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Article ; Online: Microbiome as a biomarker and therapeutic target in pancreatic cancer.

Pourali, Ghazaleh / Kazemi, Danial / Chadeganipour, Amir Shayan / Arastonejad, Mahshid / Kashani, Sara Naghizadeh / Pourali, Roozbeh / Maftooh, Mina / Akbarzade, Hamed / Fiuji, Hamid / Hassanian, Seyed Mahdi / Ghayour-Mobarhan, Majid / Ferns, Gordon A / Khazaei, Majid / Avan, Amir

BMC microbiology

2024 Volume 24, Issue 1, Page(s) 16

Abstract: ... the prognosis of patients. We also discuss novel treatment methods being used to minimize or prevent ... in the pathogenesis of PC, and the role these microorganisms might play as biomarkers in the diagnosis and determining ... these findings to improve current therapeutic strategies employed in the treatment of PC. ...

Abstract	Studying the effects of the microbiome on the development of different types of cancer has recently received increasing research attention. In this context, the microbial content of organs of the gastrointestinal tract has been proposed to play a potential role in the development of pancreatic cancer (PC). Proposed mechanisms for the pathogenesis of PC include persistent inflammation caused by microbiota leading to an impairment of antitumor immune surveillance and altered cellular processes in the tumor microenvironment. The limited available diagnostic markers that can currently be used for screening suggest the importance of microbial composition as a non-invasive biomarker that can be used in clinical settings. Samples including saliva, stool, and blood can be analyzed by 16 s rRNA sequencing to determine the relative abundance of specific bacteria. Studies have shown the potentially beneficial effects of prebiotics, probiotics, antibiotics, fecal microbial transplantation, and bacteriophage therapy in altering microbial diversity, and subsequently improving treatment outcomes. In this review, we summarize the potential impact of the microbiome in the pathogenesis of PC, and the role these microorganisms might play as biomarkers in the diagnosis and determining the prognosis of patients. We also discuss novel treatment methods being used to minimize or prevent the progression of dysbiosis by modulating the microbial composition. Emerging evidence is supportive of applying these findings to improve current therapeutic strategies employed in the treatment of PC.
MeSH term(s)	Humans ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/therapy ; Biomarkers ; Microbiota ; Anti-Bacterial Agents ; Dysbiosis/therapy ; Tumor Microenvironment
Chemical Substances	Biomarkers ; Anti-Bacterial Agents
Language	English
Publishing date	2024-01-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2041505-9
ISSN	1471-2180 ; 1471-2180
ISSN (online)	1471-2180
ISSN	1471-2180
DOI	10.1186/s12866-023-03166-4
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Article: FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization.

Pei, Xuan-Zeng / Cai, Min / Jiang, Da-Wei / Chen, Song-Hai / Wang, Qing-Qing / Lu, Hui-Min / Lu, Yi-Fan

World journal of gastrointestinal oncology

2024 Volume 16, Issue 4, Page(s) 1479–1499

Abstract: Background: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and ... investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism ... in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and ...

Abstract	Background: Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma (PDAC) metastasis. Aim: To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis. Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis. Methods: Cell culture and various experiments, including protein analysis, immunohistochemistry, and animal model experiments, were conducted. We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features. Our study analyzed the role of FAM53B in macrophage M2 polarization Results: Our research showed that there was a significant increase in FAM53B levels in PDAC tissues, which was linked to adverse tumor features. Experimental findings indicated that FAM53B can enhance macrophage M2 polarization, leading to increased anti-inflammatory factor release. The results from the mouse model further supported the role of FAM53B in PDAC metastasis, as blocking FAM53B prevented tumor cell invasion and metastasis. Conclusion: FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization. This discovery could lead to the development of new strategies for treating PDAC. For example, interfering with the FAM53B signaling pathway may prevent cancer spread. Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.
Language	English
Publishing date	2024-04-05
Publishing country	China
Document type	Journal Article
ZDB-ID	2573696-6
ISSN	1948-5204
ISSN	1948-5204
DOI	10.4251/wjgo.v16.i4.1479
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Article ; Online: The Relationship between Diabetes Mellitus and Pancreatic Cancer-Diabetes Mellitus as a Red Flag for Pancreatic Cancer.

