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Evaluation of Impact of Tall Like Receptor 4 and Liposaccharide in Pathogenesis of Hepatic Cancer

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Research Article | DOI: https://doi.org/10.31579/2690-1897/072

Evaluation of Impact of Tall Like Receptor 4 and Liposaccharide in Pathogenesis of Hepatic Cancer

  • Emadeldin R. Matar 1*
  • Mohammed H. Goda 2
  • Tamer M. Abuama 3
  • 1* Assistant Professor of Pathology, Faculty of Medicine, Al Azhar University. Egypt
  • 2 Lecturer of Surgery, Faculty of Medicine, Ain Shams University. Cairo, Egypt
  • 3 Assistant Professor of Histology, Faculty of Medicine, Al Azhar University. Egypt

*Corresponding Author: Emadeldin R. Matar, Assistant Professor of Pathology, Faculty of Medicine, Al Azhar University. Egypt.

Citation: Emadeldin R. Matar *, Mohammed H. Goda, Tamer M. Abuamara. (2021) Evaluation of impact of tall like receptor 4 and liposaccharide in pathogenesis of hepatic cancer. J. Surg Case Repo and Imag. 4(3); DOI:10.31579/2690-1897/072

Copyright: © 2021 Emadeldin R. Matar, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Received: 19 April 2021 | Accepted: 22 April 2021 | Published: 28 April 2021

Keywords: liposaccharide

Abstract

Functional TLR4 expression has been linked to HCC development. TLR4 may serve an important role in HCC development by promoting the malignant transformation of epithelial cells and tumor growth. The consequences might be dependent on the complex signaling networks triggered by TLR4 activation and the tumor microenvironment.

The study included 90 consecutive subjects classified into 3 group their age from 40 to 70 years old.

Group (I): HCC patients on top of chronic HCV infection. they were 45 patients 30 male and 15 females, their age ranged from 45 to 55 who were subdivided into 3 subgroups according to Barcelona clinic liver cancer (BCLC):

Group (Ia): included 8 HCC patients in early stage. (stage A).

Group (Ib): included 12 HCC patients in intermediate stage (stage B).

 Group (Ic): included 25 HCC patients in advanced stage. (stage C).

  • Group (II): 30 Cirrhotic patients with chronic HCV, 21 male and 9 females, their age ranged from 50 to 60. This group was subdivided into 2 subgroups according to Child–Pugh score

Group (IIa): included 8 Child–Pugh A.

Group (IIb): included 22 Child–Pugh B and C.

  • Group (III): controlled group included 15 normal subjects. 10 male and 5 females, their age ranged from 45 to 60. They were selected to match patients’ groups in demographic and socioeconomic standards.

In our study where 15 persons are control showed lower level in TLR4 with mean 1.0±0.2, however 30 patients with HCV and other 45 patients with HCC showed higher level in TLR with mean 2.27±0.6 and 4.2±1.06 respectively.

In our study there is statistically significant difference in serum TLR4 level between group (Ia) (2.25±0.5) and other subgroups which shows more increase in serum level of TLR4 in Group IB (3.2-1.06)   than Group IA. Also shows more increase in serum level of TLR4 in Group IC (4.0±2.0)   than Group IA and IB

In our study HCC group showed higher level of LPS with mean 4.5±1.26 however lower in HCV group with mean 2.9-1.0 and least in control group with mean 1.1±0.4         

In our study there is statistically significant difference in serum LPS level between group (IA) with mean 3.0±0.5 and other subgroups which shows more increase in serum level of LPS in Group IB with mean 4.4-1.0 than Group IA. Also shows more increase in serum level of LPS in Group IC with mean 4.0±1.76 than Group IA and IB

In our study there is statistically significant difference in serum LPS level between group (IIB) and group (IIA) which shows more increase in serum level of TLR4 in Group IIB with mean 2.7±1.1 than Group IIA with mean 2.20±0.2

In our study there is statistically insignificant difference of the mean value ± SD of sex as regard to LPS and TLR expression (t = 1.2, p = 0.22). (t = 0.16, p = 0.87) respectively.In our study there is statistically significant positive correlation between ALT, AST, Platelets, alpha fetoprotein and LPS as regard to TLR4  expression in group II more in IIB,C than IA . but insignificant of the mean value ± SD of other parameters.

In our study there is statistically significant difference of the mean value ± SD of ALT, AST, Platelets, alpha fetoprotein and TLR4 as regard to LPS expression in group I more in IB, C than IA. but insignificant of the mean value ± SD of other parameters.In our study there is statistically significant difference of the mean value ± SD of ALT, AST, Platelets and TLR4 as regard to LPS expression in group II more in IIB than IIA. but insignificant of the mean value ± SD of other parameters.

Conclusion: TLR4 and LPS measurement should be carried for all patient with HCV Who are at risk for HCC with close monitoring. Conduct a study on a Gut microbiota as therapeutic targets for HCC.

Introduction

Hepatocellular carcinoma (HCC)is a common malignancy in developed countries and its incidence is on the rise in the developing world. Most HCC cases (80%) occur in either sub-Saharan Africa or in Eastern Asia. North and South America, Northern Europe, and Oceania are low-rate (5.0/100,000) areas for liver cancer among most populations. (1).        

In Egypt, hepatocellular carcinoma (HCC) is the second most common cancer in men and the 6th most common cancers in women. It has been recognized that the most important clinical risk factor for the development of HCC is cirrhosis. Approximately 80% of HCCs develop in cirrhotic livers (2).

Increasing evidence indicates that the gut-liver axis is involved in HCC. Endotoxemia produced by gut microbiota may contribute to hepato- carcinogenesis and may serve as a target to the prevention or treatment of HCC. (3).             

Toll-like receptors (TLRs) , are important in  immune response that detect  conserved  pathogen  associated  molecular  patterns (PAMPs) of  intestinal microbes components, They are expressed by B lymphocytes, T lymphocytes, and fibroblast. TLRs mediate the production of pro-inflammatory cytokines and chemokine resulting in inflammation. (4)

TLR4 is an important member of TLRs, which could sense endotoxin and activate transcription factors that initiate innate immunity. TLR4 was also expressed on T lymphocyte, playing a vital role in adaptive immunity. (5)

Functional TLR4 expression has been linked to HCC development. TLR4 may serve an important role in HCC development by promoting the malignant transformation of epithelial cells and tumor growth. The consequences might be dependent on the complex signaling networks triggered by TLR4 activation and the tumor microenvironment. (6)

TLR4 is associated with cancer in several ways. Diverse cell lines and tissue samples derived from patients with head and neck, esophageal, gastric, colorectal, liver, pancreatic, skin, ovarian, cervical, and breast cancer have been shown to express increased amounts of TLR4.         

Constitutive expression of some TLR4 genetic variants has also been linked to cancer. These characteristics are therefore being considered for their prognostic value in cancer treatment.  In these scenarios of established cancer, TLR4 facilitates an environment that is suitable for continued cancer cell proliferation. Pro-cancer mechanisms could include the evasion of cancer cells from immune surveillance. (7)

Persistent activation of TLR4-induced inflammatory signaling in chronic inflammatory conditions can also contribute to carcinogenesis. Experimental evidence suggests that cancer cell migration and invasion are induced by triggering of TLR4-NF-κB under inflammatory conditions. LPS-induced TLR4-signaling also promotes cancer cell survival and proliferation in hepatocellular carcinoma. (8).

Aim of the study

1. To assess the association between Toll like receptor 4 and HCC

2. To study association between lipopolysaccharides and HCC.  

Patients and Methods

A) Patients 

This cross–section study was carried out in University Hospital, from September 2017 to September 2020. The study included 90 consecutive subjects classified    into 3group their age from 40 to 70 years old                                            

  • Group (I): HCC patients on top of chronic HCV infection. they were 45 patients 30 male and 15 females, their age ranged from 45 to 55 who were subdivided into 3 subgroups according to Barcelona clinic liver cancer (BCLC):

Group (Ia): included 8 HCC patients in early stage. (stage A).

Group (Ib): included 12 HCC patients in intermediate stage. (stage B).       

Group (Ic): included 25 HCC patients in advanced stage. (stage C).

  • Group (II): 30 Cirrhotic patients with chronic HCV, 21 male and 9 female, their age ranged from 50 to 60 .This group was  subdivided into 2 subgroups according to Child–Pugh score

Group (IIa): included 8 Child–Pugh A.

