Objective: To investigate the effects of "liver-smoothing and spirit-regulating" acupuncture on the intestinal flora, lipopolysaccharide (LPS) and the hippocampal toll-like receptor 4 (TLR4)/ transcription factor (NF)-κB signaling pathway in depressive disorder mouse model, and to explore its underlying mechanisms. Methods: Eighteen male SPF-grade C57BL/6J mice were randomly assigned to the control, model, and acupuncture groups using a random number method, with six mice in each group. The depression disorder model was induced in mice from both the acupuncture and model groups using CUMS. The mice in the acupuncture group were treated with acupuncture at the acupoints of "Baihui" (DU20), "Yintang" (DU29), "Hegu" (LI4), and "Taichong" (LR3) on the 15th day of modeling, with a duration of 20 min per session, once per day, for 2 consecutive weeks. Behavioral differences were assessed using the sucrose preference test, open field test, and forced swim test. Hematoxylin-eosin staining was used to observe pathological changes in the hippocampus and colon. The levels of the inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and LPS in the hippocampus and colon were measured using Enzyme-linked Immunosorbent Assay. Western blotting was used to detect the expression of TLR4 and NF-κB protein in the hippocampus. Changes in gut microbiota structure and abundance were analyzed by 16 S rDNA sequencing. Results: Compared to the control group, the model group showed reduced sucrose preference rate, time in the center area, and total distance, with an increase in immobility time (P<0.01). Inflammatory pathological changes were observed in the hippocampal CA1 region and colon. The contents of IL-1β, IL-6, TNF-α, and LPS in the hippocampus and colon increased (P<0.01). The protein expression levels of hippocampal TLR4 and NF-κB were increased (P<0.01). The Chao1 index was increased (P<0.01). The relative abundances of Pseudomonadales, Acinetobacter, Moraxellaceae, Solibacillus, Escherichia_shigella, Enterobacteriaceae, Enterobacterales, Dubosiella, and Erysipelottichales were decreased, while the relative abundances of Alloprevotella and gram_negative_bacteriurh_cTPY_13 were increased (P<0.05). The pathways of lipopolysaccharide biosynthesis and pathogenic Escherichia coli infection were upregulated, and the pathway of terpenoid backbone biosynthesis was downregulated (P<0.01). Compared to the model group, the acupuncture group showed increased sucrose preference, time in the center area, and total distance, with a decrease in immobility time (P<0.01). The inflammatory pathological changes in the hippocampal CA1 region and colon were alleviated. The contents of IL-1β, IL-6, TNF-α, and LPS in the hippocampus and colon were reduced(P<0.01). The protein expression levels of hippocampal TLR4 and NF-κB were reduced (P<0.01). The Chao1 index was decreased (P<0.05), and the relative abundances of Dubosiella and Erysipelotrichaceae were increased, while the relative abundance of Rikenellaceae, Alloprevotella, and gram_negative_bacteriuch_cTPY_13 were decreased(P<0.05). The pathways of lipopolysaccharide biosynthesis and pathogenic Escherichia coli infection were significantly downregulated, and the pathway of terpenoid backbone biosynthesis was upregulated (P<0.01). Conclusion " Liver-smoothing and spirit-regulating" acupuncture can improve depressive symptoms in depressive disorder mice, potentially through regulating the LPS and TLR4/NF-κB signaling pathway mediated by intestinal flora, reducing the inflammatory response of the hippocampus, and improving the pathological injury of the hippocampus.

Objective To investigate the relationship between the central foveal thickness(CFT),ellipsoid zone(EZ)interruption ratio and best corrected visual acuity(BCVA)in patients with idiopathic epiretinal membranes(iERM).Methods A retrospective case-control study was conducted.The cluster sampling method was used to select 336 iERM patients(500 eyes)who underwent physical examinations in 9 community hospitals of the Kailuan Group from 2014 to 2018.Among them,215 were male(64.0％)and 121 were female(36.0％),with an average age of 31-89(66.4±8.8)years.According to the gass classification,these patients were divided into three groups:gass 0 group(201 patients,305 eyes),gass 1 group(75 patients,101 eyes),and gass 2 group(60 patients,94 eyes).Pearson correlation analysis was used to evaluate the correlation between BCVA(converted to logMAR visual acuity)and gass classification,EZ interruption ratio,CFT.Results The average BCVA(logMAR)and CFT of 500 eyes were 0.45±0.28 and(337.6±101.8)μm,re-spectively,with EZ interruption in 86 eyes(17.2％).There were statistically significant differences in BCVA(logMAR)(0.62±0.29,0.48±0.23,0.26±0.32),CFT[(283.20±79.30)μm,(335.50±84.50)μm,(394.00±135.60)μm],and EZ interruption ratio(2.6％,20.8％,60.6％)among gass 0,gass 1 and gass 2 groups(all P＜0.05).Pearson correlation analysis showed that there was no correlation between age and BCVA among different groups(r2=0.021,P=0.314);BCVA was positively correlated with CFT(r2=0.531,P=0.000),EZ interruption ratio(r2=0.304,P=0.000),and gass classification(r2=0.587,P=0.000).Conclusion The EZ interruption may occur in the early stage of iERM.BCVA is correlated with CFT,EZ interruption ratio and gass classification;the incidence of EZ interruption in gass 2 iERM signifi-cantly increases.

Objective:To evaluate the value of ultra-widefield scanning laser ophthalmoscopy (UWFSLO) for screening diabetic retinopathy (DR).Methods:A cross-sectional study was conducted.A total of 1 288 patients (2 304 eyes) with type 2 diabetes who underwent the screening of DR were selected in Kailuan Rehabilitation Hospital in Tangshan City, Hebei Province from October 2016 to December 2016.The general information and medical records were collected.Patients completed fundus inspection by both UWFSLO and two-field 45° horizontal digital color fundus photography.The effective retinal images of the two methods were analyzed and the detection and grading of DR were compared between the two methods.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Kailuan (Group) Co., Ltd.Hospital (No.2006-5).Written informed consent was obtained from each subject.Results:After excluding the unclear and missing images, 1 857 eyes were finally included in this study.The detection rates of DR by color fundus photo, UWFSLO pseudocolor image and green channel image were 31.3%(581/1 857), 44.5%(826/1 857), and 43.4%(807/1 857), respectively, with a statistically significant difference ( χ2=85.547, P<0.001).The detection rates of DR by UWFSLO pseudocolor image and green channel image were higher than that by color fundus photo, and the differences were statistically significant (both at P<0.001).The agreement between UWFSLO and two-field 45° horizontal digital color fundus photography for grading DR severity was moderate with a Kappa value of 0.375 ( P<0.001) and a complete agreement of 64.08%.The UWFSLO green channel image and pseudocolor images had excellent consistency for grading DR severity with a Kappa value of 0.953( P=0.008) and complete agreement of 98.17%.The detection rates of microaneurysm (MA), intraretinal microvascular abnormalitie (IRMA) and neovascularization (NV) by UWFSLO pseudocolor images were lower than that by green channel images, showing statistically significant differences ( Z=-16.489, -4.198, -2.111; all at P<0.05). Conclusions:UWFSLO has better detection and grading of DR than two-field 45° horizontal digital color fundus photography, and green channel images are better at detecting MA, IRMA, and small NV lesions.UWFSLO has good application value in the screening and diagnosis of DR in large populations.

Polygala tenuifolia,commonly known as Yuanzhi(YZ)in Chinese,has been shown to possess anti-insomnia properties.However,the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear.Herein,we investigated the active components and neurochemical mechanism of YZ extracts using liquid chromatography tandem mass spectrometry(LC-MS/MS)-based pharmaco-metabolomics and mass spectrometry imaging(MSI)-based spatial resolved metabolomics.According to the results,17 prototypes out of 101 ingredients in the YZ extract were detected in both the plasma and brain,which might be the major components contributing to the sedative-hypnotic effects.Network pharmacology analysis revealed that these prototypes may exert their effects through neuroactive ligand-receptor interaction,serotonergic synapse,dopaminergic synapse,and dopaminergic synapse,among other pathways.LC-MS/MS-based targeted metabolomics and Western blot(WB)revealed that tryptophan-serotonin-melatonin(Trp-5-HT-Mel)and tyrosine-norepinephrine-adrenaline(Tyr-Ne-Ad)are the key regulated pathways.Dopa decarboxylase(DDC)upregulation and phenylethanolamine N-methyltransferase(PNMT)downregulation further confirmed these pathways.Furthermore,MSI-based spatially resolved metabolomics revealed notable alterations in 5-HT in the pineal gland(PG),and Ad in the brainstem,including the middle brain(MB),pons(PN),and hypothalamus(HY).In summary,this study illustrates the efficacy of an integrated multidimensional metabolomics approach in unraveling the sedative-hypnotic effects and neurochemical mechanisms of a Chinese herbal medicine,YZ.

Objective:To investigate the clinical features of primary intestinal lymphangiectasia (PIL).Methods:This study was a retrospective case series study. Fifty consecutive patients diagnosed with PIL in Department of Lymphatic Surgery, Beijing Shijitan Hospital, Capital Medical University from March 2019 to March 2021 were included and their clinical data was retrospectively reviewed. There were 20 males and 30 females included, with an age of ( M(IQR)) 14 (40) years (range:0 to 67 years). No patient had the family history. There were 26 children, including 9 males and 17 females, aged 0 (7) years (range:0 to 14 years). There were 24 adults, including 11 males and 13 females, aged 40 (26) years (range:20 to 67 years). The clinical manifestations and the results of laboratory examinations, gastrointestinal endoscopy, 99Tc m-labeled human albumin ( 99Tc m-HSA) scintigraphy, 99Tc m-DX scintigraphy, direct lymphangiography (DLG), histopathology, diet treatment, surgical intervention, and clinical symptom remission at discharge were collected. Comparisons between groups were performed using independent samples t-test, Mann-Whitney U test, or χ2 test. Results:Among the 50 cases of PIL, the main manifestations were edema (86.0%), diarrhea (76.0%), and abdominal effusion (48.0%). Lymphedema (36.0%) and chylous ascites (18.0%) were not rare in PIL patients. In 99Tc m-HAS scintigraphy, 95.9% (47/49) cases showed signs of intestinal protein loss, and 91.7% (44/48) ceses showed positive findings in 99Tc m-DX scintigraphy. In DLG, 97.8% (45/46) cases showed signs of thoracic duct obstruction, 82.6% (38/46) cases showed retroperitoneal lymphatic hyperplasia, and 23.9% (11/46) cases showed backflow of contrast agent into intestine. No significant difference was seen in gender, course of disease, clinical manifestation, serum level of albumin or globulin, lymphocyte count, positive rate of fecal occult blood and prevalence of lymphedema between adults and children (all P>0.05). Conclusions:The clinical presentations of PIL between children and adults had no significant difference. The diagnosis of PIL should be made according to clinical manifestation, 99Tc m-HAS scintigraphy, 99Tc m-DX scintigraphy, DLG, gastrointestinal endoscopy and pathological findings.

Objective:To investigate the clinical features of primary intestinal lymphangiectasia (PIL).Methods:This study was a retrospective case series study. Fifty consecutive patients diagnosed with PIL in Department of Lymphatic Surgery, Beijing Shijitan Hospital, Capital Medical University from March 2019 to March 2021 were included and their clinical data was retrospectively reviewed. There were 20 males and 30 females included, with an age of ( M(IQR)) 14 (40) years (range:0 to 67 years). No patient had the family history. There were 26 children, including 9 males and 17 females, aged 0 (7) years (range:0 to 14 years). There were 24 adults, including 11 males and 13 females, aged 40 (26) years (range:20 to 67 years). The clinical manifestations and the results of laboratory examinations, gastrointestinal endoscopy, 99Tc m-labeled human albumin ( 99Tc m-HSA) scintigraphy, 99Tc m-DX scintigraphy, direct lymphangiography (DLG), histopathology, diet treatment, surgical intervention, and clinical symptom remission at discharge were collected. Comparisons between groups were performed using independent samples t-test, Mann-Whitney U test, or χ2 test. Results:Among the 50 cases of PIL, the main manifestations were edema (86.0%), diarrhea (76.0%), and abdominal effusion (48.0%). Lymphedema (36.0%) and chylous ascites (18.0%) were not rare in PIL patients. In 99Tc m-HAS scintigraphy, 95.9% (47/49) cases showed signs of intestinal protein loss, and 91.7% (44/48) ceses showed positive findings in 99Tc m-DX scintigraphy. In DLG, 97.8% (45/46) cases showed signs of thoracic duct obstruction, 82.6% (38/46) cases showed retroperitoneal lymphatic hyperplasia, and 23.9% (11/46) cases showed backflow of contrast agent into intestine. No significant difference was seen in gender, course of disease, clinical manifestation, serum level of albumin or globulin, lymphocyte count, positive rate of fecal occult blood and prevalence of lymphedema between adults and children (all P>0.05). Conclusions:The clinical presentations of PIL between children and adults had no significant difference. The diagnosis of PIL should be made according to clinical manifestation, 99Tc m-HAS scintigraphy, 99Tc m-DX scintigraphy, DLG, gastrointestinal endoscopy and pathological findings.

Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ⩾ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL.
Humans ; DNA Copy Number Variations ; Nuclear Proteins/genetics* ; Central Nervous System Neoplasms/pathology* ; Transcription Factors/genetics* ; Prognosis ; Lymphoma/genetics* ; Genomics ; China ; Central Nervous System/pathology* ; Bromodomain Containing Proteins ; Cell Cycle Proteins/genetics*

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.
Humans ; Receptors, Chimeric Antigen/therapeutic use* ; Immunotherapy, Adoptive ; Hematologic Neoplasms/therapy* ; Treatment Outcome

OBJECTIVE: Bo investigate the regulatory relationship between NKD1 and YWHAE and the mechanism of NKD1 for promoting tumor cell proliferation. METHODS: HCT116 cells transfected with pcDNA3.0-NKD1 plasmid, SW620 cells transfected with NKD1 siRNA, HCT116 cells with stable NKD1 overexpression (HCT116-NKD1 cells), SW620 cells with nkd1knockout (SW620-nkd1^-/- cells), and SW620-nkd1^-/- cells transfected with pcDNA3.0-YWHAE plasmid were examined for changes in mRNA and protein expression levels of YWHAE using qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of NKD1 to the promoter region of YWHAE gene. The regulatory effect of NKD1 on YWHAE gene promoter activity was analyzed by dual-luciferase reporter gene assay, and the interaction between NKD1 and YWHAE was analyzed with immunofluorescence assay. The regulatory effect of NKD1 on glucose uptake was examined in the tumor cells. RESULTS: In HCT116 cells, overexpression of NKD1 significantly enhanced the expression of YWHAE at both the mRNA and protein levels, while NKD1 knockout decreased its expression in SW620 cells (P < 0.001). ChIP assay showed that NKD1 protein was capable of binding to the YWHAE promoter sequence; dual luciferase reporter gene assay showed that NKD1 overexpression (or knockdown) in the colon cancer cells significantly enhanced (or reduced) the transcriptional activity of YWHAE promoter (P < 0.05). Immunofluorescence assay demonstrated the binding of NKD1 and YWHAE proteins in colon cancer cells. NKD1 knockout significantly reduced glucose uptake in colon cancer cells (P < 0.01), while YWHAE overexpression restored the glucose uptake in NKD1-knockout cells (P < 0.05). CONCLUSION NKD1 protein activates the transcriptional activity of YWHAE gene to promote glucose uptake in colon cancer cells.
Humans ; Colonic Neoplasms ; HCT116 Cells ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; RNA, Messenger ; Glucose ; Calcium-Binding Proteins/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; 14-3-3 Proteins/metabolism*

Objective:To evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection in the treatment of peripheral T-cell lymphoma (PTCL) in a real-world setting.Methods:This was a real-world ambispective cohort study (MOMENT study) (Chinese clinical trial registry number: ChiCTR2200062067). Clinical data were collected from 198 patients who received mitoxantrone hydrochloride liposome injection as monotherapy or combination therapy at 37 hospitals from January 2022 to January 2023, including 166 patients in the retrospective cohort and 32 patients in the prospective cohort; 10 patients in the treatment-na?ve group and 188 patients in the relapsed/refractory group. Clinical characteristics, efficacy and adverse events were summarized, and the overall survival (OS) and progression-free survival (PFS) were analyzed.Results:All 198 patients were treated with mitoxantrone hydrochloride liposome injection for a median of 3 cycles (range 1-7 cycles); 28 cases were treated with mitoxantrone hydrochloride liposome injection as monotherapy, and 170 cases were treated with the combination regimen. Among 188 relapsed/refractory patients, 45 cases (23.9%) were in complete remission (CR), 82 cases (43.6%) were in partial remission (PR), and 28 cases (14.9%) were in disease stabilization (SD), and 33 cases (17.6%) were in disease progression (PD), with an objective remission rate (ORR) of 67.6% (127/188). Among 10 treatment-na?ve patients, 4 cases (40.0%) were in CR, 5 cases (50.0%) were in PR, and 1 case (10.0%) was in PD, with an ORR of 90.0% (9/10). The median follow-up time was 2.9 months (95% CI 2.4-3.7 months), and the median PFS and OS of patients in relapsed/refractory and treatment-na?ve groups were not reached. In relapsed/refractory patients, the difference in ORR between patients with different number of treatment lines of mitoxantrone hydrochloride liposome injection [ORR of the second-line, the third-line and ≥the forth-line treatment was 74.4% (67/90), 73.9% (34/46) and 50.0% (26/52)] was statistically significant ( P = 0.008). Of the 198 PTCL patients, 182 cases (91.9%) experienced at least 1 time of treatment-related adverse events, and the incidence rate of ≥grade 3 adverse events was 66.7% (132/198), which was mainly characterized by hematologic adverse events. The ≥ grade 3 hematologic adverse events mainly included decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and anemia; non-hematologic adverse events were mostly grade 1-2, mainly including pigmentation disorders and upper respiratory tract infection. Conclusions:The use of mitoxantrone hydrochloride liposome injection-containing regimen in the treatment of PTCL has definite efficacy and is well tolerated, and it is a new therapeutic option for PTCL patients.