Journal of Biomedical Science最新文献

{"title":"Translational research on drug development and biomarker discovery for hepatocellular carcinoma","authors":"Valerie Chew, Chien-Huai Chuang, Chiun Hsu","doi":"10.1186/s12929-024-01011-y","DOIUrl":"https://doi.org/10.1186/s12929-024-01011-y","url":null,"abstract":"Translational research plays a key role in drug development and biomarker discovery for hepatocellular carcinoma (HCC). However, unique challenges exist in this field because of the limited availability of human tumor samples from surgery, the lack of homogenous oncogenic driver mutations, and the paucity of adequate experimental models. In this review, we provide insights into these challenges and review recent advancements, with a particular focus on the two main agents currently used as mainstream therapies for HCC: anti-angiogenic agents and immunotherapy. First, we examine the pre-clinical and clinical studies to highlight the challenges of determining the optimal therapeutic combinations with biologically effective dosage for HCC. Second, we discuss biomarker studies focusing on anti-PD1/anti-PD-L1-based combination therapy. Finally, we discuss the progress made in our collective understanding of tumor immunology and in multi-omics analysis technology, which enhance our understanding of the mechanisms underlying immunotherapy, characterize different patient subgroups, and facilitate the development of novel combination approaches to improve treatment efficacy. In summary, this review provides a comprehensive overview of efforts in translational research aiming at advancing our understanding of and improving the treatment of HCC.","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139760959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan.","authors":"Siao Muk Cheng, Yung-Yeh Su, Nai-Jung Chiang, Chih-Jung Wang, Ying-Jui Chao, Chien-Jui Huang, Hui-Jen Tsai, Shang-Hung Chen, Chi-Yen Chang, Chia-Rung Tsai, Yi-Jie Li, Chia-Jui Yen, Shih-Chang Chuang, Jeffrey Shu-Ming Chang, Yan-Shen Shan, Daw-Yang Hwang, Li-Tzong Chen","doi":"10.1186/s12929-024-01008-7","DOIUrl":"10.1186/s12929-024-01008-7","url":null,"abstract":"<p><strong>Background: </strong>Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.</p><p><strong>Methods: </strong>Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHR^mut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.</p><p><strong>Results: </strong>Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHR^mut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHR^mut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHR^mut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.</p><p><strong>Conclusions: </strong>Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHR^mut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10865564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.","authors":"Wan-Ting Kuo, I-Ying Kuo, Hung-Chia Hsieh, Ssu-Ting Wu, Wu-Chou Su, Yi-Ching Wang","doi":"10.1186/s12929-024-01009-6","DOIUrl":"10.1186/s12929-024-01009-6","url":null,"abstract":"<p><strong>Background: </strong>Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear.</p><p><strong>Methods: </strong>Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept.</p><p><strong>Results: </strong>Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37⁺/PD-1⁺/TIM3⁺/CD8⁺ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1⁺ and TIM3⁺ in CD8⁺ T cells exhibiting reduced tumoricidal activity.</p><p><strong>Conclusions: </strong>Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37^high/PD-1^high/TIM3^high in tumor-infiltrating CD8⁺ T cells is a biomarker for poor prognosis in lung cancer patients.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":11.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10848371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy.","authors":"Dantong Sun, Haili Qian, Junling Li, Puyuan Xing","doi":"10.1186/s12929-024-01004-x","DOIUrl":"10.1186/s12929-024-01004-x","url":null,"abstract":"<p><p>MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Promising antibacterial efficacy of arenicin peptides against the emerging opportunistic pathogen Mycobacterium abscessus.","authors":"Magali Casanova, Marc Maresca, Isabelle Poncin, Vanessa Point, Hamza Olleik, Céline Boidin-Wichlacz, Aurélie Tasiemski, Kamel Mabrouk, Jean-François Cavalier, Stéphane Canaan","doi":"10.1186/s12929-024-01007-8","DOIUrl":"10.1186/s12929-024-01007-8","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium abscessus, a fast-growing non-tuberculous mycobacterium, is an emerging opportunistic pathogen responsible for chronic bronchopulmonary infections in people with respiratory diseases such as cystic fibrosis (CF). Due to its intrinsic polyresistance to a wide range of antibiotics, most treatments for M. abscessus pulmonary infections are poorly effective. In this context, antimicrobial peptides (AMPs) active against bacterial strains and less prompt to cause resistance, represent a good alternative to conventional antibiotics. Herein, we evaluated the effect of three arenicin isoforms, possessing two or four Cysteines involved in one (Ar-1, Ar-2) or two disulfide bonds (Ar-3), on the in vitro growth of M. abscessus.