Role of polyethylene particles in peri-prosthetic osteolysis:A review

There is convincing evidence that particles produced by the wear of joint prostheses are causal in the periprosthetic loss of bone,or osteolysis,which,if it progresses,leads to the phenomenon of aseptic loosening.It is important to fully understand the biology of this bone loss because it threatens prosthesis survival,and loosened implants can result in peri-prosthetic fracture,which is disastrous for the patient and presents a difficult surgical scenario.The focus of this review is the bioactivity of polyethylene(PE)particles,since there is evidence that these are major players in the development and progression of osteolysis around prostheses which use PE as the bearing surface.The review describes the biological consequences of interaction of PE particles with macrophages,osteoclasts and cells of the osteoblast lineage,including osteocytes.It explores the possible cellular mechanisms of action of PE and seeks to use the findings to date to propose potential nonsurgical treatments for osteolysis.In particular,a nonsurgical approach is likely to be applicable to implants containing newer,highly cross-linked PEs(HXLPEs),for which osteolysis seems to occur with much reduced PE wear compared with conventional PEs.The caveat here is that we know little as yet about the bioactivity of HXLPE particles and addressing this constitutes our next challenge.

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays critical roles in cell cycling and DNA damage response. Overexpression of PLK1 is associated with the poorer prognosis of cancers, including colorectal cancer (CRC). Although the downstream pathways of the overexpression that lead to oncogenesis have been extensively studied, little is known about the factors that cause the overexpression of PLK1 in CRC. DNA methylation was reported to be affecting the expression of PLK1 in some cancers. The study aims to investigate the contribution of genetic mutation and DNA methylation of the PLK1 gene to the overexpression of PLK1 in CRC. The study involves data mining from Catalogue of Somatic Mutations in Cancer (COSMIC) and UniProtKB, Sanger sequencing on DNA from the cell lines HCT116, SW48, Colo320DM and T84 to analyse the possible mutation of PLK1. Other than that methylation status of the PLK1 promoter in CRC are also analysed by using mass spectrometry (MS) and pyrosequencing. Data from the COSMIC show the low incidences of PLK1 mutation for CRC (3.02%) with 46 mutations identified. One of the mutation p.R337Q (c.1010G > A) is located in the D-box which is an important motif for protein ubiquitination and eventually proteasomal degradation. Hence this mutation may potentially result in stabilisation of the PLK1 protein. Mutations are detected at the upstream silencer region, the promoter region and Exon1 in HCT116 but are not located at the protein binding or functioning site. Similarly, the same mutation at promoter region is detected in SW48. Differential trends of changes in methylation status of PLK1 in the IR treated CRC cell lines detected by MS reveal the possible association between the methylation and the radiosensitivity. Furthermore, pyrosequencing shows that PLK1 methylation status in tumour tissues with high expression of PLK1 is not significantly different from those with no PLK1 expression. In conclusion, mutation of PLK1 gene is infrequent in CRC and the expression of PLK1 is unlikely to be dependent on DNA methylation in the promoter region of PLK1 in the CRC.

Serum soluble ST2 is a promising prognostic biomarker in HBV-related acute-on-chronic liver failure

BACKGROUND： The IL-33/ST2 axis is involved in the pathogenesis of many diseases such as autoimmune diseases, cancer,and heart failure. However, studies of the IL-33/ST2 pathway in HBV-related acute-on-chronic liver failure（HBV-ACLF） are lacking. The present study aimed to determine the prognostic role of serum IL-33/soluble ST2（s ST2） in HBV-ACLF.METHODS： Serum levels of IL-33 and sS T2 in healthy controls（HC, n=18）, chronic hepatitis B（CHB, n=27） and HBV-ACLF（n=51） patients at the 1st and 4th week after enrollment were detected using ELISA, and clinical data were collected. The follow-up of HBV-ACLF patients lasted for 6 months at least.RESULTS： There was no significant difference of serum IL-33 level among HC, CHB and HBV-ACLF patients at week 1.However, serum s ST2 level differed significantly among the three groups： highest in the HBV-ACLF group, moderate in the CHB group and lowest in the HC group. There was a reverse correlation between serum s ST2 level and the survival of HBV-ACLF patients. The level of serum s ST2 in HBV-ACLF survivors was significantly declined from week 1 to week 4 following the treatment, whereas that in HBV-ACLF nonsurvivors remained at a high level during the same period. Furthermore, serum sS T2 level was significantly correlated with laboratory parameters and the most updated prognostic scores（CLIF-C OF score, CLIF-C ACLF score and ACLF grades）. Thereceiver operating characteristics curves demonstrated that serum sS T2 level was a good diagnostic marker for predicting the 6-month mortality in HBV-ACLF patients, comparable to the most updated prognostic scores. Serum sS T2 cut-off points for predicting prognosis in HBV-ACLF patients were 76 ng/mL at week 1 or 53 ng/mL at week 4, respectively. HBV-ACLF patients with serum sS T2 level above the cut-off point often had a worse prognosis than those below the cut-off point.CONCLUSION： Serum s ST2 may act as a promising biomarker to assess severity and predict prognosis of patients with HBV-ACLF and help for the early identification and optimal treatment of HBV-ACLF patients at high risk of mortality.

