Temperature-controlled Smoker: Based on Intelligent Health

Management Technology

Haiyun Wang

†

, Keyu Han

†

, Ruihan Shi

, Zhenxiang Guan

and Shiqi Huang

5,*

College of Pharmacy, Zhengjiang University, Hangzhou, Zhejiang, 310058, China

School of Changzhou bilingual school, Changzhou, Jiangsu, 213000, China

Cardiff sixth form college, Cardiff, CF24 0AA, U.K.

St.Johnsbury academy, St.Johnsbury, Vermont, 05819, U.S.A.

Dalian No.24 High School, Dalian, Liaoning, 116001, China

†

Contributed equally

Keywords: Intelligent Health Management, Lung Cancer, Cigarette, Temperature, TTF-1, Napsin A, CK5/6, P40, P63.

Abstract: Intelligent Health Management (IHM) is a new industry formed by the integration of traditional health

management, artificial intelligence, big data and other new information technologies. It comprehensively

manages the individual and population health risk factors, and achieves the effective control of the occurrence

and progress of diseases with limited resources. As a major health risk factor, smoking closely connects with

the lung cancer, which is one of the leading causes of cancer death and the malignant tumors with the fastest

increase in morbidity and mortality in the world. As the yield of smoke condensate (tar) from tobaccos differs

in different burning conditions, the prediction is that the exposure to increasing temperature of smoking

increases frequency and severity of lung cancer. This paper will measure markers of lung cancer using

confocal microscopy with TTF1, Napsin A, p63, p40 and CK5/6 markers, mortality using survival curves,

tumor number, tumor size, and employing mice as laboratory animals. Positive control could be treatment

with radon or asbestos, negative control could be no smoke exposure. The results would be applied to

temperature control in e-cigarette design, providing new lung cancer prevention strategy for the intelligent

health management of smokers.

1 INTRODUCTION

Lung cancer is one of the malignant tumors with the

fastest increase in morbidity and mortality and the

biggest threat to the health and life of population (Lu,

Yu, Yi 2019)

Lung cancer is also the second most

common cancer in 2020. It is major factor that

causing of mortality in 93 countries, the incidence of

lung cancer (11.4%) is only less than breast cancer,

and lung cancer has the highest mortality rate (18.0%)

(Sung, Ferlay, Siegel, Laversanne, Soerjomataram,

Jemal, Bray 2021). A prediction in 2015 estimates

that the total cancer deaths would reach 1 359 100 in

the EU in 2015 (766 200 men and 592 900 women),

while lung cancer rates rise 9% to 14.24/100 000 and

becoming the cancer with the highest rate, reaching

and possibly overtaking breast cancer rate (Malvezzi,

Bertuccio, Rosso, Rota, Levi, Vecchia, Negri 2015)

Smoking is closely related to the occurrence of

lung cancer. Tobacco smoke can lead to abnormal

DNA methylation in cells, which in turn decreases the

expression of tumor suppressor genes, which in turn

increases the expression of KRAS gene, which

promotes cell growth. In 2012, a whole-genome

sequencing analysis of smokers and nonsmokers with

non-small cell lung cancer by researchers at the

University of Washington found that the overall

mutation rate was more than 10 times higher in

smokers than in nonsmokers, and that nearly 50

percent of smokers had Kirsten rat sarcoma viral

oncogene homolog mutations compared with

nonsmokers (Govindan, Ding, Griffith, Subramanian,

et al.)

In addition, scientists have studied smokers

and non-smokers and found that both cancer patients

and healthy people show different changes in DNA

methylation compared with non-smokers.

Tobacco tar is the product of incomplete

combustion of organic matter under anoxic condition.

It is a mixture of hydrocarbons, hydrocarbon oxides,

sulfides and nitrous compounds, including

326

Wang, H., Han, K., Shi, R., Guan, Z. and Huang, S.

Temperature-controlled Smoker: Based on Intelligent Health Management Technology.

DOI: 10.5220/0011368300003444

In Proceedings of the 2nd Conference on Artiﬁcial Intelligence and Healthcare (CAIH 2021), pages 326-332

ISBN: 978-989-758-594-4

benzopyrene, radioactive isotopes and so on. During

smoking, there are more than 3000 kinds of chemical

substances in the tobacco tar produced by tobacco

combustion, among which multi-chain aromatic

hydrocarbons and nitrosamines have strong

carcinogenic activity. What is worse, the content of

polycyclic aromatic hydrocarbons in tobacco tar is

much higher than that in tobacco itself in both types

and quantities. During smoking, tobacco tar enters the

respiratory tract of smokers with smoke flow. The

polycyclic aromatic hydrocarbons (PAHs) in tar, a

carcinogenic substance, are mostly produced during

smoking. Then tar is deposited in human lungs and

accumulates on the surface of lung. As a result, multi-

chain aromatic hydrocarbons and nitrosamines

involved in tar can lead to DNA damage of bronchial

epithelial cells through a variety of mechanisms,

making oncogenes activated and tumor suppressor

genes inactivated, thus causing cell transformation

and finally cancerization.

There are several markers are used in

immunohistochemical staining of this experiment.

First of all is TTF-1(Thyroid transcription factor 1).

It is a nuclear protein with a relative molecular weight

of 38× 103 and belong to a group of the NKx2

transcription factors. The regulation of thyroid tissue

is one of the important functions of this marker. It also

has high sensitivity and specificity in lung

adenocarcinoma with serosal effusion.

Next is P63 protein. It belongs to P53 protein

family. P63 protein’s germline mutations are

associated with severe mammary developmental

defects in both rodents and humans. Different p63

isoforms have been identified, some of which

(DeltaNp63) are preferentially expressed in the

epithelial basal cells of different organs and have

been considered as possible markers of stem cells

(Barbareschi, Pecciarini, Cangi, Macrì, Rizzo, Viale,

Doglioni 2001)

Then comes p40 protein. Actually, it is a subtype

of the P63 protein mentioned before. It is commonly

expressed in the basal cell layer or progenitor cell

layer of layered epithelial tissues, basal cells of

certain glandular epithelium and thymic epithelial

cells. p40 protein staining yields high sensitivity as

well as high specificity for distinguishing SQC from

ADC, neuroendocrine carcinomas, and malignant

mesothelioma (Tatsumori, Tsuta, Masai, Kinno,

Taniyama, Yoshida, Suzuki, Tsuda 2014)

Finally, here comes CK5/6 and Naspin A. The

former one is a basal cytokeratin with high molecular

weight (58Kda and 56Kda) (Kriegsmann, Cremer,

Zgorzelski, Harms, Muley, Winter, Kazdal, Warth,

Kriegsmann 2019)

In normal tissues, basal cells of

squamous and ductal epithelium and some squamous

germinal cells, myoepithelial cells, mesenchymal

cells are positive, and glandular epithelial cells are

negative (Gaydarov, Martinelli-Kläy, Lombardi

2021)

Therefore, it can be used for differential

diagnosis of squamous cell carcinoma and

adenocarcinoma, mesothelioma and

adenocarcinoma. It can also be used for differential

diagnosis of benign and malignant ductal epithelial

hyperplasia.

Normally, the tobacco carcinogen produced in the

process of smoking is about 1~6‰ of the weight of

the original tobacco, and the production of tobacco

carcinogen has a certain relationship with the

frequency of smoking. The more times smokers suck

in a unit of time, the more carcinogen is produced.

Smoking three puffs per minute produces almost

twice as much carcinogen as smoking one puff per

minute. The amount of carcinogen produced is also

related to the length of the cigarette, because when

the cigarette is lit, the tar smoke produced by the

cigarette passes through the unburned part of the

cigarette, some of it is absorbed by the tobacco. As

the light gets closer and closer to the end, almost all

of the carcinogen produced goes into the smoker's

respiratory tract. The ratio of the front to the back of

a cigarette is about 1:1.4, which is why cigars, pipe

cigarettes, and hookah cigarettes all produce less tar

than paper cigarettes (Hecht 2006).

Tar’s generation, enrichment, increment has a

close relationship with smoke local lighting

temperature. The majority of tobacco carcinogen

produced under 700—900℃, but during smoking,

cigarette lighting local temperature up to 600-900 ℃,

and at the same time the blazing red parts of the

temperature up to 980-1050℃, in the interval

between two smoking, the temperature dropped about

100-150 ℃. Thus, In the smoking process, most of

tobacco tar can be produced and that will affect

human health seriously. This phenomenon is also the

major cause of increasing popularity of e-cigarette. E-

cigarette is an up-to-date item that mimics a cigarette

and has the same look, smoke, taste and feel as a

cigarette. it represents alternative-to-smoking

products which produce a visible aerosol that the user

inhales. They simulate the psych behavioral aspects

of smoking dependence and deliver the chemical

component of the smoking dependence, nicotine

(Konstantinos, Gene, Stephen, Riccardo, Jonathan

2016). It vaporizes nicotine and turns it into vapor for

the user to smoke. Compared with traditional

cigarette, most e-cigarette liquid evaporates at about

220 degrees Celsius, which is mainly a physical

change. It is not easy to produce harmful substances,

Temperature-controlled Smoker: Based on Intelligent Health Management Technology

327

but traditional cigarette always has chemical reaction

during combustion. However, for some special

groups, using e-cigarette also involves drawbacks,

particularly for COPD patients. Experiment shows

that in airway cells from patients with COPD,

aerosols from an e-cigarette were associated with

similar toxicity to cigarette smoke (Carioli, Malvezzi,

Bertuccio, Boffetta, Levi, La Vecchia, Negri 2021.).

At present, e-cigarettes have already developed

temperature-controlled models, smokers can adjust

the voltage and resistance value of a specific

temperature-controlled box to get their favorite e-

cigarette taste, such temperature regulation

technology can be applied to intelligent health

management system. Health management is the

process of monitoring, analyzing, evaluating and

predicting the health status and risk factors of

individuals and groups, and intervening in health risk

factors through health consultation and guidance, In

this research, If we figure out the relationship

between cancer rates and smoking temperature, A

rigorous intelligent temperature control system could

be developed and used on e-cigarettes to monitor a

smoker's mouth temperature in real time and

automatically cool when it is above a certain level to

minimize the rate of getting cancer.

2 MATERIALS AND METHODS

2.1 Materials

Silica gel (≥99.0%), muﬄe furnace, control console,

quartz reactor (volume≈1.6 cm

). All of the reaction

processes should comply with International

Organization for Standardization of cigarette

smoking.

160 male mice (aged 6-8 weeks and 18-22g),

surgical instruments for dissection, reagent for

preparation of sectioning (4% paraformaldehyde,

saline, paraffin, PBS, etc), immunohistochemical

staining kit, marker (TTF, Napsin A, CK5/6, P40 and

P63 antibody), goat anti-rabbit IgG.

2.2 Tobacco Combustion Products

(Jebet, Kibet, Kinyanjui, Yamori

2018)

Build reactor assembly and pyrolysis product capture

unit. The combustion temperature starts from 200℃,

and products are collected every 100℃ the

temperature increases. Oxygen is delivered to the

reactor for tobacco combustion. The whole

combustion process continues for 5 minutes.

According to the temperature, six experimental

groups of products were obtained.

Tobacco tar condenses as a volatile gas phase

component in an ice bath and is collected through a

delivery pipe. At the end of each process, weigh all

products to ensure that the mass difference of

products was not more than ±5%.

2.3 Modeling and Grouping

160 male mice aged 6-8 weeks and 18-22g are

weighed and randomly divided into 8 groups with 20

rats in each group.

A. Positive control group: continuous radon

exposure for one month;

B. Negative control group: no smoke exposure,

normal culture for one month;

C. Experimental group 1-6: each group is exposed

to different tobacco smoke, whose pyrolysis

temperature are 200℃, 300℃, 400℃, 500℃, 600℃

and 700℃, treat each group for a month.

During the experiment, all mice are given a

normal diet, and each group is treated specifically as

required by radon gas or tobacco smoke on the day of

preparation. The body weights of mice are observed

daily.

2.4 Specimen Preparation

After anesthetizing the mice, the mice are first

perfused with normal saline and then perfused with

4% paraformaldehyde. Dissect the mice to judge the

number of tumors and take out the tumors. The length

and width of each tumor are measured with vernier

calipers, and the tumor volumes are calculated

according to the formula.

Tumors are placed in 4% paraformaldehyde, fixed

for 4h, then paraffin embedded and sectioned after

gradient dehydration.

2.5 Immunohistochemical Staining

The paraffin sections that have been cut will be baked

for 2h, dewaxed, hydrated, antigenic repaired,

endogenous peroxidase blocking, sealed, and then

labeled with anti-TTF, anti-Napsin A, anti-CK5/6,

anti-P40 and anti-P63 respectively according to the

protocol. Incubate at room temperature for 30 to 60

minutest, and soak in PBS or TBS for 15 minutes.

Goat anti-rabbit IgG is incubated with secondary

antibody at 25℃ for 1h, and soak in PBS or TBS for

15 minutes. DAB and H&E staining procedures are

performed according to the protocol.

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2.6 Staining Evaluation and

Interpretation (Cintrón, Martínez,

Jusino, Conte-Miller, Mendoza

2021)

Screen entire slides under light microscope to find

areas with brown signal (positive expression) in DAB

and H&E sections. For TTF-1, P40 and P63,

successful staining pattern is nuclear staining. For

Napsin A and CK5/6, successful staining pattern is

membrane labeling. Control slides are used to delete

the effect of nonspecific signal and background from

positive signal.

Using Image-pro-plus (IPP) to select area of

interesting (AOI) on the picture, measure the integral

optical density (IOD) of this area, select and measure

effective statistical area, and calculate IOD/area

(mean density).

2.7 Data Processing and Analysis

All final data are statistically analyzed using SPSS

20.0.

(1) The survival of mice is analyzed by Kaplan-

Meier survival curve;

(2) Collect IOD/area values of TTF-1, Napsin A,

CK5/6, P40 and P63 of mice in each group, all data

are expressed as mean ± standard deviation (x

± s),

and variance between different groups are analyzed

by student t test (α=0.05).

3 POSSIBLE RESULTS

3.1 Possible Result 1

The number and average size of tumors in lung tissue

and IOD values of TTF-1, Napsin A, CK5/6, P40 and

P63 are all positively related to the smoking

temperature, while the survival rate of mice is

negatively related to the smoking temperature (The

slope of the Kaplan-Meier estimator is negative, and

decreases as the temperature increases).

Table 1 shows that the number and average size of

tumors in lung tissue and IOD values of TTF-1,

Napsin A, CK5/6, P40 and P63 are all positively

related to the smoking temperature, while the survival

rate of mice is negatively related to the smoking

temperature (The slope of the Kaplan-Meier

estimator is negative, and decreases as the

temperature increases).

Table 1: Possible Result 1.

erimental Grou

(

smoke ex

osure

)

Positive Control Ne

ative Control

200℃ 300℃ 400℃ 500℃ 600℃ 700℃ Radon ex

osure no ex

osure

number of tumors + + ++ ++ ++ +++ +++ -

size of tumors + + ++ ++ ++ +++ +++ -

IOD + + ++ ++ ++ +++ +++ -

survival rate - - -- -- -- --- --- +

Note. In all the following tables, “+” represents a larger numerical value of the variables, while “-” represents a

smaller survival rate compared with the negative control group. IOD represents the IOD mean values (density)

of TTF-1, Napsin A, CK5/6, P40 and P63.

3.2 Possible Result 2

Table 2 shows that the number and average size of

tumors in lung tissue and IOD values of TTF-1,

Napsin A, CK5/6, P40 and P63 are all negatively

related to the smoking temperature, while the survival

rate of mice is positively related to the smoking

temperature (The slope of the Kaplan-Meier

estimator is negative, and increases as the

temperature increases).

Table 2: Possible Result 2.

Experimental Groups (smoke exposure) Positive Control Negative Control

200℃ 300℃ 400℃ 500℃ 600℃ 700℃ Radon exposure no exposure

number of tumors +++ ++ ++ ++ + + +++ -

size of tumors +++ ++ ++ ++ + + +++ -

IOD +++ ++ ++ ++ + + +++ -

survival rate --- -- -- -- - - --- +

Temperature-controlled Smoker: Based on Intelligent Health Management Technology

329

3.3 Possible Result 3

Table 3 shows that the number of tumors in lung

tissue and the IOD values of TTF-1, Napsin A,

CK5/6, P40 and P63 are positively related to related

to the smoking temperature. However, the size of

tumors is negatively related to the smoking

temperature, while the survival rate of mice is

positively related to the smoking temperature (The

slope of the Kaplan-Meier estimator is negative, and

increases as the temperature increases).

Table 3: Possible Result 3.

Experimental Groups (smoke exposure) Positive Control Negative Control

200℃ 300℃ 400℃ 500℃ 600℃ 700℃ Radon exposure no exposure

number of tumors + + ++ ++ ++ +++ +++ -

size of tumors +++ ++ ++ ++ + + +++ -

IOD + + + ++ ++ +++ +++ -

survival rate --- -- -- -- - - --- +

3.4 Possible Result 4

Table 4 shows that the number and average size of

tumors in lung tissue and IOD values of TTF-1,

Napsin A, CK5/6, P40 and P63 always have the

reverse relationship with the smoking temperature

compared with that of the survival rate of mice. Their

values reach peaks or valleys at the same interval

within the temperature zone, and fall or rise when

approaching the two extreme points of the

temperature zone.

Table 4: Possible Result 4.

Experimental Groups (smoke exposure)

Positive

Control

Negative

Control

200℃ 300℃ 400℃ 500℃ 600℃ 700℃

Radon

osure

no exposure

number of

tumors

+ + ++ +++ ++ + +++ -

size of tumors + + ++ +++ ++ + +++ -

IOD + + ++ +++ ++ + +++ -

survival rate - - -- --- -- - --- +

4 DISCUSSIONS

4.1 Possible Result 1

The number and average size of tumors in lung tissue

and IOD values of TTF-1, Napsin A, CK5/6, p40 and

P63 are all positively related to the smoking

temperature whilst the survival rate is negatively

correlated

The result indicates that the combustion products

at the highest temperature have most harmful effect

on lung. In this study, we showed the first time that

increasing temperature of smoking will increase

frequency and severity of lung cancer. A similar

conclusion was reached by Audriy Jebet, 2018, they

have demonstrated that various masses of tobaccos

from different cigarettes may yield different amounts

of smoke condensate (tar) depending on the nature of

tobacco, tobacco additives and tobacco growing

conditions, we have verified that using

immunohistochemical staining produces similar

results. The experimental research results will

hopefully serve as useful feedback information for

improvements for contemporary cigarette.

CAIH 2021 - Conference on Artiﬁcial Intelligence and Healthcare

330

4.2 Possible Result 2

The number and average size of tumors in lung tissue

and IOD values of TTF-1, Napsin A, CK5/6, p40 and

P63 are all negatively related to the smoking

temperature whilst the survival rate is positively

correlated

The results contradict the hypothesis, so the

hypothesis does not hold, with lower temperature, the

mice are more likely to survive. One limitation should

be noted here, when mice are directly exposed under

smoke exposure, the raised temperature may create

other risk factor for mice to catch the cancer, or kill

the mice directly which will affect the survival rate.

However, this problem could be solved if we consider

lowing the temperature of smokes simultaneously not

change the composition of the smoke.

4.3 Possible Result 3

The number and average size of tumors in lung tissue

and IOD values of TTF-1, Napsin A, CK5/6, p40 and

P63 has no relationship with the survival rate of the

mice and burning temperature of smoking.

The results are only partially support the

hypothesis, the number of the tumor and IOD values

of TTF-1, Napsin A, CK5/6, p40 and P63 are

positively correlated with the smoking temperature,

whilst the size of tumor and the survival rate are

negatively correlated. The first possible reason for

this contradiction is the temperature has no

relationship with all these factors. To prove this point

of view, the same series of experiment need to be

settled for three more times, if the results are same as

before, the supposition is being denied. Second

possible cause is there are operate misses during the

experiment. Repeat the trial and strictly follow every

step on instruction might change the results or deny

the hypothesis.

4.4 Possible Result 4

The number and average size of tumors in lung tissue

and IOD values of TTF-1, Napsin A, CK5/6, p40 and

P63 reached maximum value at 500℃ then the value

decreases.

This experiment cannot prove the validity of the

hypothesis, but provided temperature intervals where

the chance to catch the cancer is the highest. One

major reason for this phenomenon might be there is

an optimum temperature for tobacco to release the

maximum volume of combustion products. Further

study like repeat the trial using 425, 450, 500,

525,550,575℃ to find the temperature for the top risk

for the maximum number and the largest size of

tumors with the highest IOD value and lowest

survival rate. Hence, our novel findings may provide

new insights into control the temperature of smoking

to lower the risk of having cancer.

5 CONCLUSIONS

The possible result 1 can confirm that the higher the

burning temperature of the tobaccos, the greater the

possibilities for smokers to get cancer, and the

possible result 2 proved that these two factors are

negatively correlated, and then for the possible result

3, the temperature only influence the size of tumor

while the survival rate will be higher with the

increasing of the temperature. Possible results 4

provided a range of temperature for the highest

cancer mortality, which may give a feasible method

to decrease the incidence of cancer among the

smokers worldwide.

This experiment considered temperature as a

variable factor, whereas under the limited laboratory

facilities, only some reasonable possibilities can be

provided. If the experiment can be further improved

and implemented into the temperature control of e-

cigarette, the e-cigarette would cease ignition to

decrease the release of nicotine when it reaches the

most harmful temperature, and the whole process is

supposed to connect with terminal monitoring

program. This invention can become a new

achievement in the field of health management, and

decrease the cancer rate among the smokers

worldwide.

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