</p><p><strong>Methods: </strong>The respective disulfide-free AMPs, were built by replacing the Cysteines with alpha-amino-n-butyric acid (Abu) residue. We evaluated the efficiency of the eight arenicin derivatives through their antimicrobial activity against M. abscessus strains, their cytotoxicity towards human cell lines, and their hemolytic activity on human erythrocytes. The mechanism of action of the Ar-1 peptide was further investigated through membrane permeabilization assay, electron microscopy, lipid insertion assay via surface pressure measurement, and the induction of resistance assay.</p><p><strong>Results: </strong>Our results demonstrated that Ar-1 was the safest peptide with no toxicity towards human cells and no hemolytic activity, and the most active against M. abscessus growth. Ar-1 acts by insertion into mycobacterial lipids, resulting in a rapid membranolytic effect that kills M. abscessus without induction of resistance.</p><p><strong>Conclusion: </strong>Overall, the present study emphasized Ar-1 as a potential new alternative to conventional antibiotics in the treatment of CF-associated bacterial infection related to M. abscessus.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10823733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors.","authors":"Hsin-Fang Tu, Yu-Jui Kung, Ling Lim, Julia Tao, Ming-Hung Hu, Michelle Cheng, Deyin Xing, T C Wu, Chien-Fu Hung","doi":"10.1186/s12929-024-01006-9","DOIUrl":"10.1186/s12929-024-01006-9","url":null,"abstract":"<p><strong>Background: </strong>Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells.</p><p><strong>Methods: </strong>Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44^high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44^high CD8 T cells.</p><p><strong>Results: </strong>CD44^high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44^high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44^high naïve CD8 T cells revealed FLT3L to induce CD44^high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44^high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44^high CD8 T cells.</p><p><strong>Conclusions: </strong>These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells.","authors":"Chien-Hsin Huang, Tsan-Tzu Yang, Kuo-I Lin","doi":"10.1186/s12929-024-01003-y","DOIUrl":"10.1186/s12929-024-01003-y","url":null,"abstract":"<p><p>SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10821541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.","authors":"Zhao-Qing Shen, Cheng-Yen Chang, Chi-Hsiao Yeh, Chung-Kuang Lu, Hao-Chih Hung, Tai-Wen Wang, Kuan-Sheng Wu, Chien-Yi Tung, Ting-Fen Tsai","doi":"10.1186/s12929-024-01005-w","DOIUrl":"10.1186/s12929-024-01005-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperet","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139541740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool.","authors":"Daniel B Rodrigues, Rui L Reis, Rogério P Pirraco","doi":"10.1186/s12929-024-00997-9","DOIUrl":"10.1186/s12929-024-00997-9","url":null,"abstract":"<p><p>Cancer remains a serious burden in society and while the pace in the development of novel and more effective therapeutics is increasing, testing platforms that faithfully mimic the tumor microenvironment are lacking. With a clear shift from animal models to more complex in vitro 3D systems, spheroids emerge as strong options in this regard. Years of development have allowed spheroid-based models to better reproduce the biomechanical cues that are observed in the tumor-associated extracellular matrix (ECM) and cellular interactions that occur in both a cell-cell and cell-ECM manner. Here, we summarize some of the key cellular interactions that drive tumor development, progression and invasion, and how successfully are these interactions recapitulated in 3D spheroid models currently in use in the field. We finish by speculating on future advancements in the field and on how these can shape the relevance of spherical 3D models for tumor modelling.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts.","authors":"Yi-Kai Hong, Yu-Chen Lin, Tsung-Lin Cheng, Chao-Han Lai, Yi-Han Chang, Yu-Lun Huang, Chia-Yi Hung, Chen-Han Wu, Kuo-Shu Hung, Ya-Chu Ku, Yen-Ting Ho, Ming-Jer Tang, Shu-Wha Lin, Guey-Yueh Shi, John A McGrath, Hua-Lin Wu, Chao-Kai Hsu","doi":"10.1186/s12929-024-01001-0","DOIUrl":"10.1186/s12929-024-01001-0","url":null,"abstract":"<p><strong>Background: </strong>Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars.</p><p><strong>Methods: </strong>To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars.</p><p><strong>Results: </strong>The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids.</p><p><strong>Conclusions: </strong>Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.</p>","PeriodicalId":15365,"journal":{"name":"Journal of Biomedical Science","volume":null,"pages":null},"PeriodicalIF":9.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}