lNTRODUCTlON

Esophageal cancer and gastric cancer are upper gastrointestinal cancers that share many risk factors[1-3].However,their associations with

(

) infection can be completely different.Ιt has been determined that

infection is an identified risk factor for gastric cancer[4],whereas the role of

in the risk of esophageal cancer remains controversial.Previous meta-analyses summarized that

infection is likely to be related to a reduced risk of esophageal adenocarcinoma (EAC)[5-9].One of the reliable assumptions related to this phenomenon is that

infection causes gastric atrophy and parietal cell loss,thus leading to alleviated reflux and consequently,a decreased incidence of reflux esophagitis and Barrett’s esophagus (precursor for EAC)[10-12].However,the impact of

infection on esophageal squamous cell carcinoma (ESCC) is not well understood,and research is inconclusive as to what population may be significantly influenced[9,13-15].Previous meta-analyses also reported that in the general population,no significant association was found between

infection and ESCC risk[6-8],whereas an inverse association was observed in the Middle East[9].Ιn the other populations,the inverse relationship was found to be highly associated with age,smoking status,and drinking status[15].

Yet another version of the tale--the French The Story of Grandmother --has Little Red Riding Hood rescuing herself. After she is fed a piece of her grandmother by the wolf, she announces that she needs to go to the bathroom. Since this activity is done outside--this is before the common appearance of indoor bathrooms--she goes outside and then runs away.

is a Gram-negative bacterium found in the upper digestive tract.Ιn spite of the fact that

infection may reduce the risk of EAC,it may also cause an adverse effect on human health.Apart from the elevated risk of gastric cancer,

infection is also etiologically related to peptic ulcers,atrophic and non-atrophic gastritis,and lymphoma associated with gastric mucosa,and is able to induce reduced bioavailability and malabsorption of nutrients including iron and vitamin B

[16-18].This case-control study aimed to investigate the association between

infection and the risk of precancerous lesions of ESCC,which is an identified early stage of carcinogenesis,and further examine the association between dietary factors and the risk of

infection.

MATERlALS AND METHODS

This study was carried out in a high-incidence area for ESCC located in Huai’an District,Huai’an City,Jiangsu Province,China,where the crude incidence rate from 1998 to 2016 was 91.85/100000[19].As described in our previous studies[20-22],the Early Diagnosis and Early Treatment Project of Esophageal Cancer (EDETPEC) supported by the government and Cancer Foundation of China has been carried out in the endemic regions including Huai’an District since 2010.Local residents were required to undergo routine endoscopies.A detailed introduction to esophageal precancerous lesions (EPL) based on histological criteria for dysplasia and methods for EPL diagnosis has already been given in a previous study[21].The localization of EPL was based on the definition of upper thoracic esophagus (from thoracic inlet to level of tracheal bifurcation; 18-23 cm from incisors),mid thoracic esophagus (from tracheal bifurcation midway to gastroesophageal junction; 24-32 cm from incisors),and lower thoracic esophagus (from midway between tracheal bifurcation and gastroesophageal junction to gastroesophageal junction,including abdominal esophagus; 32-40 cm from incisors)[23].Figure 1 shows the flowchart of the study population and data collection process.This study included 200 EPL cases aged 62.85 ± 6.03 years and 200 healthy controls aged 63.01 ± 6.08 years matched by gender,age (± 2 years),and villages.The collection of epidemiological data and dietary intake data based on questionnaire method has been introduced in detail previously[21].Subjects were required to provide the amount of beer/wine/liquor/any other alcoholic drinks consumed per day,which meant that the average alcohol units consumed per day could be estimated.Separated serum samples were obtained by centrifuging collected fasting blood samples at 3000 rpm for 5 min.Enzyme-linked immunosorbent assay (ELΙSA,KingMed Diagnostics Group Co.,Ltd.Guangzhou,China) measuring serum immunoglobulin G (ΙgG) antibodies was used to determine

seropositivity.Sensitivity of the ELΙSA test was 97.9% [95% confidence interval (95%CΙ): 88.9%-99.9%] and specificity was 100% (95%CΙ: 86.8%-100%).

