ObjectiveTo investigate the possible mechanism of Wenfei Huaxian Decoction （温肺化纤汤） in treatment of pulmonary fibrosis in systemic sclerosis-associated interstitial lung disease （SSc-ILD）. MethodsSixty C3H/He female rats were randomly divided into a control group， a model group， a pirfenidone group， and low-， medium-， and high-dose Wenfei Huaxian Decoction groups. The SSc-ILD model mice was established by subcutaneous injection of bleomycin solution 0.04 mg/d into the back of mice for 28 days in all groups but the control group. After successful modelling， the pirfenidone group was given pirfenidone capsule 300 mg/（kg·d） by gavage， the low-， medium- and high-dose Wenfei Huaxian Decoction groups were given Wenfei Huaxian Decoction 7.81， 15.62， and 31.24 g/（kg·d） by gavage， respectively， and the control group as well as the model group were given normal saline 0.1 ml/10 g by gavage， for a total of 21 days. At the end of the intervention， HE staining and Masson staining were used to observe the pathological changes in the skin and lung tissues； the hydroxyproline content of the skin and lung tissues was detected； the protein expression levels of endoplasmic reticulum stress-related proteins glucose-regulated protein 78 （BIP） and C/EBP homologous protein （CHOP） as well as those of nuclear factor kappa B （NF-κB） pathway p65 were measured by western blot； ELISA was performed to determine the expression levels of interferon gamma （IFN-γ）， interleukin 6 （IL-6） and tumour necrosis factor alpha （TNF-α） in serum of rats. ResultsThe results of HE and Masson staining indicated that compared with the control group， the dermis significantly thickened， the number of collagen fibers significantly enlarged， and the number of inflammatory cells significantly increased in the model group； the lung tissue showed a marked inflammatory cellular response with massive collagen fibre proliferation with inflammatory cell infiltration. Compared with the model group， the skin tissue and lung tissue collagen fibre proliferation significantly reduced and inflammatory cell infiltration reduced in the pirfenidone group and all dose groups of Wenfei Huaxian Decoction， and the effects of pirfenidone group and Wenfei Huaxian Decoction medium- and high-dose groups were basically comparable. Compared with the model group， the content of hydroxyproline in skin and lung tissue， the serum level of IFN-γ， IL-6 and TNF-α， and the expression levels of BIP and CHOP protein in lung tissue increased in model group （P＜0.05）. Compared with model group， the content of hydroxyproline in skin tissue of pirfenidone group， low-and medium-dose Wenfei Huaxian Decoction groups decreased， and the content of hydroxyproline in lung tissue of medium-dose Wenfei Huaxian Decoction group decreased. The serum level of IFN-γ， IL-6， TNF-α and the expression levels of BIP， CHOP and p65 protein in lung tissue of rats in pirfenidone group and high-dose Wenfei Huaxian Decoction group decreased （P＜0.05）. The content of hydroxyproline in lung tissue of medium-dose Wenfei Huaxian Decoction group was significantly lower than that of low-dose and high-dose Wenfei Huaxian Decoction group， and the serum level of IFN-γ， IL-6， TNF-α in low- and medium-dose Wenfei Huaxian Decoction group were higher than those in high-dose Wenfei Huaxian Decoction group. The expression level of BIP protein in high-dose group was significantly lower than that in low- and medium-dose Wenfei Huaxian Decoction groups （P＜0.05）. ConclusionWenfei Huaxian Decoction can improve the skin and lung fibrosis of SSc-ILD rats， which may act through anti-inflammation， inhibition of NF-κB pathway， and then inhibition of endoplasmic reticulum stress， which ultimately blocked the fibrotic process.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death, and most patients with HCC are diagnosed at an advanced stage. Before 2017, tyrosine kinase inhibitors were the main drugs for the treatment of advanced hepatocellular carcinoma. With the emergence of immune checkpoint inhibitors (ICIs), immunotherapy has gradually brought new hope to such patients. At present, the combination of ICIs and other systemic or local treatments has become a potential strategy for the treatment of advanced hepatocellular carcinoma, and some of these combinations have been included in large-scale clinical trials. The main challenges of immunotherapy for advanced hepatocellular carcinoma include the exploration of predictive biomarkers, management of immune-related adverse events, and exploration of effective combination regimens. This article provides the latest research progress on the single or combined use of ICIs and other immunotherapy for hepatocellular carcinoma and discusses the limitations of current research and clinical application and the future development direction.

