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Background In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens.Methods In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes.Results Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of −5.2% and −3.3%; both were >−10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1–3 severity.Conclusions Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL.Trial registration number Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 μg/kg for 2 cycles; then 75 μg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

Abstract Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Background: Surveillance systems revealed that the prevalence of vancomycin-resistant Enterococcus faecium (VREfm) has increased. We aim to investigate the epidemiological and genomic characteristics of VREfm in China. Methods: We collected 20,747 non-redundant E. faecium isolates from inpatients across 19 hospitals in six provinces between January 2018 and June 2023. VREfm was confirmed by antimicrobial susceptibility testing. The prevalence was analyzed using changepoint package in R. Genomic characteristics were explored by whole-genome sequencing. Results: 5.59% (1159/20,747) of E. faecium isolates were resistant to vancomycin. The prevalence of VREfm increased in Guangdong province from 5% before 2021 to 20−50% in 2023 (p

ObjectiveTo establish a digital PCR system for accurate and sensitive quantitative detection of Helicobacter pylori (Hp). MethodsSpecific primer and probe were designed based on the Hp 16S rRNA sequence, and reference bacteria was used to conduct specificity testing. The sensitivity was detected using gradient diluted DNA as templates. The accuracy was detected using different concentration templates with multiple repeated tests. The gradient method was used to set the primer concentration and annealing temperature for optimizing reaction conditions.ResultsThe designed primers and probes could detect Hp 16S rRNA genes specifically without the interference from Escherichia coli and other bacteria. The optimal reaction temperature for the detection was 57.1 ℃, and the optimal primer concentration was 550 nmol/L. The detection limit was 0.35 copies/μL, the coefficient of variation (CV) of the detection was < 10%, and the coefficient of determination for the linear regression between dilution ratio and DNA concentration was 0.9968. ConclusionThe established digital PCR system is specific, sensitive, and highly accurate for Hp detection.

Abstract Tight sandstone has strong pore heterogeneity and complex pore structure, and the pore structure of tight sandstone varies with different permeability. To study the differences in the pore structure of tight sandstone with different permeability, this study investigated the tight sandstone of the He 8 Member in the Gaoqiao area of the Ordos Basin. Factors influencing pore formation are analyzed through experiments utilizing methods, such as distinguishing casting thin sections, scanning electron microscopy, high‐pressure mercury intrusion, and low‐temperature nitrogen adsorption. The results indicate that in this area, the pores of the tight sandstone are primarily dissolution and intercrystalline pores, with occasional intergranular pores and microcracks. Type Ⅱ samples (permeability > 0.2 × 10−3 μm2) are primarily composed of dissolution and intercrystalline pores, with a few visible intergranular and microcracks. In contrast, Type Ⅰ samples (permeability

Relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is associated with poor prognosis. As such, a comprehensive analysis of intratumoral components, intratumoral heterogeneity, and the immune microenvironment is essential to elucidate the mechanisms driving the progression of DLBCL and to develop new therapeutics. Here, we used single-cell transcriptome sequencing and conventional bulk next-generation sequencing (NGS) to understand the composite tumor landscape of a single patient who had experienced multiple tumor recurrences following several chemotherapy treatments. NGS revealed several key somatic mutations that are known to contribute to drug resistance. Based on gene expression profiles at the single-cell level, we identified four clusters of malignant B cells with distinct transcriptional signatures, showing high intra-tumoral heterogeneity. Among them, heterogeneity was reflected in activating several key pathways, human leukocyte antigen (HLA)-related molecules’ expression, and key oncogenes, which may lead to multi-drug resistance. In addition, FOXP3+ regulatory CD4+ T cells and exhausted cytotoxic CD8+ T cells were identified, accounted for a significant proportion, and showed highly immunosuppressive properties. Finally, cell communication analysis indicated complex interactions between malignant B cells and T cells. In conclusion, this case report demonstrates the value of single-cell RNA sequencing for visualizing the tumor microenvironment and identifying potential therapeutic targets in a patient with treatment-refractory DLBCL. The combination of NGS and single-cell RNA sequencing may facilitate clinical decision-making and drug selection in challenging DLBCL cases.

Abstract Background To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations. Methods A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists. Results Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility. Conclusions The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Photoperiod is a pivotal regulatory factor in the flowering of Camellia oleifera Abel. (C. oleifera). GIGANTEA (GI) serves as a pivotal regulator, not only orchestrating the intricate circadian rhythm but also governing photoperiod-dependent flowering. In order to explore the function of GI in C. oleifera (CoGI), we obtained a CoGI gene-coding sequence and analyzed a CoGI protein sequence using bioinformatics. Furthermore, we conducted a spatiotemporal expression analysis of CoGI. And a yeast two-hybridization assay was used to screen the interacting proteins of CoGI. Evolutionary analysis revealed high conservation of the CoGI protein, which clustered with the GI protein from Camellia sinensis (CsGI) on a common evolutionary branch. The expression of CoGI was different in each part, and a tissue expression analysis revealed that the relative expression level of the CoGI gene is highest in the leaves of C. oleifera, while it is at its lowest in the seed coats. Transgenic Arabidopsis thaliana (Arabidopsis) overexpressing CoGI exhibited early flowering under long-day conditions. In addition, the yeast two-hybrid library screening revealed interactions between seven C. oleifera proteins and CoGI: CoACR9, CoLAO, CoDExH12-like, CoIT1K-like, CoUPF0481, CoIDM3, and CoAt4g27190-like. The findings demonstrated that CoGI is crucial to C. oleifera’s flowering.