Group (IIb): included 22 Child–Pugh B and C.

These patients were HCV and PCR positive, Diagnosis of chronic HCV infection. Diagnosis of cirrhosis was based on clinical, laboratory and sonography. Diagnosis of HCC was based on clinical, laboratory and Radiological finding 

European Association for the Study of the Liver (EASL) guideline

On clinical management of HCC in 2000:

1. Radiological criteria: two coincident imaging technique

- Focal lesion >2 cm with arterial hypervascularization

2. Combined criteria: one imaging technique associated with AFP

- Focal lesion >2 cm with arterial hypervascularization

- AFP levels >400 ng/mL

• Four techniques considered: US, spiral CT, MRI and angiography

  • Group (III): controlled group included 15 normal subjects. 10 male and 5 females, their age ranged from 45 to 60. They were selected to match patients’ groups in demographic and socioeconomic standards.

Consent was obtained from all subjects to participate in this study. The study was approved by IRB Faculty of Medicine, Zagazig university.  

Exclusion criteria:

Patients with hepatitis B coinfection, autoimmune diseases, bilharzial infection, Diabetes, chronic diseases (Ischemic heart disease– cerebrovascular stroke –chronic renal failure). Metabolic liver diseases. (Wilson disease, hemochromatosis and iron overload disorders, alpha-1 antitrypsin disease), abnormal thyroid function, Pregnant female, recent Hepatic encephalopathy, recent upper gastrointestinal bleeding, portal vein thrombosis, Patients who started antiviral medicine or immunosuppressive medications.  and patients who received specific treatment for HCC.

B) Methods:

All patients were subjected to the following:

1-Complete history and physical examination.

2-Routine laboratory investigations including:

All patients were subjected to the following:

1-Complete history and physical examination.

2-Routine laboratory investigations including:

  • Complete blood picture.
  • Liver function tests. (ALT, AST, S.Albumin  and  S.Bilirubim)(All patients were tested for ALT, AST, S.Bilirubin and S.Albumin)  
  • Random blood sugar.
  • Hepatitis markers that include:
  • HBsAg, HBc Ab., HCV Ab.
  • PCR for HCV.
  • Anti-schistosoma Ab.
  • Serum cupper, cerioplasmin and serum iron.
  • Free t3, t4 and TSH.
  • ANA and anti-liver, kidney microsomal Ab
  • Alpha –fetoprotein.

3-specific laboratory investigations including:

  • Blood sample for analysis of TLR4 and LPS Ab. Expression by using an enzyme-linked immunosorbent assay.

Serum TLR4 (Toll-Like Receptor 4) and LPS was measured by ELISA as following:

1. Add 100μL standard or sample to each well. Incubate 90 minutes at 37℃

  • 2. Add 100μL Biotinylated Detection Ab. Incubate 1 hour at 37℃
  • 3. Aspirate and wash 3 times
  • 4. Add 100μL HRP Conjugate. Incubate 30 minutes at 37℃
  • 5. Aspirate and wash 5 times
  • 6. Add 90μL Substrate Reagent. Incubate 15 minutes at 37℃
  • 7. Add 50μL Stop Solution. Read at 450nm immediately.
  • 8. Calculation of results.

4–Radiological studies:

  • Pelvi abdominal sonar and Tri- phasic C.T.

Statistical Analysis

Data collected throughout history, basic clinical examination, laboratory investigations and outcome measures coded, entered, and analyzed using Microsoft Excel software. Data were then imported into Statistical Package for the Social Sciences (SPSS version 20.0)

Results

The mean value ± SD of different laboratory parameters of the three groups of the study. Application of ANOVA test revealed statistically significant difference in hemoglobin level between group (I) and other studied groups (f = 16.2, p < 0 xss=removed xss=removed xss=removed p =0.008), xss=removed xss=removed xss=removed xss=removed>

Shows demographic data among the three studied groups of the study.

Table (2): Comparison of Some laboratory Parameters of the Three studied groups.

 (a) Significant results when compared to Group III.

 (b) Significant results when compared to Group II.