BACKGROUND: Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL. METHODS: The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens. RESULTS: We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo . CONCLUSION Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.
Humans ; Animals ; Mice ; Rituximab/therapeutic use* ; Hippo Signaling Pathway ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Prognosis ; Semaphorins/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Membrane Proteins/genetics* ; Nerve Tissue Proteins/genetics*

Objective:To summarize the clinical characteristics and risk factors of acute rejection(AR)of transplanted pancreas and kidney after simultaneous pancreas-kidney transplantation(SPK)and explore the effects of AR on the survival of transplanted pancreas, kidney and recipients.Methods:From September 2016 to July 2022, the relevant clinical data were retrospectively reviewed for 218 recipients undergoing SPK.According to whether or not AR occurred after SPK, they were assigned into two groups of AR(n=53)and non-AR(n=165). The relevant clinical data were compared for two groups of donors and recipients and the risk factors of AR analyzed by binary Logistic regression.Kaplan-Meier method was employed for comparing the survival rates of recipients/transplanted pancreas and kidneys in two groups.Results:A total of 53 cases(24.3%)developed ARs of transplanted pancreas(n=31, 14.2%)(5 of 2 ARs), transplanted kidney(n=15, 6.9%)(1 of 2 ARs)and transplanted pancreas & kidney AR(n=11, 5.0%)(2 of 2 ARs). Tacrolimus blood levels in AR and non-AR groups were(5.8±1.2)and(6.3±1.6)μg/L and failed to attain targets in 36(67.9%)and 78(47.3%)cases.During follow-ups, the incidence of pneumonia and urinary tract infections in AR group versus non-AR group were[43.4%(23/53)vs.27.3%(45/165)and 39.6%(21/53)vs.18.8%(31/165)]and the differences were statistically significant( P=0.028 & 0.002). The results of multifactorial regression analysis revealed that sub-optimal blood level of tacrolimus was an independent risk factor for an occurrence of AR in grafts of SPK recipients( OR=2.254, 95% CI: 1.167-4.353, P=0.016). Comparisons of 1/5-year postoperative survival rates between recipients in AR and no-AR group(98.1% vs.93.9% and 92.1% vs.92.4%)indicated that the differences were not statistically significant( P=0.233 & 0.806). Through comparing 1/5-year survival rates of transplanted pancreas in AR and non-AR groups(94.3% vs.100%, 89.4% vs.98.6%), the differences were statistically significant( P=0.003 & 0.004). And 1/5-year survival rates of transplanted kidneys in AR and non-AR groups(92.5% vs.100% and 90.2% vs.100%)were compared and the differences were statistically significant(all P<0.001). Conclusions:The incidence of AR is higher in transplanted pancreas and kidney after SPK.And the incidence of pneumonia and urinary tract infection is higher in AR group than that in non-AR group.Sub-optimal blood level of tacrolimus is an independent risk factor for the occurrence of AR.The 1/5-year survival rates of transplanted pancreas and transplanted kidney are lower in AR group than those in non-AR group.It has some effect on the survival of transplanted pancreas and kidney.

