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Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)

Objective The study investigated cognitive performance and brain function between treatment-resistant depression (TRD) and non- TRD patients to find potential neurobiological markers associated with refractoriness in depression patients.Methods Fourteen TRD patients, 26 non-TRD patients and 23 healthy controls (HC) were included in the present study. The neural function of prefrontal cortex (PFC) and cognitive performance among the three group were examined using near-infrared spectroscopy (NIRS) during verbal fluency task (VFT).Results Both TRD and non-TRD groups exhibited significantly worse VFT performance and lower activation of oxygenated hemoglobin (oxy-Hb) changes in the bilateral dorsolateral PFC (DLPFC) compared to the HC group. Within the TRD and non-TRD groups, VFT performance was no significant difference, but activation of oxy-Hb changes in dorsomedial PFC (DMPFC) in TRD patients was significantly lower than non-TRD patients. In addition, activation of oxy-Hb changes in right DLPFC were negatively correlated with the severity of depressive symptoms in depression patients.Conclusion Both TRD patients and non-TRD patients exhibited lower oxy-Hb activation in DLPFC. TRD patients exhibit lower oxy- Hb activation in DMPFC than non-TRD patients. fNIRS maybe a useful tool for predict depressive patients with or without treatment resistant.

Genetic markers have emerged as one of the most promising tools for species identification and geographic traceability in biodiversity conservation and international trade of biological products. However, traditional molecular markers rarely have sufficient resolution at lower taxonomic levels, especially for discriminating closely related forest tree species and their populations. In this study, we developed a panel of RNA-Seq based SNP markers for tracing the geographic origin of an endangered conifer, Cathaya argyrophylla, which is a Tertiary relict restricted to four mountain regions in subtropical China. A total of 69 individuals from five populations (DLS, SHS, HP, BMS, and DYS) covering the entire range were used for transcriptome sequencing. Based on these transcriptomic data, we evaluated genetic variation and population structure of C. argyrophylla, and found extremely low nucleotide diversity but strong population differentiation. We also screened 113 population-specific SNP loci, including 96 for BMS, 8 for DYS, 6 for SHS, 2 for HP, and 1 for one of the three subpopulations from DLS. According to these geographically diagnostic SNPs, we designed four population-specific molecular barcodes for PCR amplification. To test the utility and efficiency of the four markers in geographic discrimination, double-blind experiment was performed using 157 individuals labelled without any locality information. We found that almost all tested individuals could be successfully assigned to their geographic localities. Our work not only sheds some new light on the genetic profile of C. argyrophylla, but also provides a practical and cost-efficient solution for geographic traceability using transcriptome-derived SNPs.

Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

Purpose Recent studies indicate that microglia and monocyte-derived macrophages (MDMs) have different roles in diseases such as stroke and spinal cord injury, yet their respective polarized phenotypes and roles remain unclear in spinal cord ischemia/reperfusion injury (SCIRI). Methods We established a mouse model of SCIRI by transient aortic occlusion followed by reperfusion. Basso mouse scale (BMS) scores were used to test the locomotor functions. The histopathological changes in spinal cord were assessed by hematoxylin-eosin staining and NF-200 immunohistochemistry. Real-time PCR, immunofluorescence and flow cytometry were employed to analyze the polarized phenotypes of the microglia and infiltrating MDMs, and the resulting inflammatory responses. Furthermore, the role of infiltrating MDMs were investigated by MDMs depletion using systemic administration of clodronate-liposomes. Results SCIRI significantly impaired locomotor function of mice, accompanied with progressed necrosis, infiltration of inflammatory cells and neuron loss in the spinal cord. M1-related pro-inflammatory markers (iNOS, CD16, CD86 and TNF-α) increased dramatically in the early phase following SCIRI. In contrast, M2-related anti-inflammatory markers (CD204 and CD206) elevated at later stage. Besides, the invading MDMs were principally pro-inflammatory M1 type, transiently restricted to the first week after SCIRI. In contrast, microglia were the main source of anti-inflammatory M2 type. Furthermore, depletion of MDMs by clodronate-liposomes significantly preserved neurological functions and relieved neuronal damage caused by SCIRI. Conclusion These findings suggested distinct polarized status of resident microglia and MDMs following SCIRI. Inhibition of the invading MDMs may represent a novel approach for SCIRI treatment.

