Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study.

BACKGROUND: Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). METHOD: Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. RESULTS: 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. CONCLUSION: For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.

Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

CircTMOD3 promotes lipopolysaccharide-induced chondrocyte apoptosis in osteoarthritis by sponging miR-27a.

INTRODUCTION: The progression of osteoarthritis (OA) requires the involvement of lipopolysaccharide (LPS)-induced inflammation, in which circTMOD3 plays an important role. We predicted that circTMOD3 could interact with miR-27a to inhibit LPS-induced chondrocyte apoptosis and explored the interaction between circTMOD3 and miR-27a in OA. MATERIALS AND METHODS: Total RNAs were isolated from cartilage tissue samples from both OA patients (n = 62) and controls (n = 62) and subjected to RT-qPCRs to determine circTMOD3 and miR-27a (mature and premature) expression. Subcellular location of circTMOD3 and its interaction with premature miR-27a were analyzed using subcellular fractionation assay and RNA-RNA pulldown assay, respectively. CircTMOD3 was overexpressed in chondrocytes to study its role in miR-27a maturation. The roles of circTMOD3 and miR-27a in LPS-induced chondrocyte apoptosis were analyzed using cell apoptosis assay. RESULTS: CircTMOD3 and premature miR-27a levels were increased while mature miR-27a level was decreased in OA. CircTMOD3 was located in both nuclear and cytoplasm fractions of chondrocytes. CircTMOD3 directly interacted with premature miR-27a and promoted LPS-induced chondrocyte apoptosis, while miR-27a inhibited LPS-induced chondrocyte apoptosis. Moreover, circTMOD3 overexpression suppressed miR-27a maturation and reduced the inhibitory effects of miR-27a on LPS-induced chondrocyte apoptosis. CONCLUSION: CircTMOD3 suppresses miR-27a maturation in OA to promote chondrocyte apoptosis induced by LPS.

Low preoperative prealbumin predicts the prevalence of complications following liver transplantation.

BACKGROUND: As a nutritional index, preoperative serum prealbumin highly correlates with surgical complications. However, the correlation between preoperative prealbumin and postoperative complications remains unclear in liver transplantation (LT). METHODS: A total of 191 patients who underwent LT between 2015 and 2019 were included in the retrospective analysis. According to a cut-off value calculated from a receiver operating characteristic (ROC) curve, the patients were divided into normal and low preoperative prealbumin groups. Univariable and multivariable logistic regression analyses were used to identify independent risk factors for postoperative complications. In addition, patients were divided into subgroups by Model for End-stage Liver Disease (MELD) score, and the association between preoperative prealbumin and postoperative complications was also assessed in each group. RESULTS: A total of 111 (58.1%) patients were included in the low prealbumin group based on a cut-off value of 120 mg/L. The area under the ROC curve (AUC) was 0.754 (95% confidence interval [CI] 0.678-0.832). Low prealbumin (95% CI 1.51-12.8, P = 0.007) was identified as a predictor for postoperative complications based on multivariable regression. In the low and normal prealbumin groups, the prevalence rates of postoperative complications were 27.5% and 8.0% (P = 0.003) in the MELD score ≤ 15 subgroup and 53.3% and 20.0% (P = 0.197) in the MELD score > 15 subgroup, respectively. CONCLUSIONS: Preoperative prealbumin was associated with postoperative complications in LT, and preoperative nutritional support benefitted postoperative recovery, especially for patients with low MELD scores.

The ROK-family regulator Rok7B7 directly controls carbon catabolite repression, antibiotic biosynthesis, and morphological development in Streptomyces avermitilis.

Carbon catabolite repression (CCR) is a common phenomenon in bacteria that modulates expression of genes involved in uptake of alternative carbon sources. In the filamentous streptomycetes, which produce half of all known antibiotics, the precise mechanism of CCR is yet unknown. We report here that the ROK-family regulator Rok7B7 pleiotropically controls xylose and glucose uptake, CCR, development, as well as production of the macrolide antibiotics avermectin and oligomycin A in Streptomyces avermitilis. Rok7B7 directly repressed structural genes for avermectin biosynthesis, whereas it activated olmRI, the cluster-situated activator gene for oligomycin A biosynthesis. Rok7B7 also directly repressed the xylose uptake operon xylFGH, whose expression was induced by xylose and repressed by glucose. Both xylose and glucose served as Rok7B7 ligands. rok7B7 deletion led to enhancement and reduction of avermectin and oligomycin A production, respectively, relieved CCR of xylFGH, and increased co-uptake efficiency of xylose and glucose. A consensus Rok7B7-binding site, 5'-TTKAMKHSTTSAV-3', was identified within aveA1p, olmRIp, and xylFp, which allowed prediction of the Rok7B7 regulon and confirmation of 11 additional targets involved in development, secondary metabolism, glucose uptake, and primary metabolic processes. Our findings will facilitate methods for strain improvement, antibiotic overproduction, and co-uptake of xylose and glucose in Streptomyces species.

