We use He, Ar, and S isotopes and isotopic end-member simulation calculations to determine the contribution of mantle-derived fluids/melts to the ore mineralization. Our He–Ar isotope data demonstrate that the ore-forming fluids are mixtures of shallow crust-derived fluid containing radiogenic 4He but no radiogenic 40Ar and magmatic fluids with mantle-derived 3He and 40Ar. The Pb–Zn–Ag deposits have a higher contribution of magmatic volatiles than the Sn-polymetallic deposits. Sulfide δ34S values of − 2.7 to − 0.6‰ in the Pb–Zn–Ag deposits are consistent with a magmatic sulfur source, whereas sulfides with δ34S values of − 12.2 to − 0.15‰ in the Sn-polymetallic deposits signal a possibly bimodal source of sulfur, i.e., crustal light sulfur mixed with magmatic sulfur. The noble gas compositions of the ore fluids are controlled by crustal thickness, high 3He fluxes (24 to 404 at/s/cm2), and low residence time (1 to 18 Myr) of He in the asthenosphere below the SGXR. Non-equilibrium open-system magma degassing is evidenced by the range of elevated values of 4He/40Ar* ratios (4.8–127). The 3He/heat ratio of the ore fluids from the Sn and Pb–Zn–Ag deposits overlap (0.01–0.76 × 10−2 cm3 STP J−1 (cubic centimeter at standard temperature and pressure per joule) and 0.02–1.08 × 10−2 cm3 STP J−1, respectively), indicating a consequence of conduction of mantle-derived heat across the magma-hydrothermal interface. Furthermore, an increasing abundance of Sn reserves in the SGXR deposits can be equated with an increase in the mantle-derived He component in the ore fluids. These findings suggest that a continuous flux of mantle-derived fluids/melts plays an essential role in Sn–Ag–Pb–Zn mineralization.

Feedbacks between climatic and geological processes are highly controversial and testing them is a key challenge in Earth sciences. The Great Escarpment of the Arabian Red Sea margin has several features that make it a useful natural laboratory for studying the effect of surface processes on deep Earth. These include strong orographic rainfall, convex channel profiles versus concave swath profiles on the west side of the divide, morphological disequilibrium in fluvial channels, and systematic morphological changes from north to south that relate to depth changes of the central Red Sea. Here we show that these features are well interpreted with a cycle that initiated with the onset of spreading in the Red Sea and involves feedbacks between orographic precipitation, tectonic deformation, mid-ocean spreading and coastal magmatism. It appears that the feedback is enhanced by the moist easterly trade winds that initiated largely contemporaneously with sea floor spreading in the Red Sea. Testing feedbacks between climatic and geological processes are challenging. Here, the authors show that geomorphological features of the southern Red Sea margin are best interpreted by a feedback cycle between orographic precipitation, mid-ocean spreading and coastal magmatism, and that the feedback is enhanced by the trade wind.

Dating of extensive alluvial fan surfaces and fluvial features in the hyperarid core of the Atacama Desert, Chile, using cosmogenic nuclides provides unrivalled insights about the onset and variability of aridity. The predominantly hyperarid conditions help to preserve the traces of episodic climatic and/or slow tectonic change. Utilizing single clast exposure dating with cosmogenic 10 Be and 21 Ne, we determine the termination of episodes of enhanced fluvial erosion and deposition occurring at ~19, ~14, ~9.5 Ma; large scale fluvial modification of the landscape had ceased by ~2–3 Ma. The presence of clasts that record pre-Miocene exposure ages (~28 Ma and ~34 Ma) require stagnant landscape development during the Oligocene. Our data implies an early onset of (hyper-) aridity in the core region of the Atacama Desert, interrupted by wetter but probably still arid periods. The apparent conflict with interpretation that favour a later onset of (hyper-) aridity can be reconciled when the climatic gradients within the Atacama Desert are considered.

Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR) + ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR + ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs. Fiancette et al. utilize models of inducible transcription factor deletion in mature tissue-resident ILCs to reveal complementary and competing transcriptional networks that determine ILC3 phenotype and functional capacity.

Poor mental health associated with the COVID-19 pandemic may prompt the utilization of various coping behaviors, including alcohol use. We aimed to investigate the relationships between mental health symptomatology and self-reported changes in alcohol consumption at the onset of the pandemic. Data were from the nationwide COVID-19 Coping Study of US adults aged ≥55 in April and May 2020 (n = 6548). We used population-weighted multivariable-adjusted multi-nomial logistic regression models to estimate odds ratios (ORs) for the associations between mental health (of depression, anxiety, and loneliness, each) and self-reported increased alcohol consumption (vs. no change in consumption). One in ten adults (717/6548; 11%) reported an increase in their alcohol consumption in the past week compared to their usual pre-COVID-19 drinking. Mental health symptomatology was associated with increased drinking since the pandemic onset (depression: OR = 2.66, 95% CI: 1.99–3.56; anxiety: OR = 1.80, 95% CI: 1.34–2.42; loneliness: OR = 2.45, 95% CI: 1.83–3.28). Participants who screened positive for all three mental health outcomes were substantially more likely to report increased alcohol consumption since the onset of the pandemic (OR = 3.87, 95% CI: 2.52–5.96, vs. no mental health outcomes). This study demonstrates potentially harmful changes in alcohol intake among middle-to-older aged adults experiencing mental health symptomatology during the early months of the COVID-19 pandemic.

Background Older adults are particularly vulnerable to the adverse health effects of extreme temperature-related events. A growing body of literature highlights the importance of the natural environment, including air pollution and sunlight, on cognitive health. However, the relationship between exposure to outdoor temperatures and cognitive functioning, and whether there exists any differences across climate region, remains largely unexplored. We address this gap by examining the temperature-cognition association, and whether there exists any variation across climate regions in a national cohort of aging adults. Methods In this cross-sectional study, we obtained data on temperature exposure based on geocoded residential location of participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. For each participant, this information was linked to their cognitive scores from Word List Learning and Recall tests to assess cognitive functioning. We used distributed lag non-linear models (dlnm) to model temperature effects over 2 days. Multivariable linear regression was used to compute temperature-cognitive functioning associations, adjusted for important covariates. Region-specific (“Dry”, “Mediterranean/oceanic”, “Tropical” and “Continental”) associations were examined by including an interaction term between climate region and temperature. Results Amongst 20,687 individuals (mean age = 67.8; standard deviation = 9.2), exposure to region-specific extreme cold temperatures in the “dry” region (e.g., Arizona) over 2 days was associated with lower cognitive scores (Mean Difference [MD]: -0.76, 95% Confidence Interval [CI]: − 1.45, − 0.07). Associations remained significant for cumulative effects of temperature over 2 days. Extremely cold exposure in the “Mediterranean/oceanic” region (e.g., California) over 2 days was also associated with significantly lower cognitive performance (MD: -0.25, 95% CI: − 0.47, − 0.04). No significant associations were observed for exposure to hot temperatures. Cognitive performance was slightly higher in late summer and fall compared to early summer. Conclusion We noted adverse cognitive associations with cold temperatures in traditionally warmer regions of the country and improved cognition in summer and early fall seasons. While we did not observe very large significant associations, this study deepens understanding of the impact of climate change on the cognitive health of aging adults and can inform clinical care and public health preparedness plans.

Inflammatory disorders of the gastro-intestinal tract are a major cause of morbidity and significant burden from a health and economic perspective in industrialized countries. While the incidence of such conditions has a strong environmental component, in particular dietary composition, epidemiological studies have identified specific hereditary mutations which result in disequilibrium between pro- and anti-inflammatory factors. The IL-1 super-family of cytokines and receptors is highly pleiotropic and plays a fundamental role in the pathogenesis of several auto-inflammatory conditions including rheumatoid arthritis, multiple sclerosis and psoriasis. However, the role of this super-family in the etiology of inflammatory bowel diseases remains incompletely resolved despite extensive research. Herein, we highlight the currently accepted paradigms as they pertain to specific IL-1 family members and focus on some recently described non-classical roles for these pathways in the gastrointestinal tract. Finally, we address some of the shortcomings and sources of variance in the field which to date have yielded several conflicting results from similar studies and discuss the potential effect of these factors on data interpretation.