Cryptogenic organic pneumonia (COP) refers to organic pneumonia that has not been identified a clear cause by current medical methods. A small proportion of COP can exhibit severe and progressive characteristics, while severe COP can cause systemic inflammatory storms and can be secondary to hemophilia. This article reported a case of acute severe COP secondary to hemophilia. A 67-year-old male patient was admitted to the hospital due to cough, shortness of breath, and fever. At first, he was misdiagnosed as severe pneumonia, but failed to receive anti infection treatments. Sputum pathogenetic examination and Macrogene testing of alveolar lavage fluid were performed, and no etiology was found to explain the patient's condition. The condition was gradually worsened and hemophilia occurred to explain, suggesting that acute severe COP was relevant. After receiving hormone treatment, the condition gradually relieved and the absorption of lung lesions improved. Hemophilia secondary to COP is rare, and the specific mechanism needs further study.
Male ; Humans ; Aged ; Hemophilia A/complications* ; Pneumonia/diagnosis* ; Bronchoalveolar Lavage Fluid ; Cough ; Dyspnea/etiology*

Objective:To study the signaling pathway of the up-regulation of claudin-5 expression by Xuebijing injection.Methods:Animal and cell models of acute respiratory distress syndrome (ARDS) were induced by lipopolysaccharide (LPS). ① In vivo study, 20 male Sprague-Dawley (SD) rats were randomly divided into 4 groups: control group, LPS group (LPS injection 10 mg/kg for 12 hours), Xuebijing control group (Xuebijing injection 1 mg/kg, twice a day, for 3 days), and Xuebijing intervention group (LPS injection after pretreatment of Xuebijing injection), according to random number method with 5 rats in each group. The lung tissues were taken to detect lung dry/wet weight ratio (W/D) and the morphological changes in each group. Claudin-5, phosphorylated forkhead box transcription factor O1 (p-FOXO1), total FOXO1 (t-FOXO1), phosphorylated Akt (p-Akt) and total Akt (t-Akt) in lung tissues were detected by immunohistochemical staining (IHC) and Western blotting. ② In vitro study, human pulmonary microvascular endothelial cells (HPMECs) were divided into 6 groups (5 holes in each group): control group, Xubijing control group (incubated with 2 g/L Xubijing for 24 hours), phosphoinositide 3-kinases (PI3K) signaling pathway LY294002 control group (incubated with 10 μmol/L LY294002 for 1 hour), LPS group (incubated with 1 mg/L LPS for 12 hours), Xubijing intervention group (incubated with 2 g/L Xuebijing for 24 hours, then with 1 mg/L LPS for 12 hours) and LY294002 intervention group (incubated with 10 μmol/L LY294002 for 1 hour, then with 2 g/L and Xubijing for 24 hours, and then with 1 mg/L LPS for 12 hours). The expression levels of claudin-5, p-FOXO1, t-FOXO1, p-Akt and t-Akt of HPMECs in each group were assessed by Western blotting. Results:In vivo study: ① Compared with the control group, the lung W/D ratio increased significantly in LPS group (6.79±0.42 vs. 4.19±0.13), and decreased significantly after the intervention of Xuebijing (4.92±0.38 vs. 6.79±0.42, P < 0.01). ② Morphological changes of lung tissue: compared with the control group, the injury of lung tissue in LPS group was more serious, which was significantly improved after Xuebijing intervention. ③ Expression levels of claudin-5, p-Akt/t-Akt and p-FOXO1/t-FOXO1: the expression levels of claudin-5, p-Akt/t-Akt and p-FOXO1/t-FOXO1 in LPS group were significantly decreased as compared with the control group (claudin-5/GAPDH: 0.33±0.03 vs. 1.03±0.07, p-Akt/t-Akt: 0.18±0.02 vs. 1.01±0.13, p-FOXO1/t-FOXO1: 0.16±0.06 vs. 1.00±0.19, all P < 0.01). After the intervention of Xuebijing, the expression levels were significantly increased as compared with the LPS group (claudin-5/GAPDH: 0.53±0.05 vs. 0.33±0.03, p-Akt/t-Akt: 0.56±0.12 vs. 0.18±0.02, p-FOXO1/t-FOXO1: 0.68±0.10 vs. 0.16±0.06, all P < 0.01). In vitro study: compared with the control group, the expression level of claudin-5 in the LPS group was significantly decreased (claudin-5/β-actin: 0.45±0.03 vs. 1.01±0.15, P < 0.01), and the expression level of claudin-5 in Xuebijing intervention group was also significantly decreased (claudin-5/β-actin: 0.80±0.08 vs. 1.01±0.15, P < 0.01). After the intervention of LY294002, the expression of claudin-5 was significantly decreased as compared with the Xubijing intervention group (claudin-5/β-actin: 0.41±0.02 vs. 0.80±0.08, P < 0.01). Conclusion:Xuebijing injection improve pulmonary vascular barrier function in rats with ARDS by up-regulating claudin-5 expression through PI3K/Akt/FOXO1 signaling pathway.

Barrett’s esophagus (BE) is the recognized precancerous lesion and risk factor for esophageal adenocarcinoma (EAC), and has a high miss diagnosis rate and low survival rate when malignantly transformed into EAC, moreover, there are only limited monitoring method and treatment. Therefore, the screening of biomarkers is highly expected, especially the risk stratification biomarkers related to the progression of malignant transformation of BE. Such biomarkers can help to determine early, quickly and accurately the disease process, and guide the stratified management and precise treatment of BE, reduce the malignancy rate and mortality. This article focused on the dynamic evolutionary process of intra‑tumor heterogeneity, and reviewed the current status and challenges of research on BE biomarkers in risk stratification from the genetics, epigenetics and serology perspectives.

This study was conducted between November to December 2020, consisting of six representative cities, Beijing, Shanghai, Shenzhen (with comprehensive smoke-free legislation), and Changsha, Chongqing, Shenyang (without comprehensive smoke-free legislation), 678 subjects were enrolled eventually, the mean age of the 678 subjects was (35.61±12.91)years old. Subjects from cities with comprehensive smoke-free legislation accounted for 49.71% of the total; male subjects accounted for 19.47%; meanwhile subjects from large, medium, and small restaurants accounted for 13.57% (92), 37.32% (253) and 49.11% (333) respectively. The analysis results indicate that the positive rate of restaurants staff of cotinine and 3′-hydroxynicotinine was lower in cities with comprehensive smoke-free legislation(34.12% vs 68.04%, χ2=78.01, P<0.001; 16.32% vs 41.94%, χ2=53.79, P<0.001), with staff from cities with comprehensive smoke-free legislation have lower concentrations of cotinine and 3′-hydroxynicotinine than their counterparts from cities without comprehensive smoke-free legislation(0.250 ng/ml vs 0.742 ng/ml, P<0.001; 0.250 ng/ml vs 0.250 ng/ml, P<0.001). No statistically significant difference in the concentration of cotinine and 3′-hydroxynicotinine in saliva between staff from restaurants of different sizes was detected ( P>0.05).

This study was conducted between November to December 2020, consisting of six representative cities, Beijing, Shanghai, Shenzhen (with comprehensive smoke-free legislation), and Changsha, Chongqing, Shenyang (without comprehensive smoke-free legislation), 678 subjects were enrolled eventually, the mean age of the 678 subjects was (35.61±12.91)years old. Subjects from cities with comprehensive smoke-free legislation accounted for 49.71% of the total; male subjects accounted for 19.47%; meanwhile subjects from large, medium, and small restaurants accounted for 13.57% (92), 37.32% (253) and 49.11% (333) respectively. The analysis results indicate that the positive rate of restaurants staff of cotinine and 3′-hydroxynicotinine was lower in cities with comprehensive smoke-free legislation(34.12% vs 68.04%, χ2=78.01, P<0.001; 16.32% vs 41.94%, χ2=53.79, P<0.001), with staff from cities with comprehensive smoke-free legislation have lower concentrations of cotinine and 3′-hydroxynicotinine than their counterparts from cities without comprehensive smoke-free legislation(0.250 ng/ml vs 0.742 ng/ml, P<0.001; 0.250 ng/ml vs 0.250 ng/ml, P<0.001). No statistically significant difference in the concentration of cotinine and 3′-hydroxynicotinine in saliva between staff from restaurants of different sizes was detected ( P>0.05).