Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2015

Open Access 01-12-2015 | Research

A prime/boost strategy using DNA/fowlpox recombinants expressing the genetically attenuated E6 protein as a putative vaccine against HPV-16-associated cancers

Authors: Massimiliano Bissa, Elena Illiano, Sole Pacchioni, Francesca Paolini, Carlo Zanotto, Carlo De Giuli Morghen, Silvia Massa, Rosella Franconi, Antonia Radaelli, Aldo Venuti

Published in: Journal of Translational Medicine | Issue 1/2015

Login to get access

Abstract

Background

Considering the high number of new cases of cervical cancer each year that are caused by human papilloma viruses (HPVs), the development of an effective vaccine for prevention and therapy of HPV-associated cancers, and in particular against the high-risk HPV-16 genotype, remains a priority. Vaccines expressing the E6 and E7 proteins that are detectable in all HPV-positive pre-cancerous and cancer cells might support the treatment of HPV-related lesions and clear already established tumors.

Methods

In this study, DNA and fowlpox virus recombinants expressing the E6F47R mutant of the HPV-16 E6 oncoprotein were generated, and their correct expression verified by RT-PCR, Western blotting and immunofluorescence. Immunization protocols were tested in a preventive or therapeutic pre-clinical mouse model of HPV-16 tumorigenicity using heterologous (DNA/FP) or homologous (DNA/DNA and FP/FP) prime/boost regimens. The immune responses and therapeutic efficacy were evaluated by ELISA, ELISPOT assays, and challenge with TC-1* cells.

Results

In the preventive protocol, while an anti-E6-specific humoral response was just detectable, a specific CD8+ cytotoxic T-cell response was elicited in immunized mice. After the challenge, there was a delay in cancer appearance and a significant reduction of tumor volume in the two groups of E6-immunized mice, thus confirming the pivotal role of the CD8+ T-cell response in the control of tumor growth in the absence of E6-specific antibodies. In the therapeutic protocol, in-vivo experiments resulted in a higher number of tumor-free mice after the homologous DNA/DNA or heterologous DNA/FP immunization.

