Spatial and temporal variations of surface background ozone in China analyzed with the grid-stretching capability of GEOS-Chem High Performance.

Surface background ozone, defined as the ozone in the absence of domestic anthropogenic emissions, is important for developing emission reduction strategies. Here we apply the recently developed GEOS-Chem High Performance (GCHP) global atmospheric chemistry model with ∼0.5° stretched resolution over China to understand the sources of Chinese background ozone (CNB) in the metric of daily maximum 8 h average (MDA8) and to identify the drivers of its interannual variability (IAV) from 2015 to 2019. The GCHP ozone simulations over China are evaluated with an ensemble of surface and aircraft measurements. The five-year national-mean CNB ozone is estimated as 37.9 ppbv, with a spatially west-to-southeast downward gradient (55 to 25 ppbv) and a summer peak (42.5 ppbv). High background levels in western China are due to abundant transport from the free troposphere and adjacent foreign regions, while in eastern China, domestic formation from surface natural precursors is also important. We find greater importance of soil nitric oxides (NOx) than biogenic volatile organic compound emissions to CNB ozone in summer (6.4 vs. 3.9 ppbv), as ozone formation becomes increasingly NOx-sensitive when suppressing anthropogenic emissions. The percentage of daily CNB ozone to total surface ozone generally decreases with increasing daily total ozone, indicating an increased contribution of domestic anthropogenic emissions on polluted days. CNB ozone shows the largest IAV in summer, with standard deviations (seasonal means) of ∼5 ppbv over Qinghai-Tibet Plateau (QTP) and >3.5 ppbv in eastern China. CNB values in QTP are strongly correlated with horizontal circulation anomalies in the middle troposphere, while soil NOx emissions largely drive the IAV in the east. El Nino can inhibit CNB ozone formation in Southeast China by increased precipitation and lower temperature locally in spring, but enhance CNB in Southwest China through increased biomass burning emissions in Southeast Asia.

Changing Responses of PM2.5 and Ozone to Source Emissions in the Yangtze River Delta Using the Adjoint Model.

China's industrial restructuring and pollution controls have altered the contributions of individual sources to varying air quality over the past decade. We used the GEOS-Chem adjoint model and investigated the changing sensitivities of PM2.5 and ozone (O3) to multiple species and sources from 2010 to 2020 in the central Yangtze River Delta (YRDC), the largest economic region in China. Controlling primary particles and SO2 from industrial and residential sectors dominated PM2.5 decline, and reducing CO from multiple sources and ≥C3 alkenes from vehicles restrained O3. The chemical regime of O3 formation became less VOC-limited, attributable to continuous NOX abatement for specific sources, including power plants, industrial combustion, cement production, and off-road traffic. Regional transport was found to be increasingly influential on PM2.5. To further improve air quality, management of agricultural activities to reduce NH3 is essential for alleviating PM2.5 pollution, while controlling aromatics, alkenes, and alkanes from industry and gasoline vehicles is effective for O3. Reducing the level of NOX from nearby industrial combustion and transportation is helpful for both species. Our findings reveal the complexity of coordinating control of PM2.5 and O3 pollution in a fast-developing region and support science-based policymaking for other regions with similar air pollution problems.

Explorations of post-gDLI low-dose cyclophosphamide for preventing severe aGVHD.

OBJECTIVE: Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious life-threatening complication. The granulocyte colony-stimulated factor mobilized donor lymphocyte infusions (gDLI) combined with chemotherapy is currently a commonly used treatment method. Nevertheless, gDLI may cause so severe acute graft-versus-host disease (aGVHD) as to impact prognosis. Posttransplant cyclophosphamide (PTCy) has been the backbone for GVHD prophylaxis by inducing tolerance to minor histocompatibility antigens in recipients, while the application of post-gDLI low-dose cyclophosphamide (PDCy) for GVHD prophylaxis has not yet been attempted. METHODS: To explore this possibility, a retrospective study was conducted. 20 patients relapsing after HSCT were administered 20 mg/kg/d cyclophosphamide（Cy）on day 3 (for matched related transplantation) or on days 3 and 4 (for haplo-identical or unrelated transplantation) after gDLI to prevent aGVHD (the PDCy group). Furthermore, through propensity score matching, 58 matched controls received other (for HID and URD) or no (for MSD) immunosuppressive therapy for GVHD prophylaxis (the Non-Cy group). RESULTS: With a median follow-up of 4.8 (0-37.1) months, the PDCy group had lower cumulative incidence of severe aGVHD (III-IV, 5 % vs 31 %, p = 0.02; II-IV, 25 % vs 52 %, p = 0.04), but no significant differences existed in 4-month OS (64 % vs 59 %, p = 0.51), 4-month CIR (20 % vs 47 %, p = 0.11), rates of objective response (68.8 % vs 54.5 %, p = 0.6) (hematological or extramedullary relapse), MRD complete response (25 % vs 42 % p = 1) and MRD response (25 % vs 50 %, p = 0.6) (molecular relapse) between the PDCy group and the Non-Cy group. The PDCy regimen didn't increase the incidence of adverse infection, hemorrhagic cystitis, and cardiac events. CONCLUSION: On the premise of safety, the PDCy regimen could effectively protest against severe aGVHD after gDLI while preserving therapeutic response rates. However, the research results still require verification through longer follow-up and large prospective randomized studies.

Efficacy of venetoclax combined with decitabine conditioning regimen for allogeneic hematopoietic stem cell transplantation in high-risk and elderly patients with myeloid neoplasms.

This prospective clinical investigation focused on the addition of venetoclax and decitabine to myeloablative conditioning regimens, targeting high-risk and elderly individuals undergoing allogeneic hematopoietic stem cell transplantation. In total, 19 patients were enrolled in the trial between December 2021 and February 2023, and their progress was monitored for a median follow-up period of 258 days, ranging from 35 to 544 days. In the initial regimen (n=11), venetoclax was administered at a dosage of 400 mg per day from day -14 to day -1, while in the modified regimen (n=8), it was administered from day -14 to day -5. Decitabine was orally administered at a dosage of 20mg/m2/day from day -7 to day -3. Grade 3/4 adverse events observed included hematological events, hypertension, infections, allergy, and increased amylase. In the entire cohort, the overall survival (OS) and relapse-free survival (RFS) rates at 6 months were 63% (95% CI, 45-89) and 63% (95% CI, 45-89), respectively. The non-relapse mortality (NRM) rate at 6 months was 37% (95% CI, 16-58), while the cumulative incidence of relapse (CIR) was 0. However, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD within 100 days was found to be 31% (95% CI, 12-53) and 26% (95% CI, 9-47), respectively. These rates indicate a relatively high occurrence, making it less suitable to administer the regimen to elderly patients. Therefore, further high-quality studies are required to enhance the conditioning regimen specifically for high-risk and elderly patients diagnosed with myeloid neoplasms. Clinical trial registration: ChiCTR2100050272.

Associations of plaque morphology and location with Intraplaque neovascularization in the carotid artery by contrast-enhanced ultrasound imaging.

Objective: Intraplaque neovascularization (IPN) is a known indicator of plaque vulnerability, and is thus considered a predictor of stroke. The morphology and location of the carotid plaque may be correlated with plaque vulnerability. Therefore, our study aimed to examine the associations of carotid plaque morphology and location with IPN. Methods: A total of 141 patients with carotid atherosclerosis (mean age, 64.99 ± 10.96 years) who underwent carotid contrast-enhanced ultrasound (CEUS) between November 2021 and March 2022 were retrospectively analyzed. IPN was graded according to the presence and location of microbubbles within the plaque. The association of IPN grade with carotid plaque morphology and location was evaluated using ordered logistic regression. Results: Of the 171 plaques, 89 (52%) were IPN Grade 0, 21 (12.2%) were Grade 1, and 61 (35.6%) were Grade 2. IPN grade significantly associated with both plaque morphology and location, with higher grades observed among Type III morphology and common carotid artery plaques. Significant negative association was further shown between IPN grade and serum high-density lipoprotein cholesterol (HDL-C) level. Plaque morphology and location, and HDL-C remained significantly associated with IPN grade after adjusting for confounding factors. Conclusion: The location and morphology of carotid plaques were significantly associated with the IPN grade on CEUS, and therefore show potential as biomarkers for plaque vulnerability. Serum HDL-C was also identified as a protective factor against IPN, and may play a role in the management of carotid atherosclerosis. Our study provided a potential strategy for identification of vulnerable carotid plaques and elucidated the important imaging predictors of stroke.

A false positive serology test of SARS­CoV­2 in a patient with Waldenström's macroglobulinemia: A case report.

The serology test of SARS-CoV-2 is one of the critical assays to make a diagnosis of SARS-CoV-2 infection. The gold immunochromatography assay (GICA) is a common measure to test SARS-CoV-2 specific IgG and IgM. The sensitivity and specificity of the assay are ~>80%. It has been reported that the result of GICA could be compromised in various situations, such as auto-immune diseases, Kawasaki disease, pregnancy or other conditions. However, following the European Hematology Association's consensus statement on the management of Waldenström's Macroglobulinemia (WM) patients, serological tests for SARS-CoV-2 specific IgM should not be affected by the total IgM or paraprotein levels. The present study reports a patient with duplicate positive serology tests of SARS-CoV-2 which is hypothesized to be due to monoclonal IgM caused by WM.

Carotid plaque score and ischemic stroke risk stratification through a combination of B-mode and contrast-enhanced ultrasound in patients with low and intermediate carotid stenosis.

Objective: The occurrence of ischemic stroke (IS) is closely related to the characteristics of carotid plaque (CP). Due to the effect of stroke risk stratification based on B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) that has not been studied in patients with low and intermediate carotid stenosis, we construct and validate a CP score and ischemic stroke risk stratification (ISRS) using a combination of B-mode and CEUS, in order to provide new convenient strategies to stratify these patients to prevent stroke. Materials and methods: This retrospective study evaluated 705 patients with low and intermediate carotid stenosis who underwent B-mode and CEUS from November 2021 to April 2023. Qualitative B-mode and CEUS features of carotid plaques were analyzed using a univariable and multivariable logistic regression to construct the CP score. Then, we combined the CP score with Essen stroke risk score (ESRS) to develop ISRS. Results: This study included a total of 705 patients with low and intermediate carotid stenosis, of which 394 were symptomatic patients (with a mean age of 71.03 ± 10.48 years) and 311 were asymptomatic patients (with a mean age of 65.13 ± 10.31 years). Plaque echogenicity, plaque morphology, carotid intima-media thickness in B-mode US and intraplaque neovascularization grading and perfusion pattern in CEUS were significantly associated with IS. The ISRS incorporating these five predictors and ESRS showed good discrimination and calibration in both primary cohort [area under the curve (AUC), 0.91; Hosmer-Lemeshow test, p = 0.903] and validation cohort (AUC, 0.84; Hosmer-Lemeshow test, p = 0.886). Conclusion: We developed an effective and practical tool to identify and stratify patients with low and intermediate carotid stenosis, based on the CP score and ISRS estimation. Our study may provide new insights into managing patients with no indication of surgery.

Chromium Oxide-modified Mesoporous Zirconium Dioxide: Efficient Heterogeneous Catalyst for the Synthesis of 5-Hydroxymethylfurfural.

A highly efficient carbohydrate conversion to 5-hydroxymethylfurfural (5-HMF) is a promising method to achieve green and sustainable development. However, most currently reported strategies are energy consuming, and the 5-HMF yield is relatively lower in the aqueous phase. Herein, a facile method is reported to obtain effective Cr/ZrO2 catalysts with high acidity and their catalytic performances were investigated for catalyzing fructose to 5-HMF at different temperatures and times. With the catalysis of 15 % Cr/ZrO2 catalyst, the highest fructose conversion of 98 %, 5-HMF yield of 48.8 %, and 5-HMF selectivity of 49.8 % are achieved in green solvent with good recyclability. The possible reaction process of the improved catalysis performance is attributed to the highly crystalline and strong acidity of the Cr/ZrO2 catalyst. The Lewis acid sites could increase the overall rate of fructose conversion by promoting side reactions and might suppress fructose to glucose isomerization. In addition, Cr leakage during the reaction might act as the Bronsted acids to catalyze the fructose dehydration to 5-HMF. The reported method of introducing chromium oxides into ZrO2 catalyst will open a new avenue to promote the practical application of biomass and sustainable development in the future.

Vancomycin, Daptomycin, Antistaphylococcal ß-Lactam, and Trimethoprim-Sulfamethoxazole Monotherapy and Combination Therapy in the Management of Methicillin-Resistant Staphylococcus aureus: A Network Meta-Analysis.

Objective: The aim was to evaluate the efficacy and safety of vancomycin or daptomycin (VAN/DAP), antistaphylococcal ß-lactam (ASBL), trimethoprim-sulfamethoxazole (TMP-SMX), and combination therapy of VAN/DAP + ASBL in the management of methicillin-resistant Staphylococcus aureus (MRSA). Methods: Databases including PubMed, Cochrane Library, Embase database, and google scholar were searched on 1 September 2021. The randomized control trials (RCTs) and comparable clinical studies of VAN/DAP, VAN/DAP + ASBL, ASBL, and TMP-SMX in the management of MRSA were identified. A network meta-analysis was conducted with STATA 14.0. Results: Seven RCTs and two matched cohorts with 1,048 patients were included in the analysis. The pooled results showed that VAN/DAP + ASBL had a significantly lower rate of persistent bacteremia >3 days than VAN/DAP alone [OR:0.46, 95%CI (0.26, 0.81), p < 0.001]. No obvious differences were observed in the outcomes of all-cause mortality, relapsed bacteremia, microbiological treatment failure, embolic or metastatic infection, and total adverse events. However, the ranking results showed that VAN/DAP + ASBL had slightly better efficacy (all-cause mortality, persistent bacteremia >3 days, duration of bacteremia, microbiological treatment failure, and relapsed bacteremia) but slightly higher adverse events than VAN/DAP alone. No obvious differences in the comparisons of VAN/DAP vs. ASBL, and VAN/DAP vs TMP-SMX in the analyzed outcomes. The ranking results revealed that ASBL and TMP-SMX did not have better efficacy or lower adverse events compared with the treatment of VAN/DAP. Conclusion: The efficacy of VAN/DAP + ASBL was slightly but not significantly better than VAN/DAP alone in the management of MRSA.

Cause of death of patients with non-muscular invasive, non-metastatic muscular invasive and metastatic bladder cancer after diagnosis.

BACKGROUND: The purpose of this study was to evaluate the various causes of death among patients with non-muscular invasive bladder cancer (NMIBC), non-metastatic muscle invasive bladder cancer (non-MMIBC) and metastatic bladder cancer (MBC) after diagnosis. METHODS: With the Surveillance, Epidemiology, and Final Results database, patients diagnosed with bladder cancer from 2004 to 2015 were identified. All causes of death and the standardization mortality ratio (SMR) were analyzed. RESULTS: A total of 111,784 NMIBC, 26,546 non-MIBC and 4,678 MBC patients were identified. For NMIBC patients, 44,638 patients died during the follow-up, including 20.57% of bladder cancer, 18% of other tumors and 61.36% of non-tumor diseases. Main causes of other tumors death were cancers from lung and bronchus [n=2,860, SMR: 1.56 (1.51-1.62)], pancreas [n=506, SMR: 1.15 (1.05-1.26)], and prostate [n=442, SMR: 0.62 (0.56-0.68)]. Main causes of non-tumor deaths were diseases of heart [n=10,007, SMR: 1.15 (1.13-1.17)], chronic obstructive pulmonary disease (COPD) [n=3,153, SMR: 1.54 (1.49-1.59)], cerebrovascular diseases [n=1,704, SMR: 0.96 (0.91-1)], alzheimers [n=1,211, SMR: 0.87 (0.82-0.92)] and diabetes mellitus [n=1,047, SMR: 1.19 (1.12-1.27)]. Among the 18829 deaths in non-MMIBC patients, 62.65% patients died of bladder cancer, 11.08% of other tumors and 26.39% of non-tumor causes. Main deaths of other cancers were tumors from lung and bronchus [n=435, SMR: 1.83 (1.66-2.01)], prostate [n=192, SMR: 2.21 (1.91-2.54)]. Main causes of non-tumor death were diseases of heart [n=1717, SMR: 1.56 (1.49-1.64)], COPD [n=561, SMR: 2.18 (2.01-2.37)], and cerebrovascular diseases [n=290, SMR: 1.28 (1.14-1.44)]. Among the 4,392 deaths of MBC patients, 3,486 (79.37%) died of bladder cancer. Main cause of other deaths included diseases of heart (n=128) and prostate cancer (n=57). CONCLUSION: For NMIBC patients, leading causes of death were diseases of heart, COPD, lung and bronchus cancer, cerebrovascular diseases, Alzheimer's, and diabetes mellitus. Leading causes of deaths for non-MMIBE patients were bladder cancer, diseases of heart, COPD, lung and bronchus cancer, cerebrovascular diseases and prostate cancer. Main causes of death for MBC patients were bladder cancer itself. Our results of all causes of death and mortality risks provided useful information for bladder cancer patients.

Impact of changes in psychological resilience during treatment with intensity-modulated radiotherapy on nasopharyngeal carcinoma patients: a prospective study.

BACKGROUND: Nasopharyngeal carcinoma (NPC) patients can undergo changes in psychological status during treatment. The aim of this prospective study was to determine the impact of the changes in psychological resilience on the quality of life (QoL) and long-term outcomes of patients. METHODS: Patients with NPC receiving intensity-modulated radiotherapy (IMRT) between March 2017 and February 2019 were prospectively included. Their psychological resilience was evaluated by the Connor-Davidson resilience scale (CD-RISC) twice. Patients were then divided into the improved psychological resilience group and the deteriorated group. All patients were followed up for at least 2 years, and acute or late severe complications were recorded. The QoL of patients was evaluated within 1 year by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (QLQ-C30) and the Head and Neck 35-questions (HN35). Logistic regression analysis was used for the analysis of risk factors of psychological resilience in NPC patients. Similarly, linear regression analysis was used for the analysis of risk factors of QoL in NPC patients. The overall survival rate and progression-free survival rate were recorded and compared between the 2 groups using Kaplan-Meier curves. RESULTS: A total of 180 patients were included. The mean CD-RISC scores before radiotherapy and after radiotherapy were 55.8±7.0 and 58.4±7.8 points, respectively. Patients were divided into 104 patients in the improved group and 76 patients in the deteriorated group. Older age, advanced stage, chemotherapy treatment, and severe complications were important risk factors according to the multivariable logistic regression analysis. There were no significant differences in QLQ-C30 and HN35 scores before radiotherapy between the 2 groups, while significant differences were found in most items in the QLQ-C30 and HN35 between the 2 groups. Deteriorated resilience was identified as an important risk factor of QoL according to the multivariable linear regression analysis. NPC patients had significantly higher overall survival and progression-free survival in the improved group than in the deteriorated group. CONCLUSIONS: Psychological resilience has an important impact on the prognosis of NPC patients, thus more attention should be paid to their psychological status during treatment with radiotherapy.

Transperitoneal versus retroperitoneal approaches of pyeloplasty in management of ureteropelvic junction obstruction: A meta-analysis.

The aim of this study was to evaluate the benefits and safety of transperitoneal and retroperitoneal pyeloplasty for ureteropelvic junction obstruction by a meta-analysis. We searched the databases including PubMed, Cochrane Library and Embase database from their inception to December 1st, 2020. Relevant literatures comparing retroperitoneal pyeloplasty with transperitoneal pyeloplasty were identified. A meta-analysis was conducted with Revman 5.3. The main outcomes included success rate, operative time, hospital stay, conversion rate of open surgery, overall complications, and detailed postoperative complications/indicators. 15 studies with 1881 patients were included. The results revealed that there were no significant differences between two approaches in success rate [OR = 1.51, 95%CI (0.94, 2.41), p = 0.09], hospital stay [MD = 0.21, 95%CI (-0.12, 0.54), p = 0.21] and overall complications [OR = 1.07, 95%CI (0.76, 1.50), p = 0.69]. The retroperitoneal approach was associated with longer operative time [MD = -26.91, 95%CI (-40.97, -12.84), p < 0.001], higher conversion rate [OR = 0.23, 95%CI (0.11, 0.47), p < 0.001] than the transperitoneal approach. As for the detailed postoperative complications/indicators, there were no significant differences between two approaches in the urinary leak, mild hematuria, fever, UPJO recurrence, infection and subcutaneous emphysema, as well as split renal function, renal pelvis anteroposterior diameter. The funnel plots showed that there were no obvious publication biases in our analysis. Therefore, we concluded that transperitoneal and retroperitoneal approaches had similar benefits and safety in success rate, hospital stay, overall complications and detailed postoperative complications/indicators. However, retroperitoneal was associated with longer operative time and higher conversion rate than transperitoneal approach. With the limitations of our study, additional high-quality studies are still essential for further evaluation.

Gastrointestinal manifestations and possible mechanisms of COVID-19 in different periods.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a pandemic worldwide. Although COVID-19 mainly affects the respiratory system, gastrointestinal (GI) manifestations have been frequently reported in such cases, even as initial symptoms. There have been several studies on different GI manifestations in patients with mild and severe disease or in remission. In this review article we summarized different GI manifestations of COVID-19 at various disease stages and the possible mechanisms based on published literatures, as well as the significance of GI manifestations in systemic inflammatory injury.

The Impact of Palliative Transurethral Resection of the Prostate on the Prognosis of Patients With Bladder Outlet Obstruction and Metastatic Prostate Cancer: A Population-Matched Study.

Objective: This study aimed to evaluate the survival outcomes of patients with bladder outlet obstruction (BOO) and metastatic prostate cancer (mPCa) after having a palliative transurethral resection of the prostate (pTURP) surgery. Methods: We identified patients with mPCa between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who received pTURP and non-surgical therapy were identified. A propensity-score matching was introduced to balance the covariate. Kaplan-Meier analysis and COX regression were conducted to evaluate the overall survival (OS) and cancer-specific survival (CSS) outcomes. Results: A total of 36,003 patients were identified; 2,823 of them were in the pTURP group and 33,180 were in the non-surgical group. The survival curves of the overall cohort showed that the pTURP group was associated with worse outcomes in both OS (HR: 1.12, 95% CI: 1.07-1.18, p < 0.001) and CSS (HR: 1.08, 95% CI: 1.02-1.15, p = 0.004) compared with the non-surgical group. The mean survival time in the overall cohort of the pTURP group was shorter than the non-surgical group in both OS [35.13 ± 1.53 vs. 40.44 ± 0.59 months] and CSS [48.8 ± 1.27 vs. 55.92 ± 0.43 months]. In the matched cohort, the pTURP group had significantly lower survival curves for both OS (HR: 1.25, 95% CI: 1.16-1.35, p < 0.001) and CSS (HR: 1.23, 95% CI: 1.12-1.35, p < 0.001) than the non-surgical group. pTURP significantly reduced the survival months of the patients (36.49 ± 0.94 vs. 45.52 ± 1.23 months in OS and 50.1 ± 1.49 vs. 61.28 ± 1.74 months in CSS). In the multivariate COX analysis, pTURP increased the risk of overall mortality (HR: 1.19, 95% CI: 1.09-1.31, p < 0.001) and cancer-specific mortality CSS (HR: 1.23, 95% CI: 1.14-1.33, p < 0.001) compared with the non-surgical group. Conclusions: For mPCa patients with BOO, pTURP could reduce OS and CSS while relieving the obstruction.

Laparoscopic treatment of a series of rare tumors, gastric schwannoma with chronic iron deficiency anemia: A case report.

INTRODUCTION AND IMPORTANCE: Gastric schwannoma is a rare and slow-growing gastrointestinal mesenchymal tumor. Gastric neurilemmoma accounts for less than 1% of all gastric tumors. Without specific clinical manifestations, it is easy to be misdiagnosed before the operation, and rupture and bleeding will lead to persistent anemia in patients. The diagnosis can only be confirmed by pathological examination. CASE PRESENTATION: A 55-year-old woman was admitted to The Second Hospital of Lanzhou University due to abdominal distension, pain, acid regurgitation, and belching. The tumor was completely removed by laparoscopy. The postoperative specimens were diagnosed as gastric neurilemmoma by pathological examination. CLINICAL DISCUSSION: Schwannoma is a benign neurogenic tumor. Complete surgical resection with a negative cutting edge is an effective method for the treatment of gastric schwannoma. Because the lesion is benign, the prognosis of the patient is good. CONCLUSION: Laparoscopic tumor resection is a choice for the treatment of gastric schwannoma, and the therapeutic effect is good.

First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors. Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules. Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors. BACKGROUND: Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors. METHODS: This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01-10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks. RESULTS: Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4-7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response. CONCLUSION: Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.

New triterpenes from Cimicifuga yunnanensis down-regulating the mRNA expression of CD147, MMP-2, and MMP-9.

Eleven new 9,19-cycloartane triterpenes (1-9, 11-12) and one undescribed lanostane-type aglycone (10) were identified from the aerial parts of Cimicifuga yunnanensis. The new structures were elucidated by analysis of spectroscopic data. Compounds 3-5, 7-9, and 11, without obvious cytotoxicity at 50 µM, were evaluated for inhibiting the mRNA expressions of atherosclerosis-related factors of CD147 (extracellular matrix metalloproteinase inducer, EMMPRIN), matrix metalloproteinase 2 (MMP-2) and MMP-9 in phorbol-12-myristate-13-acetate (PMA) induced Human monocytic THP-1 cells by using a quantitative real-time PCR method (q-PCR). Among them, aglycones 7 and 8 showed potent activities, whereas all tested glycosides were inactive. Compounds 7 and 8 suppressed the mRNA expression of CD147 in a dose-dependent manner, with an IC50 value of 3.38 ± 0.27 µM and 8.25 ± 0.33 µM, respectively. Besides, 7 dose-related down-regulated the mRNA expression of MMP-2, and MMP-9, having an IC50 value of 6.32 ± 0.31 µM and 11.57 ± 0.23 µM, respectively. Meanwhile, 8 at 10 µM reduced the mRNA expression of MMP-2 and MMP-9 by 35% and 25%, respectively. Significantly, the migration ability of the induced THP-1 cells was potently and dose-dependently inhibited by 7, with an IC50 value of 5.87 ± 0.27 µM.

Clinical Effect of Modified Ditantang Combined with Acupuncture on Syndrome of Phlegm and Blood Stasis Blocking Collaterals of Dysphagia After Apoplexy / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of modified Ditantang combined with acupuncture in the treatment of dysphagia after apoplexy （DAS） syndrome of phlegm and blood stasis blocking collaterals. Method:One hundred and eight patients were randomly divided into control group （54 cases） and observation group （54 cases） by number table. Both groups underwent nutritional management，rehabilitation training and acupuncture. Patients in control group additionally took Tongluo Huatan capsules， 3 granules/time， 3 times/day， while patients in observation received modified Ditantang. Both groups had two weeks of treatment. The Kubota's drinking water test， swallowing contrast examination （VFSS）， and standard swallowing function assessment （SSA） were conducted. Swallowing disorder specific quality of life scale （SWAL-QOL） and sputum collateral stasis syndrome were scored before and after treatment. The levels of brain-derived neurotrophic factor （BDNF）， nerve growth factor （NGF） and neuron-specific enolase （NSE） before and after treatment. The occurrence of pneumonia， malnutrition， dehydration and aspiration were then recorded. Result:The clinical effective rate was （47/49） 95.92%in the observation group， higher than （41/50） 82.00% in the control group's （<italic>χ</italic>²=4.854，<italic>P</italic><0.05）. The grade of Kubota's drinking water test in observation group was lower than that in the control group（<italic>Z</italic>=2.211，<italic>P</italic><0.05）. VFSS swallowing dysfunction in observation group was lighter than that in control group（Z=1.969，<italic>P</italic><0.05）. The scores of Kubota's drinking water test， SSA and phlegm and blood stasis blocking collateral syndrome in the observation group were all lower than those in the control group（<italic>P</italic><0.01）， while the VFSS score was higher than that in control group （<italic>P</italic><0.01）. The swallowing symptom score， other symptom scores and total SWAL-QOL scores of the observation group were higher than those of the control group（<italic>P</italic><0.01）. The levels of BDNF and NGF in the observation group were higher than those in the control group （<italic>P</italic><0.01）， but the NSE level was lower than that in the control group（<italic>P</italic><0.01）. The complication rate in the observation group was （6/49）12.24%， which was lower than （15/50）30.00% in the control group（<italic>χ</italic>²=4.668，<italic>P</italic><0.05）. Conclusion:On the basis of nutrition management and rehabilitation training， modified Ditantang combined with acupuncture can reduce the risk of dysphagia and aspiration， improve the degree of neurological deficits， improve the quality of life， and reduce complications in treatment of DAS syndrome of phlegm and blood stasis， with significant clinical efficacy.

Discovery of a New Four-Leaf Clover-Like Ligand as a Potent c-MYC Transcription Inhibitor Specifically Targeting the Promoter G-Quadruplex.

Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.

Antiacetylcholinesterase triterpenes from the fruits of Cimicifuga yunnanensis.

Two new cycloartane triterpenes, cimyunnin E (1), containing a unique oxaspiro[4.4]nonanedione moiety based on rings D and E, together with cimicifine B (2), a 25,26,27-trinortriterpene featuring a pyridine ring E, were purified from the fruits of Cimicifuga yunnanensis. Their structures were elucidated by spectroscopic methods and ECD (electronic circular dichroism calculations). Compounds 1 and 2 showed significant acetylcholinesterase (AChE) inhibition with IC50 values of 1.58 and 3.87 µM, respectively. In addition, they noticeably enhanced the neurite outgrowth of nerve growth factor (NGF) mediated PC12 cells at a concentration of 10 µM.