Somatostatin receptor 1 (SSTR1) is a crucial therapeutic target for various neuroendocrine and oncological disorders. Current SSTR1-targeted treatments, including the first-generation somatostatin analog lanreotide (Lan) and the second-generation analog pasireotide (Pas), show promise but encounter challenges related to selectivity and efficacy. This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas, revealing the distinct mechanisms of ligand-binding and activation. These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand, which are critical for receptor activation and ligand selectivity. Combined with the biochemical assays and molecular dynamics simulations, our results provide a comparative analysis of binding characteristics within the SSTR family, highlighting subtle differences in SSTR1 activation by Lan and Pas. These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.

Bilirubin,as a major endogenous substance in the human body,plays anti-inflammatory,antioxidant,and cytoprotective roles within physiological ranges,serving a critical function in maintaining metabolic balance of endogenous substances.Bilirubin metabolism is a complex physiological process regulated by multiple factors,relying on UGT1A1 enzyme catalysis and transporter protein modulation to sustain substance homeostasis.Based on the theory of traditional Chinese medicine(TCM)channel tropism and the principle of visceral syndrome differentiation,liver-channel-tropic herbs can guide medications to specific viscera and meridians,exerting targeted therapeutic effects.These herbs regulate bilirubin metabolic disorders through multi-target mechanisms,including upregulating UGT1A1 enzyme activity to promote bilirubin conjugation,modulating MRP2/OATP expression to enhance bilirubin transport,attenuating oxidative stress to reduce hepatocyte damage,inhibiting inflammatory cytokines to restore metabolic enzyme activity,activating CAR signaling pathways to regulate bile acid homeostasis.This review summarizes the mechanisms by which TCM regulates bilirubin metabolism,focuses on the role of liver meridian-targeting TCM to provide a basis for its rational clinical use,and studies the effects of liver meridian-targeting TCM on bilirubin metabolism from its core mechanisms to guide its rational use and provide new ideas for the research and development of traditional Chinese medicine.This review summarizes the mechanisms by which TCM regulates bilirubin metabolism,focusing on the actions of herbs that enter the liver meridian.Starting from the core mechanisms,it explores how liver meridian-entering herbs significantly impact bilirubin metabolism.Some of these herbs demonstrate dual-directional regulatory effects on bilirubin metabolism.This understanding guides their rational clinical use,provides novel ideas for TCM research and development,and promotes the modernization of TCM studies.

Knee osteoarthritis(OA)is a primary cause of joint dysfunction.Knee osteotomy has garnered significant attention due to its potential to delay the progression of knee OA and enhance joint function.As a pivotal biomechanical factor in the onset and progression of OA,the accurate correction of abnormal knee alignment is the central objective of knee osteotomy.This article systematically reviews the biomechanical research progress related to knee osteotomy,with a focus on the precision and personalized correction of force line.The development of new classification system and measurement technology of force line is summarized,the biomechanical mechanism of knee OA induced by abnormal mechanical load is analyzed,and the goal of force line and clinical application progress of knee osteotomy is discusses,so as to provide a new perspective and idea for the clinical treatment of knee OA with knee osteotomy.

Bilirubin,as a major endogenous substance in the human body,plays anti-inflammatory,antioxidant,and cytoprotective roles within physiological ranges,serving a critical function in maintaining metabolic balance of endogenous substances.Bilirubin metabolism is a complex physiological process regulated by multiple factors,relying on UGT1A1 enzyme catalysis and transporter protein modulation to sustain substance homeostasis.Based on the theory of traditional Chinese medicine(TCM)channel tropism and the principle of visceral syndrome differentiation,liver-channel-tropic herbs can guide medications to specific viscera and meridians,exerting targeted therapeutic effects.These herbs regulate bilirubin metabolic disorders through multi-target mechanisms,including upregulating UGT1A1 enzyme activity to promote bilirubin conjugation,modulating MRP2/OATP expression to enhance bilirubin transport,attenuating oxidative stress to reduce hepatocyte damage,inhibiting inflammatory cytokines to restore metabolic enzyme activity,activating CAR signaling pathways to regulate bile acid homeostasis.This review summarizes the mechanisms by which TCM regulates bilirubin metabolism,focuses on the role of liver meridian-targeting TCM to provide a basis for its rational clinical use,and studies the effects of liver meridian-targeting TCM on bilirubin metabolism from its core mechanisms to guide its rational use and provide new ideas for the research and development of traditional Chinese medicine.This review summarizes the mechanisms by which TCM regulates bilirubin metabolism,focusing on the actions of herbs that enter the liver meridian.Starting from the core mechanisms,it explores how liver meridian-entering herbs significantly impact bilirubin metabolism.Some of these herbs demonstrate dual-directional regulatory effects on bilirubin metabolism.This understanding guides their rational clinical use,provides novel ideas for TCM research and development,and promotes the modernization of TCM studies.