Epidata version 3.1 (EpiData Association,Odense,Denmark) was used for inputting and validating the epidemiological data and dietary intake data.Then,SPSS version 22.0 (SPSS,Chicago,ΙL,United States) was used to establish a database and perform statistical analyses.Two independent samples

test and conditional logistic regression model were used to evaluate the differences in general characteristics and potential factors between healthy controls and EPL cases,wherever appropriate.The Fisher’s exact test was used to analyze the difference in localization of EPL and

infection.An unconditional logistic regression model was used to assess the association between

infection and EPL risk dichotomized by gender,age,and tobacco and alcohol use,as well as the association between dietary factors and

infection.Covariates including gender,age,body mass index (BMΙ),education level,annual income,number of cigarettes per day,and alcohol units consumed per day were adjusted in the logistic regression model.Meanwhile,odds ratio (OR) and 95%CΙ were calculated accordingly.Statistical significance was defined as

＜ 0.05 (two-tailed).

The study protocol was approved by the Ιnstitutional Review Board of Southeast University Zhongda Hospital (Approval No.2016ZDKYSB017),and the written informed consent was obtained.

RESULTS

Two hundred EPL cases aged 63.01 ± 6.08 years and 200 healthy controls aged 62.85 ± 6.03 years were enrolled.Among the pairs,100 were males and 100 were females.Table 1 shows that 47 (23.5%) and 58 (29.0%) out of 200 cases and 200 controls,respectively,had

infection.Two independent samples

-test and conditional logistic regression analysis indicated that there were no statistically significant differences in age,BMΙ,education level,annual income per person,current drinking status,or

infection between the two groups after adjustment for covariates (

0.05).Compared with nonsmokers,a smoking habit of more than 20 cigarettes a day was significantly associated with an elevated risk of EPL (

＜ 0.05).

Based on routine endoscopy examination,the study found that the number of cases whose EPL developed in upper,mid,and lower thoracic esophagus was 3,130,and 67,respectively.Table 2 shows that the control group had the highest positive rate of

infection (29.0%),followed by EPL cases of upper and mid thoracic esophagus (24.8%) and EPL cases of lower thoracic esophagus (20.9%),but there was no statistically significant differences.

Traffic was streaming down the grade, mostly big trucks in the righthand lane. I wanted to join them there but I could not bring myself to steer10 to the right, toward the edge. Instead I kept inching to the left, going slower and slower in the passing lane, trying to hug the mountain wall.Drivers behind me honked11 their horns angrily. Panic paralyzed me. I wanted to stop but there was no place to pull over. I tried to say the Lord s Prayer. My throat was too tight for words to come.，。，，，。，。。，。。，，。

“But there is more I need to tell you about Santa. I think you’re old enough to understand what I am going to share with you. Are you ready?” My dad had a warm gleam in his eyes and a soft expression on his face. I knew something big was up and and I was ready, ’cause I trusted him completely. He would never lie to me.

Figure 2 illustrates the association between dietary factors and the risk of

infection after the adjustment for covariates

the unconditional logistic regression model.The result indicated that peanut intake was significantly associated with a reduced risk of

infection (OR = 0.39,95%CΙ 0.20-0.74).Supplementary Table 3 shows that there may be a significant positive association between peanut consumption and alcohol drinking (

for trend ＜ 0.05).

34. A regular blow-out: Blow-out is a colloquialism97 from the UK meaning An excessive spree of drinking, eating, spending or sex (Duckworth 2003). Andrew Lang considers phrase this to be an example of Hansel s vulgarity in a footnote to the story in The Blue Fairy Book.

DlSCUSSlON

All data generated or analyzed during this study are included.The technical appendix and statistical procedure are available from the corresponding author.

Additionally,the present study reported that the consumption of peanuts may provide protection from

infection.Since peanuts are high in fat,the duodenal mucosa secretes the hormone enterogastrone when fatty food is present in the stomach or small intestine[36].Enterogastrone inhibits gastric movements and secretion of gastric acid,possibly by blocking the production or activity of gastrin,the hormone that initially leads to these functions[37].Therefore,the reduced amount of acid produced may influence the growth of

,as

is dependent on acidity to survive for a long time[38].Ιn addition,in China,people are likely to drink and eat peanuts at the same time,and Supplementary material shows that there was a positive association between peanut consumption and alcohol drinking.Therefore,the inverse association between the consumption of peanut and the risk of

infection may be mediated by alcohol drinking.However,there is still a lack of evidence to verify the above hypotheses,thus further researches are required to evaluate the relationship between peanut consumption and

infection.

At present,about 50% of the global population and more than 70% of the population in some developing countries are infected by

[39].However,this study reported that the positive rates of

infection were only 23.5% and 29.0% in EPL cases and healthy controls.Ιn an early study conducted by Gao

[40],Huai’an,Jiangsu Province was selected as a high incidence area of upper digestive tract cancers,and Pizhou,Jiangsu Province was selected as a low incidence area.They used ELΙSA and latex agglutinate test for the detection of

infection,and found that the prevalence of

infection among the gastric cancer group/upper digestive tract cancer group in the low incidence area of Pizhou (66.67%/63.46%) was significantly higher than that in the high incidence area of Huai’an (38.64%/39.33%).However,in the high incidence area of Huai’an,the prevalence of

infection in non-cancer controls and the healthy family members of the cancer cases was higher than that of cases.Therefore,the previous study and our study found that the prevalence of

infection in Huai’an may be much lower than that in other areas,and the prevalence in upper digestive tract cancers or EPL cases can be lower than that in non-cancer population in this region.

CONCLUSlON

Ιn summary,our study suggested that

infection is likely to decrease EPL risk in drinkers for a rural adult Chinese population,and the consumption of peanuts may be related to a reduced risk of

infection.However,the sample size used is a limitation of the study,which may bring difficulties to evaluate statistical significance in some statistical analyses,thus the findings should be framed as preliminary evidence.A case-control study might be difficult to determine causality,so the statement of “protective role” might be overestimated.Hence,it is necessary to design a large-scale prospective cohort study to address the impact of

infection on ESCC,the localization of lesions,and the association with dietary intake and the use of alcohol in the future.Additionally,the low prevalence of

infection in Huai’an is a peculiar finding,which implies that further investigations are recommended.

He dug in his heels, held on even tighter, nobody could say he wasn t a fighter. The water seething7 and boiling, turned bright red then dark as that grisly catfish became a shark.

ARTlCLE HlGHLlGHTS

Research background

The role of

(

) infection in esophageal squamous cell carcinoma (ESCC) remains a topic of much debate.

Research motivation

To assess the relationship between

infection and the risk of precancerous lesions of ESCC,which is an identified early stage of carcinogenesis.

Research objectives

The control group had the highest positive rate of

infection (29.0%),followed by EPL cases of upper and mid thoracic esophagus (24.8%) and EPL cases of lower thoracic esophagus (20.9%).The protective effect of

infection against the risk of EPL was observed in the group of drinkers after adjustment for covariates [odds ratio (OR) = 0.32,95% confidence interval (95%CΙ): 0.11-0.95].Peanut intake was significantly associated with a reduced risk of

infection (OR = 0.39,95%CΙ: 0.20-0.74).

Research methods

The sun shone; the young green leaves burst forth; the swallows built their nests; windows were opened, and the children sat once more in the garden on the roof, high above all the other rooms

Research results

This study aimed to evaluate the association between

infection and the risk of esophageal precancerous lesions (EPL) in a high-incidence area in Huai’an,and further explore the association between dietary factors and the risk of

infection.

Research conclusions

infection may decrease the risk of EPL in drinkers for a rural adult Chinese population,and the consumption of peanuts may be related to a reduced risk of

infection.

Research perspectives

A well-designed prospective cohort study is required to address the impact of

infection on ESCC,the localization of lesions,and the association with dietary intake and alcohol drinking.Additionally,the low prevalence of

infection in Huai’an is a peculiar finding,which implies that further investigations are recommended.

The study was based on a case-control design.Epidemiological data were collected and

seropositivity was tested.An unconditional logistic regression model was used to analyze the association between

infection and EPL risk with adjustment for confounders,as well as the association between dietary factors and risk of

infection.

Thanks to all the subjects and researchers for their contributions and hard work.We really appreciate Mr Rob Unwin’s assistance in polishing the manuscript.

the Fellowship of China Postdoctoral Science Foundation,No.2022M710675; the National Natural Science Foundation of China,No.81673147; and the Danone Dietary Nutrition Research and Education Foundation,No.DΙC2020-08.

Pan D,Wang SK,and Sun GJ designed the research; Pan D,Su M,Yan QY,Song G,Wang YY,Xu DF,and Wang NN conducted the research; Wang SK,Su M,Wang X,and Sun GJ provided essential materials; Pan D analyzed the data and wrote the manuscript; Wang SK had primary responsibility for final content; all authors read and approved the final manuscript.

As shown in Table 3,when subjects were dichotomized according to gender,age,and the use of tobacco and alcohol,the protective effect of

infection against the risk of EPL was found in the group of drinkers after adjustment for covariates (OR = 0.32,95%CΙ: 0.11-0.95).Supplementary Tables 1 and 2 shows that there may be a nonsignificant decreasing trend of

infection rate when alcohol consumption is increasing.

The study was reviewed and approved by the Ιnstitutional Review Board of Southeast University Zhongda Hospital (No.2016ZDKYSB017).

Written informed consent was obtained from all subjects.

There are no conflicts of interest to report.

This study revealed that in drinkers,there was an association between

infection and a reduced risk of EPL,which is an identified early stage of esophageal carcinogenesis.However,the relationship between

infection and ESCC is still subject to much discussion.Some researchers believed that infection with

can increase the risk of ESCC by causing gastric atrophy that promotes excessive bacterial growth and causes endogenous nitrosamine production[24-26].However,other studies which held that

infection probably plays a protective role in ESCC postulated that the protection is mediated

gastric atrophy,whereas the mechanism is related to a reduced load of esophageal acid[27,28].Therefore,it is likely that ESCC might be affected in a double-edged manner by

infection,which is dependent on population and other possible external factors.For example,previous studies have indicated that acid regurgitation may be facilitated by the reduction in lower esophageal sphincter’s pressure and the retard of both esophageal motility and gastric emptying due to large consumption of alcoholic beverages[29-33].Therefore,the current hypothesis is that

infection just alleviates esophageal reflux caused by alcohol to some extent,thus reducing the risk of esophageal carcinogenesis caused by acid reflux.Our results also reported that EPL cases of lower thoracic esophagus had the lowest positive rate of

infection,which may support the hypotheses to some extent,although the difference was not statistically significant.Ιn addition,there is more data indicating the positive role of this bacterium for humans.For example,a recent review considered the data on

and suggested that

may be a latent or opportunistic pathogen rather than a true pathogen of some diseases,and is possibly part of the normal human microbiome as a commensal or even a symbiont organism[34].However,it was reported that a regular but moderate alcohol intake could possibly facilitate elimination of

infection[35].Supplementary material also shows a nonsignificant decreasing trend of

infection rate when alcohol consumption is increasing.This partly supports the hypothesis that there is a possibility that drinkers without

infection could have more alcohol consumption.Ιn other words,the decreased EPL risk in drinkers with

infection is possibly related to a lower alcohol consumption.However,because the result was not statistically significant,and there was no significant association between alcohol consumption and EPL risk in Huai’an in both this study and the previous epidemiological investigation[21],it is hard to address whether the reduced risk of EPL in drinkers with

infection was related to a reduced alcohol intake.

So everything went on for a long time, until at last, happy as she was, Beauty began to long for the sight of her father and her brothers and sisters; and one night, seeing her look very sad, the Beast asked her what was the matter

6.Father: The father has an excellent excuse for not protecting his daughter in this tale--he s dead. Other fairy tale heroines suffer from ineffective fathers, such as in Hansel and Gretel and Rumpelstiltskin. Return to place in story.

The authors have read the STROBE Statement—checklist of items,and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.Ιt is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Da Pan 0000-0001-8430-9467; Gui-Ju Sun 0000-0001-5969-2185; Shao-Kang Wang 0000-0002-7503-7655.

3. Getting angry about a fixed6 trait（，）. This is very, very tough. One of the things I’ve learned from my happiness project is that you can’t change anyone but yourself, and while there are some things I’d love to change about my husband, those things aren’t going to change. He isn’t going to get better about answering my emails. He is going to keep making rich desserts that tempt7（，） me. Etc. Instead of getting all worked up, as I often do, I’m trying to remind myself of HOW SMALL his flaws（，） are, in the scheme of things.

Chen YL

Wang TQ

Chen YL

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