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Formaldehyde (HCHO) in the atmosphere is an intermediate product from the oxidation of methane and non-methane volatile organic compounds. In remote marine regions, HCHO variability is closely related to atmospheric oxidation capacity, and modeled HCHO in these regions is usually added as a global satellite HCHO background. Thus, it is important to understand and validate the levels of satellite HCHO over the remote oceans. Here we intercompare three satellite retrievals of total HCHO columns from the Ozone Monitoring Instrument Smithsonian Astrophysical Observatory (OMI SAO (v004)) algorithm, Ozone Mapping and Profiler Suite on Suomi National Polar-orbiting Partnership Smithsonian Astrophysical Observatory (OMPS-NPP SAO) algorithm, and Ozone Monitoring Instrument Belgian Institute for Space Aeronomy (OMI BIRA) algorithm and validate them against in situ observations from the NASA Atmospheric Tomography Mission (ATom) mission. All retrievals are correlated with ATom-integrated columns over remote oceans, with OMI SAO (v004) showing the best agreement. This is also reflected in the mean bias (MB) for OMI SAO (−0.73 ± 0.87) × 1015 molec. cm−2, OMPS SAO (−0.76 ± 0.88) × 1015 molec. cm−2, and OMI BIRA (−1.40 ± 1.11) × 1015 molec. cm−2. We recommend the OMI-SAO (v004) retrieval for remote-ocean atmosphere studies. Three satellite HCHO retrievals and in situ ATom columns all generally captured the spatial and seasonal distributions of HCHO in the remote-ocean atmosphere. Retrieval bias varies by latitude and season, but a persistent low bias is found in all products at high latitudes, and the general low bias is most severe for the OMI BIRA product. Examination of retrieval components reveals that slant column corrections have a larger impact on the retrievals over remote marine regions, while AMFs play a smaller role. This study informs us that the potential latitude-dependent biases in the retrievals require further investigation for improvement and should be considered when using marine HCHO satellite data, and vertical profiles from in situ instruments are crucial for validating satellite retrievals.

Abstract Background We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs). Methods Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset. Results Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) − 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17–3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets. Conclusions We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS.

Red beds belong to slippery formations, and their rapid identification is of great significance for major scientific and engineering issues, such as geological hazard risk assessment and rapid response to geological disasters. Existing research often identifies red beds from a qualitative or semiquantitative perspective, resulting in slow recognition speed and inaccurate recognition results, making it difficult to quickly handle landslide geological disasters. Combined with the correlation between red beds' geomorphic characteristics, mineral compositions, and chemical compositions, this study established a preliminary identification quantitative criterion based on the basic chemical composition combination rules (SiO2+Al2O3, Al2O3/SiO2, FeO+Fe2O3, Fe2O3/FeO, K2O+Na2O, Na2O/K2O, CaO+MgO, and MgO/CaO) in the red beds. Following this, we perform principal component analysis on the basic chemical composition combination rules mentioned above. The results indicate that simultaneously meeting the following principal component features can serve as a rapid quantitative criterion for distinguishing red beds from other rocks: F1=-3.36–23.55; F2=-23.00–3.11; F3=-10.12–4.88; F4=-2.21–4.52; F5=-0.97–7.30; and F=-0.67–1.89. By comparing the chemical composition combinations of 15 kinds of rocks collected from China in this study, it is proven that the quantitative criterion proposed in this study is effective. The study results can be used for rapid identification of red beds, achieving risk assessment and rapid response to geological disasters such as landslides.

IntroductionBladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use.MethodsThe linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS).Results2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 – 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 – 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 – 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 – 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 – 1.54), higher socioeconomic status (OR 1.31, CI 1.06 – 1.64), and later year of diagnosis (OR 1.09, CI 1.06 – 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone.ConclusionOver a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

Extensive airborne measurements of non-methane organic gases (NMOGs), methane, nitrogen oxides, reduced nitrogen species, and aerosol emissions from US wild and prescribed fires were conducted during the 2019 NOAA/NASA Fire Influence on Regional to Global Environments and Air Quality campaign (FIREX-AQ). Here, we report the atmospheric enhancement ratios (ERs) and inferred emission factors (EFs) for compounds measured on board the NASA DC-8 research aircraft for nine wildfires and one prescribed fire, which encompass a range of vegetation types. We use photochemical proxies to identify young smoke and reduce the effects of chemical degradation on our emissions calculations. ERs and EFs calculated from FIREX-AQ observations agree within a factor of 2, with values reported from previous laboratory and field studies for more than 80 % of the carbon- and nitrogen-containing species. Wildfire emissions are parameterized based on correlations of the sum of NMOGs with reactive nitrogen oxides (NOy) to modified combustion efficiency (MCE) as well as other chemical signatures indicative of flaming/smoldering combustion, including carbon monoxide (CO), nitrogen dioxide (NO2), and black carbon aerosol. The sum of primary NMOG EFs correlates to MCE with an R2 of 0.68 and a slope of −296 ± 51 g kg−1, consistent with previous studies. The sum of the NMOG mixing ratios correlates well with CO with an R2 of 0.98 and a slope of 137 ± 4 ppbv of NMOGs per parts per million by volume (ppmv) of CO, demonstrating that primary NMOG emissions can be estimated from CO. Individual nitrogen-containing species correlate better with NO2, NOy, and black carbon than with CO. More than half of the NOy in fresh plumes is NO2 with an R2 of 0.95 and a ratio of NO2 to NOy of 0.55 ± 0.05 ppbv ppbv−1, highlighting that fast photochemistry had already occurred in the sampled fire plumes. The ratio of NOy to the sum of NMOGs follows trends observed in laboratory experiments and increases exponentially with MCE, due to increased emission of key nitrogen species and reduced emission of NMOGs at higher MCE during flaming combustion. These parameterizations will provide more accurate boundary conditions for modeling and satellite studies of fire plume chemistry and evolution to predict the downwind formation of secondary pollutants, including ozone and secondary organic aerosol.

Elevated ground-level ozone concentrations have emerged as a major environmental issue in China. Nitrogen oxide (NOx) is a key precursor to ozone formation. Although control strategies aimed at reducing NOx emissions from conventional combustion sources are widely recognized, soil NOx emissions (mainly as NO) due to microbial processes have received little attention. The impact of soil NO emissions on ground-level ozone concentration is yet to be evaluated. This study estimated soil NO emissions in China using the Berkeley–Dalhousie Soil NOx Parameterization (BDSNP) algorithm. A typical modeling approach was used to quantify the contribution of soil NO emissions to surface ozone concentration. The brute-force method (BFM) and the Ozone Source Apportionment Technology (OSAT) implemented in the Comprehensive Air Quality Model with Extensions (CAMx) were used. The total soil NO emissions in China for 2018 were estimated to be 1157.9 Gg N, with an uncertainty range of 715.7–1902.6 Gg N. Spatially, soil NO emissions are mainly concentrated in Central China, North China, Northeast China, the northern Yangtze River Delta (YRD), and the eastern Sichuan Basin, with distinct diurnal and monthly variations that are mainly affected by the temperature and timing of fertilizer application. Both the BFM and OSAT results indicate a substantial contribution of soil NO emissions to the maximum daily 8 h (MDA8) ozone concentrations by 8.0–12.5 µg m−3 on average for June 2018, with the OSAT results being consistently higher than the BFM results. The results also showed that soil NO emissions led to a relative increase in ozone exceedance days by 10.5 %–43.5 % for selected regions. Reducing the soil NO emissions resulted in a general decrease in monthly MDA8 ozone concentrations, and the magnitude of ozone reduction became more pronounced as reductions increased. However, even with complete reductions in soil NO emissions, approximately 450.3 million people are still exposed to unhealthy ozone levels, necessitating multiple control policies at the same time. This study highlights the importance of soil NO emissions for ground-level ozone concentrations and the potential for reducing NO emissions as a future control strategy for ozone mitigation in China.

Purpose: The role of postoperative radiation therapy (PORT) in early stage Merkel cell carcinoma (MCC) is controversial. We analyzed the role of PORT in preventing local recurrences (LR) among patients with low-risk, pathologic stage I MCC based on the location of the primary tumors: head/neck (HN) versus non-HN sites. Methods and Materials: One hundred forty-seven patients with MCC were identified that had “low risk” disease (pathologic T1 primary tumor, negative microscopic margins, negative pathologic node status, no immunosuppression or prior systemic therapy). LR was defined as tumor recurrence within 2 cm of the primary surgical bed, and its frequency was estimated with the cumulative incidence method. Results: Seventy-nine patients received PORT (30 HN, 49 non-HN) with a median dose of 50 Gy (range, 8-64 Gy) and 68 patients were treated with surgery alone (30 HN, 38 non-HN). Overall, PORT was associated with a decreased risk of LR (5-year rate: 0% vs 9.5%; P = .004) with 6 LRs observed in the surgery alone group. Although the addition of PORT significantly reduced LR rates among patients with HN MCC (0% vs. 21%; P = .034), no LRs were observed in patients with non-HN MCC managed with surgery alone. There was no significant difference in MCC-specific survival comparing HN versus non-HN groups, with or without PORT. Conclusions: For low-risk, pathologic stage I MCC of the extremities and trunk, excellent local control rates were achieved with surgery, and PORT is not indicated. However, PORT was associated with a significant reduction in LRs among low-risk MCC of the HN.

Introduction: Club cells are precursors for mucus-producing goblet cells. Interleukin 1β (IL-1B) is an inflammatory mediator with pro-mucin activities that increases the number of mucus-producing goblet cells. IL-1B-mediated mucin production in alveolar adenocarcinoma cells requires activation of the cAMP response element-binding protein (CREB). Whether the pro-mucin activities of IL-1B require club cell CREB is unknown.Methods: We challenged male mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-1B or vehicle. Secondarily, we studied human “club cell-like” H322 cells.Results: IL-1B increased whole lung mRNA of secreted (Mucin 5ac, Mucin 5b) and tethered (Mucin 1, Mucin 4) mucins independent of genotype. However, loss of club cell Creb1 increased whole lung mRNA of member RAS oncogene family (Rab3D), decreased mRNA of the muscarinic receptor 3 (M3R) and prevented IL-1B mediated increases in purinergic receptor P2Y, (P2ry2) mRNA. IL-1B increased the density of goblet cells containing neutral mucins in wildtype mice but not in mice with loss of club cell Creb1. These findings suggested that club cell Creb1 regulated mucin secretion. Loss of club cell Creb1 also prevented IL-1B-mediated impairments in airway mechanics. Four days of pharmacologic CREB inhibition in H322 cells increased mRNA abundance of forkhead box A2 (FOXA2), a repressor of goblet cell expansion, and decreased mRNA expression of SAM pointed domain containing ETS transcription factor (SPDEF), a driver of goblet cell expansion. Chromatin immunoprecipitation demonstrated that CREB directly bound to the promoter region of FOXA2, but not to the promoter region of SPDEF. Treatment of H322 cells with IL-1B increased cAMP levels, providing a direct link between IL-1B and CREB signaling.Conclusion: Our findings suggest that club cell Creb1 regulates the pro-mucin properties of IL-1B through pathways likely involving FOXA2.

Abstract Background Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs). Methods In this single‐institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012–03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression‐free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection. Results Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR. Conclusions In the largest study to date examining PBBMs in ICI‐treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker.

