siRNA Delivery against Myocardial Ischemia Reperfusion Injury Mediated by Reversibly Camouflaged Biomimetic Nanocomplexes.

siRNA-mediated management of myocardial ischemia reperfusion (IR) injury is greatly hampered by the inefficient myocardial enrichment and cardiomyocyte transfection. Herein, nanocomplexes (NCs) reversibly camouflaged with a platelet-macrophage hybrid membrane (HM) are developed to efficiently deliver Sav1 siRNA (siSav1) into cardiomyocytes, suppressing the Hippo pathway and inducing cardiomyocyte regeneration. The biomimetic BSPC@HM NCs consist of a cationic nanocore assembled from a membrane-penetrating helical polypeptide (P-Ben) and siSav1, a charge-reversal intermediate layer of poly(l-lysine)-cis-aconitic acid (PC), and an outer shell of HM. Due to HM-mediated inflammation homing and microthrombus targeting, intravenously injected BSPC@HM NCs can efficiently accumulate in the IR-injured myocardium, where the acidic inflammatory microenvironment triggers charge reversal of PC to shed off both HM and PC layers and allow the penetration of the exposed P-Ben/siSav1 NCs into cardiomyocytes. In rats and pigs, BSPC@HM NCs remarkably downregulates Sav1 in IR-injured myocardium, promotes myocardium regeneration, suppresses myocardial apoptosis, and recovers cardiac functions. This study reports a bioinspired strategy to overcome the multiple systemic barriers against myocardial siRNA delivery, and holds profound potential for gene therapy against cardiac injuries.

POEMS syndrome causing left ventricular hypertrophy, myocardial dysfunction, and pericardial effusion: a case report.

BACKGROUND: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is a paraneoplastic syndrome caused by a plasma cell proliferative disorder. Characteristics of POEMS syndrome include elevated pro-inflammatory and angiogenic cytokine levels that lead to multi-organ dysfunction. Patients have a variety of initial symptoms, but cardiac involvement is not common. CASE SUMMARY: We report a case of a 31-year-old Chinese woman with chief complaints of chest pain and dyspnoea who was diagnosed with POEMS syndrome. The cardiovascular system in the case study patient was characterized by pericardial effusion, enlarged left atria, abnormal myocardial segmental deformation, left ventricular hypertrophy, pulmonary hypertension, and increased glucose metabolism in the left and right ventricular myocardium. The pericardial effusion diminished, while cardiac function, left ventricular wall thickness, and pulmonary hypertension gradually returned to normal with dexamethasone and bortezomib treatment. DISCUSSION: This case suggests that cardiovascular system damage may be related to systemic diseases. Cardiovascular system damage caused by POEMS syndrome is recoverable after chemotherapy treatment. Echocardiography readily visualizes the changes in the heart of a patient with POEMS syndrome, clearly reflecting the changes in the structure and function of the heart before and after treatment.

Curcumin is a Potential Adjuvant to Alleviates Diabetic Retinal Injury via Reducing Oxidative Stress and Maintaining Nrf2 Pathway Homeostasis.

Curcumin is a natural polyphenol compound with anti-diabetic, anti-oxidative, and anti-inflammatory effects. Although many studies have reported the protective effect of curcumin in diabetes mellitus or diabetic nephropathy, there is a lack of research on curcumin in diabetic retinopathy. The purpose of this study was to investigate the therapeutic effects of curcumin on the diabetic retinal injury. Streptozotocin (STZ)-induced diabetic rats (60, n = 12 each) were respectively given curcumin orally (200 mg/kg/day), insulin subcutaneously (4-6 IU/day), and combined therapy with curcumin and insulin for 4 weeks. Retinal histopathological changes, oxidative stress markers, and transcriptome profiles from each group were observed. Curcumin, insulin, or combination therapy significantly reduced blood glucose, alleviated oxidative stress, and improved pathological damage in diabetic rats. Curcumin not only significantly reduced retinal edema but also had a better anti-photoreceptor apoptosis effect than insulin. In the early stage of diabetes, the enhancement of oxidative stress in the retina induced the adaptive activation of the nuclear factor E2-associated factor 2 (Nrf2) pathway. Treatment of curcumin alleviated the compensatory activation of the Nrf2 pathway induced by oxidative stress, by virtue of its antioxidant ability to transfer hydrogen atoms to free radicals. When curcumin combined with insulin, the effect of maintaining Nrf2 pathway homeostasis in diabetic rats was better than that of insulin alone. Transcriptomic analyses revealed that curcumin either alone, or combined with insulin, inhibited the AGE-RAGE signaling pathway and the extracellular matrix (ECM)-receptor interaction in the diabetic retina. Thus, at the early stage of diabetes, curcumin can be used to alleviate diabetic retinal injury through its anti-oxidative effect. If taking curcumin as a potential complementary therapeutic option in combination with antihyperglycemic agents, which would lead to more effective therapeutic outcomes against diabetic complications.

