Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Hepatitis B virus(HBV)infection is worldwide and poses a serious threat to human health.Existing conventional therapeutic drugs(e.g.,interferon-alpha,nucleoside analogs)can inhibit intrahepatic replication of HBV,but it is difficult to remove HBV covalently closed circular DNA(cccDNA)from the nucleus of hepatocytes,resulting in the virus not being easily cleared and the formation of a chronic infection that is difficult to cure.However,the emergence of targeted drugs is expected to destroy cccDNA making a cure for HBV infection possible.To achieve this,in vitro cell models of HBV infection and replication are needed to screen for targeted drugs.In recent years,in vitro cell models for HBV research have made fundamental progress,providing a platform for a better understanding of virus-host interactions,in vitro studies of the HBV life cycle,and the screening and evaluation of novel antiviral drugs.In this review,the research progress of HBV infection and replication cell models,and the characteristics and limitations of different cell models are reviewed,aiming to provide a basis for exploring the mechanism of complex chronic HBV infection,screening targeted drugs and selecting suitable HBV cell models in vitro.

Objective To detect the content of rheumatoid factor(RF)after RF-CIC dissociation using serum circulating immune complexes(CIC)dissociation technology and evaluate its diagnostic and clinical value in rheumatic arthritis(RA).Methods 55 RA patients diagnosed and treated in the 903rd Hospital of the People's Liberation Army from January 2024 to December 2024 were selected as the RA disease group,and 20 healthy individuals were selected as the control group.In addition,57 non RA pa-tients with symptoms resembling RA[patients with systemic lupus erythematosus(SLE),gout,ankylosing spondylitis(AS),osteo-arthritis,etc)]as the non RA disease group.Using CIC dissociation technology,RF content after RF-CIC dissociation was detect-ed in the serum of all three groups of study subjects,and C-reactive protein(CRP)and RF levels in all subjects were detected using a biochemical analyzer.Analyzed and compared the differences in the positive rate and levels of RF-CIC among three groups object of study.In addition,analyze and compare the correlation between RF-CIC and inflammatory index CRP.Results The positive rates of RF-CIC in the serum of RA disease group,non RA disease group,and control group were 87.27%(48/55),10.53%(6/57)and 0.0%(0/20),respectively,and the differences between the three groups was statistically significant(χ2=84.520,P<0.05).Further subgroup analysis showed that the RF-CIC positivity rate in the RF negative subgroup of RA disease patients[61.11%(11/18)]higher than that in the non RA disease group[1.92%(1/52)]and the control group[0%(0/20)],and the differ-ences were statistically significant(χ2=44.493,21.671,all P<0.05).The RF-CIC positivity rate was higher in RF positive pa-tients than in RF negative patients in the RA disease group(100%vs 61.11%),and the difference was statistically significant(χ2=16.487,P<0.05).The RF-CIC content in the serum of RF positive patients in the RA disease group was higher than that of RF negative patients[16.35(10.53,26.49)vs 3.57(2.53,3.89)],and the difference was statistically significant(Z=-4.243,P<0.05).Correlation analysis showed that the levels of CRP and RF in the serum of RA patients were positively correlated with the levels of RF-CIC(r=0.490,0.970,all P<0.05).Conclusion RF-CIC demonstrates high positivity even in RF-negative RA patients,and their levels correlate with CRP.RF-CIC shows potential as a serological indicator for early diagnosis and disease activity assess-ment in RA.

Objective:To analyze the clinical features and prognosis of patients with lymphoplasmacytic lymphoma/Waldenstr?m macroglobulinemia (LPL/WM) transformed into diffuse large B-cell lymphoma (DLBCL) .Methods:This study retrospectively analyzed the clinical data of five patients with LPL/WM transformed to DLBCL diagnosed and treated at a multicenter hospital in Hunan Province from December 2020 to April 2023. Clinical manifestations, treatment regimens, and therapeutic efficacy before and after the transformation were compared.Results:Of the five patients, four were male and one was female, with a median age of 64.0 (57.0–80.0) years, all of whom had abnormally increased β 2-microglobulin levels at diagnosis, and two were combined with increased lactate dehydrogenase levels. The MYD88 L265P mutation was detected in 4 patients, whereas 1 carried the FAT1 and NOTCH1 mutations, and none demonstrated CXCR4 mutations. Three patients were negative for the TP53 mutation, and two were not tested. Before transformation, three patients were treated with Bruton tyrosine kinase inhibitor therapy, and one patient was treated with the bendamustine plus rituximab regimen. All patients eventually transformed into non-growth center-derived DLBCL, with a median time to conversion of 11.8 (4.0–19.0) months, and most of them presented with weight loss, lymph node enlargement, splenomegaly, and extranodal involvement. Posttransformation, the patients were mainly treated with the rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) regimen, with an optimal outcome of partial remission. Disease progression occurred in 4 of the patients, with a median overall survival of 16.8 (10.0–26.0) months. Conclusion:Transformation from LPL/WM to DLBCL is rare. Patients should remain highly vigilant for transformation if they develop rapidly enlarging lymph nodes and/or newly involved lymph nodes, worsening systemic symptoms, and declining body mass. R-CHOP regimen may induce a partial response in some cases; however, the overall prognosis remains poor.

Objective:To analyze the clinical features and prognosis of patients with lymphoplasmacytic lymphoma/Waldenstr?m macroglobulinemia (LPL/WM) transformed into diffuse large B-cell lymphoma (DLBCL) .Methods:This study retrospectively analyzed the clinical data of five patients with LPL/WM transformed to DLBCL diagnosed and treated at a multicenter hospital in Hunan Province from December 2020 to April 2023. Clinical manifestations, treatment regimens, and therapeutic efficacy before and after the transformation were compared.Results:Of the five patients, four were male and one was female, with a median age of 64.0 (57.0–80.0) years, all of whom had abnormally increased β 2-microglobulin levels at diagnosis, and two were combined with increased lactate dehydrogenase levels. The MYD88 L265P mutation was detected in 4 patients, whereas 1 carried the FAT1 and NOTCH1 mutations, and none demonstrated CXCR4 mutations. Three patients were negative for the TP53 mutation, and two were not tested. Before transformation, three patients were treated with Bruton tyrosine kinase inhibitor therapy, and one patient was treated with the bendamustine plus rituximab regimen. All patients eventually transformed into non-growth center-derived DLBCL, with a median time to conversion of 11.8 (4.0–19.0) months, and most of them presented with weight loss, lymph node enlargement, splenomegaly, and extranodal involvement. Posttransformation, the patients were mainly treated with the rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R-CHOP) regimen, with an optimal outcome of partial remission. Disease progression occurred in 4 of the patients, with a median overall survival of 16.8 (10.0–26.0) months. Conclusion:Transformation from LPL/WM to DLBCL is rare. Patients should remain highly vigilant for transformation if they develop rapidly enlarging lymph nodes and/or newly involved lymph nodes, worsening systemic symptoms, and declining body mass. R-CHOP regimen may induce a partial response in some cases; however, the overall prognosis remains poor.

Objective To detect the content of rheumatoid factor(RF)after RF-CIC dissociation using serum circulating immune complexes(CIC)dissociation technology and evaluate its diagnostic and clinical value in rheumatic arthritis(RA).Methods 55 RA patients diagnosed and treated in the 903rd Hospital of the People's Liberation Army from January 2024 to December 2024 were selected as the RA disease group,and 20 healthy individuals were selected as the control group.In addition,57 non RA pa-tients with symptoms resembling RA[patients with systemic lupus erythematosus(SLE),gout,ankylosing spondylitis(AS),osteo-arthritis,etc)]as the non RA disease group.Using CIC dissociation technology,RF content after RF-CIC dissociation was detect-ed in the serum of all three groups of study subjects,and C-reactive protein(CRP)and RF levels in all subjects were detected using a biochemical analyzer.Analyzed and compared the differences in the positive rate and levels of RF-CIC among three groups object of study.In addition,analyze and compare the correlation between RF-CIC and inflammatory index CRP.Results The positive rates of RF-CIC in the serum of RA disease group,non RA disease group,and control group were 87.27%(48/55),10.53%(6/57)and 0.0%(0/20),respectively,and the differences between the three groups was statistically significant(χ2=84.520,P<0.05).Further subgroup analysis showed that the RF-CIC positivity rate in the RF negative subgroup of RA disease patients[61.11%(11/18)]higher than that in the non RA disease group[1.92%(1/52)]and the control group[0%(0/20)],and the differ-ences were statistically significant(χ2=44.493,21.671,all P<0.05).The RF-CIC positivity rate was higher in RF positive pa-tients than in RF negative patients in the RA disease group(100%vs 61.11%),and the difference was statistically significant(χ2=16.487,P<0.05).The RF-CIC content in the serum of RF positive patients in the RA disease group was higher than that of RF negative patients[16.35(10.53,26.49)vs 3.57(2.53,3.89)],and the difference was statistically significant(Z=-4.243,P<0.05).Correlation analysis showed that the levels of CRP and RF in the serum of RA patients were positively correlated with the levels of RF-CIC(r=0.490,0.970,all P<0.05).Conclusion RF-CIC demonstrates high positivity even in RF-negative RA patients,and their levels correlate with CRP.RF-CIC shows potential as a serological indicator for early diagnosis and disease activity assess-ment in RA.

Hepatitis B virus(HBV)infection is worldwide and poses a serious threat to human health.Existing conventional therapeutic drugs(e.g.,interferon-alpha,nucleoside analogs)can inhibit intrahepatic replication of HBV,but it is difficult to remove HBV covalently closed circular DNA(cccDNA)from the nucleus of hepatocytes,resulting in the virus not being easily cleared and the formation of a chronic infection that is difficult to cure.However,the emergence of targeted drugs is expected to destroy cccDNA making a cure for HBV infection possible.To achieve this,in vitro cell models of HBV infection and replication are needed to screen for targeted drugs.In recent years,in vitro cell models for HBV research have made fundamental progress,providing a platform for a better understanding of virus-host interactions,in vitro studies of the HBV life cycle,and the screening and evaluation of novel antiviral drugs.In this review,the research progress of HBV infection and replication cell models,and the characteristics and limitations of different cell models are reviewed,aiming to provide a basis for exploring the mechanism of complex chronic HBV infection,screening targeted drugs and selecting suitable HBV cell models in vitro.

Objective To explore changes of topological properties and functional connectivity(FC)of global brain network in breast cancer(BC)patients accompanied by emotional disorders.Methods Forty-three female BC patients(BC group)and 43 age-and education-matched healthy controls(HC group)were prospectively enrolled.The scores of fear of cancer recurrence-total(FCR-total),fear of cancer recurrence inventory(FCRI),general anxiety disorder-7(GAD-7)and patient health questionnaire-9(PHQ-9)for 43 patients in BC group,as well as of anxiety sensitivity index-3(ASI-3),meta-cognitions about health questionnaire(MCQ-HA)and EuroQoL 5-dimension 5-level questionnaire(EQ-5D-5L)for 40 patients in BC group were obtained to evaluate emotional disorders.Meanwhile,the scores of GAD-7 and PHQ-9 were obtained in HC group to exclude for anxiety and depression.Using resting-state functional MRI(rs-fMRI),topological attributes and FC of global brain network were analyzed,and the topological attribute indicators of global brain network were compared between groups.Based on voxel-wise analysis,the regions in global brain related to FC strength(FCS)correlated with each clinical scale score in BC group were analyzed,and spatial similarity analysis of FCS was performed.The correlations of FCS at brain region level and clinical scale scores in BC group were observed.Results All patients in BC group were accompanied by emotional disorders.The clustering coefficient in BC group was lower than that in HC group(t=-2.261,P=0.027).Brain regions related to FCS values correlated with each clinical scale score in BC group were widely distributed in sensorimotor network and higher-order brain network,etc.,and their FCS values were correlated.FCS of ventrolateral nucleus of right thalamus and caudate nucleus were positively correlated with FCR-total(r=0.459,P=0.004)and FCRI(r=0.488,P=0.005).Conclusion BC patients with emotions disorders had dysfunction of brain functional segregation,as well as enhanced FCS in brain regions such as ventrolateral nucleus of right thalamus and caudate nucleus.

Objective To explore changes of topological properties and functional connectivity(FC)of global brain network in breast cancer(BC)patients accompanied by emotional disorders.Methods Forty-three female BC patients(BC group)and 43 age-and education-matched healthy controls(HC group)were prospectively enrolled.The scores of fear of cancer recurrence-total(FCR-total),fear of cancer recurrence inventory(FCRI),general anxiety disorder-7(GAD-7)and patient health questionnaire-9(PHQ-9)for 43 patients in BC group,as well as of anxiety sensitivity index-3(ASI-3),meta-cognitions about health questionnaire(MCQ-HA)and EuroQoL 5-dimension 5-level questionnaire(EQ-5D-5L)for 40 patients in BC group were obtained to evaluate emotional disorders.Meanwhile,the scores of GAD-7 and PHQ-9 were obtained in HC group to exclude for anxiety and depression.Using resting-state functional MRI(rs-fMRI),topological attributes and FC of global brain network were analyzed,and the topological attribute indicators of global brain network were compared between groups.Based on voxel-wise analysis,the regions in global brain related to FC strength(FCS)correlated with each clinical scale score in BC group were analyzed,and spatial similarity analysis of FCS was performed.The correlations of FCS at brain region level and clinical scale scores in BC group were observed.Results All patients in BC group were accompanied by emotional disorders.The clustering coefficient in BC group was lower than that in HC group(t=-2.261,P=0.027).Brain regions related to FCS values correlated with each clinical scale score in BC group were widely distributed in sensorimotor network and higher-order brain network,etc.,and their FCS values were correlated.FCS of ventrolateral nucleus of right thalamus and caudate nucleus were positively correlated with FCR-total(r=0.459,P=0.004)and FCRI(r=0.488,P=0.005).Conclusion BC patients with emotions disorders had dysfunction of brain functional segregation,as well as enhanced FCS in brain regions such as ventrolateral nucleus of right thalamus and caudate nucleus.

Objective:To study the clinical manifestations and genetic characteristics of neonatal-onset primary mitochondrial disease (PMD) caused by nuclear gene mutations.Methods:From May 2020 to March 2022, the clinical data, genetic results and follow-up information of neonates with PMD admitted to the Department of Neonatology of our two hospitals were retrospectively analyzed.Results:A total of 4 patients were enrolled, all with hyperlactatemia and metabolic acidosis. In case 1, the fetal cranial MRI showed agenesis of corpus callosum. In case 2, echocardiography after birth indicated hypertrophic cardiomyopathy. Whole exome sequencing found the following mutations: EARS2 nuclear gene c.1294C>T and c.971G>T variants, COA6 nuclear gene c.411_412insAAAG variant, ACAD9 nuclear gene c.1278+1G>A and c.895A>T variants, FOXRED1 nuclear gene c.1054C>T and c.3dup variants. Mitochondrial second-generation sequencing and multiplex ligation-dependent probe amplification showed no abnormalities. Cases 1 and 3 died during the neonatal period. Case 2 died at 2-year-and-2-month of age. Case 4 was followed up to 1 year of age with developmental delay.Conclusions:The main phenotypes of neonatal-onset PMD caused by nuclear gene mutations are hyperlactatemia, refractory metabolic acidosis and cardiomyopathy, which have a poor prognosis. Proactive genetic tests are helpful for early diagnosis.