The analysis of mid-ocean ridges and hotspots that are sourced by deep-rooted mantle plumes allows us to get a glimpse of mantle structure and dynamics. Dynamical interaction between ridge and plume processes have been widely proposed and studied, particularly in terms of ridgeward plume flow. However, the effects of plate drag on plume–lithosphere and plume–ridge interaction remain poorly understood. In particular, the mechanisms that control plume flow towards vs. away from the ridge have not yet been systematically studied. Here, we use 2D thermomechanical numerical models of plume–ridge interaction to systematically explore the effects of (i) ridge-spreading rate, (ii) initial plume head radius and (iii) plume–ridge distance. Our numerical experiments suggest two different geodynamic regimes: (1) plume flow towards the ridge is favored by strong buoyant mantle plumes, slow spreading rates and small plume–ridge distances; (2) plume drag away from the ridge is in turn promoted by fast ridge spreading for small-to-intermediate plumes and large plume–ridge distances. We find that the pressure gradient between the buoyant plume and spreading ridge at first drives ridgeward flow, but eventually the competition between plate drag and the gravitational force of plume flow along the base of the sloping lithosphere controls the fate of plume (spreading towards vs. away from the ridge). Our results highlight that fast-spreading ridges exert strong plate-dragging force, which sheds new light on natural observations of largely absent plume–lithosphere interaction along fast-spreading ridges, such as the East Pacific Rise.

Fires emit sufficient sulfur to affect local and regional air quality and climate. This study analyzes SO2 emission factors and variability in smoke plumes from US wildfires and agricultural fires, as well as their relationship to sulfate and hydroxymethanesulfonate (HMS) formation. Observed SO2 emission factors for various fuel types show good agreement with the latest reviews of biomass burning emission factors, producing an emission factor range of 0.47–1.2 g SO2 kg−1 C. These emission factors vary with geographic location in a way that suggests that deposition of coal burning emissions and application of sulfur-containing fertilizers likely play a role in the larger observed values, which are primarily associated with agricultural burning. A 0-D box model generally reproduces the observed trends of SO2 and total sulfate (inorganic + organic) in aging wildfire plumes. In many cases, modeled HMS is consistent with the observed organosulfur concentrations. However, a comparison of observed organosulfur and modeled HMS suggests that multiple organosulfur compounds are likely responsible for the observations but that the chemistry of these compounds yields similar production and loss rates as that of HMS, resulting in good agreement with the modeled results. We provide suggestions for constraining the organosulfur compounds observed during these flights, and we show that the chemistry of HMS can allow organosulfur to act as an S(IV) reservoir under conditions of pH > 6 and liquid water content >10−7 g sm−3. This can facilitate long-range transport of sulfur emissions, resulting in increased SO2 and eventually sulfate in transported smoke.

Fine particulate matter (PM2.5) has altered the radiation balance on Earth and raised environmental and health risks for decades but has only been monitored widely since 2013 in China. Historical long-term PM2.5 records with high temporal resolution are essential but lacking for both research and environmental management. Here, we reconstruct a site-based PM2.5 dataset at 6 h intervals from 1960 to 2020 that combines long-term visibility, conventional meteorological observations, emissions, and elevation. The PM2.5 concentration at each site is estimated based on an advanced machine learning model, LightGBM, that takes advantage of spatial features from 20 surrounding meteorological stations. Our model's performance is comparable to or even better than those of previous studies in by-year cross validation (CV) (R2=0.7) and spatial CV (R2=0.76) and is more advantageous in long-term records and high temporal resolution. This model also reconstructs a 0.25∘ × 0.25∘, 6-hourly, gridded PM2.5 dataset by incorporating spatial features. The results show PM2.5 pollution worsens gradually or maintains before 2010 from an interdecadal scale but mitigates in the following decade. Although the turning points vary in different regions, PM2.5 mass concentrations in key regions decreased significantly after 2013 due to clean air actions. In particular, the annual average value of PM2.5 in 2020 is nearly the lowest since 1960. These two PM2.5 datasets (publicly available at https://doi.org/10.5281/zenodo.6372847, Zhong et al., 2022) provide spatiotemporal variations at high resolution, which lay the foundation for research studies associated with air pollution, climate change, and atmospheric chemical reanalysis.

Abstract Background A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual’s health and well-being. Dysregulation of neuromuscular, cardiometabolic, and endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments currently exist for SCI, the development of novel strategies to improve the functional and health status of individuals living with SCI are much needed. To address this knowledge gap, the current study will determine whether a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that consists of functional electrical stimulation of the lower extremity during leg cycling (FES-LC) plus arm ergometry (AE) administered using behavioral motivational strategies, and testosterone therapy, is more efficacious than FES-LC plus AE and placebo in improving aerobic capacity, musculoskeletal health, function, metabolism, and wellbeing in SCI. Methods This single-site, randomized, placebo-controlled, parallel group trial will enroll 88 community-dwelling men and women, 19 to 70 years of age, with cervical and thoracic level of SCI, ASIA Impairment Scale grade: A, B, C, or D, 6 months or later after an SCI. Participants randomized to the multimodality intervention will undergo 16 weeks of home-based FES-LC and AE training plus testosterone undecanoate. Testosterone undecanoate injections will be administered by study staff in clinic or by a visiting nurse in the participant’s home. The control group will receive 16 weeks of home-based FES-LC and AE exercise plus placebo injections. The primary outcome of this trial is peak aerobic capacity, measured during an incremental exercise testing protocol. Secondary outcomes include whole body and regional lean and adipose tissue mass; muscle strength and power; insulin sensitivity, lipids, and inflammatory markers; SCI functional index and wellbeing (mood, anxiety, pain, life satisfaction and depressive symptoms); and safety. Discussion We anticipate that a multimodality intervention that simultaneously addresses multiple physiological impairments in SCI will result in increased aerobic capacity and greater improvements in other musculoskeletal, metabolic, functional and patient-reported outcomes compared to the control intervention. The findings of this study will have important implications for improving the care of people living with an SCI. Trial registration ClinicalTrials.gov : ( NCT03576001 ). Prospectively registered: July 3, 2018.

Active galactic nuclei (AGN) are prime candidate sources of the high-energy, astrophysical neutrinos detected by IceCube. This is demonstrated by the real-time multimessenger detection of the blazar TXS 0506+056 and the recent evidence of neutrino emission from NGC 1068 from a separate time-averaged study. However, the production mechanism of the astrophysical neutrinos in AGN is not well established, which can be resolved via correlation studies with photon observations. For neutrinos produced due to photohadronic interactions in AGN, in addition to a correlation of neutrinos with high-energy photons, there would also be a correlation of neutrinos with photons emitted at radio wavelengths. In this work, we perform an in-depth stacking study of the correlation between 15 GHz radio observations of AGN reported in the MOJAVE XV catalog, and 10 yr of neutrino data from IceCube. We also use a time-dependent approach, which improves the statistical power of the stacking analysis. No significant correlation was found for both analyses, and upper limits are reported. When compared to the IceCube diffuse flux, at 100 TeV and for a spectral index of 2.5, the upper limits derived are ∼3% and ∼9% for the time-averaged and time-dependent cases, respectively.

The origin of high-energy galactic cosmic rays is yet to be understood, but some galactic cosmic-ray accelerators can accelerate cosmic rays up to PeV energies. The high-energy cosmic rays are expected to interact with the surrounding material or radiation, resulting in the production of gamma-rays and neutrinos. To optimize for the detection of such associated production of gamma-rays and neutrinos for a given source morphology and spectrum, a multimessenger analysis that combines gamma-rays and neutrinos is required. In this study, we use the Multi-Mission Maximum Likelihood framework with IceCube Maximum Likelihood Analysis software and HAWC Accelerated Likelihood to search for a correlation between 22 known gamma-ray sources from the third HAWC gamma-ray catalog and 14 yr of IceCube track-like data. No significant neutrino emission from the direction of the HAWC sources was found. We report the best-fit gamma-ray model and 90% CL neutrino flux limit from the 22 sources. From the neutrino flux limit, we conclude that, for five of the sources, the gamma-ray emission observed by HAWC cannot be produced purely from hadronic interactions. We report the limit for the fraction of gamma-rays produced by hadronic interactions for these five sources.

Aerosol–planetary boundary layer (PBL) interaction has been proposed as a key mechanism for stabilizing the atmosphere and exacerbating surface air pollution. Although the understanding of this process has progressed enormously, its magnitude and impact remain uncertain and vary widely concerning aerosol types, vertical distributions, synoptic conditions, etc. In this study, our primary interest is to distinguish the aerosol–PBL interaction of absorbing and scattering aerosols under contrasting synoptic patterns and aerosol vertical distributions. Detailed in situ aircraft (King Air 350) measurements and online coupled model Weather Research and Forecasting with Chemistry (WRF-Chem) simulations are explored over the North China Plain (NCP). Furthermore, a long-term PBL stability trend from 1980 to 2020 over the NCP is also investigated. The aircraft measurements and surface observations show that the surface air pollution over the city of Baoding on 3 January is heavier than that on 4 January 2020. In addition, the aerosols are restricted to the low layer on 3 January, whereas the aerosols mix more homogeneously in an upwards direction on 4 January. Thus, we focus on the 2 d with distinct synoptic circumstances, PBL stability, and aerosol vertical distributions over the NCP. According to the WRF-Chem modeling, the synoptic pattern over Baoding differs between the 2 d. The prevailing wind direction is opposite with a southwesterly wind on 3 January and a northeasterly wind on 4 January. The results indicate that the synoptic condition may affect the PBL thermal structure, thus affecting the aerosol vertical distribution. Additionally, the sensitive numerical experiments reveal that the light-absorbing and light-scattering aerosols have different effects on altering the PBL thermal structure. The inhibition effect of scattering aerosols on the PBL appears to be independent of the aerosol height distribution and solely depends on its concentration. However, the aerosol–PBL feedback of absorbing aerosols is highly dependent on its vertical distribution. Besides the 2 d case investigation, the analysis of the modeling results for nearly 1 month from 3 to 30 January 2020 in Baoding yields a more robust and representative conclusion. Our analysis highlights that we should principally concentrate on controlling the emissions of scattering aerosols under the stable stratification, while cooperating to control the emissions of scattering and absorbing aerosols in an unstable stratification. Moreover, the long-term interannual variation in the PBL stability shows a strong correlation with the East Asian winter monsoon, which seems to be valuable in determining which pollutants to target in different monsoon years and attaining more precise air pollution control. Based on the numerical simulations and observational constraints, a concept scheme description has been concluded to deepen our recognition of the interactions between thermodynamic stability and aerosols within the PBL over the NCP region.

Background Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies.Methods We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1.Results PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3β/β-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential.Conclusions Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable.

Formaldehyde (HCHO) is one of the most abundant non-methane volatile organic compounds (VOCs) emitted by fires. HCHO also undergoes chemical production and loss as a fire plume ages, and it can be an important oxidant precursor. In this study, we disentangle the processes controlling HCHO by examining its evolution in wildfire plumes sampled by the NASA DC-8 during the Fire Influence on Regional to Global Environments and Air Quality experiment (FIREX-AQ) field campaign. In 9 of the 12 analyzed plumes, dilution-normalized HCHO increases with physical age (range 1–6 h). The balance of HCHO loss (mainly via photolysis) and production (via OH-initiated VOC oxidation) seems to control the sign and magnitude of this trend. Plume-average OH concentrations, calculated from VOC decays, range from −0.5 (± 0.5) × 106 to 5.3 (± 0.7) × 106 cm−3. The production and loss rates of dilution-normalized HCHO seem to decrease with plume age. Plume-to-plume variability in dilution-normalized secondary HCHO production correlates with OH abundance rather than normalized OH reactivity, suggesting that OH is the main driver of fire-to-fire variability in HCHO secondary production. Analysis suggests an effective HCHO yield of 0.33 (± 0.05) per VOC molecule oxidized for the 12 wildfire plumes. This finding can help connect space-based HCHO observations to the oxidizing capacity of the atmosphere and to VOC emissions.

Purpose: Neutron therapy is a high linear energy transfer modality that is useful for the treatment of radioresistant head and neck (H&N) cancers. It has been limited to 3-dimensioanal conformal-based fast-neutron therapy (3DCNT), but recent technical advances have enabled the clinical implementation of intensity-modulated neutron therapy (IMNT). This study evaluated the comparative dosimetry of IMNT and 3DCNT plans for the treatment of H&N cancers. Materials and Methods: Seven H&N IMNT plans were retrospectively created for patients previously treated with 3DCNT at the University of Washington (Seattle). A custom RayStation model with neutron-specific scattering kernels was used for inverse planning. Organ-at-risk (OAR) objectives from the original 3DCNT plan were initially used and were then systematically reduced to investigate the feasibility of improving a therapeutic ratio, defined as the ratio of the mean tumor to OAR dose. The IMNT and 3DCNT plan quality was evaluated using the therapeutic ratio, isodose contours, and dose volume histograms. Results: When compared with the 3DCNT plans, IMNT reduces the OAR dose for the equivalent tumor coverage. Moreover, IMNT is most advantageous for OARs in close spatial proximity to the target. For the 7 patients with H&N cancers examined, the therapeutic ratio for IMNT increased by an average of 56% when compared with the 3DCNT. The maximum OAR dose was reduced by an average of 20.5% and 20.7% for the spinal cord and temporal lobe, respectively. The mean dose to the larynx decreased by an average of 80%. Conclusion: The IMNT significantly decreases the OAR doses compared with 3DCNT and provides comparable tumor coverage. Improvements in the therapeutic ratio with IMNT are especially significant for dose-limiting OARs near tumor targets. Moreover, IMNT provides superior sparing of healthy tissues and creates significant new opportunities to improve the care of patients with H&N cancers treated with neutron therapy.

Anthropogenic secondary organic aerosol (ASOA), formed from anthropogenic emissions of organic compounds, constitutes a substantial fraction of the mass of submicron aerosol in populated areas around the world and contributes to poor air quality and premature mortality. However, the precursor sources of ASOA are poorly understood, and there are large uncertainties in the health benefits that might accrue from reducing anthropogenic organic emissions. We show that the production of ASOA in 11 urban areas on three continents is strongly correlated with the reactivity of specific anthropogenic volatile organic compounds. The differences in ASOA production across different cities can be explained by differences in the emissions of aromatics and intermediate- and semi-volatile organic compounds, indicating the importance of controlling these ASOA precursors. With an improved model representation of ASOA driven by the observations, we attribute 340 000 PM2.5-related premature deaths per year to ASOA, which is over an order of magnitude higher than prior studies. A sensitivity case with a more recently proposed model for attributing mortality to PM2.5 (the Global Exposure Mortality Model) results in up to 900 000 deaths. A limitation of this study is the extrapolation from cities with detailed studies and regions where detailed emission inventories are available to other regions where uncertainties in emissions are larger. In addition to further development of institutional air quality management infrastructure, comprehensive air quality campaigns in the countries in South and Central America, Africa, South Asia, and the Middle East are needed for further progress in this area.

Proton therapy is a promising but controversial treatment in the management of prostate cancer. Despite its dosimetric advantages when compared with photon radiation therapy, its increased cost to patients and insurers has raised questions regarding its value. Multiple prospective and retrospective studies have been published documenting the efficacy and safety of proton therapy for patients with localized prostate cancer and for patients requiring adjuvant or salvage pelvic radiation after surgery. The Particle Therapy Co-Operative Group (PTCOG) Genitourinary Subcommittee intends to address current proton therapy indications, advantages, disadvantages, and cost effectiveness. We will also discuss the current landscape of clinical trials. This consensus report can be used to guide clinical practice and research directions.

Purpose: Advances in radiotherapy have improved tumor control and reduced toxicity in the management of nasopharyngeal carcinoma (NPC). Local failure remains a problem for some patients with advanced primary tumors, and toxicities are significant given the large treatment volume and tumor proximity to critical structures, even with modern photon-based radiotherapy. Proton therapy has unique dosimetric advantages, and recent technological advances now allow delivery of intensity-modulated proton therapy (IMPT), which can potentially improve the therapeutic ratio in NPC. We report our 2-year clinical outcomes with IMPT for NPC. Materials and Methods: We retrospectively reviewed treatment records of patients with NPC treated with IMPT at our center. Demographics, dosimetry, tumor response, local regional control (LRC), distant metastasis, overall survival, and acute and late toxicity outcomes were reviewed. Analyses were performed with descriptive statistics and Kaplan-Meier method. Toxicity was graded per Common Terminology Criteria for Adverse Events (version 4.0). Results: Twenty-six patients were treated from 2015 to 2020. Median age was 48 years (range, 19–73 years), 62% (n = 16) had T3-T4 disease, 92% (n = 24) were node positive, 92% (n = 24) had stage III-IV disease, and 69% (n = 18) had positive results for Epstein-Barr virus. Dose-painted pencil-beam IMPT was used. Most patients (85%; 22 of 26) were treated with 70 Gy(RBE) in 33 fractions once daily; 4 (15%) underwent hyperfractionated accelerated treatment twice daily. All received concurrent cisplatin chemotherapy; 7 (27%) also received induction chemotherapy. All patients (100%) completed the planned radiotherapy, and no acute or late grade 4 or 5 toxicities were observed. At median follow-up of 25 months (range, 4-60), there were 2 local regional failures (8%) and 3 distant metastases (12%). The Kaplan-Meier 2-year LRC, freedom from distant metastasis, and overall survival were 92%, 87%, and 85% respectively. Conclusion: IMPT is feasible in locally advanced NPC with early outcomes demonstrating excellent LRC and favorable toxicity profile. Our data add to the growing body of evidence supporting the clinical use of IMPT for NPC.

