Regenerative endoscopy for the treatment of difficult gastrointestinal defects: Results from a pilot trial Dania Nachira, Valerio Pontecorvi, Angelo Trivisonno, Massimiliano Papi, Maria Valeria Matteo, et al. Endoscopy, 2026 Gastrointestinal (GI) defects with inflamed, fibrotic edges are often refractory to traditional endoscopic treatments. This study evaluates the efficacy and safety of endoscopically delivered stromal vascular fraction from autologous adipose tissue (tSVFem), which promotes tissue regeneration in upper and lower GI defects without additional patient risk or cost.This pilot trial involved patients with GI defects accessible by endoscopy after traditional treatments had failed. The tSVFem was derived from harvested hip fat, which was processed and injected endoscopically into the defect margins. The primary outcome was complete defect resolution. Secondary outcomes included treatment frequency, procedure-related adverse events, and recurrence.30 patients were included: 15 with esophageal defects (median diameter 6 mm) and 15 with rectal defects (median diameter 5 mm). Of the 15 esophageal defects, 14 showed complete resolution after tSVFem injection (10 after one injection and 4 after two injections). The overall resolution rate for rectal defects was 60% (six after one treatment, one after two treatments, and two after three or four treatments). The resolution rate was 5/9 for rectal defects communicating with the urinary tract and 4/6 for those communicating with other organs. No intraprocedural or postprocedural adverse events or defect recurrence occurred.These results suggest that endoscopic injection of autologous tSVFem may treat complex esophageal and rectal defects, including those communicating with adjacent organs other than the urinary tract.
The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody-dependent cytotoxicity Sara Caratelli, Francesca De Paolis, Domenico Alessandro Silvestris, Silvia Baldari, Illari Salvatori, et al. Experimental Hematology and Oncology, 2025 Background Recent studies have shown that CD32/CD8a/CD28/CD3ζ chimeric receptor cells directly kill breast cancer cells, suggesting the existence of cell surface myeloid FcγR alternative ligands (ALs). Here, we investigated the metabolism, ALs, cytotoxicity, and immunoregulatory functions of CD64/CD28/CD3ζ in colorectal cancer (CRC) and squamous cell carcinoma of the head and neck. Methods The CD64/CD28/CD3ζ -SFG retroviral vector was used to produce viruses for T-cell transduction. T-cell expansion and differentiation were monitored via flow cytometry. Gene expression was assessed by RNA-seq. Bioenergetics were documented on a Seahorse extracellular flux analyzer. CD64/CD28/CD3ζ polarization was identified via confocal microscopy. Cytotoxicity was determined by MTT assay and bioluminescent imaging, and flow cytometry. Tridimensional antitumor activity of CD64/CD28/CD3ζ T cells was achieved by utilizing HCT116-GFP 3D spheroids via the IncuCyte S3 Live-Cell Analysis system. The intraperitoneal distribution and antitumor activity of NIR-CD64/CD28/CD3ζ and NIR-nontransduced T cells were investigated in CB17-SCID mice bearing subcutaneous FaDu Luc + cells by bioluminescent and fluorescent imaging. IFNγ was assessed by ELISA. Results Compared to CD16/CD8a/CD28/CD3ζ T cells, CD32/CD8a/CD28/CD3ζ T cells, and non-transduced T cells, CD64/CD28/CD3ζ T cells exhibited the highest levels of cell expansion and persistence capacity. A total of 235 genes linked to cell division and 52 genes related to glycolysis were overexpressed. The glycolytic phenotype was confirmed by functional in vitro studies accompanied by preferential T-cell effector memory differentiation. Interestingly, oxamic acid was found to inhibit CD64-CR T cell proliferation, indicating the involvement of lactate. Upon CD64/CD28/CD3ζ T-cell conjugation with CRC cells, CD64/CD28/CD3ζ cells polarize at immunological synapses, leading to CRC cell death. CD64/CD28/CD3ζ T cells kill SCCHN cells, and in combination with the anti-B7-H3 mAb (376.96) or anti-EGFR mAb, these cells trigger antibody-dependent cellular cytotoxicity (ADCC) in vitro under 2D and 3D conditions. The 376.96 mAb combined with CD64/CD28/CD3ζ T cells had anti-SCCHN activity in vivo. In addition, they induce the upregulation of PD-L1 and HLA-DR expression in cancer cells via IFNγ. PD-L1 positive SCCHN cells in combination with anti-PD-L1 mAb and CD64-CR T cells were killed by ADCC, which enhanced direct cytotoxicity. These findings indicate that the glycolytic phenotype is involved in CD64-CR T cell proliferation/expansion. These cells mediate long-lasting HLA-independent cytotoxicity and ADCC in CRC and SCCHN cells. Conclusions CD64/CD28/CD3ζ T cells could significantly impact the rational design of personalized studies to treat CRC and SCCHN and the identification of novel FcγR ALs in cancer and healthy cells.
Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy Silvia Baldari, Annalisa Antonini, Giuliana Di Rocco, Gabriele Toietta Cancer Innovation, 2025 BackgroundThe incidence of alcohol‐associated cancers is higher within Asian populations having an increased prevalence of an inactivating mutation in aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme required for the clearance of acetaldehyde, a cytotoxic metabolite of ethanol. The role of alcohol consumption in promoting lung cancer is controversial, and little attention has been paid to the association between alcohol drinking and pulmonary ALDH2 expression.MethodsWe performed a comprehensive bioinformatic analysis of multi‐omics data available in public databases to elucidate the role of ALDH2 in lung adenocarcinoma (LUAD).ResultsTranscriptional and proteomic data indicate a substantial pulmonary expression of ALDH2, which is functional for the metabolism of alcohol diffused from the bronchial circulation. ALDH2 expression is higher in healthy lung tissue than in LUAD and inhibits cell cycle, apoptosis, and epithelial–mesenchymal transition pathways. Moreover, low ALDH2 mRNA levels predict poor prognosis and low overall survival in LUAD patients. Interestingly, ALDH2 expression correlates with immune infiltration in LUAD.ConclusionsA better understanding of the role of ALDH2 in lung tumor progression and immune infiltration might support its potential use as a prognostic marker and therapeutic target for improving immunotherapeutic response.
Dissecting human adipose tissue heterogeneity using single‐cell omics technologies Giuliana Di Rocco, Angelo Trivisonno, Giovanni Trivisonno, Gabriele Toietta Stem Cell Research and Therapy, 2024 Single-cell omics technologies that profile genes (genomic and epigenomic) and determine the abundance of mRNA (transcriptomic), protein (proteomic and secretomic), lipids (lipidomic), and extracellular matrix (matrisomic) support the dissection of adipose tissue heterogeneity at unprecedented resolution in a temporally and spatially defined manner. In particular, cell omics technologies may provide innovative biomarkers for the identification of rare specific progenitor cell subpopulations, assess transcriptional and proteomic changes affecting cell proliferation and immunomodulatory potential, and accurately define the lineage hierarchy and differentiation status of progenitor cells. Unraveling adipose tissue complexity may also provide for the precise assessment of a dysfunctional state, which has been associated with cancer, as cancer-associated adipocytes play an important role in shaping the tumor microenvironment supporting tumor progression and metastasis, obesity, metabolic syndrome, and type 2 diabetes mellitus. The information collected by single-cell omics has relevant implications for regenerative medicine because adipose tissue is an accessible source of multipotent cells; alternative cell-free approaches, including the use of adipose tissue stromal cell-conditioned medium, extracellular vesicles, or decellularized extracellular matrix, are clinically valid options. Subcutaneous white adipose tissue, which is generally harvested via liposuction, is highly heterogeneous because of intrinsic biological variability and extrinsic inconsistencies in the harvesting and processing procedures. The current limited understanding of adipose tissue heterogeneity impinges on the definition of quality standards appropriate for clinical translation, which requires consistency and uniformity of the administered product. We review the methods used for dissecting adipose tissue heterogeneity and provide an overview of advances in omics technology that may contribute to the exploration of heterogeneity and dynamics of adipose tissue at the single-cell level.
The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer Maddalena Di Nardo, Simonetta Astigiano, Silvia Baldari, Maria Michela Pallotta, Giovanni Porta, et al. Journal of Experimental and Clinical Cancer Research, 2024 Background SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC. Methods At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo. Results We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes. Conclusions These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC.
Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, et al. Life Science Alliance, 2022 The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice from subcutaneous growth of MDA-MB-468 BC cells. RNAseq analysis identified a 42 gene fingerprint predicting BC cell sensitivity and favorable outcomes in advanced BC. ICAM1 was a major regulator of CD32-CR T cell–mediated cytotoxicity. CD32-CR T cells may help identify cell surface CD32 ligand(s) and novel prognostically relevant transcriptomic signatures and develop innovative BC treatments.
Strategies for Efficient Targeting of Tumor Collagen for Cancer Therapy Silvia Baldari, Francesca Di Modugno, Paola Nisticò, Gabriele Toietta Cancers, 2022 The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM). ECM remodeling is a hallmark of solid tumors, leading to extensive biochemical and biomechanical changes, affecting cell signaling and tumor tissue three-dimensional architecture. Increased deposition of fibrillar collagen is the most distinctive alteration of the tumor ECM. Consequently, several anticancer therapeutic strategies have been developed to reduce excessive tumor collagen deposition. Herein, we provide an overview of the current advances and challenges of the main approaches aiming at tumor collagen normalization, which include targeted anticancer drug delivery, promotion of degradation, modulation of structure and biosynthesis of collagen, and targeting cancer-associated fibroblasts, which are the major extracellular matrix producers.
HIPK2 Cooperates with KRAS Signaling and Associates with Colorectal Cancer Progression Micol Di Segni, Ilaria Virdia, Alessandra Verdina, Carla Azzurra Amoreo, Silvia Baldari, et al. Molecular Cancer Research, 2022 Homeodomain-interacting protein kinase 2 (HIPK2) is an evolutionary conserved kinase that has gained attention as a fine tuner of multiple signaling pathways, among which those commonly altered in colorectal cancer. The aim of this study was to evaluate the relationship of HIPK2 expression with progression markers and mutational pattern and gain insights into the contribution of HIPK2 activity in colorectal cancer. We evaluated a retrospective cohort of colorectal cancer samples by IHC for HIPK2 expression and by next-generation sequencing (NGS) for the detection of mutations of cancer associated genes. We show that the percentage of HIPK2-positive cells increases with tumor progression, significantly correlates with tumor–node–metastasis (TNM) staging and associates with a worse outcome. In addition, we observed that high HIPK2 expression significantly associates with KRAS mutations but not with other cancer-related genes. Functional characterization of the link between HIPK2 and KRAS show that activation of the RAS pathway either due to KRAS mutation or via upstream receptor stimulation, increases HIPK2 expression at the protein level. Of note, HIPK2 physically participates in the active RAS complex while HIPK2 depletion impairs ERK phosphorylation and the growth of tumors derived from KRAS mutated colorectal cancer cells. Overall, this study identifies HIPK2 as a prognostic biomarker candidate in patients with colorectal cancer and underscores a previously unknown functional link between HIPK2 and the KRAS signaling pathway. Implications: Our data indicate HIPK2 as a new player in the complex picture of the KRAS signaling network, providing rationales for future clinical studies and new treatment strategies for KRAS mutated colorectal cancer.
Regenerative endoscopy for the treatment of difficult gastrointestinal defects: results from a pilot trial D Nachira, V Pontecorvi, A Trivisonno, M Papi, MV Matteo, V Bove, ... Endoscopy 58 (2), 193-199 , 2026 2026 Citations: 3
The CD64/CD28/CD3ζ chimeric receptor reprograms T-cell metabolism and promotes T-cell persistence and immune functions while triggering antibody-independent and antibody … S Caratelli, F De Paolis, DA Silvestris, S Baldari, I Salvatori, A Tullo, ... Experimental Hematology & Oncology 14 (1), 17 , 2025 2025 Citations: 2
Expression pattern and prognostic significance of aldehyde dehydrogenase 2 in lung adenocarcinoma as a potential predictor of immunotherapy efficacy S Baldari, A Antonini, G Di Rocco, G Toietta Cancer Innovation 4 (1), e149 , 2025 2025 Citations: 4
Dissecting human adipose tissue heterogeneity using single‐cell omics technologies G Di Rocco, A Trivisonno, G Trivisonno, G Toietta Stem Cell Research & Therapy 15, 322 , 2024 2024 Citations: 13
The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer M Di Nardo, S Astigiano, S Baldari, MM Pallotta, G Porta, S Pigozzi, ... Journal of Experimental & Clinical Cancer Research 43, 49 , 2024 2024 Citations: 9
Cancer immunity and immunotherapy beyond COVID-19 M Bellone, A Brevi, V Bronte, S Dusi, PF Ferrucci, P Nisticò, A Rosato, ... Cancer Immunology, Immunotherapy 72 (7), 2541-2548 , 2023 2023
Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment G Sconocchia, V Lanzilli, G: Cesarini, DA Silvestris, K Rezvani, R Arriga, ... Life Science Alliance 5 (12), e202201590 , 2022 2022 Citations: 4
Strategies for efficient targeting of tumor collagen for cancer therapy S Baldari, F Di Modugno, P Nisticò, G Toietta Cancers 14 (19), 4706 , 2022 2022 Citations: 53
HIPK2 cooperates with KRAS signaling and associates with colorectal cancer progression M Di Segni, I Virdia, A Verdina, CA Amoreo, S Baldari, G Toietta, ... Molecular Cancer Research 20 (5), 686–698 , 2022 2022 Citations: 11
Cancer bio-immunotherapy XVIII annual NIBIT-(Italian network for tumor biotherapy) meeting, October 15-16, 2020 M Bellone, A Brevi, V Bronte, S Dusi, PF Ferrucci, P Nisticò, A Rosato, ... Cancer Immunology, Immunotherapy 71 (7), 1787-1794 , 2022 2022
Antibody-Independent Antitumor Effects of Cd32A-Chimeric Receptor T Cells: Implications for Breast Cancer Prognosis and Treatment G Sconocchia, G Lanzilli, V Cesarini, DA Silvestris, R Arriga, K Rezvani, ... bioRxiv, 2021.12. 22.473841 , 2021 2021
Reduction of cell proliferation by acute C2H6O exposure S Baldari, I Manni, G Di Rocco, F Paolini, B Palermo, G Piaggio, G Toietta Cancers 13 (19), 4999 , 2021 2021 Citations: 4
Successful therapy of esophageal fistulas by endoscopic injection of emulsified adipose tissue stromal vascular fraction D Nachira, A Trivisonno, G Costamagna, G Toietta, S Margaritora, ... Gastroenterology 160 (4), 1026-1028 , 2021 2021 Citations: 28
A ruthenium (II)-curcumin compound modulates NRF2 expression balancing the cancer cell death/survival outcome according to p53 status A Garufi, S Baldari, R Pettinari, MS Gilardini Montani, V D’Orazi, G Pistritto, ... Journal of Experimental & Clinical Cancer Research 39 (1), 122 , 2020 2020 Citations: 39
DHA affects microtubule dynamics through reduction of phospho-TCTP levels and enhances the antiproliferative effect of T-DM1 in trastuzumab-resistant HER2-positive breast … S D’Amico, EK Krasnowska, I Manni, G Toietta, S Baldari, G Piaggio, ... Cells 9 (5), 1260 , 2020 2020 Citations: 18
Regenerative medicine approaches for the management of respiratory tract fistulas A Trivisonno, D Nachira, I Boškoski, V Porziella, G Di Rocco, S Baldari, ... Stem Cell Research & Therapy 11 (1), 451 , 2020 2020 Citations: 27
Current biomedical use of copper chelation therapy S Baldari, G Di Rocco, G Toietta International Journal of Molecular Sciences 21 (3), 1069 , 2020 2020 Citations: 227
Extracellular vesicles–encapsulated microRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation S Baldari, G Di Rocco, A Magenta, M Picozza, G Toietta Cells 8 (12), 1560 , 2019 2019 Citations: 76
Intraoperative strategies for minimal manipulation of autologous adipose tissue for cell- and tissue-based therapies: Concise Review A Trivisonno, RW Alexander, S Baldari, SR Cohen, G Di Rocco, P Gentile, ... Stem Cells Translational Medicine 8, 1265-1271 , 2019 2019 Citations: 105
Effects of copper chelation on BRAFV600E positive colon carcinoma cells S Baldari, G Di Rocco, MC Heffern, TA Su, CJ Chang, G Toietta Cancers 11 (5), 659 , 2019 2019 Citations: 74
MOST CITED SCHOLAR PUBLICATIONS
Effects of the olive-derived polyphenol oleuropein on human health B Barbaro, G Toietta, R Maggio, M Arciello, M Tarocchi, A Galli, C Balsano International Journal of Molecular Sciences 15 (10), 18508-18524 , 2014 2014 Citations: 440
Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies S Baldari, G Di Rocco, M Piccoli, M Pozzobon, M Muraca, G Toietta International Journal of Molecular Sciences 18 (10), 2087 , 2017 2017 Citations: 309
Diabetes impairs adipose tissue–derived stem cell function and efficiency in promoting wound healing F Cianfarani, G Toietta, G Di Rocco, E Cesareo, G Zambruno, T Odorisio Wound Repair and Regeneration 21 (4), 545-553 , 2013 2013 Citations: 275
Current biomedical use of copper chelation therapy S Baldari, G Di Rocco, G Toietta International Journal of Molecular Sciences 21 (3), 1069 , 2020 2020 Citations: 227
A role for neuronal cAMP responsive-element binding (CREB)-1 in brain responses to calorie restriction S Fusco, C Ripoli, MV Podda, SC Ranieri, L Leone, G Toietta, ... Proceedings of the National Academy of Sciences 109 (2), 621-626 , 2012 2012 Citations: 187
PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile MA Croyle, HT Le, KD Linse, V Cerullo, G Toietta, A Beaudet, L Pastore Gene Therapy 12 (7), 579-587 , 2005 2005 Citations: 176
Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector G Toietta, VP Mane, WS Norona, MJ Finegold, P Ng, AF McDonagh, ... Proceedings of the National Academy of Sciences 102 (11), 3930-3935 , 2005 2005 Citations: 171
Towards therapeutic delivery of extracellular vesicles: strategies for in vivo tracking and biodistribution analysis G Di Rocco, S Baldari, G Toietta Stem Cells International 2016 (Article ID 5029619) , 2016 2016 Citations: 156
Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy A Severino, M Campioni, S Straino, FN Salloum, N Schmidt, U Herbrand, ... Journal of the American College of Cardiology 50 (11), 1029-1037 , 2007 2007 Citations: 139
Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter G Toietta, DR Koehler, MJ Finegold, B Lee, J Hu, AL Beaudet Molecular Therapy 7 (5), 649-658 , 2003 2003 Citations: 117
Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes K Sukegawa, H Nakamura, Z Kato, S Tomatsu, AM Montaño, T Fukao, ... Human Molecular Genetics 9 (9), 1283-1290 , 2000 2000 Citations: 116
Intraoperative strategies for minimal manipulation of autologous adipose tissue for cell- and tissue-based therapies: Concise Review A Trivisonno, RW Alexander, S Baldari, SR Cohen, G Di Rocco, P Gentile, ... Stem Cells Translational Medicine 8, 1265-1271 , 2019 2019 Citations: 105
Enhanced healing of diabetic wounds by topical administration of adipose tissue-derived stromal cells overexpressing Stromal-Derived Factor-1: biodistribution and engraftment … G Di Rocco, A Gentile, A Antonini, F Ceradini, JC Wu, MC Capogrossi, ... Stem Cells International 2011 (Article ID 304562) , 2010 2010 Citations: 91
A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability S Fusco, L Leone, SA Barbati, D Samengo, R Piacentini, G Maulucci, ... CELL REPORTS 14 (5), 1195-1205 , 2016 2016 Citations: 82
Harvest of superficial layers of fat with a microcannula and isolation of adipose tissue–derived stromal and vascular cells A Trivisonno, G Di Rocco, C Cannistra, V Finocchi, ST Farr, M Monti, ... AESTHETIC SURGERY JOURNAL 34 (4), 601-613 , 2014 2014 Citations: 80
Extracellular vesicles–encapsulated microRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation S Baldari, G Di Rocco, A Magenta, M Picozza, G Toietta Cells 8 (12), 1560 , 2019 2019 Citations: 76
Effects of copper chelation on BRAFV600E positive colon carcinoma cells S Baldari, G Di Rocco, MC Heffern, TA Su, CJ Chang, G Toietta Cancers 11 (5), 659 , 2019 2019 Citations: 74
Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells G Di Rocco, S Baldari, G Pani, G Toietta Cellular and Molecular Life Sciences 76 (2), 231-244 , 2019 2019 Citations: 74
Various cells retrovirally transduced with N-acetylgalactosoamine-6-sulfate sulfatase correct Morquio skin fibroblasts in vitro G Toietta, GM Severini, C Traversari, S Tomatsu, K Sukegawa, S Fukuda, ... Human Gene Therapy 12 (16), 2007-2016 , 2001 2001 Citations: 54
Strategies for efficient targeting of tumor collagen for cancer therapy S Baldari, F Di Modugno, P Nisticò, G Toietta Cancers 14 (19), 4706 , 2022 2022 Citations: 53