Popovic, Katarina / Smolović, Brigita / Martinović, Milica / Vučković, Ljiljana

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2023 Volume 32, Issue 3, Page(s) 298–305

Abstract: ... of the relationship between DM and pancreatic cancer could aid in developing novel screening and treatment strategies ... The relationship between diabetes mellitus (DM) and pancreatic cancer is complex-DM is ... both a risk factor and early sign of pancreatic cancer. DM is a risk factor for pancreatic cancer ...

Abstract	The relationship between diabetes mellitus (DM) and pancreatic cancer is complex-DM is both a risk factor and early sign of pancreatic cancer. DM is a risk factor for pancreatic cancer because it increases insulin resistance, intrapancreatic concentrations of insulin, and the bioavailability of IGF, subsequently promoting ductal cell proliferation. Accordingly, treatment targeting the insulin/IGF pathway is the focus of many researchers. Antidiabetic drugs modify the risk for pancreatic cancer-metformin's antineoplastic effect being most notable and indicating potential clinical use in pancreatic cancer. New-onset DM can also be the first manifestation of pancreatic cancer. There are several theories for the pathogenesis of DM in pancreatic cancer, the most important being that DM is a paraneoplastic syndrome caused by diabetogenic factors. As a consequence of this intricate relationship, new-onset DM after the age of 50 is considered a red flag for pancreatic cancer, prompting the need for screening in this patient population. Multiple clinical studies are currently underway exploring this matter. A better understanding of the relationship between DM and pancreatic cancer could aid in developing novel screening and treatment strategies for pancreatic cancer. This could ultimately improve the prognosis and quality of life of patients with pancreatic cancer.
MeSH term(s)	Humans ; Quality of Life ; Diabetes Mellitus/epidemiology ; Pancreatic Neoplasms/pathology ; Insulin ; Pancreatic Neoplasms
Chemical Substances	Insulin
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-22-0951
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Article: Pancreatic cancer: pathogenesis, prevention and treatment.

Sarkar, Fazlul H / Banerjee, Sanjeev / Li, Yiwei

Toxicology and applied pharmacology

2007 Volume 224, Issue 3, Page(s) 326–336

Abstract: ... knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer. ... for the prevention and/or treatment of pancreatic cancer. In this brief review, we will summarize the current ... survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against ...

Abstract	Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very important. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways among which the EGFR, Akt, and NF-kappaB pathways appear to be most relevant. Therefore, the strategies targeting EGFR, Akt, NF-kappaB, and their downstream signaling could be promising for the prevention and/or treatment of pancreatic cancer. In this brief review, we will summarize the current knowledge regarding the pathogenesis, prevention, and treatment of pancreatic cancer.
MeSH term(s)	Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Anticarcinogenic Agents/pharmacology ; Anticarcinogenic Agents/therapeutic use ; Gene Silencing ; Genetic Therapy/methods ; Humans ; Models, Biological ; Pancreatic Neoplasms/etiology ; Pancreatic Neoplasms/prevention & control ; Pancreatic Neoplasms/therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/immunology ; Receptor, Epidermal Growth Factor/physiology ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/immunology ; Receptor, ErbB-2/physiology ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/physiology
Chemical Substances	Antibodies, Monoclonal ; Anticarcinogenic Agents ; Tumor Suppressor Proteins ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2007-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2006.11.007
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Article ; Online: Nitric oxide and pancreatic cancer pathogenesis, prevention, and treatment.

Wang, Liwei / Xie, Keping

Current pharmaceutical design

2009 Volume 16, Issue 4, Page(s) 421–427

Abstract: Pancreatic cancer is hallmarked by aggressive biology and extreme lethality and very high mortality ... however. Recent identification and functional validation of nitric oxide (NO) production in pancreatic cancer ... to control pancreatic cancer development and progression requires a full understanding of the molecular ...

Abstract	Pancreatic cancer is hallmarked by aggressive biology and extreme lethality and very high mortality rates. The underlying molecular mechanism of its rapid development and progression is unclear, however. Recent identification and functional validation of nitric oxide (NO) production in pancreatic cancer suggest a role for NO in the pathogenesis of this disease. Conceivably, overproduction of NO imposes an adverse selection pressure on the tumor microenvironment, which causes genetic and epigenetic changes in tumor and tumor stromal cells and promotes the evolution of these cells into more malignant cells conferred with a tremendous survival and growth advantage. Designing effective strategies targeting NO to control pancreatic cancer development and progression requires a full understanding of the molecular mechanisms of signaling of NO production and action in the tumor microenvironment.
MeSH term(s)	Animals ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/etiology ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/prevention & control ; Drug Synergism ; Humans ; Nitric Oxide/antagonists & inhibitors ; Nitric Oxide/metabolism ; Nitric Oxide/therapeutic use ; Nitric Oxide Donors/therapeutic use ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Nitric Oxide Donors ; Tumor Suppressor Proteins ; Nitric Oxide (31C4KY9ESH)
Language	English
Publishing date	2009-10-20
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1304236-1
ISSN	1873-4286 ; 1381-6128
ISSN (online)	1873-4286
ISSN	1381-6128
DOI	10.2174/138161210790232194
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Article ; Online: 12382 Circadian Disruption in Pancreatic Cancer Carcinogenesis

Patrick B. Schwartz / Morgan T. Walcheck / Kristina A. Matkowskyj / Christopher A. Bradfield / Sean M. Ronnekleiv-Kelly

Journal of Clinical and Translational Science, Vol 5, Pp 7-

2021 Volume 8

Abstract: ... rhythms can lead to pancreas cancer development and spread, preventive and therapeutic strategies can be ... spectrum of pancreas cancer precursor lesions (pancreatic intra-epithelial neoplasia or PANIN-1, 2, 3) and ... and poor response to therapy. Identifying factors driving PDAC growth could lead to new therapeutic ...

Abstract	ABSTRACT IMPACT: Circadian disruption is known to cause significant human pathology but has not been evaluated in pancreas cancer carcinogenesis; through understanding how disruption of circadian rhythms can lead to pancreas cancer development and spread, preventive and therapeutic strategies can be devised. OBJECTIVES/GOALS: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer due to early spread and poor response to therapy. Identifying factors driving PDAC growth could lead to new therapeutic strategies. Thus, we evaluated the extent to which circadian rhythm disruption, a factor strongly associated with cancer formation, contributes to PDAC pathogenesis. METHODS/STUDY POPULATION: To achieve the objective, we evaluated mice with pancreas lineage Kras-mutation (KC mice), which are predisposed to develop the full spectrum of pancreas cancer precursor lesions (pancreatic intra-epithelial neoplasia or PANIN-1, 2, 3) and PDAC. We subjected KC mice to a light-dark phase shift protocol known to induce circadian disruption (KCCD, n = 18), and another group to standard lighting conditions (KCNC, n = 31), with equal numbers of males and females in each group. The mice were allowed access to food and water ad libitum until sacrifice at age 9 months. Histopathologic evaluation of the pancreas was then performed to assess for pancreatic inflammation, pancreatic precursor lesions (PANIN) and PDAC. Fisher’s Exact Test was used to evaluate differences in incidence. RESULTS/ANTICIPATED RESULTS: As expected, both groups of mice demonstrated 100% incidence of chronic pancreatitis and PANIN-1 (low-grade precursor lesion) at age 9 months. This is consistent with the KC phenotype. However, the KCCD mice demonstrated a significant increase in acute pancreatic inflammation (61.1% vs 19.4%, p = 0.005) compared to KCNC mice. Furthermore, intermediate grade precursor lesions (PANIN-2) were also significantly increase in the KCCD mice (38.9% vs 6.5%, p = 0.006). Incidence of high-grade precursor lesions (PANIN-3, or carcinoma in ...
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Cambridge University Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Role of Local Angiotensin II/Angiotensin Type 1-receptor Mechanisms in Adipose Tissue Dysfunction to Promote Pancreatic Cancer.

Khodashahi, Rozita / Beiraghdar, Fatemeh / Ferns, Gorgon A / Ashrafzadeh, Kiayash / Aliakbarian, Mohsen / Arjmand, Mohammad-Hassan

Current cancer drug targets

2024

Abstract: ... in the amelioration of the complications related to adipose tissue dysfunction and prevention of pancreatic cancer ... Obesity and adipose tissue dysfunction are important risk factors for pancreatic cancer ... responsible for the initiation and progression of pancreatic cancer. Due to the role of local angiotensin II ...

Abstract	Obesity and adipose tissue dysfunction are important risk factors for pancreatic cancer. Pancreatic cancer is one of the most lethal cancers globally. The renin-angiotensin system (RAS) is expressed in many tissues, including adipose tissue. Dysregulation of angiotensin II and angiotensin II receptors in adipose tissue through the activation of different signaling pathways leads to adipose tissue dysfunction, including insulin resistance, adipose tissue inflammation, adipocytokines secretion, and metabolic alterations. The pathogenesis of pancreatic cancer remains uncertain. However, there is evidence that dysregulation of local angiotensin II in adipose tissue that occurs in association with obesity is, in part, responsible for the initiation and progression of pancreatic cancer. Due to the role of local angiotensin II in the dysfunction of adipose tissue, angiotensin receptor blockers may be considered a new therapeutic strategy in the amelioration of the complications related to adipose tissue dysfunction and prevention of pancreatic cancer. This review aims to consider the biological roles of local angiotensin II and angiotensin II receptors in adipose tissue dysfunction to promote pancreatic cancer progression with a focus on adipose tissue inflammation and metabolic reprogramming.
Language	English
Publishing date	2024-02-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2064824-8
ISSN	1873-5576 ; 1568-0096
ISSN (online)	1873-5576
ISSN	1568-0096
DOI	10.2174/0115680096281059240103154836
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Article ; Online: Pancreatic Cystic Lesions

Antoinette J. Pusateri / Somashekar G. Krishna

Diseases, Vol 6, Iss 2, p

Pathogenesis and Malignant Potential

2018 Volume 50

Abstract: ... understanding of precursor lesions may enhance the ability to treat and prevent pancreatic cancer ... This review summarizes the latest literature describing what is known about the pathogenesis and malignant ... neoplasms and mucinous cystic neoplasm), solid pseudopapillary tumors and cystic neuroendocrine tumors ...

Abstract	Pancreatic cancer remains one of the most lethal cancers despite extensive research. Further understanding of precursor lesions may enhance the ability to treat and prevent pancreatic cancer. Pancreatic cystic lesions (PCLs) with malignant potential include: mucinous PCLs (intraductal papillary mucinous neoplasms and mucinous cystic neoplasm), solid pseudopapillary tumors and cystic neuroendocrine tumors. This review summarizes the latest literature describing what is known about the pathogenesis and malignant potential of these PCLs, including unique epidemiological, radiological, histological, genetic and molecular characteristics.
Keywords	pancreatic cystic lesions ; mucinous lesions ; intraductal pancreatic mucinous neoplasm ; mucinous cystic neoplasm ; solid pseudo-papillary tumors ; cystic neuroendocrine tumors ; pancreatic ductal adenocarcinoma ; Medicine ; R
Language	English
Publishing date	2018-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Inflammatory potential of diet and pancreatic cancer risk in the EPIC study.

Cayssials, Valerie / Buckland, Genevieve / Crous-Bou, Marta / Bonet, Catalina / Weiderpass, Elisabete / Skie, Guri / Aune, Dagfinn / Heath, Alicia / Nøst, Therese Haugdahl / Masala, Giovanna / Agnoli, Claudia / De Magistris, Maria Santucci / Bueno-de-Mesquita, Bas / Derksen, Jeroen / Huybrechts, Inge / Ferrari, Pietro / Franklin, Oscar / Bodén, Stina / Schulze, Matthias /

Huerta, Jose Maria / Barricarte, Aurelio / Sacerdote, Carlotta / Amiano, Pilar / Tumino, Rosario / Molina-Montes, Esther / Tjønneland, Anne / Kyrø, Cecilie / Severi, Gianluca / Boutron-Ruault, Marie-Christine / Rebours, Vinciane / Katzke, Verena / Agudo, Antonio / Jakszyn, Paula

European journal of nutrition

2022 Volume 61, Issue 5, Page(s) 2313–2320

Abstract: ... treatment of pancreatic cancer might be challenging, prevention remains the major hope for reducing ... in the pathogenesis of pancreatic cancer (PC) and on how risk may be modulated by dietary factors. Pro-inflammatory ... within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes 450,112 ...

Abstract	Purpose: There is existing evidence on the potential role of chronic inflammation in the pathogenesis of pancreatic cancer (PC) and on how risk may be modulated by dietary factors. Pro-inflammatory diets are suggested to be associated with increased risk of PC but, so far, evidence remains not conclusive. We examined the association between the dietary inflammatory potential and PC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which includes 450,112 participants. Methods: After a 14-year follow-up, a total of 1239 incident PC cases were included in this study. The inflammatory potential of the diet was estimated using an Inflammatory Score of the Diet (ISD). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between the ISD and PC were estimated using multivariable Cox regression models, adjusted for known risk factors for PC. Results: Participants with higher ISDs had a higher risk of developing PCs. In the fully adjusted multivariate model, the risk of PC increased by 11% (HR 1.11, 95% CI 1.02-1.22) for 1 point each standard deviation increase in the ISD score. Neither obesity nor any other known risk factor for PC showed statistically significant interactions. Conclusion: To the best of our knowledge, this is the first prospective study reporting a positive relationship between the inflammatory potential of diet and PC. Since early diagnosis and treatment of pancreatic cancer might be challenging, prevention remains the major hope for reducing the burden of this disease.
MeSH term(s)	Diet/adverse effects ; Humans ; Nutritional Status ; Pancreatic Neoplasms/epidemiology ; Prospective Studies ; Risk Factors
Language	English
Publishing date	2022-01-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1466536-0
ISSN	1436-6215 ; 1436-6207
ISSN (online)	1436-6215
ISSN	1436-6207
DOI	10.1007/s00394-022-02809-y
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Article ; Online: Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy.

Montenegro, María F / Martí-Díaz, Román / Navarro, Ana / Tolivia, Jorge / Sánchez-Del-Campo, Luis / Cabezas-Herrera, Juan / Rodríguez-López, José Neptuno

Cell death & disease

2023 Volume 14, Issue 11, Page(s) 761

Abstract: Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth ... inhibitors, this hypomethylating treatment could represent a therapeutic opportunity for pancreatic ... metabolic stress conditions, while at the same time promoting their pathogenesis and resistance to KRAS pathway ...

Abstract	Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth. Here, we observed that some processes that allow the maintenance of basal autophagy in pancreatic cancer cells are controlled by protein methylation. Thus, by maintaining the methylation status of proteins such as PP2A and MRAS, these cells can sustain their autophagic activity. Protein methylation disruption by a hypomethylating treatment (HMT), which depletes cellular S-adenosylmethionine levels while inducing S-adenosylhomocysteine accumulation, resulted in autophagy inhibition and endoplasmic reticulum stress-induced apoptosis in pancreatic cancer cells. We observed that by reducing the membrane localization of MRAS, hypomethylation conditions produced an imbalance in KRAS signaling, resulting in the partial inactivation of ERK and hyperactivation of the PI3K/AKT-mTORC1 pathway. Interestingly, HMT impeded CRAF activation by disrupting the ternary SHOC2 complex (SHOC2/MRAS/PP1), which functions as a CRAF-S259 holophosphatase. The demethylation events that resulted in PP2A inactivation also favored autophagy inhibition by preventing ULK1 activation while restoring the cytoplasmic retention of the MiT/TFE transcription factors. Since autophagy provides pancreatic cancer cells with metabolic plasticity to cope with various metabolic stress conditions, while at the same time promoting their pathogenesis and resistance to KRAS pathway inhibitors, this hypomethylating treatment could represent a therapeutic opportunity for pancreatic adenocarcinomas.
MeSH term(s)	Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Phosphatidylinositol 3-Kinases ; Methylation ; Cell Line, Tumor ; Pancreatic Neoplasms/genetics ; Autophagy/genetics ; Intracellular Signaling Peptides and Proteins
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; SHOC2 protein, human ; Intracellular Signaling Peptides and Proteins ; KRAS protein, human
Language	English
Publishing date	2023-11-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-023-06288-9
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