Conclusions

These data establish a preliminary indication for the prevention and treatment of HPV-related tumors by the use of DNA and avipox constructs as safe and effective immunogens following a prime/boost strategy. The combined use of recombinants expressing both E6 and E7 proteins might improve the antitumor efficacy, and should represent an important approach to control HPV-associated cancers.
Literature
1.
Zur Hausen H. Papillomaviruses in the causation of human cancers: a brief historical account. Virol. 2009;384:260–5.CrossRef
2.
Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, ElGhissassi F, et al. WHO international agency for research on cancer monograph working group: a review of human carcinogens–part B: biological agents. Lancet Oncol. 2009;10:321–2.CrossRefPubMed
3.
Doorbar J, Quint W, Banks L, Bravo I, Stoler M, Broker T, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;305:F55–70.CrossRef
4.
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Canc. 2012;131:2349–59.CrossRef
5.
Kirnbauer R, Booy N, Chengt DR, Lowy DR, Schiller JT. Papillomavirus Li major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA. 1992;89:12180–4.CrossRefPubMedCentralPubMed
6.
Hagensee ME, Yaegashi N, Galloway DA. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J Virol. 1993;67:315–22.PubMedCentralPubMed
7.
Harper DM, Franco EL, Wheeler CM, Moscicki AB, Romanowski B, Roteli-Martins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367:1247–55.CrossRefPubMed
8.
FUTURE II Study Group. Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. J Infect Dis. 2007;196:1431–2.CrossRef
9.
Hung CF, Ma B, Monie A, Tsen SW, Wu TC. Therapeutic human papillomavirus vaccines: current clinical trials and future directions. Expert Opin Biol Ther. 2008;8:421–39.CrossRefPubMedCentralPubMed
10.
Smotkin D, Wettstein F. Transcription of human papillomavirus type 16 early genes in cervical cancer and cancer-derived cell line and identification of the E7 protein. Proc Natl Acad Sci USA. 1986;83:4680–4.CrossRefPubMedCentralPubMed
11.
Androphy EJ, Hubbert NL, Schiller JT, Lowy DR. Identification of the HPV-16 E6 protein from transformed mouse cells and human cervical carcinoma cells. EMBO J. 1987;6:989–92.PubMedCentralPubMed
12.
Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 1989;8:3905–10.PubMedCentralPubMed
13.
Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA. 2000;97:12513–8.CrossRefPubMedCentralPubMed
14.
Yoshinouchi M, Yamada T, Kizaki M, Fen J, Koseki T, Ikeda Y, et al. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by E6 siRNA. Mol Ther. 2003;8:762–8.CrossRefPubMed
15.
Song S, Liem A, Miller JA, Lambert PF. Human papillomavirus type 16 E6 and E7 contribute differently to carcinogenesis. Virol. 2000;267:141–50.CrossRef
16.
Eiben GL, Da Silva DM, Fausch SC, Le Poole IC, Nishimura MI, Kast WM. Cervical cancer vaccines: recent advances in HPV research. Viral Immunol. 2003;16:111–21.CrossRefPubMed
17.
Meneguzzi G, Cerni C, Kieny MP, Lathe R. Immunization against human papillomavirus type 16 tumor cells with recombinant vaccinia viruses expressing E6 and E7. Virol. 1991;181:62–9.CrossRef
18.
Campo MS, Grindlay GJ, O’Neil BW, Chandrachud LM, McGarvie GM, Jarrett WF. Prophylactic and therapeutic vaccination against a mucosal papillomavirus. J Gen Virol. 1993;74:945–53.CrossRefPubMed
19.
Chen L, Mizuno MT, Singhal MC, Hu SL, Galloway DA, Hellström I, et al. Induction of cytotoxic T lymphocytes specific for a syngeneic tumor expressing the E6 oncoprotein of human papillomavirus type 16. J Immunol. 1992;148:2617–21.PubMed
20.
van der Burg SH, Kwappenberg KM, O’Neill T, Brandt RM, Melief CJ, Hickling JK, et al. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. Vaccine. 2001;19:3652–60.CrossRefPubMed
21.