Purpose: The diagnosis of autism spectrum disorder (ASD) is reliant on evaluation of patients’ behavior. We screened the potential diagnostic and therapeutic targets of ASD through bioinformatics analysis.Methods: Four ASD-related datasets were downloaded from the Gene Expression Omnibus database. The “limma” package was employed to analyze differentially expressed messenger (m)RNAs, long non-coding (lnc)RNAs, and micro (mi)RNAs between ASD patients and healthy volunteers (HVs). We constructed a competing endogenous-RNA (ceRNA) network. Enrichment analyses of key genes were undertaken using the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes database. The ImmucellAI database was used to analyze differences in immune-cell infiltration (ICI) in ASD and HV samples. Synthetic analyses of the ceRNA network and ICI was done to obtain a diagnostic model using LASSO regression analysis. Analyses of receiver operating characteristic (ROC) curves were done for model verification.Results: The ceRNA network comprised 49 lncRNAs, 30 miRNAs, and 236 mRNAs. mRNAs were associated with 41 cellular components, 208 biological processes, 39 molecular functions, and 35 regulatory signaling pathways. Significant differences in the abundance of 10 immune-cell species between ASD patients and HVs were noted. Using the ceRNA network and ICI results, we constructed a diagnostic model comprising five immune cell-associated genes: adenosine triphosphate-binding cassette transporter A1 (ABCA1), DiGeorge syndrome critical region 2 (DGCR2), glucose-fructose oxidoreductase structural domain gene 1 (GFOD1), glutaredoxin (GLRX), and SEC16 homolog A (SEC16A). The diagnostic performance of our model was revealed by an area under the ROC curve of 0.923. Model verification was done using the validation dataset and serum samples of patients.Conclusion:ABCA1, DGCR2, GFOD1, GLRX, and SEC16A could be diagnostic biomarkers and therapeutic targets for ASD.

TiO2 has been considered as a promising anode material for lithium-ion batteries (LIBs) due to its low cost and high stability, but its low conductivity has greatly limited its application. In this study, the nitrogen-doped TiO2 (N-TiO2) with a uniform carbon coating was prepared by the solvothermal method. According the XPS results, the nitrogen was successfully doped in the TiO2. The N-doped TiO2 electrode exhibited obviously higher lithium-ion storage performance, of which the discharge capacity was 420 mAh g−1 under the current density 0.1 A g−1. Additionally, the superior long-term cycling stability was also observed with a reversible capacity of 148 mAh g−1 after 3000 cycles under 3 A g−1 current density. The result showed that after the nitrogen doped, the replacing of lattice oxygen with nitrogen can decrease the band-gap width and improve the conductivity of titanium oxide. Meanwhile, the oxygen vacancies on the surface of the material can adsorb a large number of lithium ions and produce significant pseudo-capacitance, thus, effectively increasing the specific capacity of the material. Therefore, the N-doped TiO2 electrode can present obviously higher lithium-ion storage performance.

Background Immunotherapy has improved the prognosis of patients with advanced non-small cell lung cancer (NSCLC), but only a small subset of patients achieved clinical benefit. The purpose of our study was to integrate multidimensional data using a machine learning method to predict the therapeutic efficacy of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced NSCLC.Methods We retrospectively enrolled 112 patients with stage IIIB-IV NSCLC receiving ICIs monotherapy. The random forest (RF) algorithm was used to establish efficacy prediction models based on five different input datasets, including precontrast computed tomography (CT) radiomic data, postcontrast CT radiomic data, combination of the two CT radiomic data, clinical data, and combination of radiomic and clinical data. The 5-fold cross validation was used to train and test the random forest classifier. The performance of the models was assessed according to the area under the curve (AUC) in the receiver operating characteristic (ROC) curve. Survival analysis was performed to determine the difference in progression-free survival (PFS) between two groups with the prediction label generated by the combined model.Results The radiomic model based on the combination of precontrast and postcontrast CT radiomic features and the clinical model produced an AUC of 0.92 ± 0.04 and 0.89 ± 0.03, respectively. By integrating radiomic and clinical features together, the combined model had the best performance with an AUC of 0.94 ± 0.02. The survival analysis showed that the two groups had significantly different PFS time (P < 0.0001).Conclusion The baseline multidimensional data including CT radiomic and multiple clinical features were valuable in predicting the efficacy of ICIs monotherapy in patients with advanced NSCLC.

To investigate the clinicopathological characteristics, immunoprofile, and molecular alterations of adenoid cystic carcinoma (ACC) in children and young adults.Twelve cases of ACC were included. MYB, MYBL1, Ki-67, type IV Collagen, Laminin, and LAMB1 expression were detected by immunohistochemistry. MYB and MYBL1 rearrangements were detected by fluorescence in situ hybridization.Among 12 patients, four were female and eight were male. Seven cases (58.3%) located in major salivary glands and eight cases (66.7%) were classified as Grade I. Ten tumors (83.3%) had collagenous and hyalinized stroma. MYB was positive in 83.3% cases, and the average Ki-67 labeling index (LI) was 8.3%. LAMB1, type IV Collagen, and Laminin were positive in 91.7%, 66.7%, and 58.3% cases, respectively. Besides, three out of eight tumors had MYB rearrangement. Cases without MYB rearrangement were negative for MYBL1 expression and MYBL1 rearrangement. The average follow-up time was 91.8 months. Four patients had recurrent diseases.ACC in children and young adults was seen more frequently in males and major salivary glands. Most cases had ECM and hyaline stroma. Grade III tumors, higher Ki-67 LI, negative expression of type IV Collagen, and Laminin showed a tendency of higher recurrence rate.

Background This study aimed to understand the clinical characteristics and outcomes of children with Langerhans cell histiocytosis (LCH) in China. Methods We conducted a retrospective study of 95 paediatric patients with LCH in West China Second University Hospital of Sichuan University between July 2013 and August 2020. Results The onset age of multisystem LCH (MS-LCH) patients with risk organ (RO) involvement was younger than that of MS-LCH without RO involvement (p = .002) and single system LCH (p K, BRAF p.L485_P490delinsF, BRAF p.R506_K507insLLR, ARAF p.Q349_F351delinsL and MAP2K1 p.Q58_E62del were known mutations in the mitogen-activated protein kinase (MAPK) pathway. The BRAF-V600E genotype in the tissue and plasma prior to therapy were detected in 16 patients, and the concordance was only 37.5% (6/16). According to the modified LCH-III-based-protocol, JLSG-02 protocol chemotherapy, and vemurafenib, the estimated five-year overall survival, event-free survival (EFS) and cumulative reactivation rates of 95 patients were 98.8%, 74.6% and 24.5%, respectively. The EFS rate in good responders was better than that in poor responders at 12-week (HR = 0.022, 95%CI 0.002–0.231, p = .002), and EFS was not affected by age, RO involvement or BRAF-V600E mutation. Regarding sequelae, nine patients had central diabetes insipidus and two had growth retardation. Conclusions In this study, LCH was a highly heterogeneous disease characterized molecularly by MAPK-pathway activating mutations. Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of childhood LCH. In future, prospective clinical trials and novel therapeutic strategies should be developed to improve outcomes in paediatric patients with LCH.KEY MESSAGEChildren with Langerhans cell histiocytosis in China present highly heterogeneous clinical characteristics, with up to 60% of cases harbouring mutations in MAPK pathway.Treatment response at 12-week is associated with EFS in our study.Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of Chinese childhood LCH, but the reactivation rate is still high.

Background: Many patients with type A aortic dissection (AAD) show low lymphocyte counts pre-operatively. The present study investigated the prognostic values of lymphopenia and lymphocyte subsets for the postoperative major adverse events (MAEs) in AAD patients undergoing surgery, and explore mechanisms of lymphopenia.Methods: We retrospectively analyzed pre-operative lymphocyte counts in 295 AAD patients treated at two hospitals, and evaluated their correlation with MAEs. We prospectively recruited 40 AAD patients and 20 sex- and age-matched healthy donors (HDs), and evaluated lymphocyte subsets, apoptosis, and pyroptosis by flow cytometry.Results: Multivariable regression analysis of the retrospective cohort revealed pre-operative lymphopenia as a strong predictor of MAEs (odds ratio, 4.152; 95% CI, 2.434–7.081; p < 0.001). In the prospective cohort, lymphocyte depletion in the AAD group was mainly due to loss of CD4+ and CD8+ T cells as compared with HDs (CD4+ T cells: 346.7 ± 183.6 vs. 659.0 ± 214.6 cells/μl, p < 0.0001; CD8+ T cells: 219.5 ± 178.4 vs. 354.4 ± 121.8 cells/μl, p = 0.0036). The apoptosis rates of CD4+ and CD8+ T cells were significantly higher in AAD patients relative to HDs (both p < 0.0001). Furthermore, the pre-operative CD4+ T cells count at a cut-off value of 357.96 cells/μl was an effective and reliable predictor of MAEs (area under ROC curve = 0.817; 95% CI, 0.684-0.950; sensitivity, 74%; specificity, 81%; p < 0.005). Pre-operative lymphopenia, mainly due to CD4+ T cells exhaustion by apoptosis, correlates with poor prognosis in AAD patients undergoing surgery.Conclusion: Pre-operative lymphopenia in particular CD4+ T lymphopenia via apoptosis correlates with poor prognosis in AAD patients undergoing surgery.

One of the major mechanisms underlying plant growth-promoting rhizobacteria (PGPR) is the lowering of ethylene level in plants by deamination of 1-aminocyclopropane-1-carboxylic acid (ACC) in the environment. In the present study, using ACC as the sole nitrogen source, we screened seven ACC deaminase-producing bacterial strains from rhizosphere soils of tea plants. The strain with the highest ACC deaminase activity was identified as Serratia marcescens strain JW-CZ2. Inoculation of this strain significantly increased shoot height and stem diameter of tea seedlings, displaying significant promotive effects. Besides, S. marcescens strain JW-CZ2 displayed high ACC deaminase activities in wide ranges of ACC concentration, pH, and temperature, suggesting the applicable potential of JW-CZ2 as a biofertilizer. Genome sequencing indicated that clusters of orthologous groups of proteins (COG) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of JW-CZ2 mainly included amino acid transport and metabolism, transcription, carbohydrate transport and metabolism, inorganic ion transport and metabolism, and membrane transport. Moreover, genes in relation to phosphate solubilization, indole acetic acid (IAA) production, and siderophore were observed in the genome of JW-CZ2, and further experimental evidence demonstrated JW-CZ2 could promote solubilization of inorganic phosphate, inhibit growth of pathogenic fungi, and produce IAA and siderophore. These aspects might be major reasons underlying the plant growth-promoting function of JW-CZ2. Overall, this study provides a new S. marcescens strain, which has applicable potential as a promising biofertilizer.

This paper presents dating results of AMS 14C, 210Pb and 137Cs methods on two young peat profiles from Jinchuan Mire in southeast Jilin of China. JC1 (50-cm long) from a hummock of the mire covers 1962–2007 CE with an accumulation rate of 1.12 cm/y, whereas JCA (92-cm long) from a lawn site involves a 1000-year record with a mean sedimentation of 0.09 cm/y. Comparison of the dating results of the last 100-y part of the peat cores, chronologies based on the AMS 14C dating are most reliable, because the mobility of 210Pb and 137Cs in peat profiles causes overestimation of depositional rate with the larger errors in the deeper layers. The F14C of peat samples were significantly lower than that of the atmospheric CO2 for the post nuclear bomb period because of three reasons: (1) uptake of old CO2 dissolved in the water by aquatic plants during photosynthesis; (2) long-term mixing of the atmospheric CO2 in multiple year growth of the plants; and (3) perhaps dilution effect caused by strong surface runoff. Among these factors, Factor (1) accounts for the major influence. Hence, a “bomb 14C curve” from a peat profile is necessary for determining post bomb ages. For the pre-nuclear bomb ages, acid-base-acid (ABA) treatment of a peat sample may cause an older-than-true age due to removal of organic acids produced during photosynthesis. This observation calls for detailed investigation of mechanism study and proper pretreatment of peat samples for 14C dating. The large difference of the depositional rates in the same peatland between JC1 and JCA indicates that estimation of carbon storage in a peatland should be based on the database of multiple sites rather than a couple of cores. For the same reason, one should not use a depositional rate either from a core with distance in the same peatland or from an adjacent peatland.

Peat properties including porosity, dry bulk density (DBD), ash content (and their XRD and SEM), TOC, humification and plant macrofossil were measured in the well dated, young peat profiles of Jinchuan Mire in southeast Jilin of China. Base on the properties and depositional rates (Li et al., 2019) of JC1 (50-cm long) and JCA (92-cm long), carbon accumulation rates (RCAs) have been calculated for different periods and processes of peatland development over the past 1000 years have been described. The long term variations of the RCAs between Jinchuan Mire and nearby Baijianghe Mire (Xia et al., 2019) during the past 1000 years matched reasonably well, reflecting similar carbon accumulation rates under the same climatic control even though the plant species could be very different in the two mires. Enhanced detrital content caused by surface runoff due to heavy rains with decline of wood% in plant remains probably reflect wet climates; and vice versa. In comparisons with regional climatic records, we describe the development of Jinchuan Mire as follow: (1) relatively warm and wet climates between 1000 CE and 1150 CE reflected by dominant herb species (>95%) with low wood% and no Sphagnum%, low DBD and detritus, and high TOC% and porosity. A dry climate occurred during 1150–1200 CE to lower the water table and enable growth of mosses in the mire. (2) Wet and cooling conditions during 1200–1370 CE supported well development of Sphagnum mosses and good development of the mire. (3) A climatic change from wet/cool to cold/dry between 1370 CE and 1440 CE caused disappear of Sphagnum mosses. (4) During the Little Ice Age (1440–1850 CE), cold and dry conditions led to poor peat development without Sphagnum mosses. (5) After 1850 CE, warm and wet conditions were in favor of aquatic herb growth. (6) Human impact caused anomaly peat accumulation with mainly tree species and detritus between 1950 and 1965. The peatland has been recovered from natural condition and development of Sphagnum mosses since 1965. Estimated RCAs in the hummock site and the lawn site are 320 gC/m2/y and 63 gC/m2/y, respectively during 1970–2010. Estimation of carbon accumulation over the entire peatland needs more work.

Background and Objective. Diabetic neuropathic pain (DNP) is a common complication associated with diabetes. Currently, its underlying pathomechanism remains unknown. Studies have revealed that the recruitment of blood monocyte-derived macrophages (MDMs) to the spinal cord plays a pivotal role in different models of central nervous system injury. Therefore, the present study aimed at exploring the infiltration and function of MDMs in DNP using a mice model. Methods. Diabetes was induced using streptozotocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Quantitative analysis of CD11b was performed and visualized by immunofluorescence. Spinal cord cells were isolated from myelin and debris by Percoll gradient. Flow cytometry was used to label CD11b and CD45 antibodies to differentiate MDMs (CD45highCD11b+) from resident microglia (CD45lowCD11b+). Mice were injected with clodronate liposomes to investigate the role of MDMs in DNP. The successful depletion of monocytes was determined by flow cytometry. Results. The DNP mice model was successfully established. Compared with nondiabetic mice, diabetic mice displayed a markedly higher level of CD11b immunofluorescence in the spinal cord. The number of CD11b-positive microglia/macrophages gradually increased over the 28 days of testing after STZ injection, and a significant increase was observed on Day 14 (P<0.01) and 28 (P<0.01). Further analysis by flow cytometry showed that the infiltration of peripheral macrophages began to increase in 2 weeks (P<0.001) and reached a maximum at 4 weeks (P<0.001) post-STZ injection compared to the control. The depletion of MDMs by clodronate liposomes alleviated diabetes-induced tactile allodynia (P<0.05) and reduced the infiltration of MDMs (P<0.001) as well as the expression of IL-1β and TNF-α in the spinal cord (P<0.05). Conclusions. The infiltration of blood MDMs in the spinal cord may promote the development of painful neuropathy in diabetes.

Recent advances in the preparation and application of perovskite-type oxides as bifunctional electrocatalysts for oxygen reaction and oxygen evolution reaction in rechargeable metal-air batteries are presented in this review. Various fabrication methods of these oxides are introduced in detail, and their advantages and disadvantages are analyzed. Different preparation methods adopted have great influence on the morphologies and physicochemical properties of perovskite-type oxides. As a bifunctional electrocatalyst, perovskite-type oxides are widely used in rechargeable metal-air batteries. The relationship between the preparation methods and the performances of oxygen/air electrodes are summarized. This work is concentrated on the structural stability, the phase compositions, and catalytic performance of perovskite-type oxides in oxygen/air electrodes. The main problems existing in the practical application of perovskite-type oxides as bifunctional electrocatalysts are pointed out and possible research directions in the future are recommended.

Background To observe the dynamic changes of blood perfusion with whole-tumor computed tomography (CT) perfusion imaging using texture analysis in patients with unresectable stage IIIA/B non-small cell lung cancer (NSCLC) treated with recombinant human endostatin (Endostar). Methods This phase II clinical trial recruited 11 patients diagnosed with stage IIIA/B NSCLC. Histological examination prior to treatment revealed squamous cell carcinoma in 4 cases and adenocarcinoma in 7 cases. All patients underwent contrast-enhanced perfusion CT at baseline and a second CT scan 1 week after treatment initiation with Endostar. CT perfusion images including blood flow (BF), blood volume (BV), and permeability (PMB) were imported into OmniKinetics software to quantitatively assess the texture features. Skewness, kurtosis, and entropy were calculated at baseline and after anti-angiogenic therapy. Changes in tumor were analyzed using Wilcoxon signed-rank test. The association of parameters with survival was evaluated using Cox proportional hazards regression model. Results There were no statistical differences in the mean values of BF, BV, and PMB before and after treatment (P=0.594, 0.477 and 0.328, respectively). The skewness on BF images demonstrated significant differences at baseline and after treatment (0.6±2.7 vs. 1.0±2.6, P=0.010), while skewness of BV and PMB showed no significant variation (P=0.477 and 0.213, respectively). The kurtosis and entropy for BF, BV and PMB showed no significant differences (all P>0.05). In adenocarcinoma, the mean BF showed no significant differences at baseline and after treatment (76.5±25.7 vs. 101.2±46.4, P=0.398), while skewness for BF was significantly higher after treatment than at baseline (-0.19±3.3 vs. 0.59±3.2, P=0.028). No significant associations were found between perfusion CT imaging parameters and progression-free survival. Conclusions These results suggested that blood perfusion showed improvement with whole-tumor perfusion CT using texture analysis in patients with stage IIIA/B NSCLC treated by Endostar.

Background Screw fixation is a typical technique for the isolated subtalar joint. However, no consensus has been reached on how to select the most suitable insertion position and direction. This study aims to find the ideal screw insertion and then explore its influence on the clinical efficacy of subtalar fusion by analyzing the effects of different cannulated screw insertions on the stress distribution, anti-rotary strength, and anti-inversion/eversion strength of the subtalar joint. Methods In this study, we investigated three cannulated screw insertions for subtalar fusion: screw insertion with the most uniform stress distribution (group A), lateral-medial parallel screw insertion (group B), and traditional longitudinally parallel screw insertion (group C). The effects of these three insertions on the loading stress of the subtalar joint (including stress distribution, anti-inversion/eversion strength, and anti-rotary strength) were comparatively analyzed with the three-dimensional finite element method to screen the ideal screw insertion. Moreover, a prospective study was conducted to analyze the influence of the ideal screw insertion on subtalar fusion, including the fusion rate, fusion time, and clinical efficacy (VAS score, AOFAS score, and complications). Results Group B was worse than group A with respect to the stress distribution uniformity, but slightly better than group C, and better than both groups A and C in terms of the anti-rotary strength and anti-inversion/eversion strength. The screw insertion based on the most uniform stress distribution is not feasible in surgery. Therefore, the lateral-medial antiparallel screw insertion is the ideal insertion. From January 2012 to June 2016, 48 cases were treated by subtalar fusion with the ideal screw insertion, and then followed up for 30.6 months (12–48 months). The fusion was proved in all 48 cases with a fusion rate of 100% by X-ray or CT scan. The mean time of fusion was 12.8 weeks (12–16 weeks). The VAS score decreased from 6.00 before operation to 1.03 on the last visit (P

e18067 Background: In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), major pathological response (MPR) to neoadjuvant therapy may translate into improved survival. The combination of anti-PD-1 and chemotherapy as neoadjuvant protocol has not been well reported in OSCC. Methods: The prospective single arm trial (NCT04473716) was performed to evaluate the neoadjuvant therapy with anti-PD-1 (Toripalimab) and chemotherapy (albumin paclitaxel/cisplatin) in OSCC patients at clinical stage III and IVA (AJCC 2018). The patients received two cycles (21 days each) of intravenous albumin paclitaxel (260mg/m2), cisplatin (75mg/m2) and Toripalimab (240mg) on day 1 and day 22. Radical surgery was performed within two weeks after neoadjuvant therapy. Post-operative radiotherapy/chemoradiotherapy was performed within 1.5 months after surgery. The primary endpoints were MPR and safety. Primary tumors were assessed for the percentage of residual viable tumor cells on HE staining, and tumor with no more than 10% viable tumor cell was considered as MPR. Results: From Nov. 2020 to Apr. 2021, 20 patients were enrolled, including 16 males and 4 females, at clinical stage III (16) and IVA (4). They aged from 19 to 75 (median 54) years . The primary tumor site was eight tongue, six mouth floor, three gingiva, two retromolar trigone and one buccal mucosa. The neoadjuvant therapy was well-tolerated with low incidence of grade 3-4 adverse events (AEs) including 5% grade 4 neutropenia, 10% grade 3 leukopenia, 5% grade 3 neutropenia, hypokalemia, vomiting, and rash each. Common grade 1-2 AEs included baldness/rash/itch/pain/fatigue, AST/ALT/uric acid elevation, nausea/vomiting/diarrhea, hyperbilirubinemia, proteinuria, neutropenia/leukopenia. All AEs were relieved after expectant treatment, the subsequent standard treatment was not delayed. According to pathological evaluation, the MPR rate was 60% (12/20), including 30% (6/20) pCR. According to RECIST 1.1, radiological evaluation on neoadjuvant therapy showed two CR, ten PR, seven SD and one PD. It was significantly consistent between pathological and radiological evaluation in linear regression analysis ( P＜0.0001). Combined positive score (CPS) of PD-L1 expression in biopsy was evaluated in 19 patients, MPR was archived in all 4 patients with CPS≥10, in 6 out of 8 patients (75%) with CPS≥1, and in 5 out of 11 patients (45.5%) with CPS < 1. Conclusions: Neoadjuvant therapy with combination of Toripalimab, albumin paclitaxel, and cisplatin in resectable OSCC patients is safe and well-tolerated, with high MPR rate. Clinical trial information: NCT04473716.

Jing-Jing Sun,1,2 Xiao-Min Liu,2 Chen-Yu Shen,2 Kun Feng,1,2 Po-Zi Liu2 1School of Clinical Medicine, Medicine Institute, Tsinghua University, Beijing, China; 2Yu Quan Hospital, Clinical Neuroscience Institute, Tsinghua University, Beijing, China Purpose: Bipolar disorder (BD) patients with psychotic symptoms (BDp) worsens prognosis and decreases rates of recovery. The study investigated cognitive performance and brain function between BD patients in depressive episode with and without psychotic symptoms to find potential neurobiological markers associated with psychotic features of BD patients in depressive episode. Patients and methods: Thirty-one patients without psychotic symptoms and 29 patients with psychotic symptoms diagnosed with bipolar I disorder with a current depressive episode were included in the present study. The neural function of prefrontal cortex (PFC) and cognitive performance among BDp, BD patients without psychotic symptoms, and 23 healthy controls (HC) were examined using near-infrared spectroscopy during verbal fluency task (VFT). Results: 1) Both the BD groups exhibited significantly worse performance of VFT and lower activation of oxygenated hemoglobin (oxy-Hb) changes in the bilateral ventrolateral PFC compared with the HC group. 2) Within the BD group, VFT performance was not significantly different. 3) The prefrontal activation of oxy-Hb changes in the BDp patients was significantly lower than that in the BD patients without psychotic symptoms in the right dorsolateral PFC. 4) Activation of oxy-Hb changes in right dorsolateral PFC was negatively correlated with the severity of psychotic symptoms in BDp patients. Conclusion: The prefrontal function differs between BD patients in depressive episode with or without psychotic symptoms measured with near-infrared spectroscopy. Keywords: bipolar disorder, depressive, psychotic symptoms, near-infrared spectroscopy, verbal fluency task

To investigate the association of miR-106b-5p with neuroinflammation and microglial activation in a status epilepticus (SE) mouse model. We examined changes in the expression of microRNA-106b-5p (miRNA-106b-5p), repulsive guidance molecule A (RGMa), triggering receptor expressed on myeloid cells 2 (TREM2), and the microglia-related markers interleukin (IL)-1β, IL-4, IL-6, IL-10, inducible nitric oxide synthase (iNOS), and arginase-1 (Arg-1) in the mouse hippocampus of the lithium–pilocarpine-induced SE mouse model. Eighty-four female C57BL/6 mice were randomly divided into a normal control group (n = 12), and six SE groups (n = 12/group), which were monitored at 6 h and at 1, 3, 7, 14, and 21 days (d) post-SE induction. Unlike in the dentate gyrus, immunohistochemical staining revealed prominent neuronal swelling at 6 h, significant neuronal loss and apoptosis on day 3, and recovery by day 14 in the hippocampal cornu ammonis (CA)1 and CA3 pyramidal cells in SE mice. We noted elevated levels of miRNA-106b-5p and all microglia-related markers, which peaked at 3 days post-SE, except IL-4, which peaked at 7 days post-SE, indicating inflammation and microglial activation. RGMa and TREM2 levels decreased at 6 h post-SE. All markers but miRNA-106b-5p, RGMa, and TREM2 returned to baseline levels at 21 days post-SE. Dual luciferase reporter gene assay showed that microRNA-106b-5p can interact with RGMa. We observed that miR-106b-5p level increased while both RGMa and TREM2 levels decreased post-SE and showed associations with microglial activation and inflammation in the mouse hippocampus, suggesting their potential as SE therapeutic targets.

Langerhans cell histiocytosis (LCH) is characterized pathologically by langerin-positive (CD207+) dendritic cell proliferation and is considered by some as a myeloid neoplastic disorder. Hemophagocytic lymphohistiocytosis (HLH) is associated with immune dysregulation characterized by the accumulation of activated macrophages and hypercytokinemia. However, these 2 histiocytosis rarely coexist. Currently, the etiology, risk factors, optimal therapy, and outcomes of LCH-HLH remain unclear. We reviewed the medical records of 7 LCH-HLH patients from our hospital and analyzed 50 LCH-HLH patients reported in scientific literature. The median age of LCH onset of these 57 LCH-HLH patients was 1 year, and 91% (52/57) of patients diagnosed as LCH were less than 2 years old. Fifty-six LCH-HLH patients belonged to the multisystem LCH category and 84% (47/56) patients had risk-organ involvement. Twenty-three LCH-HLH patients were complicated with infection and 3 patients had a primary pathogenic mutation of HLH. Overall, 90% of LCH patients developed HLH at the diagnosis or during chemotherapy. Of the 57 LCH-HLH patients, 15 died. Multisystem LCH patients with risk-organ involvement under 2 years old were most likely to develop HLH when complicated with infection at diagnosis or during chemotherapy. Identifying LCH-HLH patients during early stages and treating them with prompt chemotherapy, hematopoietic stem cell transplantation, or supportive therapies are important for better survival.

Traditional 3D block matching (BM3D) algorithms are among the best denoising methods at present; however, they exhibit the issue of ringing around image edges, which makes them unable to protect image edges and details. Therefore, this paper proposes an BM3D noise processing algorithm for the diffusion equation to reduce image noise without affecting image details, specifically at the edges. This method first uses anisotropic diffusion (AD) filtering for image preprocessing, and then uses the edge direction instead of horizontal direction to search for similar blocks. The AD model is mainly improved to achieve better edges and detailed processing effects. Firstly, with the improved AD direction, a 5 × 5 edge enhancement operator model is implemented in eight directions, and the corresponding gradient information is obtained. This operator improves the processed image edges to achieve clear contours and good continuity. Next, a new calculation method for the diffusion function, whose coefficient is constructed using a hyperbolic tangent function, is introduced. The proposed method is based on the link between the image gradient and diffusion function, and it is mathematically proven that the diffusion function converges faster than the diffusion function of the model proposed by Perona and Malik. Experimental results indicate that the improved model can effectively retain the image edges and texture details, avoid edge ringing, and provide significant improvements in terms of the subjective visual effects and objective numerical indicators.

Background Bipolar depression (BD) is a unique, severe and prevalent mental illness that shares many similarities in symptoms with unipolar depression (UD). Improving precision of their diagnoses would enhance treatment outcome and prognosis for both conditions. This study aims to provide evidence from functional Near-Infrared Spectroscopy (fNIRS) as a potential tool to differentiate UD and BD based on their differences in hemodynamic change in the prefrontal cortex during verbal fluency tasks (VFT). Methods We enrolled 179 participants with clinically confirmed diagnoses, including 69 UD patients, 68 BD patients and 42 healthy controls(HC). Every participant was assessed using a 45-channel fNIRS and various clinical scales. Findings Compared with HC, region-specific fNIR leads show UD patients had significant lower hemodynamic activation in 4 particular pre-frontal regions: 1) the left dorsolateral prefrontal cortex (DLPFC), 2) orbitofrontal cortex (OFC), 3) bilateral ventrolateral prefrontal cortex (VLPFC) and 4) left inferior frontal gyrus (IFG). In contrast, BD vs. HC comparisons showed only significant lower hemodynamic activation in the LIFG area. Furthermore, compared to BD patients, UD patients showed decreased hemodynamic activation changes in the VLPFC region. Conclusion Our results show significant frontal lobe activation pattern differences between UD and BD groups. fNIRS can be a potential tool to increase diagnostic precision for these conditions. In particular, the VLPFC area holds promise to be a useful site for such differentiation for further investigations.

Sepsis is a major condition caused by an overwhelming inflammatory response to an infection. Sepsis-induced myocardial dysfunction (SIMD) is a common complication in septic patients and a major predictor of morbidity and mortality. Here, we investigated the role of tripartite motif 31 (TRIM31) protein in sepsis progression in vitro and in vivo. Quantitative real-time PCR and western blot were used to detect the expression levels of relative genes and proteins. Cell proliferation and apoptosis were evaluated to determine cell viability. H&E and IHC staining were performed to examine morphological and pathological changes in mice. ELISA assay was used to detect inflammatory factors. TRIM31 was upregulated in septic patients compared with normal people. TRIM31 depletion reduced LPS-induced apoptosis whereas TRIM31 overexpression-elevated LPS-induced apoptosis. Furthermore, TRIM31 interacted with and ubiquitinated transforming growth factor-β-activated kinase-1 (TAK1), resulting in TAK1 activation and subsequent induction of NF-κB signaling. Of note, Trim31 depletion or blockade by PDTC treatment inhibited LPS-induced apoptosis in vivo. In conclusion, TRIM31 played an important role in SIMD by activating TAK1-mediated NF-κB signaling pathway.