Objective:To explore the clinical and pathological features and survival outcomes of patients with early-onset intrahepatic cholangiocarcinoma (EOICC).Methods:This is a multicenter, retrospective cohort study. Data of 1 160 intrahepatic cholangiocarcinoma patients undergoing radical resection in 14 tertiary Grade A hospitals in China from January 2010 to November 2021 were retrospectively collected. The cohort included 632 males and 528 females, aged( M (IQR)) 61 (14) years (range: 22 to 93 years). ICC aged ≤50 years at the time of diagnosis was defined as EOICC and >50 years as late-onset intrahepatic cholangiocarcinoma (LOICC). Of these, there were 247 cases in the EOICC group and 913 cases in the LOICC. The clinical and pathological characteristics of both groups were analyzed and compared using the independent sample t-test, Mann-Whitney U test or Kaplan-Meier method. Univariate and multivariate Cox regression models for patient outcomes were constructed and forest graphed. Results:Compared with the patients in the LOICC group, patients in the EOICC group had lower carcinoembryonic antigen levels (2.5(4.0) μg/L vs. 3.1(5.2)μg/L, U=124 899, P=0.009) and CA19-9 level (63.4(524.7)U/ml vs. 77.9(611.3)U/ml, U=120 320, P=0.013), higher levels of ALT (29(35)U/L vs. 24(26)U/L, U=101 214, P=0.013), a lower score of the Eastern US Cooperative Oncology Group (0 score patients: 54.7% vs. 44.1%, χ2=12.472, P=0.014), higher TNM stage ( χ2=11.807, P=0.038), and proportion of lymph node dissection (62.3% vs. 54.1%, χ2=5.355, P=0.021). Patients in the two groups in sex, first diagnosis symptoms, intrahepatic bile duct stone history, nail protein, albumin, total bilirubin, transaminase, liver function Child-Pugh grade, T stage, stage, N stage, preoperative laparoscopic exploration proportion, tumor diameter, vascular invasion proportion, differentiation, margin, intraoperative bleeding, postoperative complications, postoperative hospital days were no statistical significance (all P>0.05). Patients in the EOICC group had better outcomes than the LOICC group (median survival time: 29.7 months vs. 25.0 months, 3-year overall survival: 45.1% vs. 37.8%, P=0.027). Conclusion:EOICC patients are better than LOICC patients in carcinoembryonic antigen, CA19-9, ALT, physical strength status and TNM stage, and the long-term prognosis is also better than LOICC patients.

Objective To study the hemodynamic characteristics of autologous arteriovenous fistula(AVF)and provide a theoretical basis for reducing its stenosis rate.Methods Bidirectional fluid-structure interaction(FSI)simulations were conducted on a modified AVF model.Flow field and wall shear stress(WSS)distributions in the internal fistula at different periods and angles in a cardiac cycle were analyzed for retrograde flow(confluence)and anterograde flow(shunt)modes in models with varying anastomosis angles.Results Under confluence modes,the WSS＜1 Pa area in the 60° anastomosis angle model was the smallest(7.027 mm2),while the 45°,60°,and 90° models showed no significant differences in eddy current size and intensity.Under shunt modes,the 45° anastomosis angle model had the smallest WSS＜1 Pa area(9.079 mm2),but the 60° model exhibited the lowest eddy current intensity and distribution area.In addition,the difference in the WSS＜1 Pa area between the 60° and 45° models was only 2.661 mm2.Conclusions Under both confluence and shunt flow modes,establishing an AVF with 60° anastomosis angle is conducive to reducing the risk of vascular stenosis in arteriovenous fistula.

Objective:To explore the clinical and pathological features and survival outcomes of patients with early-onset intrahepatic cholangiocarcinoma (EOICC).Methods:This is a multicenter, retrospective cohort study. Data of 1 160 intrahepatic cholangiocarcinoma patients undergoing radical resection in 14 tertiary Grade A hospitals in China from January 2010 to November 2021 were retrospectively collected. The cohort included 632 males and 528 females, aged( M (IQR)) 61 (14) years (range: 22 to 93 years). ICC aged ≤50 years at the time of diagnosis was defined as EOICC and >50 years as late-onset intrahepatic cholangiocarcinoma (LOICC). Of these, there were 247 cases in the EOICC group and 913 cases in the LOICC. The clinical and pathological characteristics of both groups were analyzed and compared using the independent sample t-test, Mann-Whitney U test or Kaplan-Meier method. Univariate and multivariate Cox regression models for patient outcomes were constructed and forest graphed. Results:Compared with the patients in the LOICC group, patients in the EOICC group had lower carcinoembryonic antigen levels (2.5(4.0) μg/L vs. 3.1(5.2)μg/L, U=124 899, P=0.009) and CA19-9 level (63.4(524.7)U/ml vs. 77.9(611.3)U/ml, U=120 320, P=0.013), higher levels of ALT (29(35)U/L vs. 24(26)U/L, U=101 214, P=0.013), a lower score of the Eastern US Cooperative Oncology Group (0 score patients: 54.7% vs. 44.1%, χ2=12.472, P=0.014), higher TNM stage ( χ2=11.807, P=0.038), and proportion of lymph node dissection (62.3% vs. 54.1%, χ2=5.355, P=0.021). Patients in the two groups in sex, first diagnosis symptoms, intrahepatic bile duct stone history, nail protein, albumin, total bilirubin, transaminase, liver function Child-Pugh grade, T stage, stage, N stage, preoperative laparoscopic exploration proportion, tumor diameter, vascular invasion proportion, differentiation, margin, intraoperative bleeding, postoperative complications, postoperative hospital days were no statistical significance (all P>0.05). Patients in the EOICC group had better outcomes than the LOICC group (median survival time: 29.7 months vs. 25.0 months, 3-year overall survival: 45.1% vs. 37.8%, P=0.027). Conclusion:EOICC patients are better than LOICC patients in carcinoembryonic antigen, CA19-9, ALT, physical strength status and TNM stage, and the long-term prognosis is also better than LOICC patients.

Objective To study the hemodynamic characteristics of autologous arteriovenous fistula(AVF)and provide a theoretical basis for reducing its stenosis rate.Methods Bidirectional fluid-structure interaction(FSI)simulations were conducted on a modified AVF model.Flow field and wall shear stress(WSS)distributions in the internal fistula at different periods and angles in a cardiac cycle were analyzed for retrograde flow(confluence)and anterograde flow(shunt)modes in models with varying anastomosis angles.Results Under confluence modes,the WSS＜1 Pa area in the 60° anastomosis angle model was the smallest(7.027 mm2),while the 45°,60°,and 90° models showed no significant differences in eddy current size and intensity.Under shunt modes,the 45° anastomosis angle model had the smallest WSS＜1 Pa area(9.079 mm2),but the 60° model exhibited the lowest eddy current intensity and distribution area.In addition,the difference in the WSS＜1 Pa area between the 60° and 45° models was only 2.661 mm2.Conclusions Under both confluence and shunt flow modes,establishing an AVF with 60° anastomosis angle is conducive to reducing the risk of vascular stenosis in arteriovenous fistula.

Immunotherapy has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC), however, along with the popularization of immunotherapy, immune resistance has become an unavoidable problem. Immunotherapy can induce extensive cellular and molecular alterations in the tumor microenvironment. Considering the mechanisms of immune resistance are not yet fully understood and the efficacy of standard chemotherapy regimens is limited, more effective coping strategies based on resistance mechanisms are urgently needed. In this review, we intend to summarize the known mechanisms of immune resistance and feasible strategies, so as to provide a foundation for clinicians to develop more individualized and precise regimens and finally improve patients' prognosis.
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Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/drug therapy* ; Prognosis ; Immunotherapy ; Tumor Microenvironment

Prosthetic loosening and periprosthetic inflammation, as serious complications after joint replacement surgery, often require the secondary surgery for repair, which is easy to adversely affect the physical/mental health and economic status of patients.Studies have shown that the functional phenotype expressed by macrophages by different stimuli, namely macrophage polarization state, prolonged M1 polarization can lead to the continuation of long-term inflammation, while timely and effective M2 macrophage phenotype will lead to enhanced osteogenesis and tissue remodeling cytokine secretion and subsequent osseointegration, which play a crucial role in the development and outcome of prosthetic loosening and periprosthetic inflammation.The local micro-environment of extracellular matrix (ECM) is an important factor in the activation, migration, proliferation and fusion of macrophages. Researchers have deeply understood it mainly through the crosstalk between surface properties of biomaterials and macrophages. As an effector cell, macro-phages can perform complex spatiotemporal cellular functional responses by sensing the physical and chemical environment (surface topography, wettability, chemical composition, biological proteins) represented by surface properties of biomaterials.This paper summarizes the recent findings on macrophage polarization and material surface properties.

