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Background Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. Methods CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. Results We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. Conclusions CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/β-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.

Backgrounds:. Physical activity (PA) and sedentary behavior (SB) have been associated with mortality, while the joint association with mortality is rarely reported among Chinese population. We aimed to examine the independent and joint association of PA and SB with all-cause mortality in southern China. Methods:. A cohort of 12,608 China Hypertension Survey participants aged ≥35 years were enrolled in 2013 to 2014, with a follow-up period of 5.4 years. Baseline self-reported PA and SB were collected via the questionnaire. Kaplan–Meier curves (log-rank test) and Cox proportional hazards regression were performed to evaluate the associations of PA and SB on all-cause mortality. Results:. A total of 11,744 eligible participants were included in the analysis. Over an average of 5.4 years of follow-up, 796 deaths occurred. The risk of all-cause mortality was lower among participants with high PA than those with low to moderate level (5.2% vs. 8.9%; hazards ratio [HR]: 0.75, 95% confidence interval [CI]: 0.61–0.87). Participants with SB ≥ 6 h had a higher risk of all-cause mortality than those with SB

Amyloid-β (Aβ) accumulating is considered as a causative factor for formation of senile plaque in Alzheimer’s disease (AD), but its mechanism is still elusive. The Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), a key redox cofactor for energy metabolism, is reduced in AD. Accumulative evidence has shown that the decrease of α-secretase activity, a disintegrin and metalloprotease domain 10 (ADAM10), is responsible for the increase of Aβ productions in AD patient’s brain. Here, we observe that the activity of α-secretase ADAM10 and levels of Nmnat2 are significantly decreased, meanwhile there is a simultaneous elevation of Aβ in Tg2576 mice. Over-expression of Nmnat2 increases the mRNA expression of α-secretase ADAM10 and its activity and inhibits Aβ production in N2a/APPswe cells, which can be abolished by Compound C, an AMPK antagonist, suggesting that AMPK is involved in over-expression of Nmnat2 against Aβ production. The further assays demonstrate that Nmnat2 activates AMPK by up-regulating the ratio of NAD+/NADH, moreover AMPK agonist AICAR can also increase ADAM10 activity and reduces Aβ1-40/1-42. Taken together, Nmnat2 suppresses Aβ production and up-regulates ADAM10 in AMPK activity-dependent manner, suggesting that Nmnat2 may serve as a new potential target in arresting AD.

Estradiol (E2) is involved in the regulation of emotional behavior, cognitive function, and neuroplasticity. However, peripheral E2 and central E2 levels do not always fluctuate together. The relationships of peripheral and central E2 with cognitive function are not clear. The aim of this study was to investigate whether peripheral E2, hippocampal E2, or both play a critical role in novel object recognition (NOR), and whether Kalirin-7, an important regulator of spine plasticity, is involved in the modulation of E2 on cognitive behavior. Our results showed that ovariectomy (OVX) significantly reduced serum E2 levels in the 14 weeks following the procedure. However, hippocampal E2 levels did not decrease in the OVX group compared to the sham group until after 14 weeks. Consistent with the changes in hippocampal E2 levels, the investigation ratio in the NOR test and hippocampal Kalirin-7 expression was also not lower in the OVX group than in the sham group until 14 weeks after the procedure. To confirm the relationship between hippocampal E2 levels and NOR ability, we inhibited the production of hippocampal E2 via microinjection of letrozole (LTZ; an aromatase inhibitor) into the hippocampi of rats in the control group and 8-week OVX group. The data indicated that a reduction in E2 levels in the hippocampus significantly impaired NOR ability and simultaneously decreased Kalirin-7 levels in the hippocampus. In conclusion, our study strongly demonstrates that hippocampal E2, but not peripheral E2, plays a critical role in NOR ability and that Kalirin-7 may be involved in this mechanism. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background The accuracy of estimating microvascular invasion (MVI) preoperatively in hepatocellular carcinoma (HCC) by clinical observers is low. Most recent studies constructed MVI predictive models utilizing radiological and/or radiomics features extracted from computed tomography (CT) images. These methods, however, rely heavily on human experiences and require manual tumor contouring. We developed a deep learning-based framework for preoperative MVI prediction by using CT images of arterial phase (AP) with simple tumor labeling and without the need of manual feature extraction. The model was further validated on CT images that were originally scanned at multiple different hospitals. Methods CT images of AP were acquired for 309 patients from China Medical University Hospital (CMUH). Images of 164 patients, who took their CT scanning at 54 different hospitals but were referred to CMUH, were also collected. Deep learning (ResNet-18) and machine learning (support vector machine) models were constructed with AP images and/or patients’ clinical factors (CFs), and their performance was compared systematically. All models were independently evaluated on two patient cohorts: validation set (within CMUH) and external set (other hospitals). Subsequently, explainability of the best model was visualized using gradient-weighted class activation map (Grad-CAM). Results The ResNet-18 model built with AP images and patients’ clinical factors was superior than other models achieving a highest AUC of 0.845. When evaluating on the external set, the model produced an AUC of 0.777, approaching its performance on the validation set. Model interpretation with Grad-CAM revealed that MVI relevant imaging features on CT images were captured and learned by the ResNet-18 model. Conclusions This framework provide evidence showing the generalizability and robustness of ResNet-18 in predicting MVI using CT images of AP scanned at multiple different hospitals. Attention heatmaps obtained from model explainability further confirmed that ResNet-18 focused on imaging features on CT overlapping with the conditions used by radiologists to estimate MVI clinically.