The lower parts of two glaciers in the Aru range on the western Tibetan Plateau (TP) collapsed on 17 July and 21 September 2016, respectively, causing fatal damage to local people and their livestock. The giant ice avalanches, with a total volume of 150 × 106 m3, had almost melted by September 2019 (about 30 % of the second ice avalanche remained). The impact of these extreme disasters on downstream lakes has not been investigated yet. Based on in situ observation, bathymetry survey and satellite data, we explore the impact of the ice avalanches on the two downstream lakes (i.e., Aru Co and Memar Co) in terms of lake morphology, water level and water temperature in the subsequent 4 years (2016–2019). After the first glacier collapse, the ice avalanche slid into Aru Co along with a large amount of debris, which generated great impact waves in Aru Co and significantly modified the lake's shoreline and underwater topography. An ice volume of at least 7.1 × 106 m3 was discharged into Aru Co, spread over the lake surface and considerably lowered its surface temperature by 2–4 ∘C in the first 2 weeks after the first glacier collapse. Due to the large amount of meltwater input, Memar Co exhibited more rapid expansion after the glacier collapses (2016–2019) than before (2003–2014), in particular during the warm season. The melting of ice avalanches was found to contribute to about 23 % of the increase in lake storage between 2016 and 2019. Our results indicate that the Aru glacier collapses had both short-term and long-term impacts on the downstream lakes and provide a baseline in understanding the future lake response to glacier melting on the TP under a warming climate.

The maintenance of ecological diversity depends on the strength and direction of competitive interactions, but these interactions are difficult to study in microbial communities. Here the authors use engineered E. coli strains to show that competitively weak strains can persist when pairwise interactions are asymmetrical.

Abstract LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above $${1.4 \times 10^{-48}}\, {\hbox {cm}}^{2}$$ 1.4 × 10 - 48 cm 2 for a WIMP mass of $${40}\, \hbox {GeV}/{\hbox {c}}^{2}$$ 40 GeV / c 2 and a $${1000}\, \hbox {days}$$ 1000 days exposure. LZ achieves this sensitivity through a combination of a large $${5.6}\, \hbox {t}$$ 5.6 t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.

Here we analyze regional-scale data collected on board the NOAA WP-3D aircraft during the 2013 Southeast Nexus (SENEX) campaign to study the aerosol–cloud droplet link and quantify the sensitivity of droplet number to aerosol number, chemical composition, and vertical velocity. For this, the observed aerosol size distributions, chemical composition, and vertical-velocity distribution are introduced into a state-of-the-art cloud droplet parameterization to show that cloud maximum supersaturations in the region range from 0.02 % to 0.52 %, with an average of 0.14±0.05 %. Based on these low values of supersaturation, the majority of activated droplets correspond to particles with a dry diameter of 90 nm and above. An important finding is that the standard deviation of the vertical velocity (σw) exhibits considerable diurnal variability (ranging from 0.16 m s−1 during nighttime to over 1.2 m s−1 during day), and it tends to covary with total aerosol number (Na). This σw–Na covariance amplifies the predicted response in cloud droplet number (Nd) to Na increases by 3 to 5 times compared to expectations based on Na changes alone. This amplified response is important given that droplet formation is often velocity-limited and therefore should normally be insensitive to aerosol changes. We also find that Nd cannot exceed a characteristic concentration that depends solely on σw. Correct consideration of σw and its covariance with time and Na is important for fully understanding aerosol–cloud interactions and the magnitude of the aerosol indirect effect. Given that model assessments of aerosol–cloud–climate interactions do not routinely evaluate for overall turbulence or its covariance with other parameters, datasets and analyses such as the one presented here are of the highest priority to address unresolved sources of hydrometeor variability, bias, and the response of droplet number to aerosol perturbations.

Abstract The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

Biotechnology innovations require the precise control over microbial dynamics. Here the authors engineer an inducible quorum sensing system to fine tune population and community level behaviour.

Purpose: Proton therapy can potentially improve the therapeutic ratio over conventional radiation therapy for oropharyngeal squamous cell cancer (OPSCC) by decreasing acute and late toxicity. We report our early clinical experience with intensity-modulated proton therapy (IMPT). Materials and Methods: We retrospectively reviewed patients with OPSCC treated with IMPT at our center. Endpoints include local regional control (LRC), progression-free survival (PFS), overall survival (OS), tumor response, and toxicity outcomes. Toxicity was graded as per the Common Terminology Criteria for Adverse Events v4.03. Descriptive statistics and Kaplan-Meier method were used. Results: We treated 46 patients from March 2015 to August 2017. Median age was 58 years, 93.5% were male, 67% were nonsmokers, 98% had stage III-IVB disease per the 7th edition of the AJCC [American Joint Committee on Cancer] Cancer Staging Manual, and 89% were p16 positive. Twenty-eight patients received definitive IMPT to total dose of 70 to 74.4 Gy(RBE), and 18 patients received postoperative IMPT to 60 to 66 Gy(RBE) following transoral robotic surgery (TORS). Sixty-four percent of patients received concurrent systemic therapy. There were no treatment interruptions or observed acute grade 4 or 5 toxicities. Eighteen patients had percutaneous endoscopic gastrostomy (PEG) tube placement; the majority (14) were placed prophylactically. The most common grade 3 acute toxicities were dermatitis (76%) and mucositis (72%). The most common late toxicity was grade 2 xerostomia (30%). At a median follow-up time of 19.2 months (interquartile range [IQR], 11.2–28.4), primary complete response was 100% and nodal complete response was 92%. One patient required a salvage neck dissection owing to an incomplete response at 4 months. There were no recorded local regional or marginal recurrences, PFS was 93.5%, and OS was 95.7%. Conclusion: Our early results for IMPT in OPSCC are promising with no local regional or marginal recurrences and a favorable toxicity profile. Our data add to a body of evidence that supports the clinical use of IMPT. Randomized comparative trials are encouraged.

Purpose: We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT). Methods and Materials: Patients with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03. Results: The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval [CI], 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy. Conclusions: TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.

Summary: Prolonged heat and sea salt aerosols pose a challenge for the mammalian airway, placing the protective airway surface liquid (ASL) at risk for desiccation. Thus, mammals inhabiting salt marshes might have acquired adaptations for ASL regulation. We studied the airways of the rice rat, a rodent that inhabits salt marshes. We discovered negligible Na+ transport through the epithelial sodium channel (ENaC). In contrast, carbachol induced a large Cl− secretory current that was blocked by the calcium-activated chloride channel (CaCC) inhibitor CaCCinhi-A01. Decreased mRNA expression of α, β, and γ ENaC, and increased mRNA expression of the CaCC transmembrane member 16A, distinguished the rice rat airway. Rice rat airway cultures also secreted fluid in response to carbachol and displayed an exaggerated expansion of the ASL volume when challenged with 3.5% NaCl. These data suggest that the rice rat airway might possess unique ion transport adaptations to facilitate survival in the salt marsh environment. : Bio-Electrochemistry: Physiology; Molecular Physiology Subject Areas: Bio-Electrochemistry: Physiology, Molecular Physiology

In this study, comparative corrosion protection studies of cold-rolled steel (CRS) electrodes coated with electroactive/non-electroactive epoxy thermoset (denoted as EET/NEET) composites containing dispersed reduced graphene oxide (rGO) and graphene oxide (GO) platelets are presented. All composites were obtained through the thermal ring-opening reaction of bisphenol A diglycidyl ether (DGEBA) with amino-capped aniline trimer (ACAT) or trimethylolpropane tris[poly(propylene glycol), amine terminated] ether (T-403) at a specific mixing ratio in the presence of dispersed rGO/GO were characterized Fourier Transform Infrared (FTIR) spectroscopy and Transmission Electron Microscopy (TEM). In gas permeability measurements, the GO was found to display a slightly better dispersion capability in both EET and NEET membrane than in rGO. Conductive rGO platelets were found to promote the redox behavior of EET and non-conductive GO platelets was found to depress the redox behavior of EET, as measured by electrochemical cyclic voltammetry (CV) studies. Corrosion protection of composite coatings was investigated by electrochemical corrosion measurements in saline solution. It should be noted, in the EET system, that rGO was found to exhibit better anticorrosion performance as compared to that of GO. However, in NEET system, GO was found to have better anticorrosion performance than rGO. Better anticorrosion of rGO in EET may be attributed to better synergistic effect of electro-catalytic and the oxygen barrier properties of rGO in EET. On the contrary, better anticorrosion of GO in NEET may be associated with better oxygen barrier property of GO alone in NEET than that of rGO. The passive metal oxide layer formed on the cold rolled steel (CRS) electrode induced by EET was further confirmed by Raman and Electron Spectroscopy for Chemical Analysis (ESCA).

Background: Bone metastases are common and devastating to cancer patients. Existing treatments do not specifically target the disease sites and are therefore ineffective and systemically toxic. Here we present a new strategy to treat bone metastasis by targeting both the cancer cells (“the seed”), and their surrounding niche (“the soil”), using stem cells engineered to home to the bone metastatic niche and to maximise local delivery of multiple therapeutic factors. Methods: We used mesenchymal stem cells engineered using mRNA to simultaneously express P-selectin glycoprotein ligand-1 (PSGL-1)/Sialyl-Lewis X (SLEX) (homing factors), and modified versions of cytosine deaminase (CD) and osteoprotegerin (OPG) (therapeutic factors) to target and treat breast cancer bone metastases in two mouse models, a xenograft intratibial model and a syngeneic model of spontaneous bone metastasis. Findings: We first confirmed that MSC engineered using mRNA produced functional proteins (PSGL-1/SLEX, CD and OPG) using various in vitro assays. We then demonstrated that mRNA-engineered MSC exhibit enhanced homing to the bone metastatic niche likely through interactions between PSGL-1/SLEX and P-selectin expressed on tumour vasculature. In both the xenograft intratibial model and syngeneic model of spontaneous bone metastasis, engineered MSC can effectively kill tumour cells and preserve bone integrity. The engineered MSC also exhibited minimal toxicity in vivo, compared to its non-targeted chemotherapy counterpart (5-fluorouracil). Interpretation: Our combinatorial targeting of both the cancer cells and the niche represents a simple, safe and effective way to treat metastatic bone diseases, otherwise difficult to manage with existing strategies. It can also be applied to other cell types (e.g., T cells) and cargos (e.g., genome editing components) to treat a broad range of cancer and other complex diseases. Fund: National Institutes of Health, National Cancer Institute of the National Institutes of Health, Department of Defense, California Institute of Regenerative Medicine, National Science Foundation, Baylx Inc., and Fondation ARC pour la recherche sur le cancer. Keywords: Bone metastases, Cell therapy, Mesenchymal stem cell, mRNA engineering, Combination therapy

Abstract Background Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) metastasis and chemoresistance have not been fully characterized. Methods CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1. Results CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients. Conclusions CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.