Objective:To establish a hypergravity loading model with a high-acceleration centrifugal loading device and to investigate the effects of different hypergravity loading and icariin on osteoblast adhesion and cytoskeleton.Methods:MC3T3-E1 cells were seeded in the dishes of cell culture at a density of 2×10 5/cm 2. And the experiment was divided into 6 groups: control group (without icariin and loading); simple administration group (only icariin); 10 G loading group (only loading); 10 G administration group (with icariin and loading); 40 G loading group (only loading); 40 G administration group (with icariin and loading). The experimental loading group was loaded with MC3T3-E1 cells using a high-acceleration centrifugal loader. And continuous loading for 3 d, 30 min per d. The control group and the simple administration group were exposed to normal gravity, and the remaining conditions were not different from the experimental group. Icariin was used at a concentration of 10 -7 mol/L in all administration groups, and the experiments were carried out according to the method of preventive administration. At the same time, the related molecular biological techniques such as alizarin red staining, alkaline phosphatase (ALP) activity measurement, CCK-8 cell proliferation experiment, cytoskeleton phalloidin staining, qPCR and Western Blot were used to detect the effects of icariin on osteoblasts adhesion protein integrin α5 and integrin β1 and cytoskeleton protein F-actin under hypergravity extreme mechanical environment. Results:All models were successfully prepared. The alizarin red staining: The icariin could significantly promote the formation of osteoblastic calcified nodules. And the 10 G loading could also promote the mineralization of osteoblasts and increase the number of mineralized nodules, while the mineralization and the number of mineralized nodules of osteoblasts are significantly reduced in 40 G loading. ALP activity test: The OD values of simple administration group, 10 G loading group and 40 G loading group were 0.246, 0.331 and 0.163, respectively. Compared with 0.207 in the control group, the differences were statistically significant ( P<0.05). The 10 G administration group and the 40 G administration group were 0.373 and 0.180, and the differences were statistically significant ( P<0.05). The results of CCK-8 proliferation experiments: The OD value of simple administration group were 0.650, which was statistically significant compared with 0.551 of control group ( P=0.031). The 10 G loading group and 40 G loading group were 1.193 and 0.245, and their differences with the control group were both statistically significant ( P<0.05). The OD value of 10G administration group and the 40 G administration group were 1.300 and 0.310, which were significantly different from the respective loading groups ( P<0.05). Phalloidin staining: 10 G loading significantly increased the number of cells, but the changes in cells morphology and skeleton were not obvious. 40 G loading significantly inhibited the increase of the number of cells, meanwhile, made the pseudopods of cells more shorter and even disappeared. 40 G loading made the seriously damage of the cytoskeleton and even cause the cells to death. Icariin had no effect on the cells morphology, but it did has a certain repair effect after the cells loading. The results of qPCR and Western Blot experiments all confirmed that the expressions of integrin α5, integrin β1 and F-actin were up-regulated after icariin treatment. 10 G loading could promote the expression of integrin α5, integrin β1 and F-actin, and 40 G loading significantly inhibited the expression of the mRNA and proteins. Conclusion:Both 10 G condition and icariin can promote the development, cell adhesion and the cytoskeleton's stability of osteoblasts, while 40 G has a significant inhibitory effect.

With the development of the 3rd-generation high-throughput sequencing technology and tissue engineering, recent studies show that many long-chain non-coding RNAs (LncRNAs) have played an important role in osteogenic differentiation of mesenchymal stem cells (MSCs). LncRNAs, which are involved in the regulation of mechanical regulation, further regulate bone-related cell functions and play a regulatory role at multiple levels, including transcription, post-transcriptional and epigenetic. LncRNAs may be involved in the osteogenic differentiation and bone remodeling of MSCs, the regulation of bone-related cell functions as a mechanical response molecule, as well as the pathological process of skeletal diseases.