IdeR, a DtxR Family Iron Response Regulator, Controls Iron Homeostasis, Morphological Differentiation, Secondary Metabolism, and the Oxidative Stress Response in Streptomyces avermitilis.

Iron, an essential element for microorganisms, functions as a vital cofactor in a wide variety of key metabolic processes. On the other hand, excess iron may have toxic effects on bacteria by catalyzing the formation of reactive oxygen species through the Fenton reaction. The prevention of iron toxicity requires the precise control of intracellular iron levels in bacteria. Mechanisms of iron homeostasis in the genus Streptomyces (the producers of various antibiotics) are poorly understood. Streptomyces avermitilis is the industrial producer of avermectins, which are potent anthelmintic agents widely used in medicine, agriculture, and animal husbandry. We investigated the regulatory role of IdeR, a DtxR family regulator, in S. avermitilis In the presence of iron, IdeR binds to a specific palindromic consensus sequence in promoters and regulates 14 targets involved in iron metabolism (e.g., iron acquisition, iron storage, heme metabolism, and Fe-S assembly). IdeR also directly regulates 12 targets involved in other biological processes, including morphological differentiation, secondary metabolism, carbohydrate metabolism, and the tricarboxylic acid (TCA) cycle. ideR transcription is positively regulated by the peroxide-sensing transcriptional regulator OxyR. A newly constructed ideR deletion mutant (DideR) was found to be less responsive to iron levels and more sensitive to H2O2 treatment than the wild-type strain, indicating that ideR is essential for oxidative stress responses. Our findings, taken together, demonstrate that IdeR plays a pleiotropic role in the overall coordination of metabolism in Streptomyces spp. in response to iron levels.IMPORTANCE Iron is essential to almost all organisms, but in the presence of oxygen, iron is both poorly available and potentially toxic. Streptomyces species are predominantly present in soil where the environment is complex and fluctuating. So far, the mechanism of iron homeostasis in Streptomyces spp. remains to be elucidated. Here, we characterized the regulatory role of IdeR in the avermectin-producing organism S. avermitilis IdeR maintains intracellular iron levels by regulating genes involved in iron absorption and storage. IdeR also directly regulates morphological differentiation, secondary metabolism, and central metabolism. ideR is under the positive control of OxyR and is indispensable for an efficient response to oxidative stress. This investigation uncovered that IdeR acts as a global regulator coordinating iron homeostasis, morphological differentiation, secondary metabolism, and oxidative stress response in Streptomyces species. Elucidation of the pleiotropic regulation function of IdeR provides new insights into the mechanisms of how Streptomyces spp. adapt to the complex environment.

OxyR is a key regulator in response to oxidative stress in Streptomyces avermitilis.

The role of the H2O2-sensing transcriptional regulator OxyR in oxidative stress responses in Streptomyces avermitilis was investigated. An oxyR deletion mutant was more sensitive to H2O2 and tert-butyl hydroperoxide than was the WT strain, indicating that OxyR mediates the defensive system against H2O2 and organic peroxide. Evidence presented herein suggests that in cells treated with exogenous H2O2, the oxidized form of OxyR activated expression of ahpCD by binding to a palindromic sequence of the promoter region. Oxidized OxyR also induced expression of other antioxidant enzymes (KatA1, KatA2, KatA3 and OhrB1) and oxidative stress regulators (CatR, OhrR and σR). The thiol-oxidative stress regulator gene sigR was regulated at the transcription level by OxyR. We conclude that OxyR is necessary to activate transcription of sigR from the σR-dependent promoter to express an unstable larger isoform of σR during oxidative stress. In response to oxidative stress, OxyR facilitates rapid production of H2O2-scavenging enzymes to repair oxidative damage through direct regulation and cascaded regulation of CatR, OhrR and σR.

Overexpression of a bifunctional enzyme, CrtS, enhances astaxanthin synthesis through two pathways in Phaffia rhodozyma.

BACKGROUND: A moderate-temperature, astaxanthin-overproducing mutant strain (termed MK19) of Phaffia rhodozyma was generated in our laboratory. The intracellular astaxanthin content of MK19 was 17-fold higher than that of wild-type. The TLC profile of MK19 showed a band for an unknown carotenoid pigment between those of ß-carotene and astaxanthin. In the present study, we attempted to identify the unknown pigment and to enhance astaxanthin synthesis in MK19 by overexpression of the crtS gene that encodes astaxanthin synthase (CrtS). RESULTS: A crtS-overexpressing strain was constructed without antibiotic marker. A recombinant plasmid with lower copy numbers was shown to be stable in MK19. In the positive recombinant strain (termed CSR19), maximal astaxanthin yield was 33.5% higher than MK19, and the proportion of astaxanthin as a percentage of total carotenoids was 84%. The unknown carotenoid was identified as 3-hydroxy-3',4'-didehydro-ß,Ψ-carotene-4-one (HDCO) by HPLC, mass spectrometry, and NMR spectroscopy. CrtS was found to be a bifunctional enzyme that helped convert HDCO to astaxanthin. Enhancement of crtS transcriptional level increased transcription levels of related genes (crtE, crtYB, crtI) in the astaxanthin synthesis pathway. A scheme of carotenoid biosynthesis in P. rhodozyma involving alternative bicyclic and monocyclic pathways is proposed. CONCLUSIONS: CrtS overexpression leads to up-regulation of synthesis-related genes and increased astaxanthin production. The transformant CSR19 is a stable, secure strain suitable for feed additive production. The present findings help clarify the regulatory mechanisms that underlie metabolic fluxes in P. rhodozyma carotenoid biosynthesis pathways.

The PhoP transcription factor negatively regulates avermectin biosynthesis in Streptomyces avermitilis.

Bacteria sense and respond to the stress of phosphate limitation, anticipating Pi deletion/starvation via the two-component PhoR-PhoP system. The role of the response regulator PhoP in primary metabolism and avermectin biosynthesis in Streptomyces avermitilis was investigated. In response to phosphate starvation, S. avermitilis PhoP, like Streptomyces coelicolor and Streptomyces lividans PhoP, activates the expression of phoRP, phoU, and pstS by binding to the PHO boxes in their promoter regions. Avermectin biosynthesis was significantly increased in ΔphoP deletion mutants. Electrophoretic mobility gel shift assay (EMSA) and DNase I footprinting assays showed that PhoP can bind to a PHO box formed by two direct repeat units of 11 nucleotides located downstream of the transcriptional start site of aveR. By negatively regulating the transcription of aveR, PhoP directly affects avermectin biosynthesis in S. avermitilis. PhoP indirectly affects melanogenesis on Casaminoacids Minimal Medium (MMC) lacking supplemental phosphate. Nitrogen metabolism and some key genes involved in morphological differentiation and antibiotic production in S. avermitilis are also under the control of PhoP.

Effect of repeated freeze-thaw cycles on mechanical properties of clay.

To investigate the variation in the mechanical properties of clay under freeze-thaw cycles (FTCs), a series of experiments were conducted in the laboratory. Samples with different water contents and dry densities were subjected to FTCs ranging from 0 to 11 times. Then, cohesion, shear strength, internal friction angle and elastic modulus were obtained using triaxial test. The results show that with the increase in the number of FTCs, the shear strength, cohesion and elastic modulus decreased, while the internal friction angle increased slightly. However, the variation in the internal friction angle is not obvious, and the maximum increment is within 4°. The cohesion exhibited the most decrease after the first freeze-thaw action. Besides, under a same number of FTCs, four mechanical properties are significantly affected by water content and dry density. The shear strength, cohesion, elastic modulus and internal friction angle decrease with water content while increasing with dry density. Additionally, the elastic modulus is associated with confining pressure, which increases with confining pressure. This study provides evidence for the variation in mechanical properties of the soils subjected to FTCs and guides the design and construction of the cold regional engineering.

Adequate cumulative exposure to tacrolimus and low tacrolimus variability decrease the incidence of biliary complications after liver transplantation.

BACKGROUND: Nonearly biliary complications (BCs) after liver transplantation (LT) are highly associated with immunological status. Tacrolimus is the main immunosuppressant. Whether and how tacrolimus bioavailability affects BCs is unclear. METHODS: LT recipients receiving tacrolimus-free immunosuppressants or developing BCs within 3 months after LT were excluded. Tacrolimus-related variables included trough concentration (C0), variability and cumulative exposure to tacrolimus (CET). Receiver operating characteristic (ROC) curves defined cutoff values of CET and variability. The values divided patients into adequate and low CET groups, also high and low-variability groups. Inverse probability of treatment weighting (IPTW) was used to reduce bias. Logistic regression identified risk factors. Kaplan-Meier curves were generated for survival comparison. RESULTS: 409 patients were enrolled, and 39 (9.5 %) suffered from BCs. The mean C0 values were 6.9 and 7.2 ng/mL in the BCs and BCs-free groups, respectively. CET within 3 postoperative months was 550.0 and 608.6 ng.day/mL, while the tacrolimus variability was 0.4 and 0.3, respectively. The cutoff values for CET within 3 months and variability predicting BCs were 660.5 and 0.54, respectively. Multivariable logistic regression revealed that low CET within 3 months (p = 0.005, p = 0.002) and high variability (p < 0.001, p < 0.001) were associated with BCs before and after IPTW. Appropriate CET and low variability were associated with better overall survival (p = 0.009 and 0.029). Subgroup analysis indicated that long cold ischemia time (CIT), high bilirubin and low CET had a higher relative risk and raised the incidence of BCs. CONCLUSIONS: Adequate CET and low variability of tacrolimus ameliorated nonearly BCs incidence and improved survival.

Association between Pre-operative Body Mass Index and Surgical Infection in Perihilar Cholangiocarcinoma Patients Treated with Curative Resection: A Multi-center Study.

Background: The objective of this study was to investigate the association between pre-operative body mass index (BMI) and surgical infection in perihilar cholangiocarcinoma (pCCA) patients treated with curative resection. Methods: Consecutive pCCA patients were enrolled from four tertiary hospitals between 2008 and 2022. According to pre-operative BMI, the patients were divided into three groups: low BMI (≤18.4 kg/m2), normal BMI (18.5-24.9 kg/m2), and high BMI (≥25.0 kg/m2). The incidence of surgical infection among the three groups was compared. Multivariable logistic regression models were used to determine the independent risk factors associated with surgical infection. Results: A total of 371 patients were enrolled, including 283 patients (76.3%) in the normal BMI group, 30 patients (8.1%) in the low BMI group, and 58 patients (15.6%) in the high BMI group. The incidence of surgical infection was significantly higher in the patients in the low BMI and high BMI groups than in the normal BMI group. The multivariable logistic regression model showed that low BMI and high BMI were independently associated with the occurrence of surgical infection. Conclusions: The pCCA patients with a normal BMI treated with curative resection could have a lower risk of surgical infection than pCCA patients with an abnormal BMI.

TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs.

For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC.

Shengxian decoction protects against chronic heart failure in a rat model via energy regulation mechanisms.

BACKGROUND: Chronic heart failure (CHF) is actually a disease caused by an imbalanced energy metabolism between myocardial energy demand and supply, ultimately resulting in abnormal myocardial cell structure and function. Energy metabolism imbalance plays an important role in the pathological process of chronic heart failure (CHF). Improving myocardial energy metabolism is a new strategy for the treatment of CHF. Shengxian decoction (SXT), a well-known traditional Chinese medicine (TCM) formula, has good therapeutic effects on the cardiovascular system. However, the effects of SXT on the energy metabolism of CHF is unclear. In this study, we probed the regulating effects of SXT on energy metabolism in CHF rats using various research methods. METHODS: High-performance liquid chromatography (HPLC) analysis was used to perform quality control of SXT preparations. Then, SD rats were randomly assigned into 6 groups: sham, model, positive control (trimetazidine) and high-, middle-, and low-dose SXT groups. Specific reagent kits were used to detect the expression levels of ALT and AST in rats' serum. Echocardiography was used to evaluate cardiac function. H&E, Masson and TUNEL staining were performed to examine myocardial structure and myocardial apoptosis. Colorimetry was used to determine myocardial ATP levels in experimental rats. Transmission electron microscopy was used to observe the ultrastructure of myocardial mitochondria. ELISA was used to estimate CK, cTnI, and NT-proBNP levels, and LA、FFA、MDA、SOD levels. Finally, Western blotting was used to examine the protein expression of CPT-1, GLUT4, AMPK, p-AMPK, PGC-1α, NRF1, mtTFA and ATP5D in the myocardium. RESULTS: HPLC showed that our SXT preparation method was feasible. The results of ALT and AST tests indicate that SXT has no side effect on the liver function of rats. Treatment with SXT improved cardiac function and ventricular remodelling and inhibited cardiomyocyte apoptosis and oxidative stress levels induced by CHF. Moreover, CHF caused decrease ATP synthesis, which was accompanied by a reduction in ATP 5D protein levels, damage to mitochondrial structure, abnormal glucose and lipid metabolism, and changes in the expression of PGC-1α related signal pathway proteins, all of which were significantly alleviated by treatment with SXT. CONCLUSION: SXT reverses CHF-induced cardiac dysfunction and maintains the integrity of myocardial structure by regulating energy metabolism. The beneficial effect of SXT on energy metabolism may be related to regulating the expression of the PGC-1α signalling pathway.

Development of a model based on the age-adjusted Charlson comorbidity index to predict survival for resected perihilar cholangiocarcinoma.

BACKGROUND: Perihilar cholangiocarcinoma (pCCA) has a poor prognosis and urgently needs a better predictive method. The predictive value of the age-adjusted Charlson comorbidity index (ACCI) for the long-term prognosis of patients with multiple malignancies was recently reported. However, pCCA is one of the most surgically difficult gastrointestinal tumors with the poorest prognosis, and the value of the ACCI for the prognosis of pCCA patients after curative resection is unclear. AIM: To evaluate the prognostic value of the ACCI and to design an online clinical model for pCCA patients. METHODS: Consecutive pCCA patients after curative resection between 2010 and 2019 were enrolled from a multicenter database. The patients were randomly assigned 3:1 to training and validation cohorts. In the training and validation cohorts, all patients were divided into low-, moderate-, and high-ACCI groups. Kaplan-Meier curves were used to determine the impact of the ACCI on overall survival (OS) for pCCA patients, and multivariate Cox regression analysis was used to determine the independent risk factors affecting OS. An online clinical model based on the ACCI was developed and validated. The concordance index (C-index), calibration curve, and receiver operating characteristic (ROC) curve were used to evaluate the predictive performance and fit of this model. RESULTS: A total of 325 patients were included. There were 244 patients in the training cohort and 81 patients in the validation cohort. In the training cohort, 116, 91 and 37 patients were classified into the low-, moderate- and high-ACCI groups. The Kaplan-Meier curves showed that patients in the moderate- and high-ACCI groups had worse survival rates than those in the low-ACCI group. Multivariable analysis revealed that moderate and high ACCI scores were independently associated with OS in pCCA patients after curative resection. In addition, an online clinical model was developed that had ideal C-indexes of 0.725 and 0.675 for predicting OS in the training and validation cohorts. The calibration curve and ROC curve indicated that the model had a good fit and prediction performance. CONCLUSION: A high ACCI score may predict poor long-term survival in pCCA patients after curative resection. High-risk patients screened by the ACCI-based model should be given more clinical attention in terms of the management of comorbidities and postoperative follow-up.

Preparation, characterization and in vitro study of bellidifolin nano-micelles.

Bellidifolin (BEL), a xanthone compound, has significant therapeutic effectiveness in cardiac diseases such as arrhythmias. However, BEL is limited in clinical applications by its hydrophobicity. In this work, we used BEL as the active pharmaceutical ingredient (API), and polyethylene glycol 15-hydroxy stearate (Kolliphor HS15) as the carrier to prepare BEL nano-micelles by a solvent-volatilization method. According to an analysis by differential scanning calorimetry (DSC), BEL was successfully encapsulated in HS15 as BEL nano-micelles with a 90% encapsulation rate, and particle size was 12.60 ± 0.074 nm in the shape of a sphere and electric potential was -4.76 ± 4.47 mV with good stability and sustained release characteristics. In addition, compared with free drugs, these nano-micelles can increase cellular uptake capacity, inhibit the proliferation of human cardiac fibroblasts, and down-regulate the expression of Smad-2, α-SMA, Collagen I, and Collagen III proteins in myocardial cells to improve myocardial fibrosis. In conclusion, the BEL nano-micelles can provide a new way for the theoretical basis for the clinical application of anti-cardiac fibrosis.

Imaging Findings of Hepatic Ewing's Sarcoma on Computed Tomography and Gadobenate Dimeglumine-enhanced Magnetic Resonance Imaging: A Case Report and Literature Review.

Ewing's sarcoma (ES) is a tumor that often occurs in the long bones and rarely arises from visceral organs primarily. Here, we report a case of primary hepatic ES, discuss its computed tomography (CT) and gadobenate dimeglumine-enhanced magnetic resonance (MRI) features. This is the first Chinese and fifth primary hepatic ES case reported, based on a literature review. Imaging examinations showed that the tumor was solid, with necrosis and hemorrhage. Contrast-enhanced images showed that the tumor was hypervascular and especially had heterogeneous signal intensity on hepatobiliary phase MRI images. Intratumoral vessels and vascular invasion were also present.

LncRNA PTCSC3 is upregulated in osteoporosis and negatively regulates osteoblast apoptosis.

BACKGROUND: It is known that long non-coding RNA (lncRNA) PTCSC3 is involved in thyroid cancer and glioma, but its function in osteoporosis is unknown. The aim of our study was to investigate the role of lncRNA PTCSC3 in osteoporosis. METHODS: A total of 80 patients with osteoporosis (4 clinical stages) and four corresponding groups of healthy controls were enrolled. Plasma PTCSC3 levels in the 80 osteoporosis patients and 80 healthy volunteers were measured using RT-qPCR. The diagnostic potential of plasma PTCSC3 for osteoporosis was evaluated by ROC curve analysis with healthy volunteers as the true negative cases and corresponding osteoporosis patients as the true positive cases. RESULTS: PTCSC3 was upregulated in osteoporosis patients compared with healthy controls. PTCSC3 levels increased with osteoporosis stages increasing, but not with healthy controls aging. PTCSC3 overexpression separated each stage of osteoporosis from corresponding controls. PTCSC3 overexpression promoted while PTCSC3 silencing inhibited osteoblast apoptosis. However, PTCSC3 overexpression and silencing showed no significant effect on osteoclast apoptosis. LncRNA PTCSC3 was upregulated in osteoporosis and negatively regulated osteoblast apoptosis. CONCLUSION: LncRNA PTCSC3 may serve as a potential therapeutic target for osteoporosis.

Predictive model for the intraoperative unresectability of hilar cholangiocarcinoma: Reducing futile surgical exploration.

INTRODUCTION: Surgical exploration is widely performed in hilar cholangiocarcinoma (HCCA), but the intraoperative resectability rate is only 60%-80%. Exploration substantially increases pain and mental stress, and the costs and length of hospital stay are considerably increased. Identifying preoperative risk factors associated with unresectability could decrease unnecessary exploration. MATERIALS AND METHODS: In total, 440 HCCA patients from multiple centers were enrolled. Those receiving surgical exploration were divided into the resected and unresected groups. Morphological variables including Bismuth classification, lymph node metastasis and vessel invasion were obtained from radiological exams. Logistic regression for the training cohort was used to identify risk factors for unresectability, and a nomogram was constructed to calculate the unresectability rate. A calibration curve assessed the power of the nomogram. RESULTS: Among 311 patients receiving surgical exploration, 45 (14.7%) were unresectable by intraoperative judgment. Compared with the resected group, unresected patients had similar costs (p = 0.359) and lengths of hospital stay (p = 0.439). Multivariable logistic regression of the training cohort (235 patients) revealed that CA125, Bismuth-Corlette type IV, lymph node metastasis and hepatic artery invasion were risk factors for unresectability. Liver atrophy (p = 0.374) and portal vein invasion (p = 0.114) were not risk factors. The nomogram was constructed based on the risk factors. The concordance index (C-index) values of the calibration curve for predicting the unresectability rate of the training and validation (76 patients) cohorts were 0.900 (95% CI, 0.835-0.966) and 0.829 (95% CI, 0.546-0.902), respectively. CONCLUSION: Analysis of preoperative factors could reveal intraoperative unresectability and reduce futile surgical explorations, ultimately benefiting HCCA patients.