siriraj thailand 20141022

Writing a Clinical Research Manuscript that Has Impact

Siriraj Hospital22 October 2014

Download at: edanzediting.com/siriraj2014

Dr Jeffrey RobensSenior Research Consultant

Education Group Leader

S

Be an effective communicator

Your goal is not only to be published, but also to be widely read/cited

Academic publishing

Clinical research design

Ethics

Professional writing skills

Manuscript structure

Session 1

Before you begin…

Section 1.1

Academic publishing

Academic publishing

Why English?

International language of academics

International reputation

International collaborations

Career advancement

Academic publishing

Publication success = Academic success

S

Publication Metrics and Success on the Academic Job Marketvan Dijk et al. Current Biology. 2014; 24: R516-R517.

• >25,000 researchers in PubMed• Determined which factors positively correlated

with academic success

Publication rate Especially in first few years

Impact factor Become PI more quickly

Citations Can helps those with low IFs

University rank Especially post-doc > PhD

Gender Men have better chances

Academic publishing

Writing a manuscript –4 common myths

S

My manuscript is a written record of my findings

My findings speak for themselves, even if the manuscript is written poorly

Good English means only grammar and spelling

Complex words makes my writing more impressive

Your manuscript is to communicate your findings

You need a well-written manuscript to effectively communicate your findings

Complex words makes your writing more difficult to understand

Good English means clear Englishwith high readability

Academic publishing

What do journal editors want?

Increase impact

High quality research

Interesting to journal’s readership

Original and novel research Well-designed study

Transparent reportingClinical applications

Academic publishing

Clinical relevance

Technical quality

Novelty

Surgical resections of 500 Thai HCC patients


Academic publishing

Clinical relevance

Technical quality

Novelty Surgical resections of Thai HCC patients raised in the US


Academic publishing

Clinical relevance

Technical quality

Novelty

Surgical resections of normal vs. diabetic HCC patients


Section 1.2

Identifying a good research question

Good researchquestion

Clinical research that has impact

1. Read primary literature

2. Read systematic reviews and meta-analyses

3. Identify an important question

• Is the question focused?• Do you have the expertise/resources?• What is new?• How is it clinically useful?


Reading improves manuscript writing

Read often!

Learn how native English speakers write

Learn proper argument structure

Learn manuscript structure and style

Get new ideas, identify problems

Discuss with colleagues

Good researchquestion Make time to read

Most researchers read 60–90 min per day

Spend 20–30 min every day reading abstracts

Spend 60 min 3 days a week reading papers


How to read an article

From start to finish?

Section by section?

Not efficient!

What do you want to know?

Where can you find it?


Self-assess knowledge of topic

Read Title and Abstract first

Strategies for reading

Have you read similar papers?

Familiar with the terminology?

Do you understand the relevance of the hypothesis


Read Figures and then Results

Read Discussion for interpretation

Self-assess knowledge of topic

Read Title and Abstract first

Refer to Introduction and Methods if necessary

Strategies for reading

Read last paragraph of introductionfor hypothesis/objectives


Reacting to published literature

Discuss with colleagues/co-authors:

• What was addressed, what wasn’t addressed, what could have been improved?

• Will need to discuss these points in your manuscript

Assume your idea is not new

Search for what has been done already

Read Discussion carefully for future directions

Section 1.3

Clinical research design

Research design “Hierarchy of evidence”

Randomized controlled trials

Observational studies

Cohort/case-controlled studies

Case reports

Laboratory research

Systematic reviews& meta-analyses

Research design Meta-analyses

Determine clinical efficacy/safety of an intervention based on what has already been done

• Integrates published and unpublished studies• Improves power by increasing sample size• Improves robustness by increasing heterogeneity of

sample population (broader generalization)

Research design Searching for trials

http://onlinelibrary.wiley.com/cochranelibrary/search/

Research design Clinical trials

Prospectively determines clinical efficacy/safety of a new intervention

• Single- or multi-center study?• Appropriate sample population?• Single- or double-blinded?• Placebo or active comparator control?

Consult a statistician!

Research design Clinical trial registration

Retrospective registration is sometimes possible

Should be registered before journal submission

Where to register? Thai Clinical Trials Registrywww.clinicaltrials.in.th

Research design Observational study

Determine clinical efficacy/safety of a currently used intervention

• Intervention not assigned by investigator• Does not need to be publically registered• Usually retrospective, but can be prospective• Bias can result from lack of randomization and

patient is usually not blinded

Research design Cohort/longitudinal studies

Determine risk factors for a disease

• Often prospective, but can be retrospective• Compare two similar healthy populations with

different exposures• Calculate incidence of disease• Can take a long time, risk of missing data

Research design Case-controlled studies

Retrospectively determine risk factors for a (rare) disease

• Compare sample population that has a diseases with a similar sample that does not

• Compare histories and calculate odds ratio• Sample sizes much smaller than cohort studies• Unlike cohort studies, cannot calculate incidence

Research design Case reports

Describes patient with unique presentation

• Needs to be an important unreported case• Tells a story, a timeline of events• Short, 500–1500 words• Needs to have educational value in addition to

novelty• Improves clinical reasoning skills

• Supports case-based learning

Research design Laboratory research

Determine underlying mechanism of disease or treatment

• Performed under ideal (laboratory) conditions• Important in understanding pathogenesis and drug

development• Often difficult to translate to clinical relevance

Research design Reporting guidelines

CONSORT Randomized clinical trials

PRISMA Systematic reviews &Meta-analyses

CARE Case reports

STROBE Observational studies

http://www.equator-network.org/

Research design Sample size

Expected variability in each group

Significance level

Expected difference between groups

Small sample size

Large sample size

Low High

p < 0.05 p < 0.01

Large Small

Should always do a power calculation!

Research design

Fernandes-Taylor et al. BMC Res Notes. 2011; 4: 304.

Statistical problems

Surveyed 25 editors from high impact medical journals

“…respondents expressed concern over researchers’ choice of statistical tests. Specifically, frequent problems exist in the appropriateness of statistical tests ...”

When in doubt, consult a statistician

Research design Common statistical problems: normality

Distribution of data affects analysis and presentation

• Parametric tests (e.g., t-test and ANOVA) can only be used with normally distributed data

• The mean ± SD only for normally distributed data

Simple guide:• If SD is ≥ mean, most likely not normally distributed• If SD is > 0.5 × mean, may not be normally distributed

Use Shapiro-Wilk’s W test for normality

Research design Common statistical problems: P-values

Statistical significance does not equal clinical significance!

“When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals). Avoid relying solely on statistical hypothesis testing, such as P values, which fail to convey important information about effect size and precision of estimates.”*

*http://www.icmje.org/recommendations/browse/manuscript-preparation/preparing-for-submission.html

Research design

Statistical significance does not equal clinical significance!

“After treatment, Drug A reduced LDL cholesterol by 28% (P<0.05). Therefore, Drug A is effective in reducing cholesterol levels…”

• How much is 28%? Is that a clinically relevant reduction?• How does this effect generalize to the population? What is the

95% CI?

Common statistical problems: P-values

Research design

This sample: LDL dropped 1.5 mmol/L to 3.2 mmol/L95% of similar samples, LDL expected to drop from 0.8 to 2.2 mmol/L (3.9 mmol/L to 2.5 mmol/L)

Inconclusive result!

Bad: After treatment, Drug A reduced LDL cholesterol by 28% (P<0.05).

Better: After treatment, Drug A reduced LDL cholesterol from 4.7±0.3 mmol/L to 3.2±0.6 mmol/L (P=0.02).

Best: After treatment, Drug A reduced LDL cholesterol from 4.7±0.3 mmol/L to 3.2±0.6 mmol/L (P=0.02, 95% CI: 0.8–2.2).

Good: <3.3; Borderline: 3.4–4.1; High: 4.1–4.9; Very high: >4.9 mmol/L

What does this mean?


Research design

“After treatment, Drug A reduced LDL cholesterol levels from 4.7±0.3 mmol/L to 3.2±0.6 mmol/L (P=0.02, 95% CI: 0.8–2.2). Because a minimal reduction of 1.4 mmol/L is required to be clinically effective, the efficacy of Drug A is still unclear.”

Useful to state minimum clinically effective difference


Research design Statistical tests

2 categorical endpoints

Paired (within sample)

Unpaired (between sample)

McNemar Fisher’s exact test2 treatment groups

*for sample sizes > 60

Chi-square test*2+ treatment groups

du Prel et al. Dtsch Arztebl Int 2010; 107: 343–8.

Research design

Continuous endpoints

Parametric Nonparametric

Paired Unpaired Paired Unpaired

2 groups:Paired t-test

>2 groups:Repeated measures

ANOVA

2 groups:Unpaired t-test

>2 groups:ANOVA

2 groups:Wilcoxon Signed

rank sum test

>2 groups:Friedman

test

2 groups:Mann–Whitney

U test>2 groups:

Kruskal–Wallis test

du Prel et al. Dtsch Arztebl Int 2010; 107: 343–8.

Statistical tests

Session 2

Ethics and writing skills

Section 2.1

Research and publication ethics

Customer ServiceEthics

Transparent reporting

It needs to be very clear how your study was conducted

• How patients were enrolled• Inclusion and exclusion criteria• How patients were randomized into treatment groups• Used intention-to-treat (all enrolled patients analyzed)

or per-protocol analysis (only patients that complete the study analyzed)

Patients




• Unclear data (blue vs. blue-ish)• Uninterpretable data (glucose levels in patients who

did not fast overnight)• Missing data• Why missing? E.g., outliers or lost to follow-up?• Imputed methods (e.g., last observation carried

forward)

Data




• How you analyzed your data (levels of measurement)?

• Continuous (e.g., systolic pressure in mmHg)• Nominal categories (unranked: e.g., normal vs.

abnormal blood pressure)• Ordinal categories (ranked; e.g., hypotensive, normal,

and hypertensive)

Data




• How you categorized continuous data

• Continuous: height of your patients in cm• Subjective ranking: short <150 cm, normal 151–175

cm, tall >176 cm• Logical ranking: short <1 SD of the mean, normal ±1

SD of the mean, tall >1 SD of the mean

Data

Customer ServiceEthics Ethical treatment

of humans

Informed consent

Participants in a study need to be informed of the:

• Study objectives• Potential benefits or risks involved• Confidentiality

This is usually written informed consent

Templates: http://www.who.int/rpc/research_ethics/informed_consent/en/

Customer ServiceEthics Data manipulation

Never

Fabricate data Move data on a graph

Manipulate images

Hide bad results


Four criteria for authorship

1. Significantly involved in study design, data collection/analysis

2. Writing and revising the manuscript

3. Approval of final version

4. Responsible for the content (accuracy and integrity)

http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html

Customer ServiceEthics Gift/ghost

authorshipMaking someone an author when they do

not deserve it (friends, colleagues, etc.)Gift

authorship

• Try to make paper more prestigious by adding a ‘big name’• Adding the department head to every paper from their department• Thanking someone for a contributed material

Not making someone an author when they do deserve it

Ghost authorship

• Hide conflict of interest (e.g., company employee)• If someone did not conduct the study, but wrote the paper (e.g.,

‘ghost writer’)


Professional, financial, or personal relationships that may bias your research Declare any conflicts of interest to the journal Disclose all sources of funding Disclose all personal and financial relationships Declaration of the role of the study sponsor:• study design• collection, analysis, and interpretation of data• writing of the manuscript

Conflicts of interest

Customer ServiceEthics Conflicts of interest

form


Makes readers think others’ words or ideas are your own

Plagiarism

Copying published text

Stating ideas of someone else without citing the source


Expressing published ideasusing different words

Paraphrasing

Tips on paraphrasing:1. Write about the text a couple hours later

without looking at the source2. Verbally explain ideas to a colleague3. Summarize in a flowchart (e.g., methods)

Customer ServiceEthics Good paraphrasing

24. Llovet at al. N Engl J Med. 2008; 359: 378 –390.

“This trial shows that sorafenib improves overall survival by nearly 3 months in patients with advanced liver cancer.”

Sorafenib improves survival by almost 3 months in patients with advanced liver cancer.24

Sorafenib has been shown to improve the survival of liver cancer patients. 24

Too similar!

Customer ServiceEthics ‘Salami publishing’

You cannot divide one larger paper into two or more smaller ones

• Makes readers think that these are two independent studies

• Relevant information from one paper not available to reader of other paper

• Interferes with the critical evaluation of the study

One larger paper will have more impact for the field (and more citations!)

Section 2.2

Professional writing skills

Writing skills Prepare an outline

I. IntroductionA. General backgroundB. Related studiesC. Problems in the fieldD. Aims

II. MethodsA. Subjects/Samples/MaterialsB. General methodsC. Specific methodsD. Statistical analyses

III. ResultsA. Key points about Figure 1B. Key points about Table 1C. Key points about Figure 2D. Key points about Figure 3E. Key points about Figure 4

IV. DiscussionA. Major conclusionB. Key findings that support conclusionC. Relevance to published studiesD. LimitationsE. Unexpected resultsF. ImplicationsG. Future directions

Knowing what you need to discuss, write down the key ideas

Use short bullet points to list ideas

Don’t let “writing correct English sentences” get in the way of outlining your ideas

Use reporting guidelines!

Writing skills Getting feedback

After completing your outline, discuss it with your colleagues

Make the necessary changes before you begin writing

Write your manuscript section-by-section, do not get overwhelmed by thinking about writing an entire manuscript

Set deadlines as to when the first draft of each section will be completed

Get feedback from you colleagues after each section and make changes before beginning the next section

Writing skills The ‘write’ order

Manuscript sections

• Title• Abstract• Introduction• Methods• Results• Figures• Discussion

Writing order

• Methods• Figures• Results• Discussion• Introduction• Abstract• Title

Writing skills Improving readability

Use short sentencesLimit your sentences to 15–20 words

One idea per sentence

Use active voiceMore simple, direct, and easier to read

AMA Manual of Style: “In general, authors should use the active voice…”. (10th ed., pg. 320)

Writing skills Stress position

Readers focus at the end of the sentence to determine what is important.

1. You deserve a raise, but the budget is tight.

Which sentence suggests that you will get a raise?

2. The budget is tight, but you deserve a raise.

http://writingcenter.unc.edu/handouts/flow/

Writing skills

The budget is tight, but you deserve a raise. Your salary

will increase at the beginning of next year.Stress position Topic position

The topic position introduces the idea of the current sentence

The stress position also introduces the topic of the next sentence

Stress position

Writing skills Topic position

The patient went to the hospital to see a gastroenterologist. The doctor then performed a series of diagnostic tests. The results showed the patient suffered from a bacterial infection. Antibiotics were prescribed to treat the infection before the patient developed an ulcer.

idea ideaideaidea

Topic link

sentence

Writing skills

Lung cancer is the leading cause of cancer mortality for men and women. Despite smoking prevention and cessation programs and advances in early detection, the 5-year survival rate for lung cancer is only 16% with current therapies. Although lung cancer incidence rates have recently declined in the United States, more lung cancer is now diagnosed when considered together in former- and never-smokers than in current smokers. Thus, even if all of the national anti-smoking campaign goals are met, lung cancer will remain a major public health problem for decades. New ways to treat or prevent lung cancer are therefore needed.

One potential therapeutic target for lung cancer is the Wnt signaling pathway. The canonical Wnt signaling pathway in mammals consists of a family of secreted lipid-modified Wnt protein ligands that bind to a family of 7-pass transmembrane Frizzled (Fzd) receptors, as reviewed…

Busch et al. BMC Cancer. 2012; 13: 211.

Linking your ideas in your manuscript

Topic sentence

Stress sentence

Topic sentence

Support

Writing skills

Compared with is for comparing similar things Compared to is for comparing different things

The tumors of the treatment group were compared to those of the control group.

The tumors of the treatment group were compared with those of the control group.

Common mistakes

Writing skills Common mistakes

Data is the plural form of datum

The data was analyzed...This data suggests…

The data were analyzed…These data suggest…

Writing skills

Avoid subjective terms: – Surprisingly, shockingly, unexpectedly

Surprisingly, Drug A showed increased cell death compared with that observed with Drug B.

Interestingly, Drug A showed increased cell death compared with that observed with Drug B.

Common mistakes

Writing skills

www.nature.com/nature/authors/gta/index.html#a4

Common mistakes

Nature’s guide to authors:

Nature is an international journal covering all the sciences. Contributions should therefore be written clearly and simply so that they are accessible to readers in other disciplines and to readers for whom English is not their first language.

“I should use complex words to make my writing more impressive.”

Writing skills

To ascertain the efficaciousness of the program, we interrogated the participants upon completion.

To determine the success of the program, we questioned the participants upon completion.

Simple language

Writing skills

PreferredEnoughClearDetermineTryVerySizeAskedKeepEndUse

AvoidAdequateApparentAscertainEndeavorExceedinglyMagnitudeRequestedRetainTerminateUtilization

Simple language

Session 3

Manuscript structure

Section 3.1

Main text

Coverage and Staffing Plan

Main text Introduction

General introduction

Specific aimsAims

Current state of the field

Problem in the field


Main text Specific aims

Aims…we examined the effect of the severity of kidney dysfunction on the risks of death, cardiovascular events, and hospitalization among a large, diverse group of adults.

Problem…whether chronic kidney disease independently increases the risk of any type of cardiovascular disease has not been established.In addition, few studies have investigated the association between chronic kidney disease and the risk of hospitalization…

• Identify an important problem• State aims that directly address the problem

Go et al. N Engl J Med. 2004; 351: 1296–1305.


Main text Methods

How the study was done

Treatments (controls)Patient management

Follow-up

Quantification methodsStatistical tests

Consult a statistician

Participants used

DemographicsEnrollment procedure

Inclusion/exclusion criteria

Data analysis

Study design


Main text Results

1. Study design2. Treatment efficacy3. Safety

Each subsection corresponds to

one figure

What you found, not what it means

Logical presentation

Subsections

Factual description


Main text Factual description

Drug A is more effective in treating liver cancer as we observed a 32.7% decrease in tumor size compared with only a 22.1% decrease after Drug B treatment.

The efficacy of Drug A was significantly higher than that for Drug B, with decreased tumor size 32.7% or 22.1%, respectively.

Belongs in the Discussion

Exception is when the Results and Discussion sections are combined

“These results suggest that Drug A may be more effective…”


Main text Group repetitive results

Drug A reduced tumor volume by 32.7%, increased blood pressure by 12.3%, and decreased the patient’s weight by 7.3 kg.

Drug B reduced tumor volume by 22.3%, increased blood pressure by 15.6%, and decreased the patient’s weight by 2.4 kg.

Drug C reduced tumor volume by 38.1%, increased blood pressure by 6.9%, and decreased the patient’s weight by 9.2 kg.


Main text

Patients treated with Drug C showed the greatest reduction in tumor volume (28.1%) compared with those treated with Drug A (32.7%) or Drug B (22.3%).

Drug C also had the lowest increase in blood pressure (6.9%) compared with that seen after treatment with Drug A (12.3%) or Drug B (15.65).

However, patients treated with Drug C had the highest weight gain among the three groups (Drug A, 7.3 kg; Drug B, 2.4 kg; Drug C, 9.2 kg).

Group repetitive results


Main text

Present large amount of data quickly and

efficiently

Keep it simple: use separate panels if

necessary

Must be able to stand alone: clear labels and figure legends

Usually the first thing readers will look at

Figures, graphs & tables


Main text FiguresClear figure legend

Kindlin-2 knockdown and focal adhesion localization. Confocal immunofluorescent microscopy with anti-β1 integrin and anti-paxillin on C2C12 cells transfected with RNAi and then changed to differentiation media for 2 days. Control cells show linear staining consistent with localization to costameres (arrows), as well as punctate focal contact staining (arrowheads). Focal contact proteins in the kindlin-2 RNAi cells fail to form linear structures and instead are concentrated in unusual appearing puncta (*). (Scale bar = 20 μM).

Dowling et al. (2008) BMC Cell Biol 9:36.

Clear indicators

Title of the experiment

Brief methodology

Key findings


Main text

Data aligned and formatted

Table formatting

Muñoz et al. New Engl J Med. 2003;348:518−527.

Clear and concise table caption

Abbreviations defined


Main text Use tables for large data sets

Modified from: Go et al. New Engl J Med. 2004;351:1296.

Characteristic Total Cohort(N=1,120,295)

≥ 60 ml/min/1.73 m2

(N=924,136)

< 60 ml/min/1.73 m2

(N=196,159)*

Age (yr) 52.2 ± 16.3 49.1 ± 15.1 66.6 ± 13.0

Female sex (%) 54.6 53.4 60.2

Ethnic group

White 50.9 47.2 68.6

Black 7.4 7.2 5.3

Hispanic 5.9 6.3 4.1

Asian 8.1 8.5 6.7

Mixed 2.4 2.4 2.8

Other 25.3 28.4 12.5

Medical history

Coronary heart disease

6.3 4.5 17.8

Stroke 2.6 1.7 8.3

Peripheral arterial disease

1.8 1.1 6.7

Chronic heart failure

2.1 1.0 19.8* estimations


Main text Use graphs for small data sets

Modified from: Go et al. New Engl J Med. 2014;351:1296.

Coronary hea

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Periphera

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isease

Chronic hea

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5

10

15

20

25

HealthyKidney disease

Perc

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Main text When not to use bar graphs

Bar graphs Mean ± SD Normally distributed data

What if you don’t have normally distributed data?

Should present median and interquartile range (IQR) Box plots


Main text Box plots

Hijikata et al. Hum Genetics. 2012;131:675−682.

Figure 2 Dual luciferase reporter assays. The ratios of Firefly luciferase activity (signal S) to Renilla luciferase (control C) are displayed using box and whisker plots…

Minimum25%

Median75%

Maximum


Main text Discussion

Summary of findings

Relevance of findings

Implications for the field

Similarities/differencesUnexpected resultsNegative resultsLimitations


Main text Writing a strong conclusion paragraph

Why your study is important

In conclusion, we found an independent, graded association between lower levels of the estimated GFR and the risks of death, cardiovascular events, and hospitalization. These risks were evident at an estimated GFR of less than 60 ml per minute per 1.73 m2 and substantially increased with an estimated GFR of less than 45 ml per minute per 1.73 m2. Our findings support the validity of the National Kidney Foundation staging system for chronic kidney disease but suggest that the system could be further refined, since all persons with stage 3 chronic kidney disease (GFR, 30 to 59 ml per minute per 1.73 m2) may not be at equal risk for each outcome. Our findings highlight the clinical and public health importance of chronic kidney disease that does not necessitate dialysis.

Conclusion

Key finding

Implications

Future directions

Clinical importance

Go et al. N Engl J Med. 2004; 351: 1296–1305.


Main text Linking your ideas

General background

Objectives

Methodology

Results and figures

Summary of findings

Implications for the field

Relevance of findings

Problems in the field

Logically link your ideas throughout your manuscript

Current state of the fieldIntroduction

Methods

Results

Discussion


Main text Linking your ideas

New ways to treat or prevent lung cancer are therefore needed.

This study explored the hypothesis that inhibition of TNKS…would inhibit lung cancer growth…

Pharmacological or genetic inhibition of TNKS1 and TNKS2…reduces lung cancer proliferation...

Problem

Objectives

Conclusion

Discussion

Introduction

Busch et al. BMC Cancer. 2012;13:211.


Main text Writing effective conclusions

Your conclusion is a summary of your findings

Your conclusion should be the answer to your research problem that is supported by your findings

Emphasizes how your study will help advance the field

Titles and abstracts

Section 3.2

Customer ServiceTitles and abstracts

Important points

Summarize key finding Study design Contains keywords Less than 20 words

Avoid

Effective titles

Your title should be a concise summary of your most important finding

QuestionsDescribing methodsAbbreviations“New” or “novel”

Customer ServiceTitles and abstracts Abstract

First impression of your paper

Importance of your results

Validity of your conclusions

Relevance of your aims

Judge your writing style

Probably only part that will be read


Writing clinical abstracts

Background Why does this trial/case need to be reported?

Results Treatment outcomesAdverse events

Conclusion Clinical relevanceLearning points

Patients and methods

Patient informationInterventions given

List source of funding and trial registration number after abstract


Unstructured abstract

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

Gil et al. Breast Cancer Res Treat. 2014; 147: 69‒80.


Unstructured abstract


ConclusionWe provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

ResultsErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells.

MethodsHere, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant.

Background

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low.

Customer ServiceTitles and abstracts Writing your abstract

ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.

Clinical relevance

Treatment outcomes

Interventions

Why the study needed to be done


Section 3.3

Succeeding with Edanz

Succeedingwith Edanz Why use Edanz?

Authors face many challenges when publishing their research

Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Edanz can help!



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Expert Scientific Review:• Identify areas for improvement

The study The content



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Journal Selection:Identify suitable journals based on the novelty and relevance of your findings



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Editing:Improve the English and logical

presentation of ideas



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Abstract Development:Prepare a clear abstract that summarizes the key aspects of your study



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Cover Letter Development:Communicates the significance and relevance of your study to the journal editor



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Review Edit:Improves the English of your

manuscript after revisions



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

PBP Assessment:Ensures every reviewer comment

has been properly addressed



Preparation

Journal Selection

Writing

Submission

Peer Review

Publication Success

Author-Guided Rewrite:Revise your manuscript according

to reviewer comments


Manuscript preparation Submission Revision

• Manuscript Editing• Journal Selection• Expert Scientific Review• Abstract Development

• Cover letter development• Reviewer Recommendation

• Review editing• PBP Assessment

Acceptance!

Edanz Publication Success Services

Succeedingwith Edanz Work flow

Evaluate what you think you need

Submit request via Edanz-Siriraj portal

Senior Editor assessment

Manuscript sent to expert editor

Senior Editor internal review

Your evaluation of our work

Resubmit revised manuscript

SE assessment Expert editor SE review

Submit manuscript to journal

Succeedingwith Edanz

How to maximize our services

Submit all related documents for review Manuscript Decision/rejection letters Reviewer comments

Use the second (clarification) edit• Respond to editor comments• Use even if only make minor revisions

Thank you!

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Jeffrey Robens: [email protected]

siriraj thailand 20141022

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