Introductions: The emergence of multidrug-resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA) complicates the treatment of the simplest infection. Although glycopeptides such as vancomycin still proves to be effective in treating MRSA infections, the emergence of vancomycin-resistant strains limits the long term use of this antibiotic. Bacteriophages are ubiquitous bacterial viruses which is capable of infecting and killing bacteria including its antibiotic-resistant strains. Bactericidal bacteriophages use mechanisms that is distinct from antibiotics and is not affected by the antibioticresistant phenotypes. Objectives: The study was undertaken to evaluate the possibility to isolate bacteriolytic bacteriophages against S.aureus from raw sewage water and examine their efficacy as antimicrobial agents in vitro. Methods: Bacteriophages were isolated from the raw sewage using the agar overlay method. Isolated bacteriophages were plaque purified to obtain homogenous bacteriophage isolates. The host range of the bacteriophages was determined using the spot test assay against the 25 MRSA and 36 MSSA isolates obtained from the Sarawak General Hospital. Staphylococcus saprophyticus, Staphylococcus sciuri and Staphylococcus xylosus were included as non-SA controls. The identity of the bacteriophages was identified via Transmission Electron Microscopy and genomic size analysis. Their stability at different pH and temperature were elucidated. Results: A total of 10 lytic bacteriophages infecting S.aureus were isolated and two of them namely ΦNUSA-1 and ΦNUSA-10 from the family of Myoviridae and Siphoviridae respectively exhibited exceptionally broad host range against >80% of MRSA and MSSA tested. Both bacteriophages were specific to S.aureus and stable at both physiologic pH and temperature. Conclusion: This study demonstrated the abundance of S.aureus specific bacteriophages in raw sewage. Their high virulence against both MSSA and MRSA is an excellent antimicrobial characteristic which can be exploited for bacteriophage therapy against MRSA.

BACKGROUND: The silk fibroin/type II collagen composite scaffold has been prepared by low-temperature bio-3D printing technology in the previous study and the scaffold has good mechanical properties. Studies have shown that mechanical stimulation is beneficial to bone remodeling, and gradient loading strain is beneficial to the activation of osteoblasts and osteoclasts. OBJECTIVE: To co-culture silk fibroin/type II collagen composite scaffolds with chondrocytes under compression loading, to observe the proliferation of cells, and to observe the preliminary repair effect of silk fibroin/type II collagen composite scaffold on cartilage defects. METHODS: The silk fibroin/type II collagen composite scaffold was prepared by low-temperature 3D printing to detect the porosity of the scaffold. The passage 3 mouse chondrocytes ADTC-5 were inoculated on the silk fibroin/type II collagen composite scaffold and cultured under static culture and mechanical load respectively. (1) Static culture: blank scaffold was set as control, and cell proliferation was detected by MTT assay at 1, 3, 5, 7, 10, 14 days of inoculation. (2) Culture under mechanical load: blank scaffold was set as control. At 1 day after inoculation, 0％, 1％, 5％, 10％, 15％, 20％ compressive strains were applied to the cell-scaffold complex, and continued to load for 3 days. Cell proliferation was detected by MTT assay, and the distribution, adhesion and morphology of the cells on the scaffold were observed by scanning electron microscopy and hematoxylin-eosin staining. A cartilage defect of 3.5 mm in diameter was made in the bilateral knee joint of New Zealand rabbits. The silk fibroin/type II collagen composite scaffold was implanted onto the left side, and no material was implanted onto the right side. The repair site was observed at 8 weeks after surgery. RESULTS AND CONCLUSION: (1) The porosity of the scaffold was (89.3±3.26)％, which was conducive to cell attachment. (2) After 5 days of static culture, the chondrocytes proliferated well on the surface of the composite scaffold. Under 0％, 1％, 5％, 10％, 15％, 20％ compressive strains, the cell proliferation on the scaffold first increased and then decreased, wherein the cell proliferation was highest under 10％ compressive strain, and lowest under 20％ compressive strain. (4) Under the scanning electron microscopy, the chondrocytes in the 0％ load group were distributed in the surface of the scaffold with irregularities, the cell morphology was obvious, and the cell protrusions were fully extended. There were few or no chondrocytes on the contact surface of the 10％ load group, and more cells distributed on the lateral and internal surfaces of the first layer, but the cell morphology was flat with obvious protrusions. (5) Hematoxylin-eosin staining showed that the chondrocytes in the 0％ load group were concentrated on the surface of the scaffold, and there were almost no cells in the pores, while the chondrocytes in the 10％ load group were distributed in the scaffold pores. (6) There was still a circular defect model with no scaffold implantation, and no obvious repair appeared; similar hyaline cartilage appeared in the defect after scaffold implantation, but there was no adhesion to the surrounding defected cartilage, and the new hyaline cartilage was independent. Overall, the adsorption, proliferation and growth of chondrocytes on the silk fibroin-type II collagen scaffolds is better when the compressive strain is 10％, and the composite scaffold can be used as a repair material for cartilage defects.