[Application of Two Ultrafine Chest Tube for Drainage after
Pulmonary Uniportal Video-assisted Thoracoscopic Surgery].

BACKGROUND: At present, an ultrafine chest tube combined with a traditional thick tube were often used after pulmonary uniportal video-assisted thoracoscopic surgery (U-VATS). However, the thick tube was often placed in the incision, which increased the risk of poor wound healing and postoperative pain. The aim of this study is to investigate the feasibility and safety of using two ultrafine chest tubes (10 F pigtail tube) for drainage after pulmonary U-VATS. METHODS: The medical records of patients who underwent pulmonary U-VATS during June 2018 and June 2020 in the department of cardiothoracic surgery of the second affiliated hospital of Soochow university were retrospectively reviewed to compare two different drainage strategies, receiving two 10 F pigtail tubes as chest tube (group A) or one 10 F pigtail tube as lower chest tube combined with one 24 F tube as upper chest tube (group B). RESULTS: 106 patients in group A receiving two 10 F pigtail tubes during June 2019 and June 2020 and 183 patients in group B receiving one 10 F pigtail tube as lower chest tube combined with one 24 F tube as upper chest tube during June 2018 and June 2019 were included. There was no significant difference between two groups in terms of the postoperative thoracic drainage (mL) (1st: 199.54±126.56 vs 203.59±139.32, P=0.84; 2nd: 340.30±205.47 vs 349.74±230.92, P=0.76; 3rd: 435.19±311.51 vs 451.37±317.03, P=0.70; 4th: 492.58±377.33 vs 512.57±382.94, P=0.69; Total: 604.57±547.24 vs 614.64±546.08, P=0.88), drainage time (d) (upper chest tube: 2.54±2.20 vs 3.40±2.07, P=0.21; lower chest tube: (2.24±2.43 vs 3.82±2.12, P=0.10), postoperative hospital stays (d) (6.87±3.17 vs 7.06±3.21, P=0.63), poor wound healing (0 vs 3.28%, P=0.09), replacement of lower chest tube (0.94% vs 2.19%, P=0.66) and the VAS1 (3.00±0.24 vs 2.99±0.15, P=0.63). Notably, there were significant differences between two groups in terms of the VAS2 (2.28±0.63 vs 2.92±0.59, P<0.01) and VAS3 (2.50±1.58 vs 2.79±1.53, P=0.02), as well as the frequency of using additional analgesics (25.47% vs 38.25%, P=0.03) and replacement of the upper chest tube (0 vs 4.37%, P=0.03). CONCLUSIONS: It's feasible and safe to use two 10 F pigtail tubes for drainage after pulmonary U-VATS, which can achieve less postoperative pain and lower frequency of replacement of the upper chest tube on some specific patients.

M2 macrophage-derived exosomal long non-coding RNA AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing microRNA-296 and elevating NOTCH2.

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.

A narrative review of artificial intelligence-assisted histopathologic diagnosis and decision-making for non-small cell lung cancer: achievements and limitations.

OBJECTIVE: To summarize the current evidence regarding the applications, workflow, and limitations of artificial intelligence (AI) in the management of patients pathologically-diagnosed with lung cancer. BACKGROUND: Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. AI technologies have been applied to daily medical workflow and have achieved an excellent performance in predicting histopathologic subtypes, analyzing gene mutation profiles, and assisting in clinical decision-making for lung cancer treatment. More advanced deep learning for classifying pathologic images with minimal human interactions has been developed in addition to the conventional machine learning scheme. METHODS: Studies were identified by searching databases, including PubMed, EMBASE, Web of Science, and Cochrane Library, up to February 2021 without language restrictions. CONCLUSIONS: A number of studies have evaluated AI pipelines and confirmed that AI is robust and efficacious in lung cancer diagnosis and decision-making, demonstrating that AI models are a useful tool for assisting oncologists in health management. Although several limitations that pose an obstacle for the widespread use of AI schemes persist, the unceasing refinement of AI techniques is poised to overcome such problems. Thus, AI technology is a promising tool for use in diagnosing and managing lung cancer.

Characterization of Extracapsular Lymph Node Involvement and Its Clinicopathological Characteristics in Stage II-IIIA Lung Adenocarcinoma.

BACKGROUND: The prognostic impact and clinicopathological characteristics of extracapsular lymph node involvement (ECLNI) in patients with surgically resected lung adenocarcinoma (LUAD) remain unknown in the context of the eighth edition N classification. PATIENTS AND METHODS: We retrospectively reviewed 279 patients with stage II-IIIA LUAD who underwent lobectomy and lymphadenectomy. The correlations of ECLNI presence and clinicopathological profiles were analyzed. We also assessed the impact of ECLNI on the postoperative survival of pN1 and pN2 LUAD patients. RESULTS: ECLNI-positive status was more common in patients with high lymph node yield and in patients with multiple stations involved. The logistic regression model identified tumor spread through air spaces, micropapillary component, cribriform component, and nodal stage as predictive factors for ECLNI presence. LUAD patients with ECLNI presence had an increased risk of locoregional recurrence compared with those without (p < 0.001). Presence of ECLNI was confirmed as an independent risk factor for worse recurrence-free survival (RFS) (p < 0.001) and overall survival (OS) (p < 0.001) in the entire cohort. Among the 61 patients with ECLNI(+)pN2 disease, our analysis revealed that adjuvant radiation was a significant predictor of improved RFS and OS. In addition, ECLNI status provides additional precision in stratifying pN1 and pN2 patients with significantly different RFS and OS. CONCLUSIONS: Our data suggest that ECLNI remains a strong prognosticator of unfavorable OS and RFS for LUADs in the context of the eighth edition N classification. Adjuvant radiation should be actively considered for pN1b and pN2 LUAD patients with ECLNI presence.

Comparison of sublobar resection and lobectomy for patients with small (≤2cm) second primary non-small-cell lung cancer.

BACKGROUND: This study aimed to investigate whether sublobar resection (SR) is equivalent to lobectomy for small (≤ 2 cm) second primary lung cancer (SPLC). METHODS: We identified 834 patients with T1aN0M0 SPLC from the Surveillance, Epidemiology, and End Results (SEER) database during 2000-2016. Overall survival (OS) was compared between lobectomy and SR after propensity-score matching. A total of 228 patients with SPLC were identified from three institutions in China as the validation set. RESULTS: SR was an independent risk factor for patients with 1 to 2 cm SPLC (SR vs Lob: hazard ratio [HR], 1.593; 95% confidence interval [CI], 1.186-2.141; P = .002) but not for patients with SPLC ≤ 1 cm (SR vs Lob: HR, 1.206; 95% CI, 0.790-1.841; P = .385). Subgroup analysis on the SEER data indicated that OS favored lobectomy compared with SR for contralateral SPLC ≤ 2 cm but not for ipsilateral ones (ipsilateral: P = .692; contralateral: P = .030). Our multi-institutional data also revealed that SR was equivalent to lobectomy for patients with ≤2 cm ipsilateral SPLC. CONCLUSIONS: SR is equivalent to lobectomy for SPLC ≤ 1 cm but not for SPLC > 1 to 2 cm. SR might be recommended for patients with ipsilateral small SPLC considering the difficulty in reoperations.

Self-assisted membrane-penetrating helical polypeptides mediate anti-inflammatory RNAi against myocardial ischemic reperfusion (IR) injury.

Anti-inflammatory RNA interference (RNAi) provides a promising paradigm for the treatment of myocardial ischemia reperfusion (IR) injury. To overcome the membrane barriers against intracardial siRNA delivery, various guanidinated helical polypeptides with potent and aromaticity-assisted membrane activities were herein developed and used for the delivery of siRNA against RAGE (siRAGE), a critical regulator of the pro-inflammatory cascade. Aromatic modification of the polypeptide led to notably enhanced trans-membrane siRNA delivery efficiencies, and more importantly, allowed more siRNA cargoes to get internalized via non-endocytosis, an effective pathway toward gene transfection. Subsequently, benzyl-modified polypeptide (P-Ben) was identified as the top-performing material with the highest RAGE silencing efficiency yet lowest cytotoxicity in H9C2 cells. Intracardial injection of the P-Ben/siRAGE polyplexes at 150 µg siRNA per kg led to remarkable RAGE knockdown by ∼85%, thereby attenuating the inflammatory cytokine release and reducing the cardiomyocyte apoptosis as well as myocardium fibrosis to recover the cardiac function after IR injury. This study therefore provides an effective strategy for the design of membrane-penetrating gene delivery materials, and may provide a promising addition to the anti-inflammatory treatment of myocardial IR injury.

An Oncolytic Adenovirus Targeting Transforming Growth Factor ß Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy.

In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFßRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFßRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor ß (TGFß) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8+ T lymphocytes, promoted the generation of CD4+ T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4+ T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFß and TGFß-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers.

[Progress in Basic Research and Clinical Treatment of Multiple Pulmonary Nodules].

Lung cancer leads to the highest cancer-related morbidity and mortality worldwide. With the development of multi-slice spiral computed tomography technology and the implement of lung cancer screening, more and more lung nodules have been discovered, many of which are multiple pulmonary nodules. These pulmonary nodules are usually diagnosed as multiple primary lung adenocarcinomas from a pathological perspective. For multiple nodules with different imaging features, the preferred treatment methods are different, and the treatment of each lung nodule is still controversial. In recent years, the interactions between multiple lesions and the evolution of the lesions as well as the inter-tumoral and intratumoral homogeneity and heterogeneity of the genomics also arouse attention. Our review gathered the research progress in multiple pulmonary nodules from the points of histopathology, genomics and surgical management.
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A novel AXL chimeric antigen receptor endows T cells with anti-tumor effects against triple negative breast cancers.

Identifying targets for chimeric antigen receptor-modulated T lymphocyte (CAR-T) therapy against solid tumors is an urgent problem to solve. In this study, we showed for the first time that the receptor tyrosine kinase, AXL, is overexpressed in various tumor cell lines and patient tumor tissues including triple negative breast cancer (TNBC) cell lines and patient samples, making AXL a potent novel target for cancer therapy, specifically for TNBC treatment. We also engineered T cells with a CAR consisting of a novel single-chain variable fragment against AXL and revealed its antigen-specific cytotoxicity and ability to release cytokines in a TNBC cell line and other AXL-positive tumors in vitro. Furthermore, AXL-CAR-T cells displayed a significant anti-tumor effect and in vivo persistence in a TNBC xenograft model. Taken together, our findings indicate that AXL-CAR-T cells can represent a promising therapeutic strategy against TNBC.

Semaphorin7A aggravates coxsackievirusB3-induced viral myocarditis by increasing α1ß1-integrin macrophages and subsequent enhanced inflammatory response.

Semaphorin7A (Sema7A) has been reported to play various roles in nerve axon growth, tumor suppression, and tissue remodeling, as well as regulation of intestinal inflammation diseases. Viral myocarditis (VMC) characterized by viral-myocardial-cell necrosis and inflammatory cell infiltration is a common clinical disease of the cardiovascular system. However, the role of Sema7A in coxsackievirus B3 (CVB3)-induced VMC has not been reported. In this study, we generated an acute VMC mouse model by CVB3 infection, and manipulated Sema7A expression by in vivo polyethyleneimine-mediated Sema7A down-regulation. Our results indicated that Sema7A was up-regulated in cardiomyocytes during VMC, and that Sema7A down-regulation following short hairpin RNA interference or mAb neutralization effectively protected mice from VMC. Additionally, reduced inflammatory responses were observed along with Sema7A down-regulation. Furthermore, adoptive transfer of α1ß1-integrin macrophages exacerbated CVB3-induced myocarditis, suggesting the significance of α1ß1-integrin macrophages in response to VMC. We observed that co-culture of neonatal myocardiocytes with macrophages increased the percentage of α1ß1-integrin macrophages, while Sema7A neutralization reduced α1ß1-integrin macrophages in heart tissue of VMC mice. These results demonstrated that Sema7A, as an inflammation regulator in CVB3-induced VMC, might interact with α1ß1-integrin in macrophages to enhance the inflammatory response and aggravate disease severity. Our findings provided insight into the potential role of Sema7A as a therapeutic treatment for VMC.