Abstract Background This study aimed to compare the efficacy and safety of high-dose methotrexate (HD-MTX) versus teniposide (TEN) in patients with newly diagnosed immunocompetent primary central nervous system lymphomas (PCNSLs). Methods The study included immunocompetent, adult patients with newly diagnosed PCNSL at 22 centers in China from 2007 to 2016. The patients received HD-MTX or TEN as first-line induction therapy. The objective response rate, progression-free survival, and overall survival were analyzed for each patient cohort. Results A total of 96 patients were eligible: 62 received HD-MTX, while 34 received teniposide. The overall response rate was 73.2% and 72.7% in the MTX and the TEN cohorts, respectively (P = 0.627). The median progression-free survival was 28.4 months [95% confidence interval (CI): 13.7–51.2] in the MTX cohort and 24.3 months (95% CI: 16.6–32.1) in the TEN cohort (P = 0.75). The median overall survival was 31 months (95% CI: 26.8–35.2) in the MTX cohort and 32 months (95% CI: 27.6–36.4) in the TEN cohort (P = 0.77). The incidence of any grade of coagulopathy/deep-vein thrombosis and gastrointestinal disorders was significantly higher in the MTX cohort than in the TEN cohort; no significant difference was found in the incidence of other adverse events between the two cohorts. Conclusions This was the first multicenter study using TEN as the main agent compared with HD-MTX in newly diagnosed primary CNS lymphoma. The TEN-based regimen was non-inferior to the HD-MTX-based regimen with similar overall responses. Classification of evidence This study provided Class III evidence that the teniposide-based regimen was non-inferior to high-dose methotrexate − based regimen with similar overall responses and long-time survival in immunocompetent patients with PCNSL.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee–assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5–64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200–800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

IntroductionWe aim to explore the microstructural and metabolic changes in visual pathways in patients with thyroid eye disease (TED) using 3T multi-parametric MRI.MethodsThirty-four TED patients (inactive group = 20; active group = 14; acute group = 18; chronic group = 16) and 12 healthy controls (HC) were recruited from November 2020 to July 2021. Proton magnetic resonance spectroscopy (1H-MRS), glutamate chemical exchange saturation transfer (GluCEST) and diffusion kurtosis imaging (DKI) were performed on 3.0T MR scanner. Data analysis and group comparisons were performed after MR data processing.ResultsAs compare to HC group, the levels of total choline (tCh) in optic radiation (OR) in active group ([1.404 ± 0.560] vs. [1.022 ± 0.260]; p < 0.05), together with tCh ([1.415 ± 0.507] vs. [1.022 ± 0.260]; p < 0.05) in OR in acute group were significantly increased. Glutamine (Gln) levels were higher in OR in the chronic group than those in HCs and were positively correlated with the levels of thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), free triiodothyronine (FT3) and FT4 in chronic group. Glutamate (Glu) levels by 1H-MRS did not show significant differences between any two groups. Interestingly, MTRasym (3.0 ppm) was higher in OL in inactive group, active group, acute group and chronic group than those in HCs, and was positively correlated with Glu levels in OL in 1H-MRS. Fractional anisotropy (FA) values from DKI in OR in acute group were significantly lower than those in HCs.DiscussionOur initial study demonstrate that GluCEST performs better than 1H-MRS to monitor Glu alterations in visual pathway in TED patients. Changes of brain glutamine levels in TED patients are closely related to their associated hormones alterations, indicating that disease injury status could be reflected through non-invasive metabolites detection by brain 1H-MRS. FA is the most sensitive DKI index to reveal the visual pathway impairment in TED patients. Altogether, our study revealed that 3T multiparametric MR techniques are useful to demonstrate metabolic and microstructural alterations in visual pathways in TED patients. We found that damage to visual pathways occurs in mild TED cases, which not only offers a new approach to the diagnosis of dysthyroid optic neuropathy, but also demonstrates neuropathy in TED is a gradual and continuous spatio-emporal progression.

ABSTRACT Pseudomonas aeruginosa (P. aeruginosa) is one of the leading causes of chronic infections, including reinfection, relapse, and persistent infection, especially in cystic fibrosis patients. Relapse P. aeruginosa infections are more harmful because of repeated hospitalization and undertreatment of antimicrobials. However, relapse P. aeruginosa infection in China remains largely unknown. Herein, we performed a 3-year retrospective study from 2019 to 2022 in a tertiary hospital, which included 442 P. aeruginosa isolates from 196 patients. Relapse infection was identified by screening clinical records and whole-genome sequencing (WGS). We found that 31.6% (62/196) of patients had relapsed infections. The relapse incidence of carbapenem-resistant P. aeruginosa infection (51.4%) is significantly higher than that of carbapenem-susceptible P. aeruginosa infection (20.2%, P < 0.0001). These isolates were assigned to 50 distinct sequence types and sporadically distributed in phylogeny, indicating that relapsed infections were not caused by certain lineages. Fast adaptation and evolution of P. aeruginosa isolates were reflected by dynamic changes of antimicrobial resistance, gene loss and acquisition, and single-nucleotide polymorphisms during relapse episodes. Remarkably, a convergent non-synonymous mutation that occurs in a pyochelin-associated virulence gene fptA (T1056C, M252T) could be a considerable target for the diagnosis and treatment of relapse P. aeruginosa infection. These findings suggest that integrated utilization of WGS and medical records provides opportunities for improved diagnostics of relapsed infections. Continued surveillance of the genomic dynamics of relapse P. aeruginosa infection will generate further knowledge for optimizing treatment and prevention in the future. IMPORTANCE Pseudomonas aeruginosa is a predominant pathogen that causes various chronic infections. Relapse infections promote the adaptation and evolution of antimicrobial resistance and virulence of P. aeruginosa, which obscure evolutionary trends and complicate infection management. We observed a high incidence of relapse P. aeruginosa infection in this study. Whole-genome sequencing (WGS) revealed that relapse infections were not caused by certain lineages of P. aeruginosa isolates. Genomic dynamics of relapse P. aeruginosa among early and later stages reflected a plasticity scattered through the entire genome and fast adaptation and genomic evolution in different ways. Remarkably, a convergent evolution was found in a significant virulence gene fptA, which could be a considerable target for diagnosis and treatment. Taken together, our findings highlight the importance of longitudinal surveillance of relapse P. aeruginosa infection in China since cystic fibrosis is rare in Chinese. Integrated utilization of WGS and medical records provides opportunities for improved diagnostics of relapse infections.

