The detection and complete eradication of early‐stage small tumors during hysteroscopy remains a significant clinical challenge in preserving fertility for young women with endometrial cancer (EC). The purpose of this study is to verify the feasibility of CD47 as an optical molecular imaging (OMI) target for human EC and to achieve precise localization and identification in hysteroscopic surgery. The results demonstrated that CD47 was overexpressed in EC through bioinformatics, immunohistochemistry, and qRT‐PCR. In EC cell lines, CD47‐targeted near‐infrared photoimmunotherapy (NIR‐PIT) induced cytotoxicity in a light dose‐dependent manner. Laser confocal microscopy revealed that CD47 intervention significantly increased the phagocytic effect of macrophages on EC cells. In the mice model of partial tumor resection mediated by CD47‐targeted OMI, compared to group A (immune therapy alone), group C (NIR‐PIT treatment) mice showed a reduced tumor recurrence rate after NIR‐PIT intervention. However, the difference did not reach statistical significance. We then evaluated the effect of CD47‐targeted NIR‐PIT maintenance therapy on tumor recurrence in mice. The results indicated that, compared to untreated animals, the tumor growth rate was slower in the NIR‐PIT group using CD47‐Alexa Fluor 790 (CD47‐AF790), allowing for more sustained tumor control. The freshly isolated whole uterus specimens from EC patients were co‐incubated with CD47‐AF790, and a significantly enhanced contrast of NIR visible images of tumor tissue was observed, demonstrating high sensitivity and specificity (tumor‐to‐background ratio >5.05). Finally, under fluorescence microscopy, specific fluorescent signals are observed on tumor cells. In conclusion, accurate localization and excision of EC can be accomplished by employing CD47 optical molecular contrast agents with OMI technology. This method shows potential as a viable and promising approach for the precise diagnosis of EC.
{"title":"Multimodal near‐infrared molecular imaging of ex vivo endometrial carcinoma via CD47‐based targeted tracer","authors":"Jing Lei, Dianfeng Tian, Bo Zhang, Hongrui Guo, Huancheng Su, Jinzheng Wei, Shuai Li, Sufen Li, Chao Liu, Xiaofeng Yang, Sanyuan Zhang","doi":"10.1002/btm2.10754","DOIUrl":"https://doi.org/10.1002/btm2.10754","url":null,"abstract":"The detection and complete eradication of early‐stage small tumors during hysteroscopy remains a significant clinical challenge in preserving fertility for young women with endometrial cancer (EC). The purpose of this study is to verify the feasibility of CD47 as an optical molecular imaging (OMI) target for human EC and to achieve precise localization and identification in hysteroscopic surgery. The results demonstrated that CD47 was overexpressed in EC through bioinformatics, immunohistochemistry, and qRT‐PCR. In EC cell lines, CD47‐targeted near‐infrared photoimmunotherapy (NIR‐PIT) induced cytotoxicity in a light dose‐dependent manner. Laser confocal microscopy revealed that CD47 intervention significantly increased the phagocytic effect of macrophages on EC cells. In the mice model of partial tumor resection mediated by CD47‐targeted OMI, compared to group A (immune therapy alone), group C (NIR‐PIT treatment) mice showed a reduced tumor recurrence rate after NIR‐PIT intervention. However, the difference did not reach statistical significance. We then evaluated the effect of CD47‐targeted NIR‐PIT maintenance therapy on tumor recurrence in mice. The results indicated that, compared to untreated animals, the tumor growth rate was slower in the NIR‐PIT group using CD47‐Alexa Fluor 790 (CD47‐AF790), allowing for more sustained tumor control. The freshly isolated whole uterus specimens from EC patients were co‐incubated with CD47‐AF790, and a significantly enhanced contrast of NIR visible images of tumor tissue was observed, demonstrating high sensitivity and specificity (tumor‐to‐background ratio >5.05). Finally, under fluorescence microscopy, specific fluorescent signals are observed on tumor cells. In conclusion, accurate localization and excision of EC can be accomplished by employing CD47 optical molecular contrast agents with OMI technology. This method shows potential as a viable and promising approach for the precise diagnosis of EC.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125138","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}
Tiffany Rui Xuan Gan, Lester W. J. Tan, Mathias Egermark, Anh T. L. Truong, Kirthika Kumar, Shi‐Bei Tan, Sarah Tang, Agata Blasiak, Boon Cher Goh, Kee Yuan Ngiam, Dean Ho
BackgroundStandard‐of‐care for warfarin dose titration is conventionally based on physician‐guided drug dosing. This may lead to frequent deviations from target international normalized ratio (INR) due to inter‐ and intra‐patient variability and may potentially result in adverse events including recurrent thromboembolism and life‐threatening hemorrhage.ObjectivesWe aim to employ CURATE.AI, a small‐data, artificial intelligence‐derived platform that has been clinically validated in a range of indications, to optimize and guide warfarin dosing.Patients/methodsA personalized CURATE.AI response profile was generated using warfarin dose (inputs) and corresponding change in INR between two consecutive days (phenotypic outputs) and used to identify and recommend an optimal dose to achieve target treatment outcomes. CURATE.AI's predictive performance was then evaluated with a set of metrics that assessed both technical performance and clinical relevance.Results and conclusionsIn this retrospective study of 127 patients, CURATE.AI fared better in terms of Percentage Absolute Prediction Error and Percentage Prediction Error of 20% compared to other models in the literature. It also had negligible underprediction bias, potentially translating into lower bleeding risk. Modeled potential time in therapeutic range with CURATE.AI was not significantly different from physician‐guided dosing, so it is on‐par yet provides a systematic approach to warfarin dosing, easing the mental‐burden on guesswork by physicians.This study lays the groundwork for the prospective study of CURATE.AI as a clinical decision support system. CURATE.AI may facilitate the effective use of affordable warfarin with a well‐established safety profile, without the need for costly, new oral anticoagulants. This can have significant impact both on the individual and public health.
{"title":"AI‐assisted warfarin dose optimisation with CURATE.AI for clinical impact: Retrospective data analysis","authors":"Tiffany Rui Xuan Gan, Lester W. J. Tan, Mathias Egermark, Anh T. L. Truong, Kirthika Kumar, Shi‐Bei Tan, Sarah Tang, Agata Blasiak, Boon Cher Goh, Kee Yuan Ngiam, Dean Ho","doi":"10.1002/btm2.10757","DOIUrl":"https://doi.org/10.1002/btm2.10757","url":null,"abstract":"BackgroundStandard‐of‐care for warfarin dose titration is conventionally based on physician‐guided drug dosing. This may lead to frequent deviations from target international normalized ratio (INR) due to inter‐ and intra‐patient variability and may potentially result in adverse events including recurrent thromboembolism and life‐threatening hemorrhage.ObjectivesWe aim to employ CURATE.AI, a small‐data, artificial intelligence‐derived platform that has been clinically validated in a range of indications, to optimize and guide warfarin dosing.Patients/methodsA personalized CURATE.AI response profile was generated using warfarin dose (inputs) and corresponding change in INR between two consecutive days (phenotypic outputs) and used to identify and recommend an optimal dose to achieve target treatment outcomes. CURATE.AI's predictive performance was then evaluated with a set of metrics that assessed both technical performance and clinical relevance.Results and conclusionsIn this retrospective study of 127 patients, CURATE.AI fared better in terms of Percentage Absolute Prediction Error and Percentage Prediction Error of 20% compared to other models in the literature. It also had negligible underprediction bias, potentially translating into lower bleeding risk. Modeled potential time in therapeutic range with CURATE.AI was not significantly different from physician‐guided dosing, so it is on‐par yet provides a systematic approach to warfarin dosing, easing the mental‐burden on guesswork by physicians.This study lays the groundwork for the prospective study of CURATE.AI as a clinical decision support system. CURATE.AI may facilitate the effective use of affordable warfarin with a well‐established safety profile, without the need for costly, new oral anticoagulants. This can have significant impact both on the individual and public health.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"39 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083701","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}
Stem cell therapies have emerged as a transformative approach in modern medicine, with the potential to address and possibly cure a broad spectrum of diseases. These therapies utilize living stem cells that can perform complex biological functions not replicable by traditional drugs. Stem cell therapies have an expanding therapeutic landscape, with several products already approved and numerous clinical trials underway. Among the various stem cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are most widely studied. In this review, we provide a detailed analysis of the current clinical landscape of stem cell therapies. We review 27 stem cell products that have received regulatory approvals and discuss 800 ongoing clinical trials, with a focus on HSCs and MSCs. We also discuss the critical challenges to be addressed to facilitate the clinical translation of stem cell therapies.
{"title":"Stem cell therapies in the clinic","authors":"Shrinivas Acharya, Suyog Shaha, Michael Griffith Bibbey, Malini Mukherji, Zongmin Zhao, Samir Mitragotri","doi":"10.1002/btm2.70000","DOIUrl":"https://doi.org/10.1002/btm2.70000","url":null,"abstract":"Stem cell therapies have emerged as a transformative approach in modern medicine, with the potential to address and possibly cure a broad spectrum of diseases. These therapies utilize living stem cells that can perform complex biological functions not replicable by traditional drugs. Stem cell therapies have an expanding therapeutic landscape, with several products already approved and numerous clinical trials underway. Among the various stem cell types, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are most widely studied. In this review, we provide a detailed analysis of the current clinical landscape of stem cell therapies. We review 27 stem cell products that have received regulatory approvals and discuss 800 ongoing clinical trials, with a focus on HSCs and MSCs. We also discuss the critical challenges to be addressed to facilitate the clinical translation of stem cell therapies.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"26 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125137","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}
Cardiovascular diseases (CVDs) continue to drive global mortality rates, underscoring an urgent need for advancements in healthcare solutions. The development of point‐of‐care (POC) devices that provide rapid diagnostic services near patients has garnered substantial attention, especially as traditional healthcare systems face challenges such as delayed diagnoses, inadequate care, and rising medical costs. The advancement of machine learning techniques has sparked considerable interest in medical research and engineering, offering ways to enhance diagnostic accuracy and relevance. Improved data interoperability and seamless connectivity could enable real‐time, continuous monitoring of cardiovascular health. Recent breakthroughs in computing power and algorithmic design, particularly deep learning frameworks that emulate neural processes, have revolutionized POC devices for CVDs, enabling more frequent detection of abnormalities and automated, expert‐level diagnosis. However, challenges such as data privacy concerns and biases in dataset representation continue to hinder clinical integration. Despite these barriers, the translational potential of machine learning‐assisted POC devices presents significant opportunities for advancement in CVDs healthcare.
