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The vertical distribution of carbonaceous aerosol impacts climate change, air quality and human health, but there is a lack of in-situ vertical observations of black (BC) and brown carbon (BrC). Thus, the characteristic of vertical profiles of BC concentration, particle number concentration (PNC), O3 concentration and optical absorption of BC and BrC were observed in a suburban site over North China Plain, where heavy pollution of PM2.5 and O3 always occurred in winter and summer, respectively. In winter, during a heavy pollution episode, the BC and PNC was near uniformly distributed within mixing layer (ML) (15.2 ± 6.7 μg m−3 and 678 ± 227 p cm−3, respectively) and decreased with altitude above the ML. The BC heating rate reached about 0.13 K h−1 during the heaviest pollution day. In summer, the BC concentration (2.9 ± 1.3 μg m−3) in ML during the middle O3 pollution events was higher than that (1.7 ± 0.6 μg m−3) during the light O3 pollution. The light absorption coefficients of BC at 880 nm and BrC at 375 nm measured in the early morning were lower than that in the daytime, and the contribution of BrC to total light absorption of carbonaceous aerosols was in the range of 27–47%. In addition, BC was effectively transported to high altitude than BrC in the daytime. The light absorption of secondary BrC in the daytime was higher 10–20% than that in the early morning. Simultaneously, the contribution of secondary BrC to the total BrC light absorption at 375 nm was range from 32% to 68% within 1000 m.

Aim: We aimed to quantify the effects of immune checkpoint inhibitors (ICIs) on the prognosis of COVID-19. Materials & methods: A meta-analysis was conducted and the hospitalization, severe disease and mortality rates were assessed. Thirteen studies comprising of 4614 cancer patients with COVID-19 were included. Results: When compared with cancer patients without prior ICI exposure, patients with prior ICI treatment exhibited a higher rate of hospitalization (odds ratio [OR] 2.0, 95% CI 1.19–3.38, p = 0.01). However, the OR of severe disease and mortality in ICI exposed cases was similar to non-ICI exposed patients (OR 1.55, 95% CI 0.69–3.51, p = 0.29; OR 1.12, 95% CI 0.85–1.48, p = 0.42, respectively). Conclusion: It is uncertain whether prior exposure to ICIs increases the risk of severe disease and death, however the observed OR suggest a higher rate of hospitalization., Lay abstract COVID-19 is an infectious disease caused by a virus which affected people worldwide in 2020. It mainly attacks the lungs and causes symptoms such as, fever, dry cough and fatigue. However, there is currently are no definite therapies for its treatment. Cancer patients are more vulnerable due to both the tumor itself and the anticancer treatment. At the same time, they are at higher risk of COVID-19 exposure due to the need for regular treatment and testing in hospitals. In this systematic review and meta-analysis we enrolled 13 studies. Firstly, we analyzed the rate of hospitalization, severe disease and death. Additionally, we studied the impact of immune checkpoint inhibitors on the outcome of cancer patients infected with COVID-19. Finally, our discussion focuses on what we can learn from the pandemic to provide guidance for clinical practice.

Purpose The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI); however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). Patients and methods We derived a cohort of 406 patients with unresectable/advanced HCC receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. We tested whether the development of clinically significant trAE (i.e. graded ≥2, trAE2) predicted improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) following ICI. We established an international consortium of 10 tertiary-care referral centres located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to validate this association. Results In the FDA dataset of 406 patients, 325 (80%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 258, 64%), trAE2 were reported in 228 patients (56.1%). Development of trAE2 was associated with longer OS (16.7 versus 11.2 months) and PFS (5.5 versus 2.2 months) and persisted as an independent predictor of outcome after adjusting for viral aetiology, gender, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy. In a multi-institutional cohort of 357 patients with similar characteristics mostly treated with ICI monotherapy (n = 304, 85%), the development of trAE2 was associated with longer OS (23.3 versus 12.1 months) and PFS (9.6 versus 3.9 months). TrAE2 were confirmed predictors of improved OS (HR 0.43; 95% CI:0.25–0.75) and PFS (HR 0.48; 95% CI: 0.31–0.75), with multivariable analyses confirming their association with outcome independent of clinicopathologic features of interest. Additional time-varying multivariable analyses also indicated that trAEs were associated with a decreased risk of progression (HR 0.56, 95% CI: 0.46–0.67) in the FDA dataset and death (HR 0.55; 95% CI: 0.32–0.95) in the multi-institutional dataset. Conclusion Development of trAE2 correlates with improved outcomes in patients with HCC receiving ICI in clinical trials and in routine practice. Prospective studies aimed at understanding the underlying immunologic foundations of such relationships are warranted to identify predictive biomarkers of toxicity and response.