Abstract Background The difference between clinical characteristics and outcomes between follicular lymphoma grade 1–2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1–2 for predicting prognosis and thus making treatment decisions. Methods We compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes. Results Compared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P

Abstract Background Ibrutinib has revolutionized the treatment of mantle cell lymphoma (MCL). Both ibrutinib monotherapy and ibrutinib‐based combination therapy are important salvage options for patients with relapsed/refractory (R/R) MCL. The real‐world efficacy and safety profile of the two strategies in Chinese patients with R/R MCL remain unclarified. Methods In the present study, data of 121 R/R MCL patients who received either ibrutinib monotherapy (N = 68) or ibrutinib combination therapy (N = 53) in 13 medical centers in China were retrospectively reviewed. Results With a median follow‐up of 20.5 months, the overall response rate was 60.3% versus 84.9% (p = 0.003), complete remission rate was 16.2% versus 43.4% (p

Abstract Background The aim of this study was to explore predictors and construct a nomogram for risk stratification in primary extragastric mucosa‐associated lymphoid tissue (MALT) lymphoma. Methods Extragastric MALT lymphoma cases newly diagnosed between November 2010 and April 2020 were assessed to construct a progression‐free survival (PFS)‐related nomogram. We also performed external validation of the nomogram in an independent cohort. Results We performed multivariate analyses of 174 patients from 3 hospitals who were included in the training cohort. Stage, hepatitis B virus surface antigen (HBsAg) status, and Ki67 expression were significantly associated with PFS. These three factors were used to construct a nomogram, which was shown to have a C‐index of 0.89. Two risk groups (low risk and high risk) were identified by the prognostic model. The 5‐year PFS was 98.9% for the low‐risk group and 69.3% for the high‐risk group (p

Abstract Background Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma (NHL). Due to the rarity of the disease, it is important to create a predictive model that provides treatment and prognosis for patients with PGL and physicians. Methods A total of 8898 and 127 patients diagnosed with PGL were obtained from the SEER database and from our Cancer Center as training and validation cohorts, respectively. Univariate and multivariate Cox proportional hazards models were used to investigate independent risk factors for the construction of predictive survival nomograms, and a web nomogram was developed for the dynamic prediction of survival of patients with PGL. The concordance index (C-index), calibration plot, and receiver operating characteristics (ROC) curve were used to evaluate and validate the nomogram models. Results There were 8898 PGL patients in the SEER cohort, most of whom were married men over the age of 60, 16.1% of the primary tumors were localized in the antrum and pylori of the stomach, which was similar to the composition of 127 patients in the Chinese cohort, making both groups comparable. The Nomogram of overall survival (OS) was compiled based on eight variables, including age at diagnosis, sex, race, marital status, histology, stage, radiotherapy and chemotherapy. Cancer-specific survival (CSS) nomogram was developed with eight variables, including age at diagnosis, sex, marital status, primary tumor site, histology, stage, radiotherapy and chemotherapy. The C-index of OS prediction nomogram was 0.948 (95% CI: 0.901–0.995) in the validation cohort, the calibration plots showed an optimal match and a high area below the ROC curve (AUC) was observed in both training and validation sets. Also, we established the first web-based PGL survival rate calculator ( https://yangjinru.shinyapps.io/DynNomapp/ ). Conclusion The web dynamic nomogram provided an insightful and applicable tool for evaluating PGL prognosis in OS and CSS, and can effectively guide individual treatment and monitoring.

BackgroundThe present study sought to understand how clinical factors and inflammatory biomarkers affected the prognosis of mucosa-associated lymphoid tissue (MALT) lymphoma and develop a predictive nomogram to assist in clinical practice.MethodsWe conducted a retrospective study on 183 cases of newly diagnosed MALT lymphoma from January 2011 to October 2021, randomly divided into two groups: a training cohort (75%); and a validation cohort (25%). The least absolute shrinkage and selection operator (LASSO) regression analysis was combined with multivariate Cox regression analysis to construct a nomogram for predicting the progression-free survival (PFS) in patients with MALT lymphoma. To evaluate the accuracy of the nomogram model, the area under the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were used.ResultsThe PFS was significantly associated with the Ann Arbor Stage, targeted therapy, radiotherapy, and platelet-to-lymphocyte ratio (PLR) in MALT lymphoma. These four variables were combined to establish a nomogram to predict the PFS rates at three and five years. Importantly, our nomogram yielded good predictive value with area under the ROC curve (AUC) values of 0.841 and 0.763 in the training cohort and 0.860 and 0.879 in the validation cohort for the 3-year and 5-year PFS, respectively. Furthermore, the 3-year and 5-year PFS calibration curves revealed a high degree of consistency between the prediction and the actual probability of relapse. Additionally, DCA demonstrated the net clinical benefit of this nomogram and its ability to identify high-risk patients accurately.ConclusionThe new nomogram model could accurately predict the prognosis of MALT lymphoma patients and assist clinicians in designing individualized treatments.

IntroductionVascular calcification (VC) is more likely to be detected in the chronic kidney disease (CKD) population. The mechanism of VC development from CKD is different from that for simple VC and has always been a major research area. The aim of this study was to detect alterations in the metabolome during development of VC in CKD and to identify the critical metabolic pathways and metabolites involved in its pathogenesis.MethodsRats in the model group were given an adenine gavage combined with a high-phosphorus diet to imitate VC in CKD. The aorta calcium content was measured and used to divide the model group into a VC group and non-vascular calcification group (non-VC group). The control group was fed a normal rat diet and given a saline gavage. Ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to determine the altered serum metabolome in the control, VC, and non-VC groups. The identified metabolites were mapped into the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (https://www.genome.jp/kegg/) for pathway and network analyses.ResultThere were 14 metabolites that changed significantly in the VC group, with three metabolic pathways playing critical roles in the pathogenesis of VC in CKD: steroid hormone biosynthesis; valine, leucine and isoleucine biosynthesis; and pantothenate and CoA biosynthesis.ConclusionOur results indicated changes in the expression of steroid sulfatase and estrogen sulfotransferase, and down-regulation of the in situ synthesis of estrogens in the VC group. In conclusion, the serum metabolome alters significantly during the pathogenesis of VC in CKD. The key pathways, metabolites, and enzymes we identified are worth further study and may become a promising therapeutic target for the treatment of VC in CKD.

BackgroundPituitary metastasis accounts for a very low percentage of cases of brain metastasis from lung cancer, and there are uncertainties and challenges in diagnosis and treatment. We hope to shed some light on the diagnosis and treatment by reporting a case of ALK fusion mutation-positive lung cancer pituitary metastasis.Case presentationWe report a 48-year-old female patient with an initial diagnosis of stage IVB lung adenocarcinoma with ALK fusion. The patient developed headache, dizziness, hypopituitarism and hyperprolactinemia one year after treatment with crizotinib. Later, the patient underwent neurosurgical resection of the pituitary tumor and then symptomatic relief. Postoperative pathology suggested pituitary metastasis, and the next-generation gene sequencing conducted on the pituitary metastasis indicated that secondary drug resistance mutation ALK-I1171s occurred after the ALK fusion gene.ConclusionIn this article, we present a patient with suspected pituitary metastases with lung cancer. The progression to pituitary mass resection and next-generation gene sequencing of the pituitary metastasis are suggestive for further diagnosis and treatment.