Comparative study of dendritic cells matured by using IL-1ß, IL-6, TNF-α and prostaglandins E2 for different time span.

Interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and prostaglandins E2 is considered as the standard cocktail for maturing dendritic cells (DCs). However, the appropriate time span for DC maturation with the standard cocktail remains unclear. The present study aimed to compare the differences between DCs matured with the standard cocktail for 24 and 48 h, respectively, and determine whether 24-h stimulation was sufficient for DC maturation. The findings demonstrated that, compared with DCs matured for 48 h, the levels of cluster of differentiation (CD)80, CD83, CD86 and programmed death-ligand 1 expression in DCs matured for 24 h were relatively lower. However, with the exception of CD80 whose mean fluorescence intensity (MFI) was higher in DCs matured for 48 h, the MFI values of other surface markers were comparable. Notably, the MFI of CD40 was higher in DCs matured for 24 h. In addition, the viability, T cell stimulatory capacity in allogeneic mixed lymphocyte reaction and cytokine production, including IL-12p40, IL-12p70 and IL-10, were all comparable between DCs matured for 24 and 48 h, respectively. These results indicated that 24-h stimulation may be sufficient for DC maturation when using the standard cocktail.

Transmissible endoplasmic reticulum stress from myocardiocytes to macrophages is pivotal for the pathogenesis of CVB3-induced viral myocarditis.

Infiltrating macrophages have been proven as a pivotal pathological inflammatory cell subset in coxsackievirus B3 (CVB3) induced viral myocarditis. However, the mechanisms underlying the initiation and promotion of macrophage pro-inflammatory responses are still blur. We previously reported that cardiac ER stress contributed to CVB3-induced myocarditis by augmenting inflammation. In this study, we focused on the influence of ER stress on the macrophage inflammatory responses in the viral myocarditis. We found that ER stress was robustly induced in the cardiac infiltrating macrophages from CVB3-infected mice, and robustly facilitated the production of pro-inflammatory cytokines (IL-6, IL-12, MCP-1 and IP-10). Consistently, adoptive transfer of ER stressed macrophages significantly worsened the viral myocarditis; while transfer of ER stress-inhibited macrophages obviously alleviated the myocarditis. To our surprise, this significantly activated ER stress was not directly caused by the virus stimulation, but was transferred from the CVB3-infected, ER stressed myocardiocytes via soluble molecules in a TLR2, 4-independent way. In the present study, we reported that the transmissible ER stress from the infected myocardiocytes to macrophages could augment the pro-inflammatory responses and promoted the pathogenesis of viral myocarditis. Blocking ER stress transmission, instead of inhibiting its initiation, may represent novel therapeutic strategies against viral myocarditis.

[A case-control study on the relationship between organochlorine and female breast cancer].

OBJECTIVE: To describe the serum organochlorines residues and explore the relationship between organochlorines exposure and the female breast cancer in Ningxia. METHODS: 1:1 matched case-control study based on 92 new diagnostic breast cancer patients and 92 patients without tumors from Ningxia medical university general hospital was designed. The risk factors of breast cancer were investigated by a questionnaire. GC-ECD was used to measure the serum level of organochlorines residues. The adjusted odds rations (OR) of organochlorines residues to breast cancer were evaluated by conditional Logistic regression model. RESULTS: 15 organochlorines residues could be detected in serum of cases and controls. The detecting rates of beta-HCH, delta-HCH, p,p'-DDE, PCB28 and PCB52 were higher than 90%. There were significant differences of serum level of beta-HCH, p,p'-DDE and PCB52 between cases and controls (P < 0.05). After adjusting confounding factors, serum beta-HCH, p,p'-DDE and PCB52 level were positively related to the risk of breast cancer (adjusted OR > 2, P < 0.05). CONCLUSION: Organochlorines resides, including DDT, HCH and PCB, may increase women's risk of getting breast cancer.

Pegylated interferon α-2b up-regulates specific CD8+ T cells in patients with chronic hepatitis B.

AIM: to investigate the effect of pegylated interferon (IFN) α-2b on specific CD8+ T lymphocytes in patients with chronic hepatitis B (CHB). METHODS: twenty-one patients with CHB were treated with pegylated IFN α-2b. Periphery blood mononuclear cells were isolated from fresh heparinized blood by Ficoll-Hypaque density gradient centrifugation (density: 1.077 g/L, Pharmingen) at weeks 0, 4, 8, 12, and 24, respectively. Frequency of circulating hepatitis B virus (HBV) epitope-specific CD8 T cells was detected by flow cytometry. Cytokines were detected by cytometric bead assay. RESULTS: the frequency of circulating HBV core or env-specific CD8 T cells was higher (P < 0.05), the number of HBV core specific CD8 T cells was greater at week 24 (P < 0.05), the level of Th1-type cytokines [interleukin (IL)-12, tumor necrosis factor-α, and IFN-γ] was higher, while that of Th2-type cytokines (IL-4, IL-6, and IL-10) was lower in responders than in non-responders (P < 0.05) after pegylated IFN α-2b treatment. The IL-6 level was correlated with HBV DNA (r = 0.597, P = 0.04), while the inducible protein-10 (IP-10) level was correlated with serum alanine aminotransferase (ALT) (r = 0.545, P = 0.005). The IP-10 level at week 8 after pegylated IFN α-2b treatment could predict the normalization of ALT in CHB patients (positive predict value = 56%, negative predict value = 92%). CONCLUSION: pegylated IFN α-2b can enhance the immune response of CHB patients by increasing the frequency of HBV specific CD8+ T cells and regulating the Th1/Th2 cytokines.

Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis.

There is a controversy over whether the different outcomes of prophylaxis of hepatitis B virus (HBV) recurrence are attributable to different treatments. A systematic review and a meta-analysis were conducted to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in HBV infected liver recipients. A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes. Six articles (551 patients) fulfilled the inclusion criteria. Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence [P < 0.0001; RR = 0.38; 95% CI (0.25, 0.58)], YMDD mutant [P = 0.002; RR = 0.40; 95% CI (0.23, 0.72)] and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation [P < 0.00001; RR = 0.31; 95% CI (0.21, 0.45)]. No significant differences were observed in patient survival [P = 0.59; RR = 1.02; 95% CI (0.95, 1.09)], graft survival [P = 0.56; RR = 1.02; 95% CI (0.95, 1.09)] and diseases leading to death between the two groups [HBV recurrence leading to death: P = 0.05; RR = 0.47; 95% CI (0.22, 1.02); hepatocellular carcinoma recurrence leading to death: P = 0.13; RR = 0.34; 95% CI (0.09, 1.36)]. In conclusion, combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly. Well-designed large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.

Hepatoma cells up-regulate expression of programmed cell death-1 on T cells.

AIM: To investigate the effect of hepatoma cells on up-regulation of programmed cell death-1 (PD-1), and the function of PD-1 on T cells. METHODS: HepG2 or HepG2.2.1.5 cells were co-cultured with a lymphoma cell line-Jurkat cells. PD-1 expression was detected by flow cytometry. IL-2, INF-gamma and IL-10 in culture supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Cytotoxic action of T cells was determined by MTT reduction assay-direct mononuclear cell cytotoxicity assay. RESULTS: The PD-1 expression on Jurkat cells increased by 16.17% +/- 2.5% and 17.43% +/- 2.2% after HepG2 or HepG2.2.1.5 cells were co-cultured for 48 h. The levels of IL-2, INF-gamma and IL-10 in the culture supernatant were 202.9 +/- 53.0 pg/mL, 88.6 +/- 4.6 pg/mL and 63.7 +/- 13.4 pg/mL respectively, which were significantly higher than those (102.9 +/- 53 pg/mL, 39.3 +/- 4.2 pg/mL, and 34.6 +/-13.7 pg/mL) in the control group (P < 0.05). The OD value for MTT assay in the blocking group (0.29 +/- 0.06) was significantly higher than that (0.19 +/- 0.09) in the control group (P < 0.05). CONCLUSION: PD-1 expression on Jurkat cells is up-regulated by hepatoma cells, cytokines and cytotoxic action are elevated after PD-1/PD-L1 is blocked.