Organic aerosol (OA) is one of the main components of the global particulate burden and intimately links natural and anthropogenic emissions with air quality and climate. It is challenging to accurately represent OA in global models. Direct quantification of global OA abundance is not possible with current remote sensing technology; however, it may be possible to exploit correlations of OA with remotely observable quantities to infer OA spatiotemporal distributions. In particular, formaldehyde (HCHO) and OA share common sources via both primary emissions and secondary production from oxidation of volatile organic compounds (VOCs). Here, we examine OA–HCHO correlations using data from summertime airborne campaigns investigating biogenic (NASA SEAC4RS and DC3), biomass burning (NASA SEAC4RS), and anthropogenic conditions (NOAA CalNex and NASA KORUS-AQ). In situ OA correlates well with HCHO (r=0.59–0.97), and the slope and intercept of this relationship depend on the chemical regime. For biogenic and anthropogenic regions, the OA–HCHO slopes are higher in low NOx conditions, because HCHO yields are lower and aerosol yields are likely higher. The OA–HCHO slope of wildfires is over 9 times higher than that for biogenic and anthropogenic sources. The OA–HCHO slope is higher for highly polluted anthropogenic sources (e.g., KORUS-AQ) than less polluted (e.g., CalNex) anthropogenic sources. Near-surface OAs over the continental US are estimated by combining the observed in situ relationships with HCHO column retrievals from NASA's Ozone Monitoring Instrument (OMI). HCHO vertical profiles used in OA estimates are from climatology a priori profiles in the OMI HCHO retrieval or output of specific period from a newer version of GEOS-Chem. Our OA estimates compare well with US EPA IMPROVE data obtained over summer months (e.g., slope =0.60–0.62, r=0.56 for August 2013), with correlation performance comparable to intensively validated GEOS-Chem (e.g., slope =0.57, r=0.56) with IMPROVE OA and superior to the satellite-derived total aerosol extinction (r=0.41) with IMPROVE OA. This indicates that OA estimates are not very sensitive to these HCHO vertical profiles and that a priori profiles from OMI HCHO retrieval have a similar performance to that of the newer model version in estimating OA. Improving the detection limit of satellite HCHO and expanding in situ airborne HCHO and OA coverage in future missions will improve the quality and spatiotemporal coverage of our OA estimates, potentially enabling constraints on global OA distribution.

Objective: Osteosarcoma (OS) is a malignant tumor in children, which seriously endangers children's health. However,few studies have been conducted to identify potential targets of OS. The purpose of this study was to identify the protein markers in plasma that are associated with the occurrence, metastasis, and prognosis of OS by combining multinomial analysis and constructing regression models. Materials and Methods: The miRNA expression profile GSE65071 dataset and protein expression (GSE78192) dataset were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed proteins (DEPs) and miRNAs (DEMIs) were identified from primary OS vs. normal control, and metastatic OS vs. primary OS, respectively. A miRNA-protein network was constructed based on miRNA-protein pairs. Functional analysis of DEPs involved in miRNA-protein network was utilized to obtain insights into the functions of the network. Subsequently, we screened out the genes differentially expressed similarly in both plasma and osteosarcoma tissues of OS patients. Eventually, genes in miRNA-protein network closely related to survival were identified by the intersection of lasso regression and K-M survival analysis, and Cox regression model was constructed for further analysis. Results: A total of 277 DEMIs and 50 DEPs, 3 DEMIs and 254 DEPs were identified with contact of OS occurs and metastasis. Furthermore, 11 proteins involved in miRNA-protein network were confirmed to exhibit the same dysregulation in both primary OS plasma and tissue and 3 proteins exhibit dysregulation in metastatic patients. Moreover, for patients without metastasis, UBE2S and ATXN3 not only have the same differential expression trend in both plasma and tumor tissues of OS patients, but also are closely related to the survival time of patients. Conclusions: In OS plasma, 11 proteins, including UBE2S, ATXN3 and LARP6 are potential plasma markers for the diagnosis of OS. Totally 3 proteins (UGT3A1, IGF1R and SLC7A1) were the potential plasma markers to predict metastasis of OS. Furthermore, the C-index and the AUC at 4-year of Cox regression model were 0.79 and 0.97, suggesting good reliability and potential of UBE2S and ATXN3 for prognostic prediction and targeted therapy of primary OS.

Background and Objectives. Several anesthesia techniques were applied to hemorrhoidectomy, but postoperative pain and urinary retention were still two unsolved problems. The aim of this prospective randomized study was to evaluate the effect of ultrasound-guided pudendal nerve block (PNB) combined with deep sedation compared to spinal anesthesia for hemorrhoidectomy. Methods. One hundred and twenty patients undergoing Milligan–Morgan hemorrhoidectomy were randomized to receive PNB combined with deep sedation using propofol (Group PNB, n = 60) or spinal anesthesia (Group SA, n = 60). Pain intensity was assessed using the visual analogue scale (0: no pain to 10: worst possible pain). The primary outcome was pain scores recorded at rest at 3, 6, 12, 24, 36, and 48 h and on walking at 12, 24, 36, and 48 h postoperatively. Secondary outcomes were analgesic consumption, side effects, and patient satisfaction after surgery. Results. Ultrasound-guided bilateral PNB combined with deep sedation using propofol could successfully be applied to Milligan–Morgan hemorrhoidectomy. Postoperative pain intensity was significantly lower in Group PNB compared to Group SA at rest at 3, 6, 12, 24, 36, and 48 h (p