The light-responsive nanochannel of rhodopsin gained wider research interest from its crucial roles in light-induced biological functions, such as visual signal transduction and energy conversion, though its poor stability and susceptibility to inactivation in vitro have limited its exploration. However, the fabrication of artificial nanochannels with the properties of physical stability, controllable structure, and easy functional modification becomes a biomimetic system to study the stimulus-responsive gating properties. Typically, light-responsive molecules of azobenzene (Azo), retinal, and spiropyran were introduced into nanochannels as photo-switches, which can change the inner surface wettability of nanochannels under the influence of light; this ultimately results in the photoresponsive nature of biomimetic nanochannels. Furthermore, the fine-tuning of their stimulus-responsive properties can be achieved through the introduction of host–guest systems generally combined with a non-covalent bond, and the assembling process is reversible. These host–guest systems have been introduced into the nanochannels to form different functions. Based on the host–guest system of light-responsive reversible interaction, it can not only change the internal surface properties of the nanochannel and control the recognition and transmission behaviors but also realize the controlled release of a specific host or guest molecules in the nanochannel. At present, macrocyclic host molecules have been introduced into nanochannels including pillararenes, cyclodextrin (CD), and metal–organic frameworks (MOFs). They are introduced into the nanochannel through chemical modification or host–guest assemble methods. Based on the changes in the light-responsive structure of azobenzene, spiropyran, retinal, and others with macrocycle host molecules, the surface charge and hydrophilic and hydrophobic properties of the nanochannel were changed to regulate the ionic and molecular transport. In this study, the development of photoresponsive host and guest-assembled nanochannel systems from design to application is reviewed, and the research prospects and problems of this photo-responsive nanochannel membrane are presented.

BackgroundArterial stiffness, a risk factor for atrial fibrillation (AF), is rarely applied in clinical practice because of the difficulty and high cost of its measurement. Estimated pulse wave velocity (ePWV) is a simple, reproducible, and non-invasive index of arterial stiffness. This study was to assess the predictive value of ePWV for the risk of new-onset AF.MethodsSubjects were selected from the Kailuan cohort study population who underwent initial physical examination between 2006 and 2008. A total of 96,561 subjects were ultimately included in the final analysis. ePWV was divided into four groups according to quartiles. The Kaplan–Meier method was used to calculate the cumulative incidence of AF. A Cox regression model was used to assess the predictive value of estimated arterial stiffness for new-onset AF.ResultsMean age of subjects was 51.47 ± 9.68 years, while 76,968 (79.65%) were male and 19,663 (20.35%) were female. During mean follow-up period of 11.77 years, 1,215 AF events occurred. Results of the Kaplan–Meier analysis showed that the incidence of new-onset AF increased with increase in ePWV. Cox regression analysis showed that in the total population, the incidence of new-onset AF was 1.64, 1.90, and 2.64 times higher in the medium, medium-high, and high ePWV groups, respectively, compared with the low ePWV group. When stratified according to sex, ePWV had higher predictive value in the female population.ConclusionsIncreased ePWV increases the incidence of new-onset AF, and may promote application of more aggressive primary prevention.Trial registry nameRisk factors and intervention for cardiology, cerebrovascular and related disease (Kailuan Study); URL: http://www.chictr.org.cn/showproj.aspx?proj=8050; Registration number: ChiCTR-TNRC-11001489.

ABSTRACT Purpose: To investigate the effect of genistein on inflammation and mitochondrial function of diabetic nephropathy. Methods: Diabetic nephropathy model was established in Sprague-Dawley rats. Automatic biochemical analyzer was employed to detect the kidney function index, serum creatinine, serum urea nitrogen, and 24 h-urine protein and blood glucose. Hematoxylin and eosin staining and periodic acid Schiff staining were used to observe renal morphology. Mitochondrial changes and podocyte integrity were monitored by transmission electron microscope. The expression levels of mfn2, NOX4, P53, MAPK, and NF-κB were detected by Western blotting. The changes of mitochondrial membrane potential were measured by JC-1. The level of mfn2 was assessed by immunofluorescence assay. Results: Genistein ameliorated the kidney function with reduced Scr and blood glucose. The expressions of NOX4, MAPK, p65 and p53 were downregulated, while the expression of mnf2 was the opposite in genistein-treated kidneys. Further investigations revealed that genistein reduced expansion of mesangial matrix and oxidative stress, protected podocyte integrity and increased mitochondrial membrane potential. Conclusions: Genistein could alleviate diabetic nephropathy through inhibiting MAPK/NF-κB pathway, improving mitochondrial function and anti-inflammatory.

Abstract Background Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients. Methods We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria. Results Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30–22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2–51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to

Abstract Objective This study aimed to investigate plasma neuronally derived extracellular vesicle (NDEV) levels of core pathological markers [amyloid‐β (Aβ) and phosphorylated tau] and inflammatory biomarkers, including interleukin 6 (IL‐6) and matrix metalloproteinase‐9 (MMP‐9) in patients with Alzheimer’s disease (AD). Methods Thirty‐one patients with AD and 15 cognitively normal controls (NCs) were recruited. The diagnosis of AD was supported by fluorodeoxyglucose and Pittsburgh Compound‐B PET scans. Plasma extracellular vesicles were extracted, precipitated, and enriched for neuronal source by anti‐L1CAM antibody absorption. Levels of Aβ42, P‐T181‐tau, P‐S396‐tau, IL‐6, and MMP‐9 in plasma NDEVs were quantified by enzyme‐linked immunosorbent assay (ELISA). Results Aβ42, P‐T181‐tau, and MMP‐9 levels in plasma NDEVs were significantly higher in patients with AD than NCs. However, P‐S396‐tau and IL‐6 levels in plasma NDEVs did not differ between AD patients and NCs. Moreover, there was no correlation between any of these biomarker levels and cognitive function as measured with Mini‐Mental State Examination in patients with AD. Conclusions These findings provide further support that levels of core pathological markers, including Aβ42 and P‐T181‐tau, are elevated in plasma NDEVs of patients with AD. Furthermore, MMP‐9 might play an important role in the pathogenesis of AD, and is a promising inflammatory biomarker for AD.

Abstract Progression to severe disease is a difficult problem in treating coronavirus disease 2019 (COVID‐19). The purpose of this study is to explore changes in markers of severe disease in COVID‐19 patients. Sixty‐nine severe COVID‐19 patients were included. Patients with severe disease showed significant lymphocytopenia. Elevated level of lactate dehydrogenase (LDH), C‐reactive protein (CRP), ferritin, and D‐dimer was found in most severe cases. Baseline interleukin‐6 (IL‐6) was found to be associated with COVID‐19 severity. Indeed, the significant increase of baseline IL‐6 was positively correlated with the maximal body temperature during hospitalization and with the increased baseline of CRP, LDH, ferritin, and D‐dimer. High baseline IL‐6 was also associated with more progressed chest computed tomography (CT) findings. Significant decrease in IL‐6 and improved CT assessment was found in patients during recovery, while IL‐6 was further increased in exacerbated patients. Collectively, our results suggest that the dynamic change in IL‐6 can be used as a marker for disease monitoring in patients with severe COVID‐19.

BackgroundHistiocytic sarcoma (HS) is a rare hematopoietic malignancy with an aggressive clinical presentation associated with a poor overall survival. To date, surgical resection, radiation therapy, and chemotherapy were often utilized for HS, but curative effects are rather disappointing.Case PresentationA 19-year-old female was referred to our hospital with a pathologic diagnosis of HS in December 2017. The patient had a severe airway obstruction resulting from a large mass (6.0 cm × 4.4 cm) arising from the left parapharyngeal space. She did not respond to cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP) chemotherapy, then she was switched to radiotherapy and crizotinib according to next-generation sequencing (NGS) results (mutations in MET and MAP2K1). The patient got a partial response after radiotherapy and crizotinib, then she switched to imatinib combined with thalidomide treatment. The patient got a long-term complete response from the treatment and is alive 44 months after initial diagnosis without disease progression. Further KEGG pathway enrichment analysis of NGS results from patient’s tissue revealed that phosphatidylinositol 3′ kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways were activated in this HS patient. We further performed experiments in vitro in a canine histiocytic sarcoma cell line DH82, in order to explore the possible mechanism of imatinib plus thalidomide in HS. Results of cell counting kit-8 (CCK8) assays showed that the proliferation activity of DH82 was significantly inhibited by imatinib but not thalidomide. Combined thalidomide and imatinib treatment did not improve the inhibitory effects of imatinib to DH82. Results of Western blot confirmed the inhibitory effects of imatinib on DH82 by targeting activation of MAPK and PI3K/AKT pathways.ConclusionRadiotherapy combined with targeted therapy guided by NGS may be promising, and further perspective clinical trial is warranted for the localized HS.

Chidamide has demonstrated significant clinical benefits for patients with relapsed/refractory (R/R) PTCL in previous studies. This multi-center observational study was aimed to evaluate the objective response rate (ORR), overall survival (OS), and safety of chidamide. From February 2015 to December 2017, 548 patients with R/R PTCL from 186 research centers in China were included in the study. Among the 261 patients treated with chidamide monotherapy, ORR was 58.6% and 55 patients (21.1%) achieved complete response (CR). Among the 287 patients receiving chidamide-containing combination therapies, ORR was 73.2% and 73 patients (25.4%) achieved CR. The median OS of all patients was 15.1 months. The median OS of patients receiving chidamide monotherapy and combination therapies was 433 and 463 days, respectively. These results demonstrate a significant survival advantage of chidamide treatments as compared with international historical records. Common adverse effects (AEs) were hematological toxicities. Most AEs in both monotherapy and combined treatments were grade 1–2. No unanticipated AEs occurred. In conclusion, chidamide-based therapy led to a favorable efficacy and survival benefit for R/R PTCL. Future studies should explore the potential advantage of chidamide treatment combined with chemotherapy.

Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, disulfiram (DSF) kills tumor cells via regulating multiple signaling pathways and transcription factors. However, its effect on tumor immune microenvironment (TIME) remains unclear. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through bioinformatics analysis, we found that DNMT1 was highly expressed in TNBC tissue and PD-L1 was negatively correlated with IRF7 expression. DSF reduced DNMT1 expression and activity, and hypomethylated IRF7 promoter region resulting in upregulation of IRF7. Furthermore, we found DSF enhanced PD-L1 expression via DNMT1-mediated IRF7 hypomethylation. In in vivo experiments, DSF significantly improved the response to anti-PD-1 antibody (Ab) in 4T1 breast cancer mouse model. Immunohistochemistry staining showed that granzyme B+ and CD8+ T cells in the tumor tissues were significantly increased in the combination group. By analyzing the results of the tumor tissue RNA sequencing, four immune-associated pathways were significantly enriched in the DSF joint anti-PD-1 Ab group. In conclusion, we found that DSF could upregulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate TIME to show much better antitumor efficacy than monotherapy.

Background: To date, radiographic sign clusters of multidrug-resistant pulmonary tuberculosis (MDR-TB) patients have not been reported. We conducted a study to investigate the classification and prognosis of sign clusters in pulmonary Computed Tomography (CT) images from patients with MDR-TB for the first time by using principal component analysis (PCA).Methods: The clinical data and pulmonary CT findings of 108 patients with MDR-TB in the Liupanshui Third Hospital were collected (from January 2018 to December 2020). PCA was used to analyze the sign clusters on pulmonary CT, and receiver operating characteristic (ROC) analysis was used to analyze the predictive value of the treatment outcome of MDR-TB patients.Results: Six cluster signs of MDR-TB were determined by PCA: nodules, infiltration, consolidation, cavities, destroyed lung and non-active lesions. Nine months after treatment, the area under the ROC curve (AUC) of MDR-TB patients with a cavity sign cluster was 0.818 (95% CI: 0.733–0.886), and the positive predictive value (PPV) and negative predictive value (NPV) of the treatment outcome were 79.6% (95% CI: 65.7–89.8%) and 72.9% (95% CI: 59.7–83.6%), respectively.Conclusion: PCA plays an important role in the classification of sign groups on pulmonary CT images of MDR-TB patients, and the sign clusters obtained from PCA are of great significance in predicting the treatment outcome.

Abstract Purpose The role of interim 18F‐FDG PET/CT (iPET/CT) in diffuse large B‐cell lymphoma (DLBCL) remains controversial. The purpose of this study was to assess the prognostic value of iPET/CT in patients with newly diagnosed DLBCL according to visual and semiquantitative interpretation methods. Methods A total of 129 newly diagnosed DLBCL patients with baseline PET/CT data were retrospectively screened. The iPET/CT findings were evaluated by the Deauville 5‐point scale (DS) and ΔSUVmax. Furthermore, the reduction in SUVmax incorporated with tumor size (ΔSUVmax*ΔSLD) was calculated. The optimal cutoff values of ΔSUVmax and ΔSUVmax*ΔSLD were determined by receiver operating characteristic (ROC) analysis. Kaplan‐Meier analysis was applied to test for the influence of prognostic values. Univariate and multivariate analyses were conducted to examine the potential independent impacts of iPET/CT. Results Seventy‐seven patients with PET/CT images acquired both at baseline and after four cycles of chemotherapy were finally enrolled. The optimal cutoff values for ΔSUVmax and ΔSUVmax*ΔSLD were 74% and 30%, respectively. After a median follow‐up of 23 months, iPET/CT findings were significant predictors of PFS and OS whenever iPET/CT was interpreted by DS, ΔSUVmax, or ΔSUVmax*ΔSLD methods. ΔSUVmax‐based methods were more accurate than those based on DS. The IPI, DS, ΔSUVmax, and ΔSUVmax*ΔSLD were predictive in univariate analyses. However, in the multivariate analysis, only IPI and ΔSUVmax remained independent predictors of PFS and OS. Conclusions Interim PET/CT may help to identify DLBCL patients with different prognoses. ΔSUVmax analysis shows the best accuracy and the strongest predictive value among these three methods. ΔSUVmax*ΔSLD may be a promising parameter to interpret iPET/CT images, reflecting both the changes in tumor size and metabolic activity.

Background: Antimicrobial resistance is a significant clinical problem in pediatric practice in China. Surveillance of antibiotic use is one of the cornerstones to assess the quality of antibiotic use and plan and assess the impact of antibiotic stewardship interventions.Methods: We carried out quarterly point prevalence surveys referring to WHO Methodology of Point Prevalence Survey in 16 Chinese general and children’s hospitals in 2019 to assess antibiotic use in pediatric inpatients based on the WHO AWaRe metrics and to detect potential problem areas. Data were retrieved via the hospital information systems on the second Monday of March, June, September and December. Antibiotic prescribing patterns were analyzed across and within diagnostic conditions and ward types according to WHO AWaRe metrics and Anatomical Therapeutic Chemical (ATC) Classification.Results: A total of 22,327 hospitalized children were sampled, of which 14,757 (66.1%) were prescribed ≥1 antibiotic. Among the 3,936 sampled neonates (≤1 month), 59.2% (n = 2,331) were prescribed ≥1 antibiotic. A high percentage of combination antibiotic therapy was observed in PICUs (78.5%), pediatric medical wards (68.1%) and surgical wards (65.2%). For hospitalized children prescribed ≥1 antibiotic, the most common diagnosis on admission were lower respiratory tract infections (43.2%, n = 6,379). WHO Watch group antibiotics accounted for 70.4% of prescriptions (n = 12,915). The most prescribed antibiotic ATC classes were third-generation cephalosporins (41.9%, n = 7,679), followed by penicillins/β-lactamase inhibitors (16.1%, n = 2,962), macrolides (12.1%, n = 2,214) and carbapenems (7.7%, n = 1,331).Conclusion: Based on these data, overuse of broad-spectrum Watch group antibiotics is common in Chinese pediatric inpatients. Specific interventions in the context of the national antimicrobial stewardship framework should aim to reduce the use of Watch antibiotics and routine surveillance of antibiotic use using WHO AWaRe metrics should be implemented.

Patients with advanced-stage natural killer/T-cell lymphoma (NKTCL) usually have a poor prognosis. However, there is limited data of comprehensive analysis on this particular patient population due to the rarity of the disease. The present study aimed to investigate the treatment models, survival outcomes, and prognosis of advanced-stage NKTCL. Data from 336 patients with advanced-stage NKTCL diagnosed between 2006 and 2015 in the China Lymphoma Collaborative Group database were retrospectively analyzed. The median age was 42 years and the male/female ratio was 2.4:1. About 97% of patients had stage IV disease and 77% had >1 extranodal involvement site. All patients received chemotherapy, with the most common option being asparaginase (Asp)-containing regimens (n=146; 43.5%). Among 286 patients with available response data, the overall response rate (ORR) was 57.3% with a complete remission (CR) rate of 35.7%. Asp-containing regimens led to better ORRs (86/132, 65.2% vs. 54/113, 47.8%, P = 0.006) and CR rates (60/132, 45.5% vs. 27/113, 23.9%, P < 0.001) than non-Asp-containing regimens. The expected 5-year progression-free survival (PFS) and overall survival (OS) rates were 22.6 and 32.0%, respectively, for the whole cohort. Compared to non-Asp-containing chemotherapy, Asp-containing chemotherapy improved 5-year PFS (34.2 vs. 17.1%, P < 0.001) and OS (45.3 vs. 27.8%, P < 0.001). A trend toward improvement in OS was observed when gemcitabine was added to Asp-containing chemotherapies. Moreover, those undergoing autologous hematopoietic stem cell transplantation had prolonged survival time. In conclusion, Asp-containing chemotherapy could improve the prognosis of advanced-stage NKTCL, and refinement of treatment models is warranted in the future.

The surface topographies of artificial implants including surface roughness, surface groove size and orientation, and surface pore size and distribution have a great influence on the adhesion, migration, proliferation, and differentiation of nerve cells in the nerve regeneration process. Optimizing the surface topographies of biomaterials can be a key strategy for achieving excellent cell performance in various applications such as nerve tissue engineering. In this review, we offer a comprehensive summary of the surface topographies of nerve implants and their effects on nerve cell behavior. This review also emphasizes the latest work progress of the layered structure of the natural extracellular matrix that can be imitated by the material surface topology. Finally, the future development of surface topographies on nerve regeneration was prospectively remarked.

BackgroundRefractory/relapsed angioimmunoblastic T cell lymphoma (AITL) with Evans syndrome is a very rare condition with a poor prognosis. There is no evidence-based treatment strategy for refractory/relapsed AITL with Evans syndrome.Case PresentationA 51-year-old female was admitted to our hospital with multiple enlarged bilateral cervical lymph nodes, more than 1 week-long chest distress, and night sweats in July 2014. An excision biopsy of the left cervical enlarged lymph node revealed AITL. However, the patient showed resistance to the first-line chemotherapy for AITL and was diagnosed with refractory AITL. Complete remission was achieved after the salvage treatment with the combination of chemotherapy, radiotherapy, and immunomodulatory agent lenalidomide. Unfortunately, 12 months later, the patient suffered from disease progression and was diagnosed as refractory/relapsed AITL with Evans syndrome according to the laboratory findings and imaging. With the diagnosis of refractory/relapsed AITL with Evans syndrome, the patient received the first-line treatment for Evans syndrome including prednisone and intravenous immunoglobulin. The response to the first-line treatment for Evans syndrome was poor. The combination regimen of chidamide (30 mg, po, biw) and cyclosporine were administrated considering the treatment targeting simultaneously both refractory/relapsed AITL and Evans syndrome. The efficacy evaluation was complete remission. The last follow-up of the patient was April 30th, 2020, and no evidence of disease progression was observed. The overall survival of the patient was more than 70 months.ConclusionThe treatment for refractory/relapsed AITL combined with Evans syndrome remains challenging to patients and physicians. The combination of chidamide and cyclosporine may be an effective and tolerable regimen for the intractable AITL with Evans syndrome case and more observations are necessary to identify the efficacy and safety in the future.

Melanoma is the leading cause of cancer-related death among skin tumors, with an increasing incidence worldwide. Few studies have effectively investigated the significance of an immune-related gene (IRG) signature for melanoma prognosis. Here, we constructed an IRGs prognostic signature using bioinformatics methods and evaluated and validated its predictive capability. Then, immune cell infiltration and tumor mutation burden (TMB) landscapes associated with this signature in melanoma were analyzed comprehensively. With the 10-IRG prognostic signature, melanoma patients in the low-risk group showed better survival with distinct features of high immune cell infiltration and TMB. Importantly, melanoma patients in this subgroup were significantly responsive to MAGE-A3 in the validation cohort. This immune-related prognostic signature is thus a reliable tool to predict melanoma prognosis; as the underlying mechanism of this signature is associated with immune infiltration and mutation burden, it might reflect the benefit of immunotherapy to patients.

Background: The outbreak of coronavirus disease 2019 (COVID-19) had become a global public health event. Lymphoma patients need to be distinguished from the general population because of their deficient immune status and intensive anti-tumor treatment. The impacts of cancer subtypes and treatment on COVID-19 infection are unclear.Case Presentation: We here report the case of a primary mediastinal large B-cell lymphoma patient who was infected with COVID-19 after intensive immunochemotherapy (DA-EPOCH-R). The patient developed a neutropenic fever during chemotherapy, and fever was persistent, although antibiotics were used. Initial chest CT was negative, and the patient received a throat swab test since the second CT showed evidence of pneumonia. With treatment with Arbidol Hydrochloride and LianHuaQingWen capsule, his COVID-19 was cured.Conclusions: To the best of our knowledge, this is the first report focusing on COVID-19 infection in a lymphoma patient undergoing intensive immunochemotherapy. For those patients being treated with immunochemotherapy in epidemic areas, a reduced dose intensity of intensive chemotherapy should be considered, and the effect of immunotherapies such as rituximab on COVID-19 infection should be considered. The impacts of anti-cancer treatment on COVID-19 infection need to be explored further.

Biofunctionalization of artificial nerve implants by incorporation of specific bioactive factors has greatly enhanced the success of grafting procedures for peripheral nerve regeneration. However, most studies on novel biofunctionalized implants have emphasized the promotion of neuronal and axonal repair over vascularization, a process critical for long-term functional restoration. We constructed a dual-biofunctionalized chitosan/collagen composite scaffold with Ile-Lys-Val-Ala-Val (IKVAV) and vascular endothelial growth factor (VEGF) by combining solution blending, in situ lyophilization, and surface biomodification. Immobilization of VEGF and IKVAV on the scaffolds was confirmed both qualitatively by staining and quantitatively by ELISA. Various single- and dual-biofunctionalized scaffolds were compared for the promotion of endothelial cell (EC) and Schwann cell (SC) proliferation as well as the induction of angiogenic and neuroregeneration-associated genes by these cells in culture. The efficacy of these scaffolds for vascularization was evaluated by implantation in chicken embryos, while functional repair capacity in vivo was assessed in rats subjected to a 10 mm sciatic nerve injury. Dual-biofunctionalized scaffolds supported robust EC and SC proliferation and upregulated the expression levels of multiple genes and proteins related to neuroregeneration and vascularization. Dual-biofunctionalized scaffolds demonstrated superior vascularization induction in embryos and greater promotion of vascularization, myelination, and functional recovery in rats. These findings support the clinical potential of VEGF/IKVAV dual-biofunctionalized chitosan/collagen composite scaffolds for facilitating peripheral nerve regeneration, making it an attractive candidate for repairing critical nerve defect. The study may provide a critical experimental and theoretical basis for the development and design of new artificial nerve implants with excellent biological performance.

Objective: To investigate the diagnosis and treatment of synchronous lymphoma and digestive system carcinoma and review literature.Materials and Methods: We retrospectively analyzed the clinical data of four cases of synchronous lymphoma and digestive system carcinoma treated at our hospital. The clinical manifestations, pathological results, and treatment strategies were investigated.Results: One of the four cases was diagnosed as follicular lymphoma with gastric adenocarcinoma, and the other three were diagnosed as diffuse large B-cell lymphoma with digestive system adenocarcinoma in the liver, sigmoid colon, and duodenum papilla, respectively. The second carcinoma was initially discovered incidentally because of the stage examination of lymphoma or the patient's poor response to treatment. The diagnosis of synchronous lymphoma and digestive system carcinoma depended mainly on the pathological examination.Conclusions: The accurate diagnosis of synchronous malignancies is challenging because they rarely occur. We suggest a scrupulous re-biopsy of extranodal lesions in patients with lymphoma to improve the diagnostic accuracy of related double primary tumors. Age, performance status, symptoms, pathological types, and tumor staging should be considered when formulating a treatment strategy. The systemic treatment regimens should include drugs targeting the synchronous tumors in question, and these remain to be explored further.