The gut microbiome is increasingly being described as one of the underlying mechanisms for development of immune checkpoint inhibitor (ICI)-induced colitis. Similarities in gut microbiome profiles have been found among various diseases associated with intestinal inflammation, including inflammatory bowel disease. Certain bacterial species have been reported to be preventive for colitis, as well as beneficial for cancer outcome, in patients receiving ICI therapy. Alternatively, other bacterial classes have been shown to be associated with immunologic alterations causing intestinal inflammation with subsequent increase in the risk of ICI-related colitis. Gut microbiome manipulation by fecal transplantation has been proposed as one of the modalities to ameliorate inflammation in patients with ICI-related colitis refractory to immunosuppressive therapy. Additional investigations are needed to clarify the role of gut microbiome in the pathogenesis of ICI-related colitis.

PURPOSE The risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

Background Immune checkpoint inhibitor therapy has significantly improved the outcomes of various advanced malignancies that were deemed unruly prior to its invention. Immune-mediated diarrhea and enterocolitis are among the most frequently encountered adverse events of immune checkpoint inhibitor therapy. Given the increasing use of these therapies in the treatment of an ever-growing number of malignancies, providing appropriate treatment for such adverse effects has become crucial. Methods In this review, we summarize the current body of evidence concerning the management of immune-mediated diarrhea and enterocolitis. Additionally, management of immune-mediated diarrhea and enterocolitis is likened to that of inflammatory bowel disease, given the resemblance between both entities in pathogenesis and clinical features. Reviewing the literature raised several points regarding this devastating toxicity that still need further investigation by future efforts. Results Endoscopic and histologic evaluation is pivotal in the assessment of immune-mediated diarrhea and enterocolitis and provides vital information regarding the severity of the disease to guide treatment. Corticosteroids are the main therapy for immune-mediated diarrhea and enterocolitis, with infliximab and vedolizumab as second-line agents. Recently, fecal microbiota transplantation has emerged as a treatment option for immune-mediated diarrhea and enterocolitis that is refractory to corticosteroids. Restarting immune checkpoint inhibitor therapy after resolution of immune-mediated diarrhea and enterocolitis carries a risk of recurrence that is mostly controllable with current immune-suppressive treatment. Conclusions Lastly, we propose a management algorithm for immune-mediated diarrhea and enterocolitis. Prospective research, preferably as collaborative efforts from oncology and gastroenterology specialists, is needed to refine the management of immune-mediated diarrhea and enterocolitis.

The structure of the boundary layer affects the evolution of ozone (O3), and research into this structure will provide important insights for understanding photochemical pollution. In this study, we conducted a one-month observation (from June 15 to July 14, 2016) of the boundary layer meteorological factors as well as O3 and its precursors in Luancheng County, Shijiazhuang (37°53′N, 114°38′E). Our research showed that photochemical pollution in Shijiazhuang is serious, and the mean hourly maximum and mean 8-hr maximum O3 concentrations are 97.9 ± 26.1 and 84.4 ± 22.4 ppbV, respectively. Meteorological factors play a significant role in the formation of O3. High temperatures and southeasterly winds lead to elevated O3 values, and at moderate relative humidity (40%–50%) and medium boundary layer heights (1200–1500 m), O3 production sensitivity occurred in the transitional region between volatile organic compounds (VOC) and nitrogen oxides (NOx) limitations, and the O3 concentration was the highest. The vertical profiles of O3 were also measured by a tethered balloon. The results showed that a large amount of O3 was stored in the residual layer, and the concentration was positively correlated with the O3 concentration measured the previous day. During the daytime of the following day, the contribution of O3 stored in the residual layer to the boundary layer reached 27% ± 7% on average.

