Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Objective:Hepatocyte nuclear factor 4α(HNF4 A)has been demonstrated to be an oncogene in gastric cancer(GC).However,the roles of different HNF4 A isoforms derived from the 2 different promoters(P1 and P2)and the underlying mechanisms remain obscure.Methods:The expression and prognostic values of P1-and P2-HNF4 A were evaluated in The Cancer Genome Atlas(TCGA)databases and GC tissues.Then,functional assays of P1-and P2-HNF4 A were conducted both in vivo and in vitro.High-throughput RNA-seq was employed to profile downstream pathways in P1-and P2-HNF4 A-overexpressing GC cells.The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays.Results:HNF4 A amplification was a key characteristic of GC in TCGA databases,especially for the intestinal type and early stage.Moreover,P1-HNF4 A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues(P<0.05),but no significant differences were found in P2-HNF4 A expression(P>0.05).High P1-HNF4 A expression indicated poor prognoses in GC patients(P<0.01).Furthermore,P1-HNF4 A overexpression significantly promoted SGC7901 and BGC823 cell proliferation,invasion and migration in vitro(P<0.01).Murine xenograft experiments showed that P1-HNF4 A overexpression promoted tumor growth(P<0.05).Mechanistically,RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4 A-overexpressing GC cells.Finally,chemokine(C-C motif)ligand 15 was identified as a direct target of P1-HNF4 A in GC tissues.Conclusions:P1-HNF4 A was the main oncogene during GC progression.The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.

MG7-Ag, hTERT, and TFF2 identified high-risk intestinal metaplasia and constituted a prediction model for gastric cancer

To the Editor:Gastric cancer(GC)ranks third in incidence and mortality both worldwide and in China.[1,2]Intestinal metaplasia(IM)significantly increases risk of GC so that identifying high-risk IM patients who will progress to GC is crucial.Currently,the effect of many risk-stratification methods for gastric precancerous lesions(GPLs)was minimal.Monoclonal gastric cancer 7 antigen(MG7-Ag)combined with cyclooxygenase-2 has been shown earlywarning value for the progression of GPLs.[3]The expression of human telomerase reverse transcriptase(hTERT)was proven to be related to state of cell proliferation in IM tissue.[4]Loss expression of trefoil factor family 2(TFF2)from spasmolytic polypeptideexpressing metaplasia to IM may lead to a hyperproliferation and deleterious mutations.[5]We tried to construct and verify a multimolecular prediction model included MG7-Ag and hTERT and TFF2,which could identify high-risk IM patients and have early-warning value for GC.

Efficacy and safety of triple therapy containing berberine,amoxicillin,and vonoprazan for Helicobacter pylori initial treatment:A randomized controlled trial

Background:With the development of traditional Chinese medicine research,berberine has shown good efficacy and safety in the eradication of Helicobacter pylori(H.pylori).The present study aimed to evaluate the efficacy and safety of triple therapy containing berberine,amoxicillin,and vonoprazan for the initial treatment of H.pylori.Methods:This study was a single-center,open-label,parallel,randomized controlled clinical trial.Patients with H.pylori infection were randomly(1:1:1)assigned to receive berberine triple therapy(berberine 500 mg,amoxicillin 1000 mg,vonoprazan 20 mg,A group),vonoprazan quadruple therapy(vonoprazan 20 mg,amoxicillin 1000 mg,clarithromycin 500 mg,colloidal bismuth tartrate 220 mg,B group),or rabeprazole quadruple therapy(rabeprazole 10 mg,amoxicillin 1000 mg,clarithromycin 500 mg,colloidal bismuth tartrate 220 mg,C group).The drugs were taken twice daily for 14 days.The main outcome was the H.pylori eradication rate.The secondary outcomes were symptom improvement rate,patient compliance,and incidence of adverse events.Furthermore,factors affecting the eradication rate of H.pylori were further analyzed.Results:A total of 300 H.pylori-infected patients were included in this study,and 263 patients completed the study.An intention-to-treat(ITT)analysis showed that the eradication rates of H.pylori in berberine triple therapy,vonoprazan quadruple therapy,and rabeprazole quadruple therapy were 70.0%(70/100),77.0%(77/100),and 69.0%(69/100),respectively.The per-protocol(PP)analysis showed that the eradication rates of H.pylori in these three groups were 81.4%(70/86),86.5%(77/89),and 78.4%(69/88),respectively.Both ITT analysis and PP analysis showed that the H.pylori eradication rate did not significantly differ among the three groups(P>0.05).In addition,the symptom improvement rate,overall adverse reaction rate,and patient compliance were similar among the three groups(P>0.05).Conclusions:The efficacy of berberine triple therapy for H.pylori initial treatment was comparable to that of vonoprazan quadruple therapy and rabeprazole quadruple therapy,and it was well tolerated.It could be used as one choice of H.pylori initial treatment.

Current situation and risk factors for Helicobacter pylori eradication failure in Northwest China:a real-world evidence study

To the Editor:Helicobacter pylori(H.pylori)is estimated to affect approximately half of the world’s population,especially in most developing countries.[1]Eradication of H.pylori has been proven to promote peptic ulcer healing and reduce the incidence of gastric cancer.Previous studies have reported that the northwest region of China has a high H.pylori infection rate of 51.8%.[2]However,the H.pylori eradication rate is declining every year,primarily due to increasing antibiotic resistance,notably clarithromycin,[3]and various other factors may also impact H.pylori eradication.Consequently,this study was conducted to elaborate on the situation of H.pylori eradication in Northwest China and evaluate the related risk factors for eradication failure to explore possible solutions.