Knee osteoarthritis(OA)is a primary cause of joint dysfunction.Knee osteotomy has garnered significant attention due to its potential to delay the progression of knee OA and enhance joint function.As a pivotal biomechanical factor in the onset and progression of OA,the accurate correction of abnormal knee alignment is the central objective of knee osteotomy.This article systematically reviews the biomechanical research progress related to knee osteotomy,with a focus on the precision and personalized correction of force line.The development of new classification system and measurement technology of force line is summarized,the biomechanical mechanism of knee OA induced by abnormal mechanical load is analyzed,and the goal of force line and clinical application progress of knee osteotomy is discusses,so as to provide a new perspective and idea for the clinical treatment of knee OA with knee osteotomy.

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.
Humans ; Neoplasms/pathology* ; Biomarkers ; Prognosis ; Oceans and Seas ; China/epidemiology*

The aim of this study was to investigate the effect of transmembrane 9 superfamily protein member 2 (TM9SF2) in proliferation and migration of triple negative breast cancer cell line MDA-MB-231.The expression of TM9SF2 in triple negative breast cancer cell line MDA-MB-231 and nontumorigenic mammary epithelial cell line MCF-10A were measured by Western blot. MDA-MB-231 cells were treated with siRNA-TM9SF2 to knock-down the expression of TM9SF2. The effect of silencing TM9SF2 was measured with Western blot.The proliferation of cells was tested by MTS,and the migration was measured with Transwell and wound-healing assay.Proteins related to proliferation (PI3K,AKT,SRC and ERK) and migration (Snail,Slug and N-cadherin) were measured with Western blot.Protein expressions of TM9SF2 was better improved in triple negative breast cancer MDA-MB-231 cell line than MCF-10A.Compared with the control group, the siRNA-TM9SF2 infected group had lower expressions of PI3K, Snail, Slug and N-cadherin, and at the same time phosphorylation of AKT was decreased. The results suggest TM9SF2 can promote the proliferation and metastasis of triple negative breast cancer MDA-MB-231 cell line.

Objective: To analyze the clinical characteristics of cases of novel coronavirus pneumonia and a preliminary study to explore the relationship between different clinical classification and liver damage. Methods: Consecutively confirmed novel coronavirus infection cases admitted to seven designated hospitals during January 23, 2020 to February 8, 2020 were included. Clinical classification (mild, moderate, severe, and critical) was carried out according to the diagnosis and treatment program of novel coronavirus pneumonia (Trial Fifth Edition) issued by the National Health Commission. The research data were analyzed using SPSS19.0 statistical software. Quantitative data were expressed as median (interquartile range), and qualitative data were expressed as frequency and rate. Results: 32 confirmed cases that met the inclusion criteria were included. 28 cases were of mild or moderate type (87.50%), and four cases (12.50%) of severe or critical type. Four cases (12.5%) were combined with one underlying disease (bronchial asthma, coronary heart disease, malignant tumor, chronic kidney disease), and one case (3.13%) was simultaneously combined with high blood pressure and malignant tumor. The results of laboratory examination showed that the alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and total bilirubin (TBil) for entire cohort were 26.98 (16.88 ~ 46.09) U/L and 24.75 (18.71 ~ 31.79) U/L, 39.00 (36.20 ~ 44.20) g/L and 16.40 (11.34- ~ 21.15) mmol/L, respectively. ALT, AST, ALB and TBil of the mild or moderate subgroups were 22.75 (16.31- ~ 37.25) U/L, 23.63 (18.71 ~ 26.50) U/L, 39.70 (36.50 ~ 46.10) g/L, and 15.95 (11.34 ~ 20.83) mmol/L, respectively. ALT, AST, ALB and TBil of the severe or critical subgroups were 60.25 (40.88 ~ 68.90) U/L, 37.00 (20.88 ~ 64.45) U/L, 35.75 (28.68 ~ 42.00) g/L, and 20.50 (11.28 ~ 25.00) mmol/L, respectively. Conclusion The results of this multicenter retrospective study suggests that novel coronavirus pneumonia combined with liver damage is more likely to be caused by adverse drug reactions and systemic inflammation in severe patients receiving medical treatment. Therefore, liver function monitoring and evaluation should be strengthened during the treatment of such patients.

ObjectiveTo investigate the risk factors and insulin resistance (IR) of nonalcoholic fatty liver disease (NAFLD) with a normal visceral adipose tissue (VAT) area. MethodsA total of 45 NAFLD persons with a normal VAT area who were admitted to Quanzhou First Hospital Affiliated to Fujian Medical University from June 2017 to May 2018 were enrolled as observation group, and 27 non-NAFLD patients with a normal VAT area were enrolled as control group. VAT area, waist circumference, fasting blood glucose (FBG), and fasting insulin (FINS) were measured for both groups, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, and the correlation of IR with the indices including waist circumference was analyzed. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups. Pearson correlation analysis and Spearman correlation analysis were used to investigate the correlation of normally and non-normally distributed continuous data. A forward logistic regression analysis was used to identify related risk factors. ResultsThe NAFLD group had a significantly higher level of IR than the control group, and there was a significant difference in HOMA-IR between the two groups (2.66(1.59-4.06) vs 1.84(125-2.47), Z=364.000, P=0005). IR was positively correlated with FBG (r=0.412, P=0.005), FINS (r=0.789, P＜0001), and TG (r=0.306, P=0041). IR was negatively correlated with HDL(r=-9398,P=0007). The multivariate regression analysis showed that waist circumference was an independent risk factor for NAFLD with a normal VAT area (regression coefficient = 0.181, odds ratio = 1.198, 95% confidence interval: 1.099-1.306, P＜0.001). ConclusionThere is a certain degree of IR in NAFLD patients with a normal VAT, and waist circumference is an independent risk for NAFLD with a normal VAT.

Background Sclera remodeling process in axial elongation is one of the main pathological mechanisms of axial myopia progression.Studies confirmed that transforming growth factor-β1(TGF-β1) participates in the sclera remodeling process,and Smad3 is one of TGF-β1 downstream signal gene transcriptive factors,so to explore its role in sclera remodeling process of myopic eyes is of great significance for pathogenesis and prevention research of myopia.Objective This study was to investigate the expressions of type Ⅰ collagen and Smad3,a TGF-31 downstream target,in sclera of form deprivation myopic (FDM) eyes and explore the impact of TGF-β1-Smad3-type Ⅰ collagen signaling pathway on collagen remodeling in myopic sclera.Methods Seventy-five 1-week-old guinea pigs were randomly divided into normal control group (25 guinea pigs) and FDM group (50 guinea pigs).Monocular FDM was induced by occluding the left eyes of guinea pigs in FDM group with translucent latex balloons for 2,4,6 weeks,respectively,and consecutive occluding for 4 weeks followed by uncovering for 1 week (4/-1 weeks).The refractive power was detected by retinoscopy and axial length was measured with A-type ultrasound.Immunohistochemistry and reverse transcription-PCR were employed to detect the dynamic expressions of type Ⅰ collagen and Smad3 protein ad mRNA in the sclera of guinea pigs with emmetropia and experimental myopia,ard the relationship between collagen Ⅰ and Smad3 levels was analyzed.Results The refraction was hypermetropic in both normal control group and FDM group before occluding of eyes (P＞0.05),and the hypermetropic power was gradually reduced over time in the normal control group.In the FDM group,the refractive power was gradually changed from (+2.09 ± 0.31)D before occluding to (-1.23±0.69),(-4.17±0.59),(-7.07±0.56) and (-4.30±0.58)D,and the axial length was increased from (5.93-±0.39)mm to (6.62±0.36),(7.30±0.34),(7.99--0.32),and (7.21 ±0.36) mm at weeks 2,4,6,and 4/-1 after occluding,respectively,indicating significant differences in refractive power and axial length over time in the FDM group from normal control group and self-control group (all at P＜0.05).The expressions of Smad3 and type Ⅰ collagen protein and mRNA in the sclera of the FDM group was significantly lower than those of the control group and self-control group in various time points (all at P＜0.05).The positive correlation were found in the expression of Smad3 on the myopic sclera with that of type Ⅰ collagen in both protein and mRNA levels (protein:r=0.993,P＜0.05;mRNA:r=0.954,P＜0.05).Conclusions The myopic power and ocular axis increase dependent upon occluding time,and the expressions of Smad3 and type Ⅰ collagen in the sclera are correspondingly weakened in FDM eyes.A consistent expression trend is found between Smad3 and type Ⅰ collage,suggesting Smad3 and type Ⅰ collagen participate in the regulation of sclera remodeling in myopia by TGF-β1-Smad3-Collagen Ⅰ signaling pathway.