Background and Aims The aim of this study was to examine clinical outcomes and adverse events (AEs) of self-expandable metal stents (SEMSs) in the management of malignant colonic obstruction (MCO). Methods Patients with SEMSs for MCO treated at our institution from 2007 to 2016 were included. Clinical success was defined as successful oral intake after the procedure and technical success as stent deployment across the stricture in the desired location. Results Of 199 patients, the mean age was 58, 54% were men, and 99% had stage IV cancer. MCO etiology was colorectal cancer in 82% and extrinsic compression in 17%. Technical success was achieved in 99.5% and clinical success in 89%. The SEMSs were palliative in 97% and were a bridge to surgery in 4%. MCO occurred in the left side of the colon in 90%, transverse in 4.5%, and ascending colon in 5.5%. SEMSs were placed in curved segments in 30% and straight segments in 70%. Tandem SEMSs were required in 27 patients. Forty-six patients had 48 AEs (24%), including 2% periprocedure, 15% postprocedure, and 83% after 72 hours. Stent-related AEs (n = 25) included persistent obstruction (n = 14), occlusion (n = 10), and failure of expansion (n = 1). Procedural AEs (n = 23) included minor bleeding (n = 2), perforations (n = 4), abdominal pain (n = 12), stent migration (n = 4), and respiratory insufficiency (n = 1). Repeat procedures were performed in 21 of 46 patients. After SEMSs, 48 patients underwent surgery, including resection with primary anastomosis (n = 8), resection with definitive stoma (n = 18), and diverting stoma without resection (n = 19). Mean time to surgery after SEMS placement was 175 days. Postsurgical AEs occurred in those with resections (leak, 2; infection, 2). Of 104 receiving bevacizumab, 22% had AEs, including 1 perforation compared with 3 in the nonbevacizumab group (P = .549). Mean overall survival was 5.6 months. Extrinsic compression and curved strictures were associated with poor clinical success by univariate analysis and etiology (noncolonic with poor outcome) by multivariate analysis. Conclusions SEMSs for MCO has high technical but suboptimal clinical success. Curved strictures and extrinsic compression are associated with poor outcomes. The perforation rate was not higher in the bevacizumab compared with the nonbevacizumab group, although this should be further validated in a larger population.

PURPOSE Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-4.

Immune checkpoint inhibitors (ICIs) have emerged as a novel therapeutic class for various malignancies. Their immune upregulation promotes significant anti-tumor effect, but simultaneously, can also result in treatment-limiting immune-related adverse events (irAEs). The data on upper gastrointestinal (GI) tract irAEs are sparse. We herein describe a case of steroid-dependent upper GI toxicity with nivolumab (an anti-programmed death [PD] protein-1) that achieved clinical and histological remission with vedolizumab treatment (a GI tract targeted anti-integrin antibody). A 65-year-old male patient with progressive lung cancer was treated with nivolumab and following 16 cycles, developed severe nausea, vomiting, and epigastric abdominal cramps requiring five hospitalizations. His initial esophagogastroduodenoscopy (EGD) showed active inflammation in both the stomach and duodenum. Nivolumab was discontinued, but despite treatment with multiple steroid courses, his symptoms always recurred during prednisone taper. Clinical remission was ultimately achieved with vedolizumab. His last EGD after five infusions of vedolizumab demonstrated resolution of inflammation. His lung cancer has since relapsed and the treatment plan was to resume nivolumab concurrently with vedolizumab. In conclusion, ICIs, such as nivolumab, have emerged as therapy for various malignancies. Their use can be associated with various irAEs including the upper GI adverse events which is uncommon. This case scenario showed that vedolizumab can provide a steroid-sparing therapeutic effect to achieve remission of upper GI irAEs even in cases where multiple steroid courses have failed.

Acid‐sensing ion channel 1a (ASIC1a) allows Na+ and Ca2+ flow into cells. It is expressed during inflammation, in tumour and ischaemic tissue, in the central nervous system and non‐neuronal injury environments. Endoplasmic reticulum stress (ERS) is caused by the accumulation of misfolded proteins that interferes with intracellular calcium homoeostasis. Our recent reports showed ASIC1a and ERS are involved in liver fibrosis progression, particularly in hepatic stellate cell (HSC) activation. In this study, we investigated the roles of ASIC1a and ERS in activated HSC. We found that ASIC1a and ERS‐related proteins were up‐regulated in carbon tetrachloride (CCl4)‐induced fibrotic mouse liver tissues, and in patient liver tissues with hepatocellular carcinoma with severe liver fibrosis. The results show silencing ASIC1a reduced the expression of ERS‐related biomarkers GRP78, Caspase12 and IREI‐XBP1. And, ERS inhibition by 4‐PBA down‐regulated the high expression of ASIC1a induced by PDGF, suggesting an interactive relationship. In PDGF‐induced HSCs, ASIC1a was activated and migrated to the cell membrane, leading to extracellular calcium influx and ERS, which was mediated by PI3K/AKT pathway. Our work shows PDGF‐activated ASIC1a via the PI3K/AKT pathway, induced ERS and promoted liver fibrosis progression.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visitNCCN.org.

Background Immune checkpoint inhibitor (ICI)-induced pancreatic injury (ICIPI) is not well documented in the literature. We aimed to describe the clinical characteristics and outcomes of patients who developed ICIPI. Methods We reviewed the medical records of consecutive patients who had a confirmed diagnosis of ICIPI (Common Terminology Criteria for Adverse Events grade ≥ 3 lipase elevation with or without clinical symptoms) from April 2011 through April 2018. Results Among the 2,279 patients received ICI and had lipase values checked thereafter, 82 (4%) developed ICIPI. Overall, 65% of patients received inhibitors of programmed death protein-1 or its ligand. Compared with asymptomatic presentation, patients who had clinical symptoms of pancreatitis (n = 32) had higher levels of lipase (P = 0.032), more frequent imaging evidence of pancreatitis (P = 0.055), and more frequent hospitalization (P

Gastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors’ (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients’ survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model. This is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan–Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables. A total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2–3 (HR 2.57, 95%CI 1.44–4.57; P

It is well known that the diabetes mellitus complicates liver fibrosis with high morbidity, and Acid-sensing ion Channel 1a (ASIC1a) plays an important role in the development of diabetes and liver fibrosis. However, the underlying mechanism about how diabetes influences the progression of liver fibrosis remains unclear. This study was to investigate the relationship between autophagy and ASIC1a in the process of liver fibrosis under hyperglycemia. Interestingly, our study showed that the autophagy was elevated in the livers from diabetes combined with liver fibrosis double model in vivo and also in rat hepatic stellate cell line HSC-T6 after stimulation with high glucose and platelet-derived growth factor (PDGF) in vitro, and this response could be attenuated by treatment with ASIC1a nonspecific inhibitor Amiloride or specific ShRNA for ASIC1a. Furthermore, inhibition of autophagy treated with 3-MA significantly attenuated HSC-T6 activation and proliferation. Mechanistically, CaMKKβ/ERK pathway was activated in HSC-T6 after stimulation with high glucose and PDGF, and could be suppressed by Amiloride. Collectively, we concluded that autophagy induced by ASIC1a contributes to HSC-T6 activation, which ing pathway.

Background Eosinophilic colitis (EoC) is a rare form of eosinophilic gastrointestinal disease characterized by diffuse eosinophilic infiltration in the deep lamina propria of colonic mucosa. The pathophysiology is unclear, but EoC has been associated with multiple known risk factors. Aim The aim of this study was to characterize the clinical characteristics and disease course of patients with EoC at a major cancer center. Material and methods We retrospectively reviewed colonic samples obtained between January 2000 and December 2018 from our institutional database and included cases with significant colonic eosinophilia. Baseline clinical data and EoC-related clinical course and outcomes were documented. Results Forty-one patients were included. One fourth had coexisting autoimmune conditions. Seventy-eight percent had a cancer diagnosis. Half the patients received chemotherapy, with a median duration of 180 days between chemotherapy and EoC onset. Symptoms were present in 76% of patients. Diarrhea was more prevalent in patients who received chemotherapy (85% vs. 42%). Median duration of EoC symptoms was 30 days in patients with cancer and 240 days in those without cancer (P=0.03). Most patients (88%) had normal colonoscopy findings. Fifteen percent of patients required hospitalization. All-cause mortality was 37%, mostly related to underlying malignancy and organ failure. Conclusions EoC in cancer patients appears to have more diarrhea-predominant symptoms, particularly in patients receiving chemotherapy, but a shorter disease duration compared with patients without cancer. Hospitalization can be required for serious cases. Treatment may be reserved for patients requiring symptom management, as most patients with EoC have good clinical outcomes regardless of treatment.