Analysis of risk factors associated with primary bile reflux:A multicenter cross-sectional study

To the Editor:Bile reflux(BR),also known as duodenogastric reflux,refers to the reflux of duodenal contents such as bile,pancreatic juice,and duodenal juice into the stomach.BR that occurs without gastric surgery is called primary bile reflux(PBR).^([1])A retrospective study showed that the prevalence of PBR in patients with chronic gastritis was as high as 20.5%.^([2])BR can contribute to the development of upper gastrointestinal diseases,^([3–5])but the corresponding risk factors are currently unknown.We aimed to identify the related risk factors for PBR.

Bile reflux and bile acids in the progression of gastric intestinal metaplasia

Gastric intestinal metaplasia(GIM)is a precancerous lesion of gastric cancer(GC)and is considered an irreversible point of progression for GC.Helicobacter pylori infection can cause GIM,but its eradication still does not reverse the process.Bile reflux is also a pathogenic factor in GIM and can continuously irritate the gastric mucosa,and bile acids in refluxed fluid have been widely reported to be associated with GIM.This paper reviews in detail the relationship between bile reflux and GIM and the mechanisms by which bile acids induce GIM.

Efficacy and safety of high-dose esomeprazole–amoxicillin dual therapy for Helicobacter pylori rescue treatment:a multicenter,prospective,randomized,controlled trial

Background:High-dose dual therapy(HDDT)with proton pump inhibitors(PPIs)and amoxicillin has attracted widespread attention due to its favorable efficacy in eradicating Helicobacter pylori(H.pylori).This study aimed to compare the efficacy and safety of high-dose PPI-amoxicillin dual therapy and bismuth-containing quadruple therapy for H.pylori rescue treatment.Methods:This was a prospective,randomized,multicenter,non-inferiority trial.Patients recruited from eight centers who had failed previous treatment were randomly(1:1)allocated to two eradication groups:HDDT(esomeprazole 40 mg and amoxicillin 1000 mg three times daily;theHDDTgroup)and bismuth-containing quadruple therapy(esomeprazole 40 mg,bismuth potassium citrate 220 mg,and furazolidone 100 mg twice daily,combined with tetracycline 500 mg three times daily;the tetracycline,furazolidone,esomeprazole,and bismuth[TFEB]group)for 14 days.The primary endpoint was the H.pylori eradication rate.The secondary endpoints were adverse effects,symptom improvement rates,and patient compliance.Results:A total of 658 patients who met the criteria were enrolled in this study.The HDDT group achieved eradication rates of 75.4%(248/329),81.0%(248/306),and 81.3%(248/305)asdetermined by the intention-to-treat(ITT),modified intention-totreat(MITT),and per-protocol(PP)analyses,respectively.The eradication rates were similar to those in the TFEB group:78.1%(257/329),84.2%(257/305),and 85.1%(257/302).The lower 95%confidence interval boundary(9.19%in the ITT analysis,9.21%in the MITT analysis,and9.73%in the PP analysis)was greater than the predefined non-inferiority margin of10%,establishing a non-inferiority of the HDDT group vs.the TFEB group.The incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group(11.1%vs.26.8%,P<0.001).Symptom improvement rates and patients’compliance were similar between the two groups.Conclusions:Fourteen-day HDDT is non-inferior to bismuth-containing quadruple therapy,with fewer adverse effects and good treatment compliance,suggesting HDDT as an alternative for H.pylori rescue treatment in the local region.Trial registration:Clinicaltrials.gov,NCT04678492.

Observation on therapeutic efficacy of ursodeoxycholic acid in Chinese patients with primary biliary cirrhosis:a 2-year follow-up study

The efficacy of ursodeoxycholic acid(UDCA)on long-term outcome of primary biliary cirrhosis(PBC)has been less documented in Chinese cohort.We aimed to assess the therapeutic effect of UDCA on Chinese patients with PBC.In the present study,67 patients with PBC were treated with UDCA(13–15 mg∙kg^(-1)∙day^(-1))and followed up for 2 years to evaluate the changes of symptoms,laboratory values and histological features.As the results indicated,fatigue and pruritus were obviously improved by UDCA,particularly in patients with mild or moderate symptoms.The alkaline phosphatase andγ-glutamyl transpetidase levels significantly declined at year 2 comparing to baseline values,with the most profound effects achieved in patients at stage 2.The levels of alanine aminotransferase and aspartate aminotransferase significantly decreased whereas serum bilirubin and immunoglobulin M levels exhibited no significant change.Histological feature was stable in patients at stages 1–2 but still progressed in patients at stages 3–4.The biochemical response of patients at stage 2 was much better than that of patients at stages 3–4.These data suggest that,when treated in earlier stage,patients in long-term administration of UDCA can gain favorable results not only on symptoms and biochemical responses but also on histology.It is also indicated that later histological stage,bad biochemical response and severe symptom may be indicators of poor prognosis for UDCA therapy.