Naive T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy. Infections induce activation of naive T cells for protective immunity, but insights for this host-pathogen crosstalk are still missing. Here the authors show that infection-induced type I interferon (IFN-I) signaling promote the differentiation, expansion and functional maturation of naive CD8 T cells, particularly for low affinity clones, to enhance anti-microbial immunity.

Purpose: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM. Patients and Methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety. Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred. Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Background The lesion of primary gastric non-Hodgkin’s lymphoma (PGL) originates from the submucosa, so conventional gastroscopy has limited diagnostic potential. This study evaluated the diagnosis and follow-up value of endoscopic ultrasonography (EUS) in PGL. Methods Seventy-nine patients diagnosed with PGL either by EUS and biopsy pathology or by postoperative pathology were included in the study. All subjects underwent EUS with deep targeted biopsy and regular follow-up. Results We found sensitivity and specificity of EUS combined with deep targeted biopsy for PGL as 87.3% (69/79) and 80.0% (20/25) respectively, and the diagnostic accuracy as 85.6% (89/104). EUS combined with deep targeted biopsy had significantly greater diagnostic accuracy than gastroscopy [85.6% (89/104) vs. 57.7% (60/104); (P

COVID-19 has shown that a highly specific and rapid diagnostic system is a necessity. A spectral imaging-based surface plasmon resonance (SPRi) platform with an integrated microfluidic biosensor to detect oligonucleotide sequences has been proposed to be a promising alternative for infectious diseases due to its safe and straightforward use. Approaches to reduce the DNA probe loading onto gold nanoparticles with various types of polyethylene glycol (PEG) were explored. Here, we demonstrated the stability of functionalised gold nanoparticles with unmodified PEG whilst lowering the probe loading density. The system was evaluated by performing the detection of a mimicking COVID-19 target sequence, single point-mutation sequence and fully mismatch sequence. Highly specific binding of the mimicking COVID-19 target sequence was observed and analysed by the spectral imaging SPR approach. Our work has demonstrated the potential of a controlled probe density using unmodified PEG as an especially promising functionalisation strategy in SPR spectral imaging assays.

The effects of primary tumor location on colorectal liver metastasis (CRLM) and post-hepatic-metastasectomy overall survival (OS) are controversial. This study evaluated the difference in post-hepatic-metastasectomy OS among right-sided colon, left-sided colon, and rectal cancer groups. In total, 381 patients who underwent curative-intent CRLM resection were enrolled. Patients were grouped based on the primary tumor location (right-sided, left-sided, and rectum). The Kaplan–Meier analysis and log-rank test were performed for survival analysis. The univariate and multivariate analyses of clinical and pathological factors were performed using the Cox proportional hazards model. Significant OS difference was noted among the three groups (log-rank, p = 0.014). The multivariate analysis revealed a 32% lower death risk in left-sided colon cancer compared with right-sided colon cancer (hazard ratio [HR] 0.68, p = 0.042), whereas no OS difference was noted between the rectal cancer and right-sided colon cancer groups. The left- versus right-sided OS advantage was noted only in the KRAS wild-type subgroup (HR 0.46, p = 0.002), and a rectal versus right-sided OS disadvantage was noted in the KRAS mutant subgroup (HR 1.78, p = 0.03). The CRLM post-hepatic-metastasectomy OS was superior in left-sided colon cancer than in right-sided colon cancer and was similar in rectal and right-sided colon cancer. The OS difference in different primary tumor locations is dependent on KRAS mutation status, with a decreased left- versus right-sided death risk noted only in KRAS wild-type colon cancer and an increased rectal versus right-sided death risk noted only in KRAS mutant colon cancer.

Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger (P-Rex) proteins control many fundamental cellular functions including cell migration, actin cytoskeletal rearrangement and adhesion in many cancers. However, P-Rex1 expression and its prognostic effect and possible clinical value are not clearly elucidated in human oral squamous cell carcinoma (OSCC). Here, OSCC tissue microarrays were used to verify the expression levels of P-Rex1, coinhibitory immune checkpoints and tumor associated macrophage (TAM) markers, and to analyze the relationship between PREX1 expression levels and clinicopathological characteristics in OSCC. The study found that P-Rex1 expression was elevated in OSCC compared to dysplasia and normal mucosa (P