Serological thymidine kinase 1 (STK1p) is a reliable proliferation marker for prognosis, monitoring tumour therapy, and relapse. Here we investigated the use of STK1p in health screening for early detection of pre-malignant and malignant diseases. The investigation was based on 35,365 participants in four independent health screening studies in China during 2005–2019 based on Real World Data. All participants were clinically examined. The concentration of STK1p was determined by a sensitive chemiluminescent dot blot ECL assay. The ROC-value of the STK1p assay was 0.96. At a cut-off STK1p value of 2.0 pM, the likelihood (+) value was 236.5, and the sensitivity and the specificity were 0.78 and 0.99, respectively. The relative number of city-dwelling people with elevated STK1p values (>2.0 pM) was 0.8% (198/26,484), while the corresponding value for the group of oil-field workers was 5.8% (514/8,355). The latter group expressed significantly higher frequency of refractory anaemia, fatty liver, and obesity, compared to the city dwellers, but no cases of breast hyperplasia or prostate hyperplasia were observed. Furthermore, people working in oil drilling/oil transportation showed higher STK1p values and higher frequency of pre-malignancies and benign diseases than people working in the oil-field administration. In the STK1p elevated group of the city-dwelling people, a statistically significantly higher number of people were found to have malignancies, pre-malignancies of all types, moderate/severe type of hyperplasia of breast or prostate, or refractory anaemia, or to be at high risk for hepatitis B, compared to people with low STK1p values (

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4

Clarifying the relationship between meteorological factors and ozone can provide scientific support for ozone pollution prediction, but the effects of boundary layer meteorology, especially boundary layer height and turbulence, on ozone pollution are rarely studied. Here, ozone and its related meteorological factors were observed in summer in Shijiazhuang, a city with the most serious ozone pollution on the North China Plain. The forced and free convection boundary layers were classified using ground remote observations. After eliminating the forced convection condition, strong free convection conditions, exhibiting a high boundary layer height, high wind speed, strong turbulence and large-scale free convection velocity, were found to be beneficial for the aggravation of ozone pollution. Combined with the ozone profile detected by a tethered balloon, the ozone chemical budget was calculated using the differences in the column ozone concentrations between the morning and afternoon, and the results confirmed the impact of free convection intensity on ozone pollution. The change in ozone sensitivity from VOCs sensitivity to NOx sensitivity driven by strong free convection was the main reason for the deterioration of ozone pollution. This study clarified the impact of boundary layer meteorology on ozone and its sensitivity and has important practical significance for ozone pollution prevention and early warning.

Ustekinumab for Refractory Colitis Two patients in whom severe refractory autoimmune colitis developed after cancer treatment with immune checkpoint inhibitors had a response to a course of subcuta...

Oxygenated volatile organic compounds (OVOCs) are important precursors of secondary air pollutants. However, knowledge of the vertical characteristics of OVOCs in the lower troposphere is lacking. Pairs of OVOCs samples were simultaneously collected via 2,4-dinitrophenylhydrazine (DNPH) near the ground and in the upper boundary layer (at 500 m in winter and 600 m in summer) with a tethered balloon in Shijiazhuang in January and June 2019. The samples were analyzed via high-performance liquid chromatography (HPLC), and 26 vertical profiles of 13 OVOCs were obtained in this study. In winter, the average concentrations of the total OVOCs (TOVOCs) in the upper boundary layer and near the ground were 7.9 ± 4.1 ppbv and 5.5 ± 2.8 ppbv, respectively; while in summer, the average concentrations were 7.1 ± 3.5 ppbv and 6.5 ± 2.7 ppbv, respectively. Acetone, formaldehyde and acetaldehyde were the three main components accounting for more than 80% of the TOVOCs. Significant vertical differences were observed before sunrise in winter and in the afternoon in summer. The TOVOCs concentration in the residual layer (8.4 ± 3.6 ppbv) was higher than that near the ground (6.0 ± 2.5 ppbv), while in the summer afternoon, the concentration in the upper mixing layer (ML) (9.5 ± 2.2 ppbv) was higher than that near the ground (5.8 ± 3.1 ppbv). OVOCs sources were examined with a positive matrix factorization (PMF) model. In winter, the small-molecule carbonyls (SMCs) in the upper boundary layer are mainly derived from secondary + long-lived species (68.4%) because volatile organic compounds at high concentrations were oxidized into OVOCs. In summer, the SMCs in the upper ML were mainly affected by elevated industrial point source emissions (42.9%). These data indicate that vertical gradient observations of SMCs are an important supplement to advance current air pollution research.

High loads of ground-level ozone have occurred with the implementation of the Air Pollution Prevention and Control Action Plan. However, the long temporal variation in precursor nonmethane hydrocarbons (NMHCs) has rarely been studied. In this study, we examined the evolution of NMHCs in Beijing based on ambient measurements from 2000 to 2019. The results indicated that the annual variation of ambient NMHCs during 2000 and 2019 could be divided into two stages. The mixing ratios of NMHCs rapidly rose during 2000 and 2009 (1.76 ppbv/year) but exhibited a downward trend from 2009 to 2019 at rate of 0.80 ppbv/yr. Moreover, the notable decrease in alkenes and aromatics after 2009 led to a sharp decrease in the propylene-equivalent concentration (PEC) (-0.80 ppbv/year). Implementation of emission reduction measures in Beijing have effectively reduced the contribution of vehicle-related sources, but the contribution of solvent usage and fuel consumption increased, which will become the focus of VOC control in Beijing in the future.

High ozone concentrations promote the formation of nitrate in the nocturnal residual layer (RL), but this phenomenon has not been confirmed by direct observation. In this study, ozone, water-soluble ions in PM2.5 and the corresponding meteorological factors in the stable boundary layer, RL and mixing layer were observed by portable instruments carried on a tethered balloon over the North China Plain. The ozone concentration significantly increased in the RL compared to that in the stable boundary layer, while particulate nitrate significantly decreased, except in the clouds. Unfavorable environmental conditions, i.e., high temperature, low relative humidity, low aerosol surface area, and weak particle acidity, are not conducive to dinitrogen pentoxide uptake and hydrolysis to form particulate nitrate in the RL, and are conducive to the volatilization of nitrate to a gaseous state. Thus, our observations differed from traditional reports and confirmed that the morning peak of particulate nitrate at ground level is not related to the downward transport of nitrate from the RL. In addition, evidence for nitrate formation in cloudy weather is provided, and the possible impact on ozone is discussed.

In order to reduce the depletion of land natural capital and develop economy simultaneously, it is necessary to study how to achieve the strong decoupling relationship between them. However, so far such studies have been relatively limited. Thus, taking the case of Ningxia Hui Autonomous Region, China, this paper firstly analyzes the state of land natural capital utilization in 1999&ndash, 2017 by using improved ecological footprint. Then, decoupling state is quantified by Tapio decoupling model. Last, major driving factors on the decoupling relationship are explored with combination of LMDI decomposition and Kaya identity equation. Results showed that: (1) Both natural capital flows and stock depletion of cultivated land decrease obviously during the transition to corn-based intensive ecological agriculture. Grassland and water are the most unsustainable development sectors among all land types with their stock depletion intensified. Forest land and construction land could basically meet the consumer demand, but the flow occupancy of construction land is the fastest-growing segment. (2) Decoupling relationship is in an alternating state between weak decoupling and strong decoupling in 1999&ndash, 2017. Wherein, the cultivated land and forest land showed a preferred decoupling state, followed by grassland, while the water and construction land showed the unfavorable expansive negative decoupling and weak decoupling. (3) Decomposition results show that intensity effect is the major factor that promotes the decoupling while economic effect inhibits the decoupling, but this negative impact is weakening in the process of industrial transformation. The other three factors affect less on the decoupling. This study has a certain reference value to construct an ecological civilization in eco-fragile regions and formulate relevant policies on the increase of land natural capital efficiency.

Pollutant gases, such as CO, NO2, O3, and SO2 affect human health, and low-cost sensors are an important complement to regulatory-grade instruments in pollutant monitoring. Previous studies focused on one or several species, while comprehensive assessments of multiple sensors remain limited. We conducted a 12-month field evaluation of four Alphasense sensors in Beijing and used single linear regression (SLR), multiple linear regression (MLR), random forest regressor (RFR), and neural network (long short-term memory (LSTM)) methods to calibrate and validate the measurements with nearby reference measurements from national monitoring stations. For performances, CO &gt, O3 &gt, NO2 &gt, SO2 for the coefficient of determination (R2) and root mean square error (RMSE). The MLR did not increase the R2 after considering the temperature and relative humidity influences compared with the SLR (with R2 remaining at approximately 0.6 for O3 and 0.4 for NO2). However, the RFR and LSTM models significantly increased the O3, NO2, and SO2 performances, with the R2 increasing from 0.3&ndash, 0.5 to &gt, 0.7 for O3 and NO2, and the RMSE decreasing from 20.4 to 13.2 ppb for NO2. For the SLR, there were relatively larger biases, while the LSTMs maintained a close mean relative bias of approximately zero (e.g., &lt, 5% for O3 and NO2), indicating that these sensors combined with the LSTMs are suitable for hot spot detection. We highlight that the performance of LSTM is better than that of random forest and linear methods. This study assessed four electrochemical air quality sensors and different calibration models, and the methodology and results can benefit assessments of other low-cost sensors.

Background: Current treatment guidelines for IMDC recommend steroids as first-line therapy, followed by SITs (infliximab or vedolizumab) for refractory cases. We aimed to compare the efficacy of these two SITs and their impact on cancer outcomes. Methods: We performed a multicenter, retrospective observational cohort study of patients with IMDC who received SITs following steroids from 2016 to 2020. Patients’ demographic, clinical, and overall survival data were collected and analyzed. Findings: A total of 184 patients (62 vedolizumab, 94 infliximab, 28 both) were included. The efficacy of achieving clinical remission of IMDC was similar (89% vs 88%, P =0.79) between the two groups. Compared with infliximab group, vedolizumab group had a shorter steroid exposure (35 vs. 50 days, P

Immune checkpoint blockade (ICB) for cancer is associated with high response rates but also high rates of adverse events. To elucidate the underlying immunobiology, we profiled gene expression in intestinal, colitis, and tumor tissue from ICB-treated patients, with parallel studies in preclinical models, and validated our findings in a review of clinical cohort treated with interleukin-6 blockade. Expression of interleukin-6, neutrophil and chemotactic markers was higher in colitis than in normal intestinal tissue. The genes upregulated in colitis were not upregulated in responding tumors from patients receiving ICB. In murine models, interleukin-6 blockade was associated with improved tumor control and a higher density of CD4/CD8 effector T-cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined interleukin-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. Interleukin-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

Contains fulltext : 237881.pdf (Publisher’s version ) (Open Access) Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Under weak weather systems, pollutants circulate on plains and hillsides by means of oscillatory mountain-plain breezes (MPB). To investigate the impact of MPB on ambient volatile organic compounds (VOCs) on the northern edge of the North China Plain (NCP) region, synchronous online VOCs observations were first performed in the southwestern (Beijing, urban area) and northeastern (Xinglong, background area) of the dominant wind directions from September 11, 2020, to October 13, 2020. The results revealed that during the observation period, the average mixing ratios of TVOCs in Beijing and Xinglong were 32.5 ± 21.6 and 14.2 ± 8.6 ppbv, respectively, and a coincident temporal evolution trend of VOCs was observed at the two sites. Combined with the results of the backward trajectory, southerly air transport led to a significant increase in VOCs concentration, and southerly airflow was usually accompanied by apparent MPB circulation. Furthermore, the occurrence of MPB led to a sharp increase (1.5 times) in VOCs concentration in both Beijing and Xinglong. This study indicates that the periodic oscillation of the MPB leads to the large-scale pollution of "garbage out and garbage in", and the VOCs discharged by industry are the key to future control.

BackgroundImmune-mediated diarrhea and colitis (IMDC) is currently diagnosed and monitored by evaluating clinical symptoms. Deep remission is determined by endoscopic and histologic evaluation of the disease process. However, repeating these invasive procedures frequently can become cumbersome. We sought to assess the role of fecal calprotectin (FC) concentration as a non-invasive biomarker of endoscopic or histologic remission.MethodsWe performed a retrospective study of patients with IMDC who were tested for FC at IMDC onset and after IMDC treatment between June 2016 and March 2020. Patient demographics, clinical variables, and FC data were collected and analyzed to determine the optimal cut-off FC concentration to predict endoscopic and histologic remission.ResultsOur sample comprised 77 patients with a median age of 62 years; 66% were male and 94% were Caucasian. Sixty-five patients (84%) achieved clinical remission, 46 (60%) achieved endoscopic remission, and 24 (31%) achieved histologic remission after IMDC treatment. FC concentrations decreased from the time of IMDC onset to the end of treatment (p<0.001). High FC concentrations were associated with evident endoscopic inflammation (p=0.003) and acute/chronic active colitis (p=0.025) which positively correlated with the Mayo Endoscopic Subscore (r=0.615, p=0.001) at the time of IMDC onset. In patients who achieved endoscopic remission after treatment, a significantly lower FC concentration was observed at IMDC onset (p=0.006) and after treatment (pConclusionsFC concentration may serve as a non-invasive biomarker to predict endoscopic and histologic remission in patients receiving treatment for IMDC, minimizing the need for frequent invasive endoscopies. Future prospective studies are needed to provide further insight on the role of this marker in disease surveillance.

