DNA methylation biomarkers for early detection of gastric and colorectal cancers

Cancer is one of the leading causes of death worldwide.The early diagnosis of cancer remains one of the greatest cancer research challenges.Epigenetic alterations,such as altered DNA methylation,that occur during the early stages of carcinogenesis have been proposed as candidate cancer biomarkers.In recent years detection of small amounts of methylated DNA in samples,including blood and stool,has demonstrated the feasibility of DNA methylation as a molecular cancer biomarker.The translational promise of aberrant DNA methylation includes screening and detecting cancer,evaluating prognosis,assessing treatment efficacy,and detecting minimal residual disease(Figure 1).

Investigating the Effect of COVID-19 Infection on Professional Athletes’ Post-Infection with a Focus on Fatigue and Chronic Fatigue Syndrome

Introduction and Objectives: COVID-19 has been reported to cause long-term sequela including persistent fatigue and Chronic Fatigue Syndrome (CFS) in the general population. However, it remains to be seen if similar effects are observed in an athlete population. The aetiology and pathophysiology are poorly understood but is thought to be multi-factorial. Patient reported outcome measures are commonly used to improve patient-centred outcomes (PROMs). They are essential to assess patient quality of life post-COVID infection. This paper aims to assess the effect of COVID-19 on athletes’ long-term fatigue and CFS and identify the PROMs used to characterise this. Methodology: Articles were selected for extraction based on the eligibility criteria and PRISMA guidelines. The inclusion criteria required papers to assess competitive athletes over eighteen years of age who were clinically diagnosed with COVID-19. Articles were extracted to assess different variables including type of sport, type of athlete and ethnicity. Key terms were obtained using MeSH trees and utilised with Web of Science and NCBI Pubmed. Papers were graded by quality using the Hawker quality assessment tool. Results and Discussion: Forty articles (N = 40) were identified for full-text screening (N = 8). Eight were selected for extraction based on the eligibility criteria. Data was obtained on athlete characteristics, sport characteristics, properties of PROM measurement techniques and fatigue presentation. Male athletes were found to be 10% - 50% more likely than female athletes to suffer from persistent fatigue symptoms (N = 2). Persistent fatigue was present in 9% - 10% Athletes from mixed backgrounds and genders (N = 2). Initial fatigue was documented to be between 47% - 56% (N = 2). A heterogenous range of PROMs were utilised to assess symptoms including fatigue and excluded emotional or mental fatigue. Conclusion: COVID-19 is associated with signs of persisting fatigue and potentially CFS in athlete populations. More work needs to be done to develop standardised and validated PROMs specific to CFS.

Inhibition of EGFR attenuates EGF-induced activation of retinal pigment epithelium cell via EGFR/AKT signaling pathway

AIM:To explore the effect of epidermal growth factor receptor(EGFR)inhibition by erlotinib and EGFR siRNA on epidermal growth factor(EGF)-induced activation of retinal pigment epithelium(RPE)cells.METHODS:Human RPE cell line(ARPE-19 cells)was activated by 100 ng/mL EGF.Erlotinib and EGFR siRNA were used to intervene EGF treatment.Cellular viability,proliferation,and migration were detected by methyl thiazolyl tetrazolium(MTT)assay,bromodeoxyuridine(BrdU)staining assay and wound healing assay,respectively.EGFR/protein kinase B(AKT)pathway proteins and N-cadherin,α-smooth muscle actin(α-SMA),and vimentin were tested by Western blot assay.EGFR was also determined by immunofluorescence staining.RESULTS:EGF treatment for 24h induced a significant increase of ARPE-19 cells’viability,proliferation and migration,phosphorylation of EGFR/AKT proteins,and decreased total EGFR expression.Erlotinib suppressed ARPE-19 cells’viability,proliferation and migration through down regulating total EGFR and AKT protein expressions.Erlotinib also inhibited EGF-induced an increase of proliferative and migrative ability in ARPE-19 cells and clearly suppressed EGF-induced EGFR/AKT proteins phosphorylation and decreased expression of N-cadherin,α-SMA,and vimentin proteins.Similarly,EGFR inhibition by EGFR siRNA significantly affected EGF-induced an increase of cell proliferation,viability,and migration,phosphorylation of EGFR/AKT proteins,and up-regulation of N-cadherin,α-SMA,and vimentin proteins.CONCLUSION:Erlotinib and EGFR-knockdown suppress EGF-induced cell viability,proliferation,and migration via EGFR/AKT pathway in RPE cells.EGFR inhibition may be a possible therapeutic approach for proliferative vitreoretinopathy(PVR).

Use of endolumenal functional lumen imaging probe in investigating paediatric gastrointestinal motility disorders

Investigating gastrointestinal(GI)motility disorders relies on diagnostic tools to assess muscular contractions,peristalsis propagation and the integrity and coordination of various sphincters.Manometries are the gold standard to study the GI motor function but it is increasingly acknowledged that manometries do not provide a complete picture in relation to sphincters competencies and muscle fibrosis.Endolumenal functional lumen imaging probe(EndoFLIP)an emerging technology,uses impedance planimetry to measure hollow organs cross sectional area,distensibility and compliance.It has been successfully used as a complementary tool in the assessment of the upper and lower oesophageal sphincters,oesophageal body,the pylorus and the anal canal.In this article,we aim to review the uses of EndoFLIP as a tool to investigate GI motility disorders with a special focus on paediatric practice.The majority of EndoFLIP studies were conducted in adult patients but the uptake of the technology in paediatrics is increasing.EndoFLIP can provide a useful complementary data to the existing GI motility investigation in both children and adults.

Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway

AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family in physiological and pathophysiological process and diseases

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family(PGC-1s),consisting of three members encompassing PGC-1a,PGC-1β,and PGC-1-related coactivator(PRC),was discovered more than a quarter-century ago.PGC-1s are essential coordinators of many vital cellular events,including mitochondrial functions,oxidative stress,endoplasmic reticulum homeostasis,and inflammation.Accumulating evidence has shown that PGC-1s are implicated in many diseases,such as cancers,cardiac diseases and cardiovascular diseases,neurological disorders,kidney diseases,motor system diseases,and metabolic disorders.Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s.Furthermore,discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods.In this review,we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network,discuss the physio-pathological roles of PGc-1s in human diseases,review the application of PGC-1s,including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies,and suggest several directions for future investigations.This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

Iron and liver fibrosis: Mechanistic and clinical aspects

Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore,understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly,highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.

Hepatic steatosis and fibrosis: Non-invasive assessment

Chronic liver disease is a major cause of morbidity and mortality worldwide and usually develops over many years, as a result of chronic inflammation and scarring, resulting in end-stage liver disease and its complications. The progression of disease is characterised by ongoing inflammation and consequent fibrosis, although hepatic steatosis is increasingly being recognised as an important pathological feature of disease, rather than being simply an innocent bystander. However, the current gold standard method of quantifying and staging liver disease, histological analysis by liver biopsy, has several limitations and can have associated morbidity and even mortality. Therefore, there is a clear need for safe and noninvasive assessment modalities to determine hepatic steatosis, inflammation and fibrosis. This review covers key mechanisms and the importance of fibrosis and steatosis in the progression of liver disease. We address non-invasive imaging and blood biomarker assessments that can be used as an alternative to information gained on liver biopsy.

Macrophage regulation of graft-vs-host disease

Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy,but graft-vs-host disease(GVHD)has limited the survival quality and overall survival of hematopoietic stem cell transplantation.Understanding of the immune cells’reaction in pathophysiology of GVHD has improved,but a review on the role of macrophages in GVHD is still absent.Studies have observed that macrophage infiltration is associated with GVHD occurrence and development.In this review,we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD,focusing on the macrophage recruitment and infiltration,macrophage polarization,macrophage secretion,and especially interaction of macrophages with other immune cells.We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD.Based on distinguishing pathology of acute and chronic GVHD,macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD.However,the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization.In addition,interaction of macrophages with alloreactive T cells plays an important role in acute GVHD.Meanwhile,the interaction among macrophages,B cells,fibroblasts,and CD4+T cells participates in chronic GVHD development.

High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells

BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a common cause of liver disease worldwide and is a growing epidemic. A high ratio of omega-6 fatty acids to omega-3 fatty acids in the diet has been implicated in the development of NAFLD. However, the inflicted cellular pathology remains unknown. A high ratio may promote lipogenic pathways and contribute to reactive oxygen species(ROS)-mediated damage, perhaps leading to mitochondrial dysfunction.Therefore, these parameters were investigated to understand their contribution to NAFLD development.AIM To examine the effect of increasing ratios of omega-6:3 fatty acids on mitochondrial function and lipid metabolism mediators.METHODS Hep G2-derived VL-17 A cells were treated with normal(1:1, 4:1) and high(15:1,25:1) ratios of omega-6: omega-3 fatty acids [arachidonic acid(AA):docosahexaenoic acid(DHA)] at various time points. Mitochondrial activity and function were examined via MTT assay and Seahorse XF24 analyzer, respectively.Triglyceride accumulation was determined by using Enzy Chrom? and levels of ROS were measured by fluorescence intensity. Protein expression of the mediators of lipogenic, lipolytic and endocannabinoid pathways was assessed by Western blotting.RESULTS High AA:DHA ratio decreased mitochondrial activity(P < 0.01;up to 80%) and promoted intracellular triglyceride accumulation(P < 0.05;40%-70%).Mechanistically, it altered the mediators of lipid metabolism;increased the expression of stearoyl-Co A desaturase(P < 0.05;22%-35%), decreased the expression of peroxisome proliferator-activated receptor-alpha(P < 0.05;30%-40%) and increased the expression of cannabinoid receptor 1(P < 0.05;31%).Furthermore, the high ratio increased ROS production(P < 0.01;74%-115%) and reduced mitochondrial respiratory functions such as basal and maximal respiration, ATP production, spare respiratory capacity and proton leak(P < 0.01;35%-68%).CONCLUSION High AA:DHA ratio induced triglyceride accumulation, increased oxidative stress and disrupted mitochondrial functions. Stimulation of lipogenic and steroidal transcription factors may partly mediate these effects and contribute to NAFLD development.

Cultivated Cordyceps: A Tale of Two Treasured Mushrooms

Ophiocordyceps sinensis and Cordyceps militaris both contain many bioactive compounds that confer potential therapeutic benefits. This review discusses the possible use of cultivated C. militaris as an effective substitute for native O. sinensis in the face of ever-increasing prices of O. sinensis because of its short supply. On the one hand, cultivated C. militaris contains higher levels of cordycepin when compared with that of wild-type O. sinensis and cultivation of C. militaris has been shown to be capable of reducing the risk of heavy metal contamination. On the other hand, there is a paucity of robust in vivo studies and randomized controlled tests comparing the pharmacology and use of C. militaris and O. sinensis. For extraction of cordycepin as western-style tablets, the use of cultivated C. militaris rather than O. sinensis represents the most appropriate future approach. For many other purposes, comparative pharmacology and clinical trials are in urgent needs.

Age-related modifications of macrophages influenced by “inflammageing”in graft vs. host disease

Most studies focus on the adaptive immune cells in the GVHD pathogenesis,while little is known about innate immune cells in GVHD occurrence and development,especially macrophages.Meanwhile,a higher incidence of graft versus host disease(GVHD)is also found in the elderly patients.Though advances have been made in the modification of macrophages influenced by the inflamm-ageing,there is still no review on the role of macrophages in GVHD and the association between GVHD and the altered macrophages by inflamm-ageing.In this review,we focus on the potential age-related modifications of macrophage in GVHD,which contributes to the change of morbidity and mortality of GVHD.Via literature review,we found that the infiltration of macrophages is associated with GVHD and macrophages are modified in inflamm-ageing state,including the proliferation,migration,phagocytosis,antigen presentation,interaction with other immune cells,and pro-fibrosis.We suppose that altered macrophage functions in inflamm-ageing state contribute to GVHD in elderly patients.

Non-alcoholic fatty liver disease:Is surgery the best current option and can novel endoscopy play a role in the future?

alcohol as the leading cause of cirrhosis in the Western world.There remains to be a licensed pharmacological treatment for NAFLD.Weight loss is advised for all patients with NAFLD.Many patients however,struggle to lose the recommended weight with lifestyle modification alone.Many drugs have either failed to show significant improvement of steatosis or are poorly tolerated.Bariatric surgery has been shown to reduce liver steatosis and regress liver fibrosis.The pathophysiology is not fully understood,however recent evidence has pointed towards changes in the gut microbiome following surgery.Novel endoscopic treatment options provide a minimally invasive alternative for weight loss.Randomised controlled trials are now required for further clarification.

Target specificity of selective bioactive compounds in blocking α-dystroglycan receptor to suppress Lassa virus infection: an in silico approach

Lassa hemorrhagic fever,caused by Lassa mammarenavirus(LASV)infection,accumulates up to 5000 deaths every year.Currently,there is no vaccine available to combat this disease.In this study,a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block theα-dystroglycan(α-DG)receptor and prevent LASV influx.Following rigorous absorption,distribution,metabolism,and excretion(ADME)and quantitative structure-activity relationship(QSAR)profiling,molecular docking was conducted with the top ligands against theα-DG receptor.The compounds chrysin,reticuline,and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity.Post-docking analysis revealed that interactions with Arg76,Asn224,Ser259,and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands.Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes.In-depth assessment of root-mean-square deviation(RMSD),root mean square fluctuation(RMSF),polar surface area(PSA),B-Factor,radius of gyration(Rg),solvent accessible surface area(SASA),and molecular surface area(MolSA)values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes.To authenticate the potentialities of the ligands as target-specific drugs,an in vivo study is underway in real time as the continuation of the research.

When and how does brain-derived neurotrophic factor activate Nrf2 in astrocytes and neurons？

Circadian rhythm protects neurons：Although the master clock entrains the whole body rhythm,peripheral tissues also express core clock transcription factors Clock and Bmal1,which regulate expression of clock genes including Period（Per）and Cryptochrome（Cry）proteins.Complexes of Per and Cry proteins repress Bmal1-and Clock-mediated transcription forming a negative feedback loop,which regulates nearly a 24 hours self-sustained rhythm including energy metabolism.

Comprehensive Analysis of Pan-African Mitochondrial DNA Variation Provides New Insights into Continental Variation and Demography

Africa is the cradle of all human beings, and although it has been the focus of a number of genetic studies, there are many questions that remain unresolved. We have performed one of the largest and most comprehensive meta-analyses of mitochondrial DNA （mtDNA） lineages carried out in the African continent to date. We generated high-throughput mtDNA single nucleotide polymorphism （SNP） data （230 SNPs） from 2024 Africans, where more than 500 of them were additionally genotyped for the control region. These data were analyzed together with over 12,700 control region profiles collected from the literature, representing more than 300 population samples from Africa. Insights into the African homeland of humans are discussed. Phylogeographic patterns for the African continent are shown at a high phylogeographic resolution as well as at the population and regional levels. The deepest branch of the mtDNA tree, haplogroup L0, shows the highest sub-haplogroup diversity in Southeast and East Africa, suggesting this region as the homeland for modem humans. Several demographic estimates point to the coast as a facilitator of human migration in Africa, but the data indicate complex patterns, perhaps mirroring the effect of recent continental-scaled demographic events in re-shaping African mtDNA variability.

The Role of Chinese Medicine in Cancer Care——a Critical Review

Traditional Chinese medicine(TCM) has been widely used in China and other East Asian countries for helping cancer patients. However, it is unavailable to most patients who are treated in NHS in UK, due to there is not enough evidence in using TCM in cancer patients, To try to establish the evidence base for using TCM in cancer patients management, the author reviewed the current available clinical reports to TCM treatment of cancer patients, mainly those of randomly assigned and controlled clinical trials(RCTs) with bigger samples, from maintaining the quality of life, enhancing immune system, remedying the side effects from radiotherapy and chemotherapy respectively, and to propose a role of TCM as an assistant therapy to the main therapies. We then concluded that TCM holds its unique value in maintaining good quality of life, and to help the patients through the operation, chemotherapy and radiotherapy to achieve better outcomes.

Advances in Space Medicine Applied to Pandemics on Earth

Preparation and planning are critical when facing an epidemic or pandemic.Timely solutions must be incorporated in addition to existing guidelines in the case of a fast-spreading epidemic.Advances in space health have been driven by the need to preserve human health in an austere environment,in which medical assistance or resupply from the ground is not possible.This paper speculates on the similarities between human spaceflight and epidemics,extended to pandemics,identifying implementable solutions for immediate use by healthcare personnel and healthcare systems.We believe aerospace medical research can be seen as a resource to improve terrestrial medical care and the management of patients on Earth.

Intestinal heme absorption in hemochromatosis gene knock-out mice

AIM To investigat the influence of hemochromatosis gene(Hfe) mutation on ^(59)Fe labelled duodenal heme absorption in mice.METHODS Heme absorption was measured in Hfe wild type and Hfe^((-/-)) mice by the duodenal tied loop and by oral gavage methods. The m RNA expression of heme oxygenase(HO-1), Abcg2 and Flvcr1 genes and levels were determined by quantitative polymerase chain reaction.RESULTS Heme absorption was significantly increased in homozygous Hfe^((-/-)) mice despite significant hepatic and splenic iron overload. While duodenal HO-1 mRNA was highly expressed in the wild type and Hfe^((-/-)) heme-treated group following 24 h heme administration, Flvcr1 a mRNA decreased. However, Abcg2 mRNA expression levels in duodenum remained unchanged. CONCLUSION Heme absorption was enhanced in Hfe^((-/-)) mice from both duodenal tied-loop segments and by oral gavage methods. HO-1 m RNA levels were enhanced in mice duodenum after 24 h of heme feeding and may account for enhanced heme absorption in Hfe^((-/-)) mice. Implications for dietary recommendations on heme intake by Hfe subjects to modulate iron loading are important clinical considerations.

Telomere Elongation in the Breast Cancer Cell Line 21NT after Treatment with an Epigenetic Modifying Drug

Background: Telomere length dysregulation plays a major role in cancer development and aging. Telomeres are maintained by a group of specialized genes known as shelterin and shelterin-associated proteins. In breast cancer lines it has been shown that shelterin proteins are dysregulated thereby affecting the telomere stability and contributing to the neoplastic conversion of the mammary epithelial cells. Interestingly, the regulation of some of the shelterin genes is thought to be controlled epigenetically. Methods and Results: In this study, we set out to measure the effect of increased shelterin gene expression on telomere length in breast cancer cell line 21NT treated with 5-aza-2-deoxycytidine (5-aza-CdR) using known telomere length assays. We measured telomere lengths using: Telomere Restriction Fragment length (TRF), absolute quantitative-PCR and cytogenetic Interphase Quantitative Fluorescent in situ Hybridization (iQ-FISH). We found that non-cytotoxic levels of 5-aza-CdR affect telomere lengths by causing a significant and stable increase in telomere lengths of the breast cancer cell line. The increase in telomere lengths was consistently observed when various telomere length methods were used. Conclusions: Further investigation is required to understand the underlying mechanism involved, and the significance of telomere length elongation in relation to clinical outcome when epigenetic modifying drugs are utilized.