Chen CH, Wang TL, Ji H, Hung CF, Pardoll DM, Cheng WF, et al. Recombinant DNA vaccines protect against tumors that are resistant to recombinant vaccinia vaccines containing the same gene. Gene Ther. 2001;8:128–38.CrossRefPubMed
22.
Porgador A, Irvine KR, Iwasaki A, Barber BH, Restifo NP, Germain RN. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med. 1998;188:1075–82.CrossRefPubMedCentralPubMed
23.
Hsieh CJ, Kim TW, Hung CF, Juang J, Moniz M, Boyd DA, et al. Enhancement of vaccinia vaccine potency by linkage of tumor antigen gene to gene encoding calreticulin. Vaccine. 2004;22:3993–4001.CrossRefPubMed
24.
Lamikanra A, Pan ZK, Isaacs SN, Wu TC, Paterson Y. Regression of established human papillomavirus type 16 (HPV-16) immortalized tumors in vivo by vaccinia viruses expressing different forms of HPV-16 E7 correlates with enhanced CD8(+) T-cell responses that home to the tumor site. J Virol. 2001;75:9654–64.CrossRefPubMedCentralPubMed
25.
Borysiewicz LK, Fiander A, Nimako M, Man S, Wilkinson GW, Westmoreland D, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet. 1996;347:1523–7.CrossRefPubMed
26.
Adams M, Borysiewicz L, Fiander A, Man S, Jasani B, Navabi H, et al. Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine. 2001;19:2549–56.CrossRefPubMed
27.
Baldwin PJ, van der Burg SH, Boswell CM, Offringa R, Hickling JK, Dobson J, et al. Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a therapeutic vaccination for vulval and vaginal intraepithelial neoplasia. Clin Cancer Res. 2003;9:5205–13.PubMed
28.
Smyth LJ, Van Poelgeest MI, Davidson EJ, Kwappenberg KM, Burt D, Sehr P, et al. Immunological responses in women with human papillomavirus type 16 (HPV-16)-associated anogenital intraepithelial neoplasia induced by heterologous prime-boost HPV-16 oncogene vaccination. Clin Cancer Res. 2004;10:2954–61.CrossRefPubMed
29.
Acres B, Bonnefoy JY. Clinical development of MVA-based therapeutic cancer vaccines. Expert Rev Vaccines. 2008;7:889–93.CrossRefPubMed
30.
Brun JL, Dalstein V, Leveque J, Mathevet P, Raulic P, Baldauf JJ, et al. Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy. Am J Obstet Gynecol. 2011;204:169-e1-8.CrossRefPubMed
31.
Chen CH, Wang TL, Hung CF, Pardoll DM, Wu TC. Boosting with recombinant vaccinia increases HPV-16 E7-specific T cell precursor frequencies of HPV-16 E7-expressing DNA vaccines. Vaccine. 2000;18:2015–22.CrossRefPubMed
32.
Mackova J, Stasikova J, Kutinova L, Masin J, Hainz P, Simsova M, et al. Prime/boost immunotherapy of HPV16-induced tumors with E7 protein delivered by Bordetella adenylate cyclase and modified vaccinia virus Ankara. Cancer Immunol Immunother. 2006;55:39–46.CrossRefPubMed
33.
Wlazlo AP, Deng H, Giles-Davis W, Ertl HC. DNA vaccines against the human papillomavirus type 16 E6 or E7 oncoproteins. Cancer gene Ther. 2004;11:457–64.CrossRefPubMed
34.
Fiander AN, Tristram A, Davidson EJ, Tomlinson AE, Man S, Baldwin PJ, et al. Prime-boost vaccination strategy in women with high-grade, noncervical anogenital intraepithelial neoplasia: clinical results from a multicenter phase II trial. Int J Gynecol Cancer. 2006;16:1075–81.CrossRefPubMed
35.
Blanchard TJ, Alcami A, Andrea P, Smith GL. Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine. J Gen Virol. 1998;79:1159–67.PubMed
36.
Drexler I, Heller K, Wahren B, Erfle V, Sutter G. Highly attenuated modified vaccinia virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but not in various human transformed and primary cells. J Gen Virol. 1998;79:347–52.PubMed
37.
Radaelli A, De Giuli Morghen C, Zanotto C, Pacchioni S, Bissa M, Franconi R, et al. A prime/boost strategy by DNA/fowlpox recombinants expressing a mutant E7 protein for the immunotherapy of HPV-associated cancers. Virus Res. 2012;170:44–52.CrossRefPubMed
38.
39.
Bissa M, Pacchioni S, Zanotto C, De Giuli Morghen C, Radaelli A. GFP co-expression reduces the A33R gene expression driven by a fowlpox vector in replication permissive and non-permissive cell lines. J Virol Methods. 2013;187:172–6.CrossRefPubMed
40.
Pacchioni S, Bissa M, Zanotto C, De Giuli Morghen C, Illiano E, Radaelli A. L1R, A27L, A33R and B5R vaccinia virus genes expressed by fowlpox recombinants as putative novel orthopoxvirus vaccines. J Transl Med. 2013;11:95.CrossRefPubMedCentralPubMed
41.
Nominé Y, Masson M, Charbonnier S, Zanier K, Ristriani T, Deryckere F, et al. Structural and functional analysis of E6 oncoprotein: insights in the molecular pathways of human papillomavirus-mediated pathogenesis. Mol Cell. 2006;21:665–78.CrossRefPubMed
42.
Ristriani T, Fournane S, Orfanoudakis G, Masson M. A single-codon mutation converts HPV16 E6 oncoprotein into a potential tumor suppressor, which induces p53-dependent senescence of HPV-positive HeLa cervical cancer cells. Oncogene. 2009;28:762–72.CrossRefPubMed
43.
Venuti A, Massa S, Mett V, Vedova LD, Paolini F, Franconi R, et al. An E7-based therapeutic vaccine protects mice against HPV16 associated cancer. Vaccine. 2009;27:3395–7.CrossRefPubMed
44.
Pacchioni S, Volonté L, Zanotto C, Pozzi E, De Giuli Morghen C, Radaelli A. Canarypox and fowlpox viruses as recombinant vaccine vectors: an ultrastructural comparative analysis. Arch Virol. 2010;155:915–24.CrossRefPubMed
45.
Rosel JL, Earl PL, Weir J, Moss B. Conserved TAAATG sequence at the transcriptional and translational initiation sites of vaccinia virus late genes deduced by structural and functional analysis of the hindlll H genome fragment. J Virol. 1986;60:436–49.PubMedCentralPubMed
46.
Pozzi E, Basavecchia V, Zanotto C, Pacchioni S, De Giuli Morghen C, Radaelli A. Construction and characterization of recombinant fowlpox viruses expressing human papilloma virus E6 and E7 oncoproteins. J Virol Methods. 2009;158:184–9.CrossRefPubMed
47.
Radaelli A, De Giuli Morghen C. Expression of HIV-1 envelope gene by recombinant avipoxvirus. Vaccine. 1994;12:1101–9.CrossRefPubMed
48.
Zanotto C, Pozzi E, Pacchioni S, Bissa M, De Giuli Morghen C, Radaelli A. Construction and characterisation of a recombinant fowlpox virus that expresses the human papilloma virus L1 protein. J Transl Med. 2011;9:190–200.CrossRefPubMedCentralPubMed
49.
Pozzi E, Zanotto C, Pacchioni S, De Giuli Morghen C, Radaelli A. MHC-restricted CTL assay: an improved method based on naïve and SV40-immortalized rabbit epidermal target cells. J Virol Methods. 2009;155:77–81.CrossRefPubMed
50.
Radaelli A, Pozzi E, Pacchioni S, Zanotto C, De Giuli Morghen C. Fowlpox virus recombinants expressing HPV-16 E6 and E7 oncogenes for the therapy of cervical carcinoma elicit humoral and cell-mediated responses in rabbits. J Transl Med. 2010;8:40.CrossRefPubMedCentralPubMed
51.
Bissa M, Pacchioni S, Zanotto C, De Giuli Morghen C, Illiano E, Granucci F, et al. Systemically administered DNA and fowlpox recombinants expressing four vaccinia virus genes although immunogenic do notprotect mice against the highly pathogenic IHD-J vaccinia strain. Virus Res. 2013;178:374–82.CrossRefPubMed
52.
Radaelli A, Bonduelle O, Beggio P, Mahe B, Pozzi E, Elli V, et al. Prime-boost immunization with DNA, recombinant fowlpox virus and VLP(SHIV) elicit both neutralizing antibodies and IFNgamma-producing T cells against the HIV-envelope protein in mice that control env-bearing tumour cells. Vaccine. 2007;25:2128–38.CrossRefPubMed
53.
Peng S, Ji H, Trimble C, He L, Tsai YC, Yeatermeyer J, et al. Development of a DNA vaccine targeting human papillomavirus type 16 oncoprotein E6. J Virol. 2004;78:8468–76.CrossRefPubMedCentralPubMed
54.
Jochmus I, Osen W, Altmann A, Buck G, Hofmann B, Schneider A, et al. Specificity of human cytotoxic T lymphocytes induced by a human papillomavirus type 16 E7-derived peptide. J Gen Virol. 1997;78:1689–95.PubMed
55.
Nominé Y, Charbonnier S, Ristriani T, Stier G, Masson M, Cavusoglu N, et al. Domain substructure of HPV E6 oncoprotein: biophysical characterization of the E6 C-terminal DNA-binding domain. Biochemistry. 2003;42:4909–17.CrossRefPubMed
56.
Sedman SA, Barbosa MS, Vass WC, Hubbert NL, Haas JA, Lowy DR, et al. The full-length E6 protein of human papillomavirus type 16 has transforming and trans-activating activities and cooperates with E7 to immortalize keratinocytes in culture. J Virol. 1991;65:4860–6.PubMedCentralPubMed
57.
Mizuuchi M, Hirohashi Y, Torigoe T, Kuroda T, Yasuda K, Shimizu Y, et al. Novel oligomannose liposome-DNA complex DNA vaccination efficiently evokes anti-HPV E6 and E7 CTL responses. Exp Mol Pathol. 2012;92:185–90.CrossRefPubMed
58.
Kanodia S, Da Silva DM, Kast WM. Recent advances in strategies for immunotherapy of human papillomavirus-induced lesions. Int J Cancer. 2008;122:247–59.CrossRefPubMed
59.
Gissmann L. Modern uterine cytopathology. Meisels A and Morin C, editors. Chicago: ASCP Press. 2007;169–200.
60.
Meyer SI, Fuglsang K, Blaakaer J. Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination. Acta Obstet Gynecol Scand. 2014. doi:10.1111/aogs.12480.
61.
Peng S, Song L, Knoff J, Wang JW, Chang YN, Hannaman D, et al. Control of HPV-associated tumors by innovative therapeutic HPV DNA vaccine in the absence of CD4+ T cells. Cell Biosci. 2014;4:11.CrossRefPubMedCentralPubMed
62.
Brandsma JL, Shlyankevich M, Su Y, Zelterman D, Rose J, Buonocore L. Reversal of papilloma growth in rabbits therapeutically vaccinated against E6 with naked DNA and/or vesicular stomatitis virus vectors. Vaccine. 2010;28:8345–51.CrossRefPubMedCentralPubMed
63.
Brandsma JL, Shlyankevich M, Zelterman D, Su Y. Therapeutic vaccination of rabbits with a ubiquitin-fused papillomavirus E1, E2, E6 and E7 DNA vaccine. Vaccine. 2014;25:6158–63.CrossRef
64.
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med. 2012;4:155ra138.CrossRefPubMedCentralPubMed
65.
Massa S, Simeone P, Muller A, Benvenuto E, Venuti A, Franconi R. Antitumor activity of DNA vaccines based on the Human Papillomavirus-16 E7 protein genetically fused to a plant virus coat protein. Hum Gene Ther. 2008;19:354–64.CrossRefPubMed
66.
Whitehead M, Ohlschläger P, Almajhdi FN, Alloza L, Marzábal P, Meyers AE, et al. Human papillomavirus (HPV) type 16 E7 protein bodies cause tumour regression in mice. BMC Cancer. 2014;14:367.CrossRefPubMedCentralPubMed
67.
Skinner MA, Laidlaw SM, Eldaghayes I, Kaiser P, Cottingham MG. Fowlpox virus as a recombinant vaccine vector for use in mammals and poultry. Expert Rev Vaccines. 2005;4:63–76.CrossRefPubMed
Metadata
Title
A prime/boost strategy using DNA/fowlpox recombinants expressing the genetically attenuated E6 protein as a putative vaccine against HPV-16-associated cancers
Authors
Massimiliano Bissa
Elena Illiano
Sole Pacchioni
Francesca Paolini
Carlo Zanotto
Carlo De Giuli Morghen
Silvia Massa
Rosella Franconi
Antonia Radaelli
Aldo Venuti
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2015
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-015-0437-9

Other articles of this Issue 1/2015

Journal of Translational Medicine 1/2015 Go to the issue

Research

Cell mediated immunity against HPV16 E2, E6 and E7 peptides in women with incident CIN and in constantly HPV-negative women followed-up for 10-years

Research

Myostatin and IGF-I signaling in end-stage human heart failure: a qRT-PCR study

Research

Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer

Research

Understanding the molecular aspects of oriental obesity pattern differentiation using DNA microarray

Review

Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases

Methodology

A workflow-driven approach to integrate generic software modules in a Trusted Third Party
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits