Efficacy of ginseng-based Renshenguben oral solution for cancer-related fatigue among patients with advanced-stage hepatocellular carcinoma:A prospective multicenter cohort study

Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and safety of Renshenguben(RSGB)oral solution,a ginseng-based traditional Chinese medicine,in alleviating CRF in patients with advanced hepatocellular carcinoma(HCC)receiving antitumor treatment.Methods:In this prospective,open-label,controlled,multicenter study,patients with advanced HCC at BCLC stage C and a brief fatigue inventory(BFI)score of≥4 were enrolled.Participants were assigned to the RSGB group(RSGB,10 mL twice daily)or the control group(with supportive care).Primary and secondary endpoints were the change in multidimensional fatigue inventory(MFI)score,and BFI and functional assessment of cancer therapy-hepatobiliary(FACT-Hep)scores at weeks 4 and 8 after enrollment.Adverse events(AEs)and toxicities were assessed.Results:A total of 409 participants were enrolled,with 206 assigned to the RSGB group.At week 4,there was a trend towards improvement,but the differences were not statistically significant.At week 8,the RSGB group exhibited a significantly lower MFI score(P<0.05)compared to the control group,indicating improved fatigue levels.Additionally,the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8(P<0.05).Subgroup analyses among patients receiving various antitumor treatments showed similar results.Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI,BFI,and FACT-Hep scores at week 8.No serious drug-related AEs or toxicities were observed.Conclusions:RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period,with no discernible toxicities.These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.

Potential clinical application of microRNAs in bladder cancer

Bladder cancer(BC)is the tenth most prevalent malignancy globally,presenting significant clinical and societal challenges because of its high incidence,rapid progression,and frequent recurrence.Presently,cystoscopy and urine cytology serve as the established diagnostic methods for BC.However,their efficacy is limited by their invasive nature and low sensitivity.Therefore,the development of highly specific biomarkers and effective noninvasive detection strategies is imperative for achieving a precise and timely diagnosis of BC,as well as for facilitating an optimal tumor treatment and an improved prognosis.microRNAs(miRNAs),short noncoding RNA molecules spanning around 20–25 nucleotides,are implicated in the regulation of diverse carcinogenic pathways.Substantially altered miRNAs form robust functional regulatory networks that exert a notable influence on the tumorigenesis and progression of BC.Investigations into aberrant miRNAs derived from blood,urine,or extracellular vesicles indicate their potential roles as diagnostic biomarkers and prognostic indicators in BC,enabling miRNAs to monitor the progression and predict the recurrence of the disease.Simultaneously,the investigation centered on miRNA as a potential therapeutic agent presents a novel approach for the treatment of BC.This review comprehensively analyzes biological roles of miRNAs in tumorigenesis and progression,and systematically summarizes their potential as diagnostic and prognostic biomarkers,as well as therapeutic targets for BC.Additionally,we evaluate the progress made in laboratory techniques within this field and discuss the prospects.

A Meta-Analysis of the Prognostic and Clinicopathological Significance of circZFR in Human Gastrointestinal Cancers

Background: Studies of gastrointestinal (GIT) cancers have shown that circZFR could be involved in the development and progression of various GIT cancers. However, small sample sizes limit the clinical significance of these studies. Here, a meta-analysis was conducted to ascertain the actual involvement of circZFR in the development and prognosis of GIT cancers. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched up to December 31, 2023. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to evaluate the association between circZFR expression and overall survival (OS). Publication bias was measured using the funnel plot and Egger’s test. Results: 10 studies having 659 participants were enrolled for meta-analysis. High circZFR expression was associated with poor OS (HR = 1.4, 95% CI: 1.20, 1.70). High circZFR expression also predicted larger tumor size (OR = 4.38, 95% CI 2.65, 7.25), advanced clinical stage (OR = 5.33, 95% CI 3.10, 9.16), and tendency for distant metastasis (OR = 2.89, 95% CI: 1.62, 5.11), but was not related to age, gender, and histological grade. Conclusions: In summary, high circZFR expression was associated with poor OS, larger tumor size, advanced stage cancer and tendency for distant metastasis. These findings suggested that circZFR could be a prognostic marker for GIT cancers.

Klebsiella pneumoniae infections after liver transplantation:Drug resistance and distribution of pathogens,risk factors,and influence on outcomes

BACKGROUND Liver transplantation(LT)is the only curative treatment for end-stage liver disease.However,LT recipients are susceptible to infection,which is the leading cause of early mortality after LT.Klebsiella pneumoniae infections(KPIs)in the bloodstream are common in LT recipients.We hypothesized that KPIs and carbapenemresistant Klebsiella pneumoniae(CRKP)infections may affect the outcomes of LT recipients.AIM To assess KPI incidence,timing,distribution,drug resistance,and risk factors following LT and its association with outcomes.METHODS This retrospective study included 406 patients undergoing LT at The Third Xiangya Hospital of Central South University,a tertiary hospital,from January 2015 to January 2023.We investigated the risk factors for KPIs and assessed the impact of KPIs and CRKP infections on the prognosis of LT recipients using logistic regression analysis.RESULTS KPI incidence was 7.9%(n=32),with lung/thoracic cavity the most frequent site of infection;the median time from LT to KPI onset was 7.5 d.Of 44 Klebsiella pneumoniae isolates,43(97.7%)and 34(77.3%)were susceptible to polymyxin B or ceftazidime/avibactam and tigecycline,respectively;>70%were resistant to piperacillin/tazobactam,ceftazidime,cefepime,aztreonam,meropenem,and levofloxacin.Female sex[odds ratio(OR)=2.827,95%confidence interval(CI):1.256-6.364;P=0.012],pre-LT diabetes(OR=2.794,95%CI:1.070-7.294;P=0.036),day 1 post-LT alanine aminotransferase(ALT)levels≥1500 U/L(OR=3.645,95%CI:1.671-7.950;P=0.001),and post-LT urethral catheter duration over 4 d(OR=2.266,95%CI:1.016-5.054;P=0.046)were risk factors for KPI.CRKP infections,but not KPIs,were risk factors for 6-month all-cause mortality post-LT.CONCLUSION KPIs occur frequently and rapidly after LT.Risk factors include female sex,pre-LT diabetes,increased post-LT ALT levels,and urethral catheter duration.CRKP infections,and not KPIs,affect mortality.

Construction and evaluation of a liver cancer risk prediction model based on machine learning

BACKGROUND Liver cancer is one of the most prevalent malignant tumors worldwide,and its early detection and treatment are crucial for enhancing patient survival rates and quality of life.However,the early symptoms of liver cancer are often not obvious,resulting in a late-stage diagnosis in many patients,which significantly reduces the effectiveness of treatment.Developing a highly targeted,widely applicable,and practical risk prediction model for liver cancer is crucial for enhancing the early diagnosis and long-term survival rates among affected individuals.AIM To develop a liver cancer risk prediction model by employing machine learning techniques,and subsequently assess its performance.METHODS In this study,a total of 550 patients were enrolled,with 190 hepatocellular carcinoma(HCC)and 195 cirrhosis patients serving as the training cohort,and 83 HCC and 82 cirrhosis patients forming the validation cohort.Logistic regression(LR),support vector machine(SVM),random forest(RF),and least absolute shrinkage and selection operator(LASSO)regression models were developed in the training cohort.Model performance was assessed in the validation cohort.Additionally,this study conducted a comparative evaluation of the diagnostic efficacy between the ASAP model and the model developed in this study using receiver operating characteristic curve,calibration curve,and decision curve analysis(DCA)to determine the optimal predictive model for assessing liver cancer risk.RESULTS Six variables including age,white blood cell,red blood cell,platelet counts,alpha-fetoprotein and protein induced by vitamin K absence or antagonist II levels were used to develop LR,SVM,RF,and LASSO regression models.The RF model exhibited superior discrimination,and the area under curve of the training and validation sets was 0.969 and 0.858,respectively.These values significantly surpassed those of the LR(0.850 and 0.827),SVM(0.860 and 0.803),LASSO regression(0.845 and 0.831),and ASAP(0.866 and 0.813)models.Furthermore,calibration and DCA indicated that the RF model exhibited robust calibration and clinical validity.CONCLUSION The RF model demonstrated excellent prediction capabilities for HCC and can facilitate early diagnosis of HCC in clinical practice.

GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines

BACKGROUND Thrombocytopenia 2,an autosomal dominant inherited disease characterized by moderate thrombocytopenia,predisposition to myeloid malignancies and normal platelet size and function,can be caused by 5’-untranslated region(UTR)point mutations in ankyrin repeat domain containing 26(ANKRD26).Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1)have been identified as negative regulators of ANKRD26.However,the positive regulators of ANKRD26 are still unknown.AIM To prove the positive regulatory effect of GATA binding protein 2(GATA2)on ANKRD26 transcription.METHODS Human induced pluripotent stem cells derived from bone marrow(hiPSC-BM)INTRODUCTION Ankyrin repeat domain containing protein 26(ANKRD26)acts as a regulator of adipogenesis and is involved in the regulation of feeding behavior[1-3].The ANKRD26 gene is located on chromosome 10 and shares regions of homology with the primate-specific gene family POTE.According to the Human Protein Atlas database,the ANKRD26 protein is localized to the Golgi apparatus and vesicles,and its expression can be detected in nearly all human tissues[4].Moreover,UniProt annotation revealed that ANKRD26 is localized in the centrosome and contains coiled-coil domains formed by spectrin helices and ankyrin repeats[5,6].The most common disease related to ANKRD26 is thrombocytopenia 2(THC2),which is a rare autosomal dominant inherited disease characterized by lifelong mild-to-moderate thrombocytopenia and mild bleeding[7-9].Caused by the variants in the 5’-untranslated region(UTR)of ANKRD26,THC2 is defined by a decrease in the number of platelets in circulating blood and results in increased bleeding and decreased clotting ability[8,10].Due to the point mutations that occur in the 5’-UTR of ANKRD26,its negative transcription factors(TFs),Runt related transcription factor 1(RUNX1)and friend leukemia integration 1(FLI1),lose their repression effect[11].The persistent expression of ANKRD26 increases the activity of the mitogen activated protein kinase and extracellular signal regulated kinase 1/2 signaling pathways,which are potentially involved in the regulation of thrombopoietin-dependent signaling and further impair proplatelet formation by megakaryocytes(MKs)[11].However,the positive regulators of ANKRD26,which might be associated with THC2 pathology,are still unknown.

Novel intervention for alcohol-associated liver disease

A recently published article in the World Journal of Gastroenterology clarified that elafibranor,a dual peroxisome proliferator activated receptorα/δ(PPARα/δ)agonist,reduced inflammation and fibrosis in alcohol-associated liver disease(ALD).This letter aims to discuss the findings presented in that article.ALD is a global health problem,and no effective drugs has been approved by the Food and Drug Administration to cure it.Thus,finding targeted therapies is of great urgency.Herein,we focus on the pathogenesis of ALD and the role of PPARα/δin its development.Consistent with the conclusion of the article of interest,we think that elafibranor may be a promising therapeutic option for ALD,due to the pivotal involvement of PPARα/δin the pathogenesis of the disease.However,its treatment dose,timing,and side effects need to be further investigated in future studies.

Innovative mesenchymal stem cell treatments for fatty liver disease

The incidence of non-alcoholic fatty liver disease(NAFLD)and alcohol-associated liver disease(ALD)is increasing year by year due to changes in the contemporary environment and dietary structure,and is an important public health problem worldwide.There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies.Mesenchymal stem cells(MSCs)have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD.NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different,but both involve disease processes such as hepatocellular steatosis and potential fibrosis,cirrhosis,and even hepatocellular carcinoma.MSCs have metabolic regulatory,anti-apoptotic,antioxidant,and immunomodulatory effects that together promote liver injury repair and functional recovery,and have demonstrated positive results in preclinical studies.This editorial is a continuum of Jiang et al’s review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD.They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and fibrosis.Based on recent advances,we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD,providing useful information for their clinical application.

Realm of hepatitis E:Challenges and opportunities

Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.

Effects of Dezocine and Propofol Combination on Plasma 5-HT and ET Levels in Stroke Patients Undergoing Thrombolysis

Objective: To investigate the effect of dezocine combined with propofol on brain metabolism in patients undergoing cerebral thrombosis thrombolysis. Methods: A total of 86 stroke patients admitted between July 2022 and December 2023 were randomly divided into two groups: Group A (study group) and Group B (control group), with 43 patients in each group. Both groups underwent intra-arterial thrombolysis therapy. Group B received dezocine for anesthesia, while Group A received a combination of dezocine and propofol. Plasma concentrations of 5-hydroxytryptamine and endothelin, as well as brain metabolic indicators, were compared between the two groups immediately after anesthesia, at 1 hour post-reperfusion, and 3 hours post-reperfusion. Results: There were no significant differences in the levels of 5-hydroxytryptamine and endothelin between the two groups immediately after anesthesia and at 1 hour post-reperfusion (P > 0.05). However, at 3 hours post-reperfusion, the levels of 5-hydroxytryptamine and endothelin in Group A were significantly lower than those in Group B. Furthermore, in Group A, the levels of 5-hydroxytryptamine and endothelin at 3 hours post-reperfusion were lower compared to the levels at 1 hour post-reperfusion (P < 0.05). Conclusion: Dezocine combined with propofol can effectively improve the quality of anesthesia and has a minimal effect on brain metabolic indices, suggesting reduced damage to brain metabolism.

Comparison and Analysis of Clinical Characteristics of Common COVID-19 and NSIP Patients

Objective:To investigate the relationship between coronavirus disease 2019(COVID-19)and non-specific interstitial pneumonia(NSIP),with a focus on the clinical features of COVID-19 and NSIP,and the key points of differential diagnosis.Methods:The clinical data of 20 patients with common-type COVID-19 and NSIP admitted to Linyi People’s Hospital from January 21,2020,to June 21,2022,were retrospectively analyzed.Gender,age,history of residence in Hubei province,underlying diseases,clinical manifestations,laboratory test results(including blood routine indexes,inflammatory markers,liver function indexes,and coagulation indexes),and computed tomography(CT)scan images were compared between the two groups.Results:COVID-19 patients were younger than NSIP patients(P<0.05).Nine COVID-19 patients had a travel history to Hubei province,while none of the NSIP patients did(P<0.05).Eight COVID-19 patients had underlying chronic conditions,fewer than the NSIP group(12 patients;P<0.05).Both groups experienced symptoms such as shortness of breath,expectoration,fatigue,and runny nose,but fever and cough were more severe and more frequent in the COVID-19 group.Compared to normal reference ranges,both groups exhibited normal white blood cell counts(WBC)and liver function indexes,but elevated lymphocyte counts(LYMP),inflammatory markers,and coagulation indexes,with reduced neutrophil counts(NE).WBC and LYMP were higher in the COVID-19 group compared to the NSIP group.Male patients in the COVID-19 group had higher erythrocyte sedimentation rates and C-reactive protein values than those in the NSIP group,while procalcitonin levels were lower in the COVID-19 group,although the differences were not statistically significant(all P>0.05).The NE count in the COVID-19 group was significantly lower than in the NSIP group(P<0.05).Alanine aminotransferase,total bilirubin,and indirect bilirubin were significantly higher in the COVID-19 group compared to the NSIP group(P<0.05).Chest CT scans of both groups showed bilateral patchy ground-glass opacities,but the lesions in COVID-19 patients were scattered.NSIP patients’chest CTs showed diffuse lesions centered around the hilum or multiple lesions in both lungs,with pleural involvement being rare.Conclusion:While there are certain specific clinical,laboratory,and imaging findings in both COVID-19 and NSIP,the specificity of these features is not high.Differentiating the two requires careful consideration of epidemiological history,nucleic acid testing,and antigen-antibody levels.

Dual effects of 8-Br-cAMP on differentiation and apoptosis of human esophageal cancer cell line Eca-109

AIM: To investigate the effects of 8-Br-cAMP on differentiation and apoptosis of human esophageal cancer cell line Eca-109, and the related gene expression.METHODS: The cultured Eca-109 cells were divided into four groups: E1 group (co-cultured with 8-Br-cAMP for 24 h); E2 group (co-cultured with 8-Br-cAMP for 48 h); C1 group (treated without 8-Br-cAMP for 24 h); and C2 group (treated without 8-Br-cAMP for 48 h). The same concentration of cell suspension of each group was dropped separately onto the slides and nitrocellulose membranes (NCM). The biotin-labeled cDNA probes for c-myc, wild-type (wt) p53, bcl-2 and iNOS were prepared for in situ hybridization. The expressions of epidermal growth factor receptor (EGFR), p38 kinase, FAS, FasL and caspase-3 were detected using immunocytochemistry, and the NOS activity and the ratio of differentiated cells/proliferating cells were examined by cytochemistry. Immunocytochemistry, cytochemistry,and in situ hybridization were separately carried out on both slides and NCM specimens for each group. In addition, TUNEL was used to detect the cell apoptosis rate in each group.RESULTS: The apoptotic rate of E2 group was significantly higher compared to E1 group, while there was no difference in the ratio of differentiated cells/ proliferating cells between E1 and E2 groups. The signals of wt p53 and iNOS were markedly stronger, while the signals of c-myc and EGFR were obviously weaker in E1 group than those in C1 group (P＜0.05). Moreover, the signals of wt p53, iNOS, p38 kinase, caspase-3 and NOS activity were significantly stronger, whereas, the signals of bcl-2, c-myc and Fas/FasL were markedly weaker in E2 group than those in C2 group (P＜0.05). CONCLUSION: The differentiation and apoptosis of human esophageal cancer cell Eca-109 can be induced after 24- and 48-h treatment with 8-BrcAMP, respectively. Upregulation of wt p53, iNOS and downregulation of c-myc may be associated with differentiation and apoptosis of Eca-109 cells.Furthermore, upregulation of FasL, p38 kinase and caspase-3 as well as downregulation of bcl-2, and Fas may be involved in the apoptosis of Eca-109 cells.

Protective effect of DNA vaccine with the gene encoding 55kDa antigen fragment against Pneumocystis carinii in mice

Objective:To evaluate the protective effect of DNA vaccine with the gene encoding 55kDa antigen fragment of Pneumocystis carinii(P.carina) against P.carina in mice.Methods:The fragment of the antigen within p55(p55-582) was cloned.Then recombinant plasmid was constructed based on the eukaryotic expression vector pcDNA3.1(+).BALB/c mice were used as experimental models to examine the immunogenicity of pcDNA3.1(+)-p55-582.ELBA and RTPCR were used to evaluate the role of this kind of DNA vaccine.Results:The results of western blot indicated that the recombinant DNA[pcDNA3.1(+)-p55-582]could be expressed correctly and had antigenicity in transfected COS-7 cells.ELBA and RT-PCR showed that pcDNA3.1(+)- p55-582 elicited antibody production,stimulated lymphocyte proliferation and provided partial protection by reducing the P.carina burden.Conclusions:The data demonstrate that pcDNA3.1(+)-p55-582 might be potent vaccination that can afford the partial protection for the immunized animals.

Diagnostic value of gamma-glutamyltransferase/aspartate aminotransferase ratio, protein induced by vitamin K absence or antagonist II, and alpha-fetoprotein in hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Researchers have investigated the diagnostic value of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and obtained abundant clinical diagnostic data. However, PIVKA-II and AFP have unsatisfactory specificity and sensitivity in the diagnosis of early-stage HBV-related HCC. Gamma-glutamyltransferase (γ-GT) and aspartate aminotransferase (AST) are common biomarkers for evaluating liver function, and we hypothesized that the γ-GT/AST ratio in combination with PIVKA-II and AFP would improve the diagnosis of early-stage HBV-related HCC. AIM To evaluate the diagnostic value of γ-GT/AST ratio alone or in combination with PIVKA-II and AFP in HBV-related HCC. METHODS Serum levels of γ-GT, AST, PIVKA-II, and AFP were detected and analysed in 176 patients with HBV-related HCC and in 359 patients with chronic hepatitis B. According to tumour size and serum level of HBV DNA, HBV-related HCC patients were divided into the following categories: Early-stage HCC patients, HCC patients, HBV DNA positive (HBV DNA+) HCC patients, and HBV DNA negative (HBV DNA-) HCC patients. Receiver-operating characteristic (ROC) curves were used to analyse and compare the diagnostic value of the single and combined detection of various biomarkers in different types of HBV-related HCC. RESULTS Tumour size was positively correlated with serum levels of PIVKA-II and AFP in HCC patients (r = 0.529, aP < 0.001 and r = 0.270, bP < 0.001, respectively), but there was no correlation between tumour size and the γ-GT/AST ratio (r = 0.073, P = 0.336). The areas under the receiver-operating characteristic curves (AUROCs) of the γ-GT/AST ratio in early-stage HCC patients, HBV DNA+ HCC patients and HBV DNA- HCC patients were not significantly different from that in the total HCC patients (0.754, 0.802, and 0.705 vs 0.779, respectively;P > 0.05). When PIVKA-II was combined with the γ-GT/AST ratio in the diagnosis of earlystage HCC, HCC, and HBV DNA+ HCC, the AUROCs of PIVKA-II increased, with values of 0.857 vs 0.835, 0.925 vs 0.913, and 0.958 vs 0.954, respectively. When AFP was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, HBV DNA+ HCC, and HBV DNA- HCC, the AUROCs of AFP increased, with values of 0.757 vs 0.621, 0.837 vs 0.744, 0.868 vs 0.757, and 0.840 vs 0.828, respectively. CONCLUSION The γ-GT/AST ratio may be better than PIVKA-II and AFP in the diagnosis of early-stage HBV-related HCC, and its combination with PIVKA-II and AFP can improve the diagnostic value for HBV-related HCC.

CR6-interacting factor-1 contributes to osteoclastogenesis by inducing receptor activator of nuclear factor κB ligand after radiation

BACKGROUND Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury.Receptor activator of nuclear factor κB ligand(RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood.AIM To investigate the role of CR6-interacting factor-1(Crif1) in osteoclastogenesis after radiation and its possible mechanism.METHODS C57 BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of wholebody sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells(BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. Clus Pro and Inter Pro Surf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate(c AMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt(WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BMMSCs, and Vero cells.RESULTS Crif1 expression increased in bone marrow cells after radiation in mice.Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression,resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A(PKA)agonist(forskolin) and inhibitor(H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the c AMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the c AMP/PKA pathway.CONCLUSION Crif1 promotes RANKL expression via the c AMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.

Prognostic factors for pN2 non-small cell lung cancer:a comprehensive evidence from 73 studies involving 23,772 patients

Obojective Non-small-cell lung cancer(NSCLC)is a common malignancy.pN2 NSCLC,with pathologically confirmed ipsilateral mediastinal/subcarinal nodes metastasis,has been known as a very heterogeneous subgroup in terms of its anatomical,biological and patient characteristics.Prognostic factors based on patient characteristics were not well determined yet in this subgroup,and there is currently no standard treatment recommendation for these heterogeneous pN2 subjects.Apparent disagreements and inconsistency exist in study reports concerning the prognostic significance of certain factors in pN2 NSCLC,especially regarding to the issue about whether skip N2 metastasis benefit from surgery.Methods We therefore performed this comprehensive summary of the published literatures to draw a more precise and less uncertain conclusion.After a comprehensive literature search,a total of 73 studies involving 23,773 subjects were included according to eligibility criteria.Results As expected,most of the investigated factors,such as old age,male,advanced pathological T stage,advanced clinical N stage,multiple N2 stations,extended surgical resection(pneumonectomy),and incomplete resection,but not post-operation treatment(eg.chemotherapy and radiotherapy)were significantly associated with poor survival.However,skip N2 metastasis was favourable prognostic factors in operable pN2 NSCLC subjects.Other factors(histological type and primary tumour side)were neutral in terms of association with overall survival.We highlighted a number of important prognostic factors for pN2 NSCLC patients.Particularly,patients with skip N2 disease benefit from surgery.Conclusion Our findings could be used as reference information for decision-making in clinical practice and future study design.

Examination of Huntington's disease in a Chinese family

We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington＇s disease. Among 17 family members across three generations, four patients （Ⅱ2, Ⅱ6, Ⅲ5, and Ⅲ9） show typical Huntington＇s disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members （Ⅱ2, Ⅱ6, and Ⅲ5）. Moreover, genetic analysis identified abnormally amplified CAG sequence repeats （〉 40） in two members （Ⅲ5 and Ⅲ9）. Among borderline cases, with clinical symptoms and brain imaging features of Huntington＇s disease, two cases were identified （Ⅱ2 and Ⅱ6）, but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington＇s disease. Our findings suggest that clinical diagnosis of Huntington＇s disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.

Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential

Colorectal cancer(CRC)is presently the second most prevalent global mortalityinducing cancer.CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment.In addition,non-neoplastic cell activities within tumor microenvironments for CRC development have been established.However,interleukin(IL)-33,secreted by such cell types,plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment.IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity(ST)2 receptor.Therefore,how to coordinate tumor microenvironment,design and optimize treatment strategies suitable for CRC,based on IL-33/ST2 signal is a challenge.Even though it has established influences upon immunitylinked conditions,IL-33 effects on CRC progression and prevention and related mechanisms are still controversial.Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention.Moreover,IL-33/ST2 signaling is a potential therapeutic target for CRC.

A hiddenly high hepatitis C virus related liver disease burden among Chinese patients with non-liver disease complaints: A hospital based study from 2013 to 2017

Objective: To determine the frequency of anti-HCV antibody positivity in patients with nonliver disease complaints, to explore whether anti-HCV positive patients had been properly advised and visited hepatologists for further assessments, and to investigate their clinical characteristics as well as the HCV treatment status.Methods: A hospital based survey of nonliver disease patients with anti-HCV positive and their attending physicians was conducted to determine: 1.were the patients adequately advised of the implication of anti-HCV positive finding; 2.to what extent the patients were aware of potential chronic liver disease associated with HCV infection and whether they sought for further assessments and care of hepatologists.Results: A total of 295 294 non-liver disease patients were tested for anti-HCV antibody, and 2 778 of them were found to be positive(0.94%).However, only 45.10%(1 253/2 778) of the anti-HCV antibody(+) patients were referred to hepatologists and received HCV RNA test.In addition, 34.10%(312/915) and 1.42%(13/915) of them had already advanced to cirrhosis and hepatocellular carcinoma(HCC), respectively.Further analysis showed that the patients who declined antiviral therapy were older, with lower education and lower income, possessed poorer knowledge on the risk of chronic hepatitis C, and had more severe liver diseases.Surprisingly, 65% of the surveyed physicians did not know the genotype-guided treatment duration suggested by the guidelines.Alarmingly, 22% of the surveyed physicians did not know the standard assays for the diagnosis of HCV infection.Conclusions: Our findings highlight the challenge and hidden enormous burden of chronic HCV infection among patients with non-liver disease complaints in China.

Truncating PICK1 Variant Identified in Azoospermia Affected Mitochondrial Dysfunction in Knockout Mice

Objective The protein interacting with C kinase 1(PICK1)plays a critical role in vesicle trafficking,and its deficiency in sperm cells results in abnormal vesicle trafficking from Golgi to acrosome,which eventually disrupts acrosome formation and leads to male infertility.Methods An azoospermia sample was filtered,and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient.We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene,c.364delA(p.Lys122SerfsX8),and this protein structure truncating variant seriously affected the biological function.Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology(CRISPRc).Results The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities,as well as dysfunctional mitochondrial sheath formation.Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice.Moreover,the mitochondrial dysfunction was verified in the mice.These defects in the male PICK1 knockout mice may have eventually led to complete infertility.Conclusion The c.364delA novel variant in the PICK1 gene associated with clinical infertility,and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.