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

Gastric stump (&ldquo, remnant&rdquo, ) cancer is the development of a malignancy related to previous gastric surgery. Prognosis in gastric stump cancer, compared with that in primary gastric cancer, is still controversial. From January 1988 to December 2012 at a single medical centre in Taiwan, 105 patients with gastric stump cancer, including 85 with previous peptic ulcer disease and 20 with previous gastric cancer, were analyzed for clinicopathologic characteristics and overall survival (os). The 5-year os rates for patients with gastric stump cancer and with primary gastric cancer were 51.2% and 54.5% respectively (p = 0.035). Analysis of clinicopathologic characteristics indicated that, compared with patients having primary gastric cancer, those with gastric stump cancer had more lymph node metastasis (p < 0.001) and had been diagnosed at a more advanced stage (p = 0.047). Multivariate analysis with os as an endpoint showed that age [p = 0.015, hazard ratio (hr): 2.300, 95% confidence interval (ci): 1.173 to 4.509], tumour size (p = 0.037, hr: 1.700, 95% ci: 1.031 to 2.801), stromal reaction (p = 0.021, hr: 1.802, 95% ci: 1.094 to 2.969), and pathologic N category (p = 0.001, hr: 1.449, 95% ci: 1.161 to 1.807) were independent predictors in gastric stump cancer. The os rates for patients with gastric stump cancer who previously had gastric cancer or peptic ulcer disease were 72.9% and 50.0% respectively (p = 0.019). The Borrmann classification was more superficial (p = 0.005), lymph node metastases were fewer (p = 0.004), and staging was less advanced (p = 0.025) in patients with gastric stump cancer who previously had gastric cancer than in their counterparts who previously had peptic ulcer disease. Survival is poorer in patients with gastric stump cancer who previously had peptic ulcer disease than in those who previously had primary gastric cancer. Patients with gastric stump cancer who previously had gastric cancer and could receive curative gastrectomy tended to have a better prognosis because of a more superficial Borrmann classification. Regular follow-up in patients who have undergone gastric surgery is recommended for the early detection of gastric stump cancer.

Total laparoscopic donor right hepatectomy (TLDRH) for adult living liver donors has been reported by a few experienced centers, but with limited cases, its safety and feasibility remain controversial. We report our experience initiating TLDRH using a stepwise approach to gradually convert laparoscopy-assisted donor right hepatectomy (LADRH) to TLDRH. We retrospectively analyzed the data of 61 LADRHs, 56 conventional open donor right hepatectomies (CODRHs), and 3 TLDRHs performed between March 2014 and June 2018. There were no significant differences in perioperative outcomes between donors undergoing LADRH and CODRH, except for a slight elevations in the operative time (436.5 vs 392.9 min, p

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

Probiotics are known as "live microorganisms" and have been proven to have a health effect on hosts at the proper dose. Recently, a kind of probiotic mixture including eight live bacterial strains, VSL#3, has attracted considerable attention for its combined effect. VSL#3 is the only probiotic considered as a kind of medical food; it mainly participates in the regulation of the intestinal barrier function, including improving tight junction protein function, balancing intestinal microbial composition, regulating immune-related cytokine expression and so on. The objective of this review is to discuss the treatment action and mechanism for the administration of VSL#3 in chronic diseases of animals and humans (including children). We found that VSL#3 has a therapeutic or preventive effect in various systemic diseases per a large number of studies, including digestive systemic diseases (gastrointestinal diseases and hepatic diseases), obesity and diabetes, allergic diseases, nervous systemic diseases, atherosclerosis, bone diseases, and female reproductive systemic diseases.

Background: Currently, the identification of Clara cell and type II alveolar epithelial cell-type cancer cells requires electron microscopy, which is a time-consuming and expensive process involving a complicated tissue sampling procedure. The aim of this study was to identify unique biomarkers for Clara cell and type II alveolar epithelial cell-type lung cancer cells, respectively, with proteomic profiling. Methods: Six human lung adenocarcinoma cell lines (A549, NCI-H358, NCI-H1650, HCC827, NCI-H1395, and NCI-H1975) were investigated for their ultrastructural characteristics. The differentially expressed proteins (DEPs) were screened between NCI-H358 cells (Clara cell type) and A549 cells (type II alveolar epithelial cell type) using two-dimensional difference gel electrophoresis (2D-DIGE) and matrix- assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS/MS), and then they were validated by western blot. The protein expression levels of endoplasmic reticulum oxidoreductin 1-α (ERO1L), Clara cell 10-kD protein (CC10), and surfactant protein C (SP-C) were also determined in the six cell lines assayed. Results: NCI-H358 cells featured Clara cell differentiation; A549, NCI-H1975, and HCC827 cells had characteristics of type II alveolar epithelial cells; and NCI-H1395 and NCI-H1650 cells had no differentiation characteristics of any lung adenocarcinoma cell type. Five DEPs including ubiquitin carboxyl- terminal hydrolase isozyme L1 (UCHL1), cytokeratin 19 (CK19), cytokeratin 8 (CK8), ERO1L, and peroxiredoxin 2 (PRDX2) between NCI-H358 and A549 cells were identified for further validation; however, none of them showed suitability as an effective biomarker. Similarly, CC10 and SP-C were not appropriate biomarkers. Conclusions: Cytological subtypes of NCI-H1975 and HCC827 cells were identified, but no promising biomarker was discovered in the present study.

Background Identifying practical and distinguished indicators and influencing factors of male aging may be useful in predicting subsequent aging trends, designing personalized prevention, and improving lifestyle and health. Methods A cross-sectional, population-based study was performed in Jiashan County, China in 2016. A total of 690 local male residents, aged 40 to 80 years, were eligible for recruitment. Demographic and lifestyle information was collected through structured interviews. A self-designed head scale, the Medical Outcomes Study 36-item Short Form (SF-36), International Index of Erectile Function (IIEF5), Aging Males’ Symptoms (AMS), and International Prostate Symptom Score (IPSS) were used. Analysis of variance, local polynomial regression smoothing curves, multiple linear regression, and partial correlation analyses were performed. Results All the scales deteriorated with increasing age (P P P = 0.03); nutrition modified the relationship between age and SF-36 (P Conclusions Recession of reproductive health may be a distinct predictor of male aging. The associations of social inequalities or personality and health offer potential interventions for men’s health in aging. Self-reported scales may limit the precision and more physical fitness tests could be combined for a more precise assessment.

We report the design and synthesis of a series of three-dimensional (3D) covalent organic frameworks (COFs) as immunogenic cell death (ICD) inducers for cancer immunotherapy. Three triple-topic amine building blocks, inactive to inducing ICD, were used to construct three COFs, COF-607, COF-608, and COF-609, with outstanding ICD eliciting efficiency. Mechanism studies revealed that after linking these ICD inert monomers into the COF backbone, the optical properties of these COFs could be systematically tuned to achieve excellent reactive oxygen species (ROS) production performance. This combined with 3D cross-linked pores, mimicking lung structure, favor the exchange and diffusion of oxygen and ROS, leading to excellent inducing ICD efficacy. One member, COF-609, is capable of triggering abscopal and long-lasting immune memory effects in a mouse model of breast cancer with >95% mice survival after being treated with COF-609+αCD47 for 110 days.

The clinical and molecular characteristics of localized diffuse large B-cell lymphoma (DLBCL) with single nodal (SN) or single extranodal (SE) involvement remain largely elusive in the rituximab era. The clinical data of 181 patients from a retrospective cohort and 108 patients from a phase 3 randomized trial NHL-001 (NCT01852435) were reviewed. Meanwhile, genetic aberrations, gene expression pattern, and tumor immunophenotype profile were revealed by DNA and RNA sequencing of 116 and 53 patients, respectively. SE patients showed similar clinicopathological features as SN patients, except for an increased percentage of low-intermediate risk in the National Comprehensive Cancer Network–International Prognostic Index. According to the molecular features, increased MPEG1 mutations were observed in SN patients, while SE patients were associated with upregulation of TGF-β signaling pathway and downregulation of T-cell receptor signaling pathway. SE patients also presented immunosuppressive status with lower activity of killing of cancer cells and recruiting dendritic cells. Extranodal involvement had no influence on progression-free survival (PFS) or overall survival (OS) in localized DLBCL. Serum lactate dehydrogenase >3 upper limit of normal was an independent adverse prognostic factor for OS, and ATM mutations were related to inferior PFS. Although the overall prognosis is satisfactory, specific clinical, genetic, and microenvironmental factors should be considered for future personalized treatment in localized DLBCL.

Background The incidence of primary intestinal diffuse large B-cell lymphoma (PI-DLBCL) is much lower than primary gastric DLBCL, and large-scale analyses on the clinical characteristics, molecular features, therapeutic strategies, and risk stratification have been seldomly performed in PI-DLBCL. Methods To assess prognostic model development, 107 PI-DLBCL patients diagnosed before 2014 were studied for prognosis factors including different primary involved sites and treatment strategies. For internal validation, a non-random split sample set with 77 PI-DLBCL patients after 2014 was included for validation of the prognosis factors. Results Patients with an ileocecal lesion presented with better survival time than those with non-ileocecal sites, with surgical resection significantly influencing the prognosis. Non-ileocecal patients who underwent surgery with lymphadenectomy had superior overall survival (OS) and progression-free survival (PFS) compared to those receiving surgery without lymphadenectomy or those not receiving (without) surgery. For ileocecal patients, surgery with or without lymphadenectomy resulted in better OS and PFS than those without surgery. For biomarker analysis, only BCL-2 >50% or Ki67 >80% on tumor cells indicated poor clinical outcome. In multivariate analysis, age, Eastern Cooperative Oncology Group (ECOG) score, and site of origin were independent prognostic factors for inferior OS in PI-DLBCL. A prognosis model was set up based on age, ECOG score, and site of origin, and validated well. Conclusions The prognosis in patients with PI-DLBCL with ileocecal involvement showed was better than those with non-ileocecal involvement. Surgical strategy can impact the clinical outcome of PI-DLBCL patients.

Plasmablastic lymphoma (PBL) is a rare and aggressive hematological malignancy. PBL commonly occurs in immune incompetent patients, such as those with human immunodeficiency virus (HIV), post-transplant status, or immunosenescence. Given its rarity, there is no specific standard treatment for PBL. However, small case series have shown that intensive chemotherapies combined with anti-myeloma agents such as bortezomib and lenalidomide were effective in treating PBL. Unfortunately, some fragile patients could not tolerate intensive chemotherapeutic regimens, especially the elderly patients. Here we presented a 76-year-old female PBL patient refractory to miniCHOP regimen combined with bortezomib but achieved complete remission when treated with tislelizumab combined with lenalidomide, indicating that immune therapy may be a potential treatment for PBL. To our knowledge, this is the first chemoresistant PBL patient that has been successfully treated with checkpoint inhibitor plus lenalidomide, thus providing new insight towards PBL management.