Table (3): Comparison of the mean value ± SD of the serum TLR4 Level among 3 studied groups, among three subgroups in group I and  among 2 subgroups in  group II
Table (4): Comparison of the mean value ± SD of the serum LPS Level among 3 studied groups, among 3 subgroups in group I and among 2 subgroups in group II 

KW (Kruskal Wallis Test). statistically significant difference in serum TLR4 level between group (III) and other studied groups which shows increase in serum level of TLR4 in Group I   and Group II In comparison to Group III. + P < 0>

Table (5):Comparison of mean value ± SD between LPS expression and Gender in group I:

a) Significant results when compared to Group III.

 (b) Significant results when compared to Group II.

Statistically significant difference in serum TLR4 level between group (Ia) and other subgroups which shows more increase in serum level of TLR4 in Group IB than Group IA. Also shows more increase in serum level of TLR4 in Group IC than Group IA and IB. statistically significant difference in serum TLC4 level between group (IIB) and group (IIA) which shows more increase in serum level of TLR4 in Group IIB than Group IIA. statistically significant difference in serum LPS level between group (III) and other studied groups. which shows increase in serum level of LPS in Group I and Group II In comparison to Group III + P < 0>

Table (6): Comparison of mean value ± SD between TOL4 expression and Gender in group I:
Table (6): Comparison of mean value ± SD between TOL4 expression and Gender in group I:

(a) Significant results when compared to Group III.

(b) Significant results when compared to Group II.

Shows a statistically insignificant difference of the mean value ± SD of sex as regard to LPS [removed]t = 1.2, p = 0.22).

Shows a statistically insignificant difference of the mean value ± SD of sex as regard to TOL4 [removed]t = 0.16, p = 0.87).

A statistically significant difference in serum LPS level between group (IIB) and group (IIA) which shows more increase in serum level of TLR4 in Group IIB   than Group IIA (table 7).

Table (7): Correlation between TLR and other parameters in groupI:

A statistically significant positive correlation between ALT, AST, Platelets, alpha fetoprotein and LPS as regard to TLR4 expression in group II more in IIB, C than IA. but insignificant of the mean value ± SD of other parameters. A statistically significant difference of the mean value ± SD of ALT, AST, Platelets and LPS   as regard to TLR4 expression in group II more in IIB than IIA. but insignificant of the mean value ± SD of other parameters (table 8).

Table (8): Correlation between TLR and other parameters in group II:

 

A statistically significant difference of the mean value ± SD of ALT, AST, Platelets, alpha fetoprotein and TLR4 as regard to LPS expression in group I more in IB, C than IA. but insignificant of the mean value ± SD of other parameters. A statistically significant difference of the mean value ± SD of ALT, AST, Platelets and TLR4 as regard to LPS expression in group II more in IIB than IIA. but insignificant of the mean value ± SD of other parameters. (table 9)

Table (9):    Correlation between LPS and other parameters in group I:
Table (10):    Correlation between LPS and other parameters in group II: 

Decision

HCC is the sixth most common cancer worldwide and the third most common cause of cancer death. In Egypt, liver cancer forms 1.68% of   the total malignancies. HCC constitutes 70.48% of all liver tumors among Egyptians. (9).

Cirrhosis is a primary risk factor for HCC. Independently of the presence of cirrhosis, HBV infection increases the danger, whereas liver cancer against the background of HCV infection is almost exclusively seen in those with advanced fibrosis and cirrhosis. An emerging risk factor for HCC, at least in the Western world, appears to be cirrhosis secondary to NASH. Additionally, there has been a higher rate of cancer in those with diabetes, and it is unclear whether this is mediated via NASH-related cirrhosis or is independent of the presence of liver disease. (10).