{"title":"Machine learning‐assisted point‐of‐care diagnostics for cardiovascular healthcare","authors":"Kaidong Wang, Bing Tan, Xinfei Wang, Shicheng Qiu, Qiuping Zhang, Shaolei Wang, Ying‐Tzu Yen, Nan Jing, Changming Liu, Xuxu Chen, Shichang Liu, Yan Yu","doi":"10.1002/btm2.70002","DOIUrl":"https://doi.org/10.1002/btm2.70002","url":null,"abstract":"Cardiovascular diseases (CVDs) continue to drive global mortality rates, underscoring an urgent need for advancements in healthcare solutions. The development of point‐of‐care (POC) devices that provide rapid diagnostic services near patients has garnered substantial attention, especially as traditional healthcare systems face challenges such as delayed diagnoses, inadequate care, and rising medical costs. The advancement of machine learning techniques has sparked considerable interest in medical research and engineering, offering ways to enhance diagnostic accuracy and relevance. Improved data interoperability and seamless connectivity could enable real‐time, continuous monitoring of cardiovascular health. Recent breakthroughs in computing power and algorithmic design, particularly deep learning frameworks that emulate neural processes, have revolutionized POC devices for CVDs, enabling more frequent detection of abnormalities and automated, expert‐level diagnosis. However, challenges such as data privacy concerns and biases in dataset representation continue to hinder clinical integration. Despite these barriers, the translational potential of machine learning‐assisted POC devices presents significant opportunities for advancement in CVDs healthcare.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083700","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}
Tiffany Hood, Pierre Springuel, Fern Slingsby, Viktor Sandner, Winfried Geis, Timo Schmidberger, Nicola Bevan, Quentin Vicard, Julia Hengst, Noushin Dianat, Qasim A. Rafiq
Chimeric antigen receptor T cell (CAR‐T) therapies show high remission rates for relapsed and refractory leukemia and lymphoma. However, manufacturing challenges hinder their commercial viability and patient accessibility. This study applied quality‐by‐design principles to identify perfusion critical process parameters for CAR‐T expansion in stirred tank bioreactors to maximize yields. A design of experiments in the Ambr® 250 High Throughput Perfusion small‐scale bioreactor revealed that earlier perfusion starts (48 h vs. 96 h post‐inoculation) and higher perfusion rates (1.0 VVD vs. 0.25 VVD) significantly increased cytotoxic CAR‐T cell yields without compromising critical quality attributes. Optimizing perfusion improved growth kinetics and yields across donor samples, achieving densities >21 × 106 cells/mL in 7 days, outperforming traditional fed‐batch and static flask cultures. This study underscores the importance of optimizing perfusion parameters to maximize CAR‐T yields and quality and highlights the utility of scale‐down models in reducing time, costs and risks associated with process development.
{"title":"Establishing a scalable perfusion strategy for the manufacture of CAR‐T cells in stirred‐tank bioreactors using a quality‐by‐design approach","authors":"Tiffany Hood, Pierre Springuel, Fern Slingsby, Viktor Sandner, Winfried Geis, Timo Schmidberger, Nicola Bevan, Quentin Vicard, Julia Hengst, Noushin Dianat, Qasim A. Rafiq","doi":"10.1002/btm2.10753","DOIUrl":"https://doi.org/10.1002/btm2.10753","url":null,"abstract":"Chimeric antigen receptor T cell (CAR‐T) therapies show high remission rates for relapsed and refractory leukemia and lymphoma. However, manufacturing challenges hinder their commercial viability and patient accessibility. This study applied quality‐by‐design principles to identify perfusion critical process parameters for CAR‐T expansion in stirred tank bioreactors to maximize yields. A design of experiments in the Ambr® 250 High Throughput Perfusion small‐scale bioreactor revealed that earlier perfusion starts (48 h vs. 96 h post‐inoculation) and higher perfusion rates (1.0 VVD vs. 0.25 VVD) significantly increased cytotoxic CAR‐T cell yields without compromising critical quality attributes. Optimizing perfusion improved growth kinetics and yields across donor samples, achieving densities >21 × 10<jats:sup>6</jats:sup> cells/mL in 7 days, outperforming traditional fed‐batch and static flask cultures. This study underscores the importance of optimizing perfusion parameters to maximize CAR‐T yields and quality and highlights the utility of scale‐down models in reducing time, costs and risks associated with process development.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"49 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056247","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}
Nayiri M. Kaissarian, Stephanie L. Sandefur, Arnab Ghosh, Upendra K. Katneni, Wendy Walton, Christopher C. Frye, Anton A. Komar, Chava Kimchi‐Sarfaty
Monoclonal antibodies (mAbs) are commonly used biologic therapeutics with a wide variety of clinical applications. During the development process, manufacturers consider different production parameters to improve protein yield and achieve appropriate quality of the product. Synonymous gene recoding is one of such attributes that is often considered and implemented to enhance protein expression. However, it has to be used with caution, as it may lead to protein misfolding and ER stress, which complicates efforts to manufacture the desired mAb. To investigate how changing mRNA sequence composition under different protein production parameters might affect the quality of recombinantly produced mAbs, we performed a comprehensive and systematic study assessing impact of synonymous gene recoding (commonly referred to as codon optimization) strategies in the context of varied cell culture parameters on product quality, biochemical and functional characteristics. We report the impact of these parameters on mAb glycosylation profiles, charge variant profile, aggregation, fragmentation, and mAb functional response from combinations of different production parameters. These results uncovered a complex interplay of sequence composition and manufacturing parameters and emphasize the importance of assessing changes to key quality attributes when optimizing mAb manufacturing, including the use of synonymous gene recoding.
{"title":"Investigating the impact of synonymous gene recoding on a recombinantly expressed monoclonal antibody under different process parameters","authors":"Nayiri M. Kaissarian, Stephanie L. Sandefur, Arnab Ghosh, Upendra K. Katneni, Wendy Walton, Christopher C. Frye, Anton A. Komar, Chava Kimchi‐Sarfaty","doi":"10.1002/btm2.10750","DOIUrl":"https://doi.org/10.1002/btm2.10750","url":null,"abstract":"Monoclonal antibodies (mAbs) are commonly used biologic therapeutics with a wide variety of clinical applications. During the development process, manufacturers consider different production parameters to improve protein yield and achieve appropriate quality of the product. Synonymous gene recoding is one of such attributes that is often considered and implemented to enhance protein expression. However, it has to be used with caution, as it may lead to protein misfolding and ER stress, which complicates efforts to manufacture the desired mAb. To investigate how changing mRNA sequence composition under different protein production parameters might affect the quality of recombinantly produced mAbs, we performed a comprehensive and systematic study assessing impact of synonymous gene recoding (commonly referred to as codon optimization) strategies in the context of varied cell culture parameters on product quality, biochemical and functional characteristics. We report the impact of these parameters on mAb glycosylation profiles, charge variant profile, aggregation, fragmentation, and mAb functional response from combinations of different production parameters. These results uncovered a complex interplay of sequence composition and manufacturing parameters and emphasize the importance of assessing changes to key quality attributes when optimizing mAb manufacturing, including the use of synonymous gene recoding.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"206 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054910","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}
Amir Hejri, Micah A. Chrenek, Nolan T. Goehring, Isabella I. Bowland, Richard Noel, Jiong Yan, John M. Nickerson, Mark R. Prausnitz
Novel therapeutics have emerged for treating neurodegenerative eye diseases but are limited by non‐optimal methods of ocular administration. Subretinal injection is the preferred method of delivery for retinal gene and stem‐cell therapies, but its invasive and complex surgical procedure is a major limiting factor in clinical investigations and practice. Here, we engineered a novel trans‐scleral injection technique to safely administer to the subretinal space in a simple, non‐surgical, and minimally invasive procedure. Subretinal injection using this technique in rodents and rabbits took <1 min per injection and did not require a surgical microscope. Extensive safety examinations in rats showed that the injection technique reliably administered into the subretinal space with no incidence of retinal perforation, little or no choroidal bleeding, and no evidence of retinal toxicity. We further found that repeated subretinal injection in the same eye, in rats, was well tolerated. The developed technique may enable non‐surgical subretinal injection without vitrectomy, potentially increasing safety, efficacy, and access to ocular therapies.
{"title":"A non‐surgical method for subretinal delivery by trans‐scleral microneedle injection","authors":"Amir Hejri, Micah A. Chrenek, Nolan T. Goehring, Isabella I. Bowland, Richard Noel, Jiong Yan, John M. Nickerson, Mark R. Prausnitz","doi":"10.1002/btm2.10755","DOIUrl":"https://doi.org/10.1002/btm2.10755","url":null,"abstract":"Novel therapeutics have emerged for treating neurodegenerative eye diseases but are limited by non‐optimal methods of ocular administration. Subretinal injection is the preferred method of delivery for retinal gene and stem‐cell therapies, but its invasive and complex surgical procedure is a major limiting factor in clinical investigations and practice. Here, we engineered a novel trans‐scleral injection technique to safely administer to the subretinal space in a simple, non‐surgical, and minimally invasive procedure. Subretinal injection using this technique in rodents and rabbits took <1 min per injection and did not require a surgical microscope. Extensive safety examinations in rats showed that the injection technique reliably administered into the subretinal space with no incidence of retinal perforation, little or no choroidal bleeding, and no evidence of retinal toxicity. We further found that repeated subretinal injection in the same eye, in rats, was well tolerated. The developed technique may enable non‐surgical subretinal injection without vitrectomy, potentially increasing safety, efficacy, and access to ocular therapies.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"59 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054907","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}
Autism spectrum disorder (ASD) is a group of developmental diseases, which still lacks effective treatments. Pregnant exposure of Valproic acid (VPA) is an important environmental risk factor for ASD, but it's long‐term effects on the development of human neural cells, particularly in vivo, and the corresponding treatment have yet been fully investigated. In the present study, we first made a humanized ASD mouse model by transplanting VPA‐pretreated human neural progenitor cells (hNPCs) into the cortex of immune‐deficient mice. In comparison with wild type and control chimeric mice, ASD chimeric mice (VPAhNPC mice) exhibit core syndromes of ASD, namely dramatic reduction of sociability, social interaction and social communication, and remarkable increase of stereotype repetitive behaviors and anxiety‐like behaviors. At cellular level, VPA‐pretreatment biased the differentiation of human excitatory neurons and their axonal projections in host brain. Chemogenetic suppression of human neuronal activity restored most behavior abnormalities of VPAhNPC mice. Further, specific modulation of human neurons by a newly developed transcranial magnetic stimulation (TMS) device which could precisely target hPNCs effectively recued the core syndromes of ASD‐like behaviors, restored the excitatory‐inhibitory neuronal differentiation and axonal projection, and reversed the expression of over half of the VPA‐affected genes. These data demonstrated that VPAhNPC mice could be used as a humanized model of ASD and that precisely targeted TMS could ameliorate the VPA‐biased human neuronal differentiation in vivo.
{"title":"Amelioration of biased neuronal differentiation in humanized mouse model of valproic acid‐induced autism by precisely targeted transcranial magnetic stimulation","authors":"Yilin Hou, Youyi Zhao, Dingding Yang, Tingwei Feng, Yuqian Li, Xiang Li, Zhou'an Liu, Xiao Yan, Hui Zhang, Shengxi Wu, Xufeng Liu, Yazhou Wang","doi":"10.1002/btm2.10748","DOIUrl":"https://doi.org/10.1002/btm2.10748","url":null,"abstract":"Autism spectrum disorder (ASD) is a group of developmental diseases, which still lacks effective treatments. Pregnant exposure of Valproic acid (VPA) is an important environmental risk factor for ASD, but it's long‐term effects on the development of human neural cells, particularly in vivo, and the corresponding treatment have yet been fully investigated. In the present study, we first made a humanized ASD mouse model by transplanting VPA‐pretreated human neural progenitor cells (hNPCs) into the cortex of immune‐deficient mice. In comparison with wild type and control chimeric mice, ASD chimeric mice (<jats:sup>VPA</jats:sup>hNPC mice) exhibit core syndromes of ASD, namely dramatic reduction of sociability, social interaction and social communication, and remarkable increase of stereotype repetitive behaviors and anxiety‐like behaviors. At cellular level, VPA‐pretreatment biased the differentiation of human excitatory neurons and their axonal projections in host brain. Chemogenetic suppression of human neuronal activity restored most behavior abnormalities of <jats:sup>VPA</jats:sup>hNPC mice. Further, specific modulation of human neurons by a newly developed transcranial magnetic stimulation (TMS) device which could precisely target hPNCs effectively recued the core syndromes of ASD‐like behaviors, restored the excitatory‐inhibitory neuronal differentiation and axonal projection, and reversed the expression of over half of the VPA‐affected genes. These data demonstrated that <jats:sup>VPA</jats:sup>hNPC mice could be used as a humanized model of ASD and that precisely targeted TMS could ameliorate the VPA‐biased human neuronal differentiation in vivo.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"38 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030923","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}
Spencer R. Marsh, Claire E. Beard, Robert G. Gourdie
Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >1012 EVs/mL) of nanovesicles extractable from a single liter of milk (>1014 EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non‐immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene‐editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large‐scale implementation, rigorous attention to safe, industrial‐scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.
{"title":"Milk extracellular vesicles: A burgeoning new presence in nutraceuticals and drug delivery","authors":"Spencer R. Marsh, Claire E. Beard, Robert G. Gourdie","doi":"10.1002/btm2.10756","DOIUrl":"https://doi.org/10.1002/btm2.10756","url":null,"abstract":"Mammalian milk, a multifaceted developmental biofluid, has attracted new attention due to its diverse constituents and their implications for health and disease. Among these constituents, extracellular vesicles (EVs) have emerged as focal points of investigation. EVs, including exosomes and small EVs, have demonstrated biological activity in preclinical studies—including reports of enhancement of cognition and neural complexity, promotion of gastrointestinal development, barrier function and microbiome richness, the bolstering of immune response, and facilitation of musculoskeletal maturation in neonates. The richness of milk as a source of EVs is noteworthy, with hundreds of milliliters (at >10<jats:sup>12</jats:sup> EVs/mL) of nanovesicles extractable from a single liter of milk (>10<jats:sup>14</jats:sup> EVs/starting liter of milk). Techniques such as tangential flow filtration hold promise for scalable production, potentially extending to thousands of liters. Together with the scale and increasing sophistication of the dairy industry, the abundance of EVs in milk underscores their commercial potential in various nutraceutical applications. Beyond natural bioactivity, milk EVs (mEVs) present intriguing possibilities as orally deliverable, non‐immunogenic pharmaceutical carriers, with burgeoning interest in their utilization for heart disease and cancer chemotherapy and as vectors for gene‐editing modules such as CrispR. This review synthesizes current knowledge on mEV biogenesis, characterization, isolation methodologies, and cargo contents. Moreover, it delves into the therapeutic potential of mEVs, both as inherently bioactive nanovesicles and as versatile platforms for drug delivery. As efforts progress toward large‐scale implementation, rigorous attention to safe, industrial‐scale production and robust assay development will be pivotal in harnessing the translational promise of small EVs from milk.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"25 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027199","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}
Christian R. Moya‐Garcia, Meghana Munipalle, Alain Pacis, Nader Sadeghi, Maryam Tabrizian, Nicole Y. K. Li‐Jessen
Tumor resistance to chemotherapy is a common cause of cancer recurrence in patients with head and neck squamous cell carcinoma. The goal of this study is to establish and characterize a chemoresistant laryngeal cancer cell model and test its potential utility for chemosensitizing therapy. At the genotypic level, RNA sequencing confirmed that the cells acquired putative resistance with upregulated docetaxel‐resistant (DR) genes (e.g., TUBB3, CYP24A1) and signaling pathways (e.g., PI3K/mTOR, autophagy). For phenotypic analysis, DR cells were co‐cultured with laryngeal fibroblasts in a 2‐channel microfluidic chip that mimics a hypoxic tumor core in vivo. A drug sensitivity test with a chemosensitizer, metformin (MTF), was performed on the laryngeal tumor‐on‐a‐chip. Compared to non‐treated controls, MTF‐primed cancer cells exhibit higher sensitivity