D2 receptors (D2Rs) located in both pre- and postsynaptic membranes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) are involved in the stress response and associated behaviors. The role of D2Rs in chronic unpredictable stress (CUS)-induced depression-like behaviors is not clear. Quinpirole (a D2R agonist) and eticlopride (a D2R antagonist) were stereotactically delivered into the NAc before Sprague Dawley rats underwent CUS. CUS-induced depression-like behaviors were accompanied by a significant decrease in both the dopamine (DA) level and D2R expression in the NAc. Eticlopride reversed CUS-induced depression-like behavior and rescued the DA levels in the NAc, and microinjection of DA into the NAc of CUS individuals had the same effect as eticlopride. By contrast, delivery of quinpirole into the NAc of control animals induced depression-like behaviors accompanied by a decrease in the DA level in the NAc. These results show that DA plays a key role in CUS-induced depression-like behaviors and the D2R exerts a presynaptic negative feedback on DA levels during CUS. Microinjection of quinpirole into the NAc also decreased the level of the kalirin-7 protein in the NAc of both control and stressed animals, while eticlopride increased its level in the NAc of rats. In agreement with these results, intraperitoneal injection of eticlopride in mice also caused an increase in both the kalirin-7 protein level in the NAc and spine density in MSNs, while quinpirole reduced them. These results suggest that regulation of kalirin-7 through D2R in the NAc is a general pathway in rats and mice, and is involved in CUS-induced depression-like behaviors. Kalirin-7 may be directly regulated through the D2R postsynaptic pathway or indirectly through the presynaptic pathway in the NAc. The interaction between D2R and kalirin-7 needs to be investigated further.

OBJECTIVES The purpose of this study was to develop a deep-learning framework for the diagnosis of chronic otitis media (COM) based on temporal bone computed tomography (CT) scans. DESIGN A total of 562 COM patients with 672 temporal bone CT scans of both ears were included. The final dataset consisted of 1147 ears, and each of them was assigned with a ground truth label from one of the 3 conditions: normal, chronic suppurative otitis media, and cholesteatoma. A random selection of 85% dataset (n = 975) was used for training and validation. The framework contained two deep-learning networks with distinct functions: a region proposal network for extracting regions of interest from 2-dimensional CT slices; and a classification network for diagnosis of COM based on the extracted regions. The performance of this framework was evaluated on the remaining 15% dataset (n = 172) and compared with that of 6 clinical experts who read the same CT images only. The panel included 2 otologists, 3 otolaryngologists, and 1 radiologist. RESULTS The area under the receiver operating characteristic curve of the artificial intelligence model in classifying COM versus normal was 0.92, with sensitivity (83.3%) and specificity (91.4%) exceeding the averages of clinical experts (81.1% and 88.8%, respectively). In a 3-class classification task, this network had higher overall accuracy (76.7% versus 73.8%), higher recall rates in identifying chronic suppurative otitis media (75% versus 70%) and cholesteatoma (76% versus 53%) cases, and superior consistency in duplicated cases (100% versus 81%) compared with clinical experts. CONCLUSIONS This article presented a deep-learning framework that automatically extracted the region of interest from two-dimensional temporal bone CT slices and made diagnosis of COM. The performance of this model was comparable and, in some cases, superior to that of clinical experts. These results implied a promising prospect for clinical application of artificial intelligence in the diagnosis of COM based on CT images.

Background: Deceleration capacity (DC) is a non-invasive marker for cardiac autonomic dysfunction; however, few studies have shown that the influence factors of cardiac autonomic dysfunction and the correlations between DC and stroke risk in paroxysmal atrial fibrillation (AF). We aimed to explore the influencing factors of abnormal DC and the relationships between DC and stroke risk in patients with paroxysmal AF. Methods: The study included hospitalized paroxysmal AF patients with DC measurements derived from 24-h Holter electrocardiography recordings taken between August 2015 and June 2016. Multivariable regression analysis was performed to evaluate the associations between correlated variables and abnormal DC values. The relationship between DC and ischemic stroke risk scores in patients with paroxysmal AF was analyzed. Results: We studied 259 hospitalized patients with paroxysmal AF (143 [55.2%] male, mean age 66.4 ± 12.0 years); 38 patients of them showed abnormal DC values. In the univariate analysis, age, hypertension, heart failure, and previous stroke/transient ischemic attack (TIA) were significantly associated with abnormal DC values. Among these factors, a history of previous stroke/TIA (odds ratio = 2.861, 95% confidence interval: 1.356–6.039) were independently associated with abnormal DC values in patients with paroxysmal AF. The abnormal DC group showed a higher stroke risk with the score of congestive heart failure, hypertension, age >75 years, diabetes mellitus, previous stroke and TIA (CHADS2) (2.25 ± 1.48 vs. 1.40 ± 1.34, t = -4.907, P = 0.001) and CHA2DS2-vascular disease, age 65–74 years and female category (VASc) (3.76 ± 1.95 vs. 2.71 ± 1.87, t = -4.847, P = 0.001) scores. Correlation analysis showed that DC was negatively correlated with CHADS2 scores (r = -0.290, P 0.001). Conclusions: Lower DC is closely associated with previous stroke/TIA, and is also correlated negatively with higher stroke risk scores in patients with paroxysmal AF. It could be a potential indicator of stroke risk in paroxysmal AF patients. Key words: Deceleration capacity; Atrial fibrillation; Stroke; Cardiac autonomic

Significance The advent of high-speed atomic force microscopy (HS-AFM) changed the field of biology considerably. HS-AFM is the only method where in situ dynamics of biological samples and imaging can be coupled with a spatial resolution of 1 to 5 nm in the horizontal direction. Unlike electron or cryo-electron microscopy, HS-AFM does not require fixation or freezing of the samples, and has the ability to derive kinetic parameters by recording the live movements of single-molecule dynamics. In this paper, we used HS-AFM to investigate directly the mechanisms of cardiac muscle activation. We visualized the muscle regulatory tropomyosin–troponin complex movements during activation by calcium or myosin (motor that drives contraction), and the structural transitions that happen during these events., High-speed atomic force microscopy (HS-AFM) can be used to study dynamic processes with real-time imaging of molecules within 1- to 5-nm spatial resolution. In the current study, we evaluated the 3-state model of activation of cardiac thin filaments (cTFs) isolated as a complex and deposited on a mica-supported lipid bilayer. We studied this complex for dynamic conformational changes 1) at low and high [Ca2+] (pCa 9.0 and 4.5), and 2) upon myosin binding to the cTF in the nucleotide-free state or in the presence of ATP. HS-AFM was used to directly visualize the tropomyosin–troponin complex and Ca2+-induced tropomyosin movements accompanied by structural transitions of actin monomers within cTFs. Our data show that cTFs at relaxing or activating conditions are not ultimately in a blocked or activated state, respectively, but rather the combination of states with a prevalence that is dependent on the [Ca2+] and the presence of weakly or strongly bound myosin. The weakly and strongly bound myosin induce similar changes in the structure of cTFs as confirmed by the local dynamical displacement of individual tropomyosin strands in the center of a regulatory unit of cTF at the relaxed and activation conditions. The displacement of tropomyosin at the relaxed conditions had never been visualized directly and explains the ability of myosin binding to TF at the relaxed conditions. Based on the ratios of nonactivated and activated segments within cTFs, we proposed a mechanism of tropomyosin switching from different states that includes both weakly and strongly bound myosin.

Summary Background Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. Methods In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology–Oncology Programs Evaluation System in China. Young patients (16–60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61–80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1–5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01852435 . Findings From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6–77·6) and in the R-CEOP70 group was 72·4% ([66·5–77·5]; HR 1·00 [0·73–1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1–93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7–82·3]; 0·44 [0·25–0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4–83·7%]; 0·49 [0·27–0·86]; p=0·017). Grade 3–4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. Interpretation R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. Funding National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

Summary Background Abdominal ascites is a common problem in general surgery. The causes include parasitic diseases, tuberculosis, malignancies, hypoalbuminemia, abdominal inflammatory diseases, and peritonitis. Eosinophilic gastroenteritis (EG) has also been reported to be an infrequent cause. To our knowledge, most instances of abdominal ascites from EG have occurred in adults and been reported by physicians or gastroenterologists. Herein, we report a small series of children who presented with eosinophilic ascites from a surgeon’s perspective. Methods Five children with EG (male: 3; female: 2) were selected for review of medical data and diagnostic reports. Results The patients typically presented with intermittent abdominal pain (n = 5), diarrhea and nausea (n = 2), abdominal distension (n = 2), fever (n = 2), and histories of allergic disease (n = 3). Peripheral eosinophilia was regularly noted, three children showing elevated IgE levels. Abdominal ultrasound and CT performed in each instance demonstrated abdominal ascites. Surgical intervention was elected in two patients. Dietary control and a methylprednisolone regimen were then instituted in all children, followed by full clinical remissions. After a regular follow-up, all patients are doing well. Conclusions Surgeons should be aware of EG as a rare cause of ascites, even in a pediatric population and especially in children with strong histories of allergic diseases, peripheral blood eosinophilia, and/or family histories of EG. It is important to avoid unnecessary surgical intervention, because dietary control and methylprednisolone treatment are effective remedies.

Background This study aimed to investigate the association of pre-treatment inflammatory status with survival time and to develop a prognostic nomogram incorporating inflammatory cytokines in non-Hodgkin's lymphoma. Methods A total of 228 patients with diffuse large B-cell lymphoma (DLBCL) received R-CHOP-based regimens from a prospective randomized study (NCT01852435) were included as a training cohort. Other cohorts of 886 lymphoma patients were served as validation cohorts. Lymphocyte-monocyte ratio (LMR), serum levels of soluble interleukin s(IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α), were assessed before treatment. Least absolute shrinkage and selection operator (LASSO) regression were used to select variables for nomogram of overall survival (OS). The predictive accuracy of the nomogram was determined by concordance index (C-index). Findings The nomogram included lactate dehydrogenase (LDH), sIL-2R, TNF-α and decreased LMR. The C-index of the nomogram for OS prediction were range from 0.61 to 0.86 for training cohort of DLBCL and validation cohorts of DLBCL, PTCL, NKTCL and ASCT, which were superior to the predictive power of International Prognostic Index (IPI, 0.67 to 0.84) or NCCN-IPI (0.59 to 0.78), but not in those of indolent lymphoma like FL and MALT. Interpretations The nomogram incorporating inflammatory cytokines provides a useful tool for risk stratification in aggressive non-Hodgkin's lymphomas. Fund National Natural Science Foundation of China, the Shanghai Commission of Science and Technology, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of SHDC, and Chang Jiang Scholars Program.

Background The mechanical work and the actin-activated ATP kinetics in skeletal muscles are closely associated with two surface loops that are present in the myosin molecule: loop 1 and loop 2. They are located close to the ATP-loop (loop 1), and the actin binding domain (loop 2). In this study we investigated the roles of loops 1 and 2 in the regulation of the load-dependent velocity of actin sliding and ATPase activity. Methods Heavy meromyosin (HMM) from rabbit skeletal muscle was subjected to limited tryptic proteolysis to obtain fragments containing different amounts of loops 1 and 2. The amino-acid sequences of these fragments were confirmed with quantitative mass-spectrometry. The velocity of actin motility propelled by the HMM fragments was measured using in-vitro motility assays, with varying loads induced by the addition of different concentrations of α-actinin. Results The load-dependent velocity of the myosin-propelled actin motility, and the fraction of actin filaments motility, were decreased in close association with the depletion of loop 1 in the HMM. The ATPase activity was decreased in close association with depletion of loops 1 and 2. Conclusions Loop 1 is responsible for regulating the load-dependent velocity of actin motility. General significance Myosin-actin interaction is closely regulated by two flexible loops in the structure of myosin. The results of this study are important for the understanding of the molecular mechanisms of contraction, and therefore the most basic functions of life, such as locomotion, heart beating, and breathing.

Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigeneses, especially nasopharyngeal carcinoma (NPC). In present study, we aim to investigate the role of LINC00319 in the NPC carcinogenesis. It was indicated that LINC00319 was markedly increased in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00319 indicated the poor prognosis of NPC patients. Silence of LINC00319 was able to suppress NPC cell growth in vitro while overexpression of LINC00319 inversed this process. Moreover, in vivo tumor xenografts were established using CNE-1/SUNE-1 cells to investigate the function of LINC00319 in NSCLC tumorigenesis. Rescue assay was performed to further confirm that LINC00319 contributed to NPC progression by regulating miR-1207-5p/KLF12 signal pathway. Taken together, our study discovered the oncogenic role of LINC00319 in clinical specimens and cellular experiments, showing the potential LINC00319/miR-1207-5p/KLF12 pathway. This results and findings provide a novel insight for NPC tumorigenesis.

Glioblastoma (GBM) is the most common malignant tumor originating in the brain parenchyma. The invasive and infiltrative properties of glioblastoma result in poor clinical prognosis to conventional therapies. Emerging reports on microRNAs as important regulators during the process of EMT provide new insights into treating glioblastoma through new targets. However, underlying molecular mechanism of the regulation of miR-101-3p in glioblastoma remains unclear. Level of miR-101-3p was determined in GBM cell lines by qRT-PCR. MTT, colony formation and transwell assays were utilized to evaluate functions of overexpression of miR-101-3p/knock down of TRIM44 on proliferation, migration and invasion in GBM cells. Direct interaction between miR-101-3p and TRIM44 was validated using dual luciferase reporter system and impacts of overexpression of miR-101-3p/knock down of TRIM44 on regulation of EMT markers were assessed by Western blotting. MiR-101-3p was validated to be repressed expressed in glioblastoma cancer cell lines. Both overexpression of miR-101-3p and knock down of TRIM44 attenuated proliferation, migration and invasion of glioblastoma cell lines in vitro. TRIM44 was shown to promote EMT in GBM progress and reverse inhibitory function of miR-101-3p. MiR-101-3p was found to suppress the expression of TRIM44 via directly targeting its 3′UTR. Our findings suggested miR-101-3p regulated proliferation and migration of glioblastoma cells through attenuating TRIM44 induced EMT via direct targeting 3′UTR of TRIM44, which provided preliminary study of potential therapeutic target in future GBM treatment.

Background: Follicular lymphoma (FL) is a malignancy of lymphocytes derived from germinal center (GC). Hepatitis B virus (HBV) infection may increase the incidence of FL. Here, we performed an integrated genomic and transcriptomic analysis to identify molecular characteristics and therapeutic targets for HBV-associated FL.Methods: A total of 253 patients with newly diagnosed FL were enrolled. Whole-genome sequencing (n=13) and whole-exome sequencing (n=87) were performed on tumor samples of 100 patients. Among them, 84 patients were available for transcriptomic sequencing data. Moreover, biological function of immune modulator TNFAIP3 mutation was investigated in vitro using FL cell line SC-1 and in vivo using zebrafish xenograft model.Results: By characterizing altogether 253 FL patients, we showed that patients with HBV infection (surface antigen positive, HBsAg+) were significantly associated with younger age, more frequent spleen involvement, advanced histological grade, higher proliferation index, and poorer progression-free survival. By whole-genome/exome and targeted sequencing, we observed increased mutations in immune modulators (TNFAIP3, CD70, CXCR4, PIM1, KLF2, FAS, CD58, and CD83), decreased mutations in epigenetic modifiers (KMT2D and CREBBP), and low incidence of BCL2 translocation as the core oncogenic program of HBsAg+ FL. By transcriptomic sequencing, we further showed that HBsAg+ FL was enriched by immune-related pathways, antigen processing and presentation and IFN signatures, as well as inflamed signatures and infiltration of CD8+T and Th1 cells, with malignant lymphocytes transiting to post-GC phenotype. In the co-culture system of FL cell line SC-1 with peripheral blood mononuclear cells mimicking in vivo situation, TNFAIP3 mutations induced overexpression of TIGIT on CD8+T cells and VISTA on Th1 cells, both of which were downregulated by lenalidomide, resulting in sensitivity of TNFAIP3-mutant cells to lenalidomide treatment in co-culture system and in zebrafish xenograft model. Of note, negative prognostic impact of HBV infection on patients treated with rituximab-based immunochemotherapy could be overcome by rituximab and lenalidomide.Conclusions: HBV-associated FL may be considered as a specific subtype, based on distinct immune modulator mutations, and CD8+T- and Th1-enriched post-GC phenotype. Moreover, these findings provided new insights into the pathogenetic role of HBV in FL and the potential benefit of immunomodulatory agents in treating HBV-associated FL.

Constipation is the most common complaint in childhood, affecting an estimated 20% of children globally (1). The treatment strategies of childhood constipation consist of diet control, behavioral intervention, and oral laxatives (2,3). Given its higher success rate and fewer side effects, the laxative PEG3350 has been considered the first choice (4). However, the effectiveness of PEG3350 laxative does not last, or it does not work after long-term use (5). Therefore, additional treatment interventions are necessary. With an unsatisfactory response to current treatments, many patients seek help from Chinese Herbal Medicine (CHM) (6). For thousands of years, CHM has been the main medical method in China (7,8). Traditional CHM theory holds that the transit of the digestive system depends on Qi. Although the cause of constipation originates from the colon and intestine, it is closely related to the function of the spleen and stomach. Functional weakness in the spleen and stomach leads to food and Qi stagnation. Food stagnation slows gastrointestinal motility, and Qi stagnation disturbs the tone of the stomach and descending movement of the intestine. Food and Qi stagnation further cause heat accumulation in the large intestine, and the pathological heat causes constipation by drying the intestine (7–9). In children, both spleen and stomach functions are very vulnerable because they are still in growth and development. The substantial function has not yet been fully established, and functional weakness of the spleen and stomach is in fact a physiological characteristic. On the other hand, childhood constipation is generally considered as a continuation of infant constipation because most of the childhood constipation has been reported to appear at the onset of babies and infants, although the pathophysiological basis is multifactorial (10). In babies and infants, solid feeding is introduced and the eating behavior coverts from swallowing to chewing. Because breastfeeding contributes to acceptance of a novel dietary and solid feeding introduction, it has been recommended in many guidelines and practices (11–13). However, many mothers would rather formula milk than breast milk; an improper formula-fed duration might increase the risk of eating disorders (12,13). The quantity, quality, and time of food introduction can all place a heavy burden on the baby's digestive system causing food and Qi stagnation (14). Therefore, a physiological weakness of the spleen and stomach in children and a long duration of improper feeding style from the onset of babies and infants are the main sources of childhood constipation; the principles of treatment must pay attention to these pathophysiological bases accordingly. In the documented traditional medicine dictionary (Pi Wei Lun), the prescription XiaojiDaozhi Decoction has been well described. The prescription consists of 12 kinds of CHMs. Through the combined action of these CHMs, XiaojiDaozhi Decoction can wake up gastric and Qi function, eliminate food stagnation, and remove pathological heat accumulation. In the modern medicine, XiaojiDaozhi Decoction has been proven to contain components beneficial to gastrointestinal peristalsis. Pharmacological studies have shown that Fructus Aurantii can alleviate small intestinal spasms (15). Accumulated solid or accumulated shell can increase the rhythm of gastrointestinal contraction (16). Rhubarb mainly contains onion-brewed derivatives, such as emodin formic acid glucoside, rhein-8-glucoside, and a variety of sennosides (17). Cannabis seeds were found to interact with alkaline intestinal liquid to produce fatty acids in the intestine, which stimulated the intestinal wall and enhanced intestinal peristalsis (18). Consequently, the effects of XiaojiDaozhi Decoction may be related to the promotion of bowel motility and digestive secretion, and it can be used in the treatment of constipation. Concerning the pathophysiological basis of childhood constipation and the pharmacological effects, XiaojiDaozhi Decoction was considered for the treatment of childhood constipation, holding the principle of promoting Qi movement, relieving Qi stagnation, and removing pathological heat accumulation (19). However, there is still a lack of evidence-based support for the treatment of childhood constipation by XiaojiDaozhi Decoction. Therefore, we designed a randomized, controlled, double-blind clinical trial to confirm the efficacy and safety of XiaojiDaozhi Decoction in the treatment of childhood constipation.