In our study we found that HCC is more prevalent in old men farmer with lower socioeconomic standards. Our study Shows statistically significant difference in serum TLR4 level between HCC group and other studied groups. This is in agreement with Yuan X. et al. that Shows statistically significant difference in serum TLR4 level between normal subject and HCV, HCC Patients. They stated that Persistent activation of   TLR4 - induced inflammatory signaling in chronic inflammatory conditions could contribute to carcinogenesis., (11) Mai CW, Kang YB, Pichika MR.  show statistically significant difference in serum TLR4 level between normal subject and HCC Patients. Their evidence based on elevation in TLR expression and dysfunctional immunity within the tumor microenvironment with cancer progression and reduced patient survival in a number  of  solid  tumors.  TLR activation can enhance regulatory T-cell suppressor function, favoring tumor development. and proliferation in hepatocellular carcinoma. (12)

We found also in our study that HCC group showed higher expression of LPS with range 2.5-5.76 however lower in HCV group with range 2-3.8 and least in control group with range 0.6-1.5 %.   this agree with Liu X, et al.,2010 who stated that HCC group showed higher expression of LPS   however lower in HCV patients provide  evidence  that  LPS induced TLR4 signaling promotes HCC cell invasion in vitro and in vivo, and a  high expression of TLR4 in HCC tissues was strongly associated with both  poor cancer-free survival and overall survival in patients, which   indicates that LPS is closely related to tumor invasion and metastasis, rather than only anti-tumor effects. (13)

In our study we found that the level of TLR 4 and LPS in the serum is higher in advanced stage of HCC (Group 1C) more than other stages this may be due to release of more cytokines from advanced tumor. 

Ageing is associated with impaired PRR signaling, which may partly be accounted for by the reported alterations in Toll-like receptor (TLR) expression by innate immune cells from older adults, compared with those from younger individuals. Decreased surface expression of TLRs has been associated with diminished TLRs induced cytokine production in human monocytes from older individuals. Although substantial age-associated decreases in TLR gene expression have been reported in mice, the pattern is less clear in humans (Van Duin, D. et al.2017).

   Sex differences in immune responses have evolved in diverse species ranging from insects to lizards, birds, and mammals; in all of these species, both innate and adaptive immune responses are typically lower in males than in females. In Drosophila melanogaster, for example, many of the genes that encode for innate signaling proteins are found on the X chromosome and show sex specific induction following fungal or bacterial infection (15).

Northoff H ET AL. stated that There were sex-specific differences in activation of inflammation-related pathways TLRs, cytosolic DNA sensing, and RIG-I like receptors, who found that men expressed higher numbers of activated genes at each time point after exercise even though  luteal-phase  women  showed  a greater extent of pathway  activation  than men. This difference may relate to genetic, immunological difference between our patients and their patients. (16)

According to our study there is a statistically insignificant difference of the mean value ± SD of sex as regard to serum level of LPS. also Shows a statistically insignificant difference of the mean value ± SD of sex as regard to serum level of TOL4. This may be due to small sample size.

TLR4 and LPS had highly significant correlation to both ALT and AST levels. This means that the inflammation of the liver is strongly related to TLR4 and LPS level. Our results agree with Ceccarelli et al, 2015 who reported that LPS and TLR4 levels are related to the severity of inflammation evident in liver histopathology (17).

LPS enhance the signal transduction of β2GPI in liver cancer cells leading to activation of NF-κB, which triggered downstream signal transduction and increased the expression of downstream factors. (e.g., tumor necrosis factor alpha, TNF-α; interleukin-1 beta, IL-1β and alpha-fetoprotein, AFP) This suggests that LPS enhancement of β2GPI signal transduction may play a role in promoting the development of liver cancer. (18)

Agents with TLR4-antagonistic activity have been shown to reduce inflammation-induced carcinogenesis by suppressing the TLR4-induced NF-κB signaling. Curcumin, the main constituent of the spice turmeric, has been found to most likely bind to MD2, thus competing with LPS, A number of synthetic curcuminoids, such as EF24, have also been found to have anti-inflammatory activity (19).

While TLR4 antagonists could help reduce progression of inflammation-induced carcinogenesis or metastasis, TLR4 agonists have been shown to induce anti-tumor immunity in patients and models of established cancer (15).

Conclusion

We concluded that there is strong relationship between TLR4, LPS and pathogenesis of hepatocellular carcinoma so that every cirrhotic patient with high risk of developing HCC should be close monitoring by measurement of serum TLR4 and LPS level owing to decrease incidence of developing HCC.

TLR4 and LPS measurement should be carried for all patient with HCV Who are at risk for HCC with close monitoring.  Conduct a study on a Gut microbiota as therapeutic targets for HCC.  

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Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner