Objective:To investigate the intervention effect and mechanism of regulating miR-155 on young rats with dysfunction of blood coagulation.Methods:Twenty-six healthy and clean SD male rats were selected to establish the coagulopathy models.Twenty-four rats successfully established models and were randomly divided into three groups:model group,up-regulated miR-155 group and down-regulated miR-155 group,with 8 rats in each group.The expression of miR-155 was detected by real-time fluorescence quantitative polymerase chain reaction.The changes of coagulation factors and coagulation indicators were observed.Liver pathological tissues were observed by HE staining.The expressions of HMGB1-RAGE/TLRs-NF-κB signaling pathway related proteins were detected by Western blot.Results:Compared with model group,the expressions of HMGB1,RAGE,TLR2,TLR4 and NF-κB were significantly increased in up-regulated miR-155 group(all P＜0.05),while decreased in down-regulated miR-155 group(all P＜0.05).Compared with model group,the expressions of coagulation factor Ⅱ,Ⅶ,Ⅸ,and X were significantly decreased in up-regulated miR-155 group(all P＜0.05),while increased in down-regulated miR-155 group(P＜0.05).There was no significant difference in the expression of coagulation factor Ⅺ among the three groups(P＞0.05).Compared with model group,the levels of prothrombin time(PT)and activated partial thromboplastin time(APTT)were lower and fibrinogen(FIB)was higher in up-regulated miR-155 group(all P＜0.05),while in the down-regulated miR-155 group they were opposite.Conclusion:Down-regulation of miR-155 can effectively improve coagulation factors and coagulation indexes and inhibit inflammation in young rats with dysfunction of blood coagulopathy,and the mechanism may be related to HMGB1-RAGE/TLRs-NF-κ B signaling pathway.

Aim To investigate the synergistic sensiti-zation effect of saikosaponin D(SSD)combined with temozolomide(TMZ)on glioblastoma cells(GBM)and its molecular mechanism.Methods The sensitiv-ity of RG-2,U251 and LN-428 GBM cell lines to SSD and TMZ was analyzed by CCK-8 method combined with HE staining,and the optimal compatible concen-tration was screened.The effect of HE staining com-bined with Hoechst fluorescence staining on the prolif-eration of GBM cell line was detected by clonal forma-tion experiment.The autophagosome formation of GBM cells was observed by monodansylcadaverine(MDC)staining.The expression and distribution of endoplas-mic reticulum stress-related factors and apoptosis and autophagy proteins were detected by Western blot and ICC.Results The sensitivity order of GBM cells to TMZ was RG-2＞U251＞LN-428.The results of com-bined administration showed the synergistic inhibitory effect of SSD combined with TMZ on proliferation of GBM cell lines,which was confirmed by cell cloning formation experiment.Compared with the TMZ group,Hoechst fluorescence staining showed a significant in-crease in the number of nuclear bright staining in the combined administration group.MDC fluorescence staining showed that there were more dense green parti-cles in the cytoplasm of SSD/TMZ plus group than that of TMZ group.Western blot results showed that com-pared with TMZ group,the expression of ER stress markers GRP78,CHOP,p-PERK and ATF6 signifi-cantly increased in SSD/TMZ group(P＜0.05).The expressions of apoptosis proteins caspase-12,caspase-9,caspase-3,cleaved caspase-3,Bax and autophagy proteins LC3 and Beclin-1 significantly increased(P＜0.05),which were verified by ICC test.Conclusions SSD can cooperate with TMZ to inhibit the prolifera-tion of GBM cells and induce apoptosis and autophagy,and enhance the sensitivity of GBM cells to TMZ by ac-tivating endoplasmic reticulum stress pathway.

Arrhythmia is an external manifestation of cardiac electrophysiological disorder. It exists in healthy people and patients with various heart diseases, which is often associated with other cardiovascular diseases. The contraction and diastole of myocardium are inseparable from the movement of ions. There are many ion channels in the membrane and organelle membrane of myocardium. The dynamic balance of myocardial ions is vital in maintaining myocardial electrical homeostasis. Potassium ion channels that have a complex variety and a wide distribution are involved in the whole process of resting potential and action potential of cardiomyocytes. Potassium ion channels play a vital role in maintaining normal electrophysiological activity of myocardium and is one of the pathogenesis of arrhythmia. Traditional Chinese medicine(TCM)has unique advantages in treating arrhythmia for its complex active components and diverse targets. A large number of TCM preparations have definite effect on treating arrhythmia-related diseases, whose antiarrhythmic mechanism may be related to the effect on potassium channel. This article mainly reviewed the relevant studies on the active components in TCM acting on different potassium channels to provide references for clinical drug use and development.
Humans ; Potassium Channels ; Medicine, Chinese Traditional ; Anti-Arrhythmia Agents/therapeutic use* ; Arrhythmias, Cardiac/drug therapy* ; Heart Diseases/drug therapy* ; Ions

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

N-methyl-D-aspartate receptor (NMDAR),an important ionic glutamate receptor and a ligand and voltage-gated ion channel characterized by complex composition and functions and wide distribution,plays a key role in the pathological and physiological process of diseases or stress states.NMDAR can mediate apoptosis through different pathways such as mitochondrial and endoplasmic reticulum damage,production of reactive oxygen species and peroxynitrite,and activation of mitogen-activated protein kinase and calpain.This paper reviews the structure,distribution,and biological characteristics of NMDAR and the mechanisms of NMDAR-mediated apoptosis.
Apoptosis ; Humans ; Mitogen-Activated Protein Kinases/metabolism* ; Reactive Oxygen Species/metabolism* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Signal Transduction

OBJECTIVE: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen. METHODS: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed. RESULTS: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD^- high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients. CONCLUSION The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD^- high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.
Busulfan ; Cladribine ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute/therapy* ; Retrospective Studies ; Transplantation Conditioning

Objective: To analyze the genetic landscape of 52 fusion genes in patients with de novo acute lymphoblastic leukemia (ALL) and to investigate the characteristics of other laboratory results. Methods: The fusion gene expression was retrospectively analyzed in the 1 994 patients with de novo ALL diagnosed from September 2016 to December 2020. In addition, their mutational, immunophenotypical and karyotypical profiles were investigated. Results: In the 1 994 patients with ALL, the median age was 12 years (from 15 days to 89 years). In the panel of targeted genes, 15 different types of fusion genes were detected in 884 patients (44.33%) and demonstrated a Power law distribution. The frequency of detectable fusion genes in B-cell ALL was significantly higher than that in T-cell ALL (48.48% vs 18.71%), and fusion genes were almost exclusively expressed in B-cell ALL or T-cell ALL. The number of fusion genes showed peaks at<1 year, 3-5 years and 35-44 years, respectively. More fusion genes were identified in children than in adults. MLL-FG was most frequently seen in infants and TEL-AML1 was most commonly seen in children, while BCR-ABL1 was dominant in adults. The majority of fusion gene mutations involved signaling pathway and the most frequent mutations were observed in NRAS and KRAS genes. The expression of early-stage B-cell antigens varied in B-cell ALL patients. The complex karyotypes were more common in BCR-ABL1 positive patients than others. Conclusion: The distribution of fusion genes in ALL patients differs by ages and cell lineages. It also corresponds to various gene mutations, immunophenotypes, and karyotypes.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Child, Preschool ; Gene Expression ; Genes, ras ; Humans ; Infant ; Infant, Newborn ; Middle Aged ; Oncogene Fusion ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism* ; Retrospective Studies ; Young Adult

Objective: To investigate the mutational features of the immunoglobulin heavy chain variable region (IgHV) gene in patients with chronic lymphocytic leukemia (CLL) using immunophenotypic and molecular genetic methods. Methods: The laboratory results of 266 CLL patients who underwent IgHV gene examination at Sino-US diagnostics laboratory from February 2020 to February 2021 were analyzed for the IgVH mutational status and presence of specific IgVH fragments. In addition, their immunophenotypic, molecular, chromosomal karyotypic, and FISH profiles were investigated and correlated with the IgVH mutational status. Results: Among 266 patients, 172 were male and 94 were female, with a media age of 67 years (20-82 years).There were more patients with mutated IgHV (m-IgHV) than unmutated IgHV (un-IgHV) (69.2%∶30.8%). There was association of VH family and the presence of gene fragments: the overall incidence of VH families including VH3 family (142/266, 53.4%), VH4 family (75/266, 28.2%), and VH1 family (34/266, 12.8%) was about 95%, among which the proportion of VH4-34 (26/266, 9.8%), VH3-23 (25/266, 9.4%), VH3-7 (24/266, 9.0%), and VH4-39 (16/266, 6.0%) was about 35%. VH3-20 and VH3-49 only occurred in un-IgHV (P<0.05). In addition, the expression rates of CD38 (26.3% vs. 3.0%), CD79b (71.1%∶45.5%) and 11q deletion (25.5%∶5.3%) were higher in un-IgHV, and single trisomy 12 (37.9%∶5.6%) were more commonly found in m-IgHV (P<0.05). MYD88 was one of the major mutation genes in m-IgHV, while ATM had the highest mutation rate in un-IgHV. Conclusion: CLL patients have differential expression in terms of IgHV gene mutations, correlating to their immunophenotype and genetics characteristics.
Male ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics* ; Immunoglobulin Variable Region/genetics* ; Genes, Immunoglobulin Heavy Chain ; Mutation ; Immunoglobulin Heavy Chains/genetics* ; Prognosis

ObjectiveTo explore the material basis and mechanism of Nardostachyos Radix et Rhizoma （NRER）-Agrimoniae Herba （AH）， the herbal pair effective in regulating the liver， invigorating Qi， and calming palpitations， in the treatment of premature ventricular contractions （PVCs） by network pharmacology and molecular docking. MethodThe chemical components and targets of NRER and AH were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） combined with relevant literature. GeneCards，Online Mendelian Inheritance in Man（OMIM），and DrugBank were used to predict the potential targets against PVCs. STRING platform was used for protein-protein interaction （PPI） analysis. Metascape platform was used for Gene Ontology（GO） and Kyoto Encyclopedia of Genes and Genomes（KEGG） enrichment analysis. Cytoscape 3.8.0 was used to construct the NRER-AH component-potential target-signaling pathway network. The main target proteins underwent molecular docking to the active components of NRER-AH by AutoDock 4.2.6. ResultThe targets of nine active components in NRER-AH （such as quercetin，kaempferol，and acacetin） against PVCs mainly involved tumor necrosis factor （TNF），mitogen-activated protein kinase 1（MAPK1），and protein kinase B1（Akt1）. The potential targets were mainly enriched in 26 signaling pathways，such as pathways in cancer and the advanced glycosylation end product （AGE）-receptor of advanced glycosylation end product（RAGE） signaling pathway. The results of molecular docking showed that the majority of the active components （92.59%） of NRER-AH had good binding activities with the main target proteins TNF，MAPK1，and Akt1. ConclusionThe active components of NRER-AH can regulate cardiac ion channels，resist inflammation， and combat oxidative stress to treat PVCs through multi-target and multi-pathway interventions. They can also improve symptoms related to depression and anxiety by inhibiting monoamine oxidase activity and protecting nerves from damage. This study is expected to provide research ideas and the theoretical basis for further exploring the material basis and mechanism of NRER-AH in the treatment of PVCs.