Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

Objectives:To examine the risk factors of anastomotic leakage for low rectal cancers undergoing laparoscopic intersphincteric resection (ISR), and to construct a nomogram prediction model for it.Methods:The perioperative data of 302 low rectal cancer patients undergoing laparoscopic ISR by the same surgical team of Department of General Surgery, Peking University First Hospital between January 2012 and January 2019 were retrospectively reviewed. There were 190 males and 112 females, aging 60(14) years (range: 20 to 84 years). χ 2 test, independent sample t test, U test and Logistic regression analysis were used to analyze the risk factors for anastomotic leakage. R software was used to complete the drawing of the nomogram prediction model, and the receiver operating characteristic curve was used to evaluate the predictive ability of the nomogram prediction model. Results:There were 24 patients (7.9%) had anastomotic leakage among the 302 patients enrolled, including 10 cases of grade A leakage, 9 cases of grade B leakage, and 5 cases of grade C leakage. Out of the 24 patients, 2 patients (8.3%) died, 3 patients (12.5%) received leakage-related reoperation. Median healing time of the anastomotic leakage was 74 (58) days (range: 14 to 180 days). Univariate analysis showed male gender ( P=0.009), preoperative serum albumin concentration ( P=0.004), neoadjuvant radiochemotherapy ( P=0.017), preserving left colonic artery ( P=0.002) and performing a diverting ileostomy ( P=0.015) were significantly correlated with anastomotic leakage. Logistic multivariate analysis showed male gender ( OR=6.052, 95% CI: 1.535 to 23.860, P=0.010), neoadjuvant radiochemotherapy ( OR=4.098, 95% CI: 1.318 to 12.821, P=0.015), no preserving left colonic artery ( OR=16.699, 95% CI: 3.051 to 91.406, P=0.001) and not performing a diverting ileostomy ( OR=21.218, 95% CI: 4.341 to 103.710, P<0.01) were independent risk factors for anastomotic leakage. According to the results of multi-factor regression analysis, the nomogram prediction model was constructed. The area under the curve of the nomogram prediction model was 0.840 (95% CI: 0.766 to 0.914). After internal verification, the concordance index value of the model was 0.840. Conclusion:Male gender, neoadjuvant radiochemotherapy, no preserving left colonic artery and not performing a diverting ileostomy are independent risk factors for anastomotic leakage for low rectal cancers undergoing laparoscopic ISR.

Objectives:To examine the risk factors of anastomotic leakage for low rectal cancers undergoing laparoscopic intersphincteric resection (ISR), and to construct a nomogram prediction model for it.Methods:The perioperative data of 302 low rectal cancer patients undergoing laparoscopic ISR by the same surgical team of Department of General Surgery, Peking University First Hospital between January 2012 and January 2019 were retrospectively reviewed. There were 190 males and 112 females, aging 60(14) years (range: 20 to 84 years). χ 2 test, independent sample t test, U test and Logistic regression analysis were used to analyze the risk factors for anastomotic leakage. R software was used to complete the drawing of the nomogram prediction model, and the receiver operating characteristic curve was used to evaluate the predictive ability of the nomogram prediction model. Results:There were 24 patients (7.9%) had anastomotic leakage among the 302 patients enrolled, including 10 cases of grade A leakage, 9 cases of grade B leakage, and 5 cases of grade C leakage. Out of the 24 patients, 2 patients (8.3%) died, 3 patients (12.5%) received leakage-related reoperation. Median healing time of the anastomotic leakage was 74 (58) days (range: 14 to 180 days). Univariate analysis showed male gender ( P=0.009), preoperative serum albumin concentration ( P=0.004), neoadjuvant radiochemotherapy ( P=0.017), preserving left colonic artery ( P=0.002) and performing a diverting ileostomy ( P=0.015) were significantly correlated with anastomotic leakage. Logistic multivariate analysis showed male gender ( OR=6.052, 95% CI: 1.535 to 23.860, P=0.010), neoadjuvant radiochemotherapy ( OR=4.098, 95% CI: 1.318 to 12.821, P=0.015), no preserving left colonic artery ( OR=16.699, 95% CI: 3.051 to 91.406, P=0.001) and not performing a diverting ileostomy ( OR=21.218, 95% CI: 4.341 to 103.710, P<0.01) were independent risk factors for anastomotic leakage. According to the results of multi-factor regression analysis, the nomogram prediction model was constructed. The area under the curve of the nomogram prediction model was 0.840 (95% CI: 0.766 to 0.914). After internal verification, the concordance index value of the model was 0.840. Conclusion:Male gender, neoadjuvant radiochemotherapy, no preserving left colonic artery and not performing a diverting ileostomy are independent risk factors for anastomotic leakage for low rectal cancers undergoing laparoscopic ISR.

Echinococcosis is a disease caused by the Echinococcus species that parasitizes in humans. Alveolar echinococcosis (AE) which is caused by Echinococcus multilocularis is harmful to humans. AE mainly occurs in the liver and can be transferred to retroperitoneal lymph nodes, lung, brain, bone, spleen and other organs through lymphatic and blood vessels. Cholangiocarcinoma can occur in the intrahepatic and extrahepatic bile ducts and is more common in the hilar. We reported a case of hilar bile duct alveolar echinococcosis which was originally misdiagnosed an cholangiocarcinoma.
Bile Ducts ; Bile Ducts, Extrahepatic ; Bile ; Blood Vessels ; Brain ; Cholangiocarcinoma ; Echinococcosis ; Echinococcus ; Echinococcus multilocularis ; Humans ; Liver ; Lung ; Lymph Nodes ; Spleen