Chicoric acid (CA), a natural phenolic acid, has been used as a nutraceutical food ingredient due to its powerful antioxidant, anti-HIV and anti-diabetic bioactivities. CA could be partly metabolized into caffeic acid (CFA) and caftaric acid (CTA) on cytochrome P450s in rat liver microsomes. To compare the protective effects of CA and its metabolites on biomolecules and inflammatory responses, oxidative damage induced by free radicals in vitro and microglial inflammation triggered by lipopolysaccharide in BV2 cells were constructed. Results showed that CA, CTA and CFA all significantly inhibited protein degradation and carbonylation induced by hydroxyl radicals and alcoxyl radicals, and suppressed hemin/nitrite/H2O2 triggered-nitration. Moreover, CA, CTA and CFA all exerted remarkable inhibition capacities on linoleic acid and soybean lecithin liposomes peroxidation in a dose-dependent manner, and restrained the oxidation of herring sperm DNA, as well as the breakage of pBR322 plasmid DNA. Furthermore, CA and its metabolites suppressed lipopolysaccharide-induced decline of BV2 cell viability and the production of NO and ROS. However, bioactivities of CA were significantly stronger than those of its metabolites within a certain concentration range. This study provides scientific basis for the application of CA and its metabolites as nutrition and natural antioxidants. Keywords: Chicoric acid and its metabolites, Oxidative damage, Biomolecules, Microglia, Inflammation

The application of biological nitrogen and phosphorus removal processes in high-altitude areas faces severe challenges due to low temperature, low atmosphere pressure and low oxygen concentration. In this study, a simultaneous nitrification, denitrification and phosphorus removal (SNDPR) system was operated under low atmosphere pressure. The chemical oxygen demand (COD) concentrations in influent were decreased from 300 mg/L (stage I) to 200 mg/L (stage II), corresponding to the low COD concentration of sewage in high-altitude areas. The removal of COD and total phosphate was efficient at the H1 reactor (72 kPa). The removal rates of COD and total phosphate were 94.08% (stage I), 90.66% (stage II) and 98.43% (stage I), 99.34% (stage II), respectively, which were similar to L1 (100 kPa). The removal rates of total inorganic nitrogen and simulation nitrification and denitrification were from 81.21% (stage I) and 59.48% (stage I) to 72.86% (stage II) and 31.95% (stage II), respectively, which were also improved compared to L1. Cycle experiment results indicated that the activity of phosphorus accumulating organisms was enhanced, while the ammonia oxidation process was inhibited under low atmosphere pressure.

Abstract The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.

The competing endogenous RNA (ceRNA) networks are an effective method for investigating cancer; however, construction of ceRNA networks among different subtypes of breast cancer has not been previously performed. Based on analysis of differentially expressed RNAs between 150 triple-negative breast cancer (TNBC) tissues and 823 non–triple-negative breast cancer (nTNBC) tissues downloaded from TCGA database, a ceRNA network was constructed based on database comparisons using Cytoscape. Survival analysis and receiver operating characteristic curve data were combined to screen out prognostic candidate genes, which were subsequently analyzed using co-expressed functionally related analysis, Gene Set Variation Analysis (GSVA) pathway-related analysis, and immune infiltration and tumor mutational burden immune-related analysis. A total of 190 differentially expressed lncRNAs (DElncRNAs), 48 differentially expressed mRNAs (DEmRNAs), and 13 differentially expressed miRNAs (DEmiRNAs) were included in the ceRNA network between TNBC and nTNBC subtypes. Gene ontology analysis of mRNAs coexpressed with prognostic candidate lncRNAs (AC104472.1, PSORS1C3, DSCR9, OSTN-AS1, AC012074.1, AC005035.1, SIAH2-AS1, and ERVMER61-1) were utilized for functional prediction. Consequently, OSTN-AS1 was primarily related to immunologic function, for instance, immune cell infiltration and immune-related markers coexpression. The GSVA deviation degree was increased with OSTN increased expression. In addition, many important immune molecules, such as PDCD1 and CTLA-4, were strongly correlated in terms of their quantitative expression. Competing endogenous RNA networks may identify candidate therapeutic targets and potential prognostic biomarkers in breast cancer. In particular, OSTN-AS1 serves as a novel immune-related molecule and could be involved in immunotherapy efforts in the future.

To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3-4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses.

Reactive oxygen species (ROS) primarily produced via NADPH oxidase play an important role for killing microorganisms in neutrophils. In this study we examined if ROS production in Human promyelocytic leukemia cells (HL60) differentiated into neutrophil-like cells (dHL60) induces ER stress and activates the unfolded protein response (UPR). To cause ROS production cells were treated with PMA or by chronic hyperglycemia. Chronic hyperglycemia failed to induce ROS production and did not cause activation of the UPR in dHL60 cells. PMA, a pharmacologic NADPH oxidase activator, induced ER stress in dHL60 cells as monitored by IRE-1 and PERK pathway activation, and this was independent of calcium signaling. The NADPH oxidase inhibitor, DPI, abolished both ROS production and UPR activation. These results show that ROS produced by NADPH oxidase induces ER stress and suggests a close association between the redox state of the cell and the activation of the UPR in neutrophil-like HL60 cells.

Nanoscale particles have become promising materials in many fields, such as cancer therapeutics, diagnosis, imaging, drug delivery, catalysis, as well as biosensors. In order to stimulate and facilitate these applications, there is an urgent need for the understanding of the interaction mode between the nano-particles and proteins. In this study, we investigate the orientation and adsorption between several enzymes (cytochrome c, RNase A, lysozyme) and 4 nm/11 nm silica nanoparticles (SNPs) by using molecular dynamics (MD) simulation. Our results show that three enzymes are adsorbed onto the surfaces of both 4 nm and 11 nm SNPs during our MD simulations and the small SNPs induce greater structural stabilization. The active site of cytochrome c is far away from the surface of 4 nm SNPs, while it is adsorbed onto the surface of 11 nm SNPs. We also explore the influences of different groups (-OH, -COOH, -NH2 and CH3) coated onto silica nanoparticles, which show significantly different impacts. Our molecular dynamics results indicate the selective interaction between silicon nanoparticles and enzymes, which is consistent with experimental results. Our study provides useful guides for designing/modifying nanomaterials to interact with proteins for their bio-applications.