Bacterial infection triggers and complicates acute-on-chronic liver failure in patients with hepatitis B virus-decompensated cirrhosis: A retrospective cohort study

BACKGROUND Reports on bacterial infection(BI)in decompensated cirrhosis(DC)is mainly from alcoholic cirrhosis.The role of BI as a trigger or complication of acute-onchronic liver failure(ACLF)in patients with hepatitis B virus decompensated cirrhosis(HBV-DC)remains to be investigated.AIM To investigate the impact of BI on the outcomes of the patients with HBV-DC admitted into the hospital with or without ACLF.METHODS This retrospective study included patients with HBV-DC admitted to two tertiary centers in China.In-hospital overall survival,90-d transplant-free survival,5-year post-discharge survival,and cumulative incidence of ACLF were evaluated.Risk factors for death were analyzed considering liver transplantation as a competing event.RESULTS A total of 1281 hospitalized HBV-DC patients were included;284 had ACLF at admission.The overall prevalence of BI was 28.1%.The patients with BI had a significantly lower in-hospital survival and transplant-free 90-d survival than those without,in both the patients admitted with and without ACLF.The presence of BI significantly increased the risk of developing ACLF[subdistribution hazard ratio(sHR)=2.52,95%CI:1.75-3.61,P<0.001]in the patients without ACLF.In the patients discharged alive,those who had an episode of BI had a significantly lower 5-year transplant-free survival.BI was an independent risk factor for death in the patients admitted without ACLF(sHR=3.28,95%CI:1.93-5.57),while in ACLF admissions,the presence of pneumonia,but not other type of BI,independently increased the risk of death(sHR=1.87,95%CI:1.24-2.82).CONCLUSION BI triggers ACLF in patients with HBV-DC and significantly impairs short-term survival.HBV-DC patients should be monitored carefully for the development of BI,especially pneumonia,to avoid an adverse outcome.

Irinotecan therapy and molecular targets in colorectal cancer: A systemic review

Irinotecan is the second line chemotherapy for advanced stage colorectal cancer (CRC) after failure of first line chemotherapy with oxaliplatin and 5-fluorouracil. The aim of this review is to analyse the data on irinotecan as second line chemotherapy for advanced CRC and the potential roles of the molecular markers, p53 and vascular endothelial growth factor (VEGF) in the management of advanced CRC. Thus, the English literature from 1980 to 2008 concerning irinotecan, p53, VEGF and CRC was reviewed. On review, Phase and clinical trials showed thatirinotecan improves pain-free survival, quality of life, 1-year survival, progression-free survival and overall survival in advanced CRC. p53 and VEGF were expressed in CRC and had a predictive power of aggressive clinical behaviour in CRC. Irinotecan sensitizes p53 wild type, mutant and null cells to Fasmediated cell apoptosis in CRC cells. Wild type p53 cells were more sensitive to irinotecan than mutated p53. Irinotecan has an anti-VEGF effect inhibiting endothelial cell proliferation, increasing apoptosis and reducing microvascular density which is onlylimited by irinotecan toxicity levels. To conclude, irinotecan improves the patient's quality of life and the survival rates of patients with advanced CRC. p53 and VEGF status of the patients' tumour is likely to affect the responsiveness of CRC to irinotecan. It is recommended that studies of the expression of these molecular markers in relation to chemoresponsiveness ofirinotecan should be carried out for better management of patients with advanced CRC.

A Simulation for Flavivirus Infection Decoy Responses

In this work, we discuss the development of simulation code for a model of the cross-reactive adaptive immune response seen in flavivirus infections. The model specifically addresses flavivirus pathogen virulence in G0?vs G1?cell states. The MHC-I upregulation of resting cells (G0 state) allows the T-cells generated for flavivirus peptide antigens to attack healthy cells also. The cells in G1?state are not upregulated as much and so virus hides in them and hence is propagated upon rupture. Hence, this type of model is referred to as a decoy model because the immune system is decoyed into preferentially recognizing the upregulated cells while the virus actively propagates in another small, but important, cell population. We show that the generic assumption of upregulation via a model which includes the?G0/G1?differential upregulation leads to immunopathological consequences. We outline the details behind the simulation code decisions and provide some theoretical justification for our model of collateral damage and upregulation.

Using a Collateral Damage Model to Explain Survival Data in West Nile Virus Infections

Simulation code for a model of the adaptive immune response seen in flavivirus infections is used to explain the immunopathological consequences seen in West Nile Virus virus (WNV) infections. We use a model that specifically handles the differences in how the virus infects resting cells, the G0 state, versus dividing cells, the G1 state, which includes vastly increased MHC-I upregulation for resting cells over dividing cells. The simulation suggests how the infection progresses in a one host model and the results shed insight into the unusual survival curve data obtained for this infection: there is an increase in health even though viral load has increased.

Histological Outcome of Fuzheng Huayu plus Entecavir Combination Therapy in Chronic Hepatitis B Patients with Significant Liver Fibrosis

Publications>Journals>Journal of Clinical and Translational Hepatology>Article Full Text ORIGINAL ARTICLE OPEN ACCESS Histological Outcome of Fuzheng Huayu plus Entecavir Combination Therapy in Chronic Hepatitis B Patients with Significant Liver Fibrosis Hong-Lian Gui#,1,Chang-Qing Zhao#,2,Yan Wang3,Hong-Tu Gu2,Wei-Jing Wang1,4,Wei Cai1,Qing Guo1,Shi-San Bao5,Lie-Ming Xu*,2 and Qing Xie*,1 Author information Journal of Clinical and Translational Hepatology 2020;8(3):277-284DOI:10.14218/JCTH.2020.00004 Abstract Background and Aims:To evaluate the efficacy of Fuzheng Huayu(FZHY),a Chinese herbal formula,plus entecavir(ETV)in regression of liver fibrosis in chronic hepatitis B(CHB)patients with significant fibrosis/cirrhosis.Methods:The current study was a two-center,randomized,double-blind and placebo-controlled pilot study.Fifty-two currently untreated chronic hepatitis B patients with Ishak fibrosis score≥3 points were identified and 1:1 randomized into FZHY plus ETV combination and placebo plus ETV groups.The second liver biopsy was performed after 48-week treatment.Necroinflammatory improvement and regression of fibrosis were assessed.Fine changes in different collagen features in paired liver biopsies were evaluated by dual-photon microscopy for both groups.Results:Forty-nine patients completed the full course of treatment;forty-six of them underwent second liver biopsy(for which twenty-two were in the combination group and twenty-four were in the control group).Compared to those in the control group,patients in the combination group had significantly higher rate of fibrosis regression(82%vs.54%)(p<0.05).Furthermore,the necroinflammatory improvement was greater in the combination group than in the control group(59%vs.25%,p<0.05).Among the more than 80 collagen parameters in the dual-photon analysis,5 decreased significantly in the combination group compared to the control group(p<0.05).However,no significant improvement was detected in either biochemical,virologic or serologic responses between these two groups at week 48.Conclusions:The combination therapy of FZHY plus ETV for 48 weeks resulted in a higher rate of necroinflammatory improvement and fibrosis regression than ETV alone in chronic hepatitis B patients with significant fibrosis/cirrhosis.The clinical trial number is ChiCTR-TRC-11001377.

Aggregation-induced emission luminogen for specific identification of malignant tumour in vivo

Colorectal cancer(CRC)is still a major killer,mainly due to the lack of early detection biomarker with sensitivity/specificity.Conventional histopathology is the gold standard approach in practice,but there are still some issues(false diagnosis and long waiting period).Aggregation-induced emission(AIE)is a novel photophysical phenomenon which has been widely utilized for biological imaging in vitro,including malignant cells,showing remarkable imaging contrast and enhanced emission in high concentrated state.However,it is unclear if AIE dyes can identify malignant cells specifically in vivo.A great challenge for specific labeling of malignant cells is probably ascribed to the complex compositions in tumor tissues.Herein,an AIE dye-based mitochondria-targeted histological staining strategy was employed to localize cancer and the metastatic track in the fresh colorectal cancer.This novel approach holds great potential to revolutionize the clinical diagnosis and intervention for devastating malignancy.

Environmental insults:critical triggers for amyotrophic lateral sclerosis

Background:Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons.As a complex disease,the ageing process and complicated gene-environment interactions are involved in the majority of cases.Main body:Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies,while environmental insults remain a suspected but largely unexplored source of risk.Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS,but none so far has proved conclusive.We propose a new ALS model which links the current knowledge of genetic factors,ageing and environmental insults.This model provides a mechanism as to how ALS is initiated,with environmental insults playing a critical role.Conclusion:The available evidence has suggested that inherited defect(s)could cause mitochondrial dysfunction,which would establish the primary susceptibility to ALS.Further study of the underlying mechanism may shed light on ALS pathogenesis.Environmental insults are a critical trigger for ALS,particularly in the aged individuals with other toxicant susceptible genes.The identification of ALS triggers could lead to preventive strategies for those individuals at risk.