Pollutant gases, such as CO, NO2, O3, and SO2 affect human health, and low-cost sensors are an important complement to regulatory-grade instruments in pollutant monitoring. Previous studies focused on one or several species, while comprehensive assessments of multiple sensors remain limited. We conducted a 12-month field evaluation of four Alphasense sensors in Beijing and used single linear regression (SLR), multiple linear regression (MLR), random forest regressor (RFR), and neural network (long short-term memory (LSTM)) methods to calibrate and validate the measurements with nearby reference measurements from national monitoring stations. For performances, CO > O3 > NO2 > SO2 for the coefficient of determination (R2) and root mean square error (RMSE). The MLR did not increase the R2 after considering the temperature and relative humidity influences compared with the SLR (with R2 remaining at approximately 0.6 for O3 and 0.4 for NO2). However, the RFR and LSTM models significantly increased the O3, NO2, and SO2 performances, with the R2 increasing from 0.3–0.5 to >0.7 for O3 and NO2, and the RMSE decreasing from 20.4 to 13.2 ppb for NO2. For the SLR, there were relatively larger biases, while the LSTMs maintained a close mean relative bias of approximately zero (e.g.

In this work, the porous cellulose-agarose microspheres with high specific surface area and enhanced mechanical strength are prepared by a novel chemical crosslinking method. The crosslinking reaction homogeneously proceeds between polysaccharides, and the covalent bonding network is generated to replace the inherent hydrogen bonding network of cellulose. The prepared microspheres exhibit low crystallinity of 12.45%, which means high content of amorphous regions. The micro-meso-macroporous structure of microspheres in morphology is conducive to high permeability and adsorption capacity, and the microspheres possess high specific surface area of 183.81 m2/g. The affinity chromatographic microspheres are prepared by immobilizing Cu2+, which exhibits high adsorption capacity of 197.65 mg/g for bovine hemoglobin (BHb), fast adsorption rate wihin 40 minutes, well-selectivity, and excellent recyclability in ten cycles. We expect that this work to provide an outstanding candidate for the high performance of biomacromolecular purification.

The impact of corticosteroid therapy (CT) on efficacy of immune checkpoint inhibitors (ICI) is undefined in hepatocellular carcinoma (HCC). We evaluated whether CT administered at baseline (bCT) or concurrently with ICI (cCT) influences overall (OS), progression-free survival (PFS) and overall response rates (ORR) in 341 patients collected across 3 continents. Of 304 eligible patients, 78 (26%) received >10 mg prednisone equivalent daily either as bCT (n=14, 5%) or cCT (n=64, 21%). Indications for CT included procedure/prophylaxis (n=37, 47%), management of immune-related adverse event (n=27, 35%), cancer-related symptoms (n=8, 10%) or comorbidities (n=6, 8%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in univariable and multivariable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (p

Background: The influence of prior exposure to immune checkpoint inhibitors (ICIs) on the coronavirus disease 2019 (COVID-19) infection remains unknown. Methods: We searched the PubMed, Embase, and Web of Science databases from the inception of each database through August 8, 2020. We included studies that reported ICI use in cancer patients and their prognosis in the context of COVID-19. Raw data from the included studies were pooled to determine effect estimates. Chi-squared and I2 tests were used to calculate heterogeneity among the included studies.Results: Eighteen studies were included for the systematic review, and 8 of those were included in the meta-analysis. Patients with prior ICI treatment exhibited a higher rate of hospitalization (OR [odds ratio] 2.6, 95% CI 1.45-4.68, p=0.001; I2=0%) and severe disease (OR 1.98, 95% CI 1.14-3.43, p=0.015). However, the OR of mortality in ICI-exposed cases was similar to non-ICI exposed patients (OR 0.90, 95% CI 0.60-1.34, p= 0.60; I2=49%). No statistically significant difference in mortality was observed between patients exposed to ICI and other antitumor treatments.Conclusions: Although a higher rate of hospitalization and severe disease was observed, prior exposure to ICI did not significantly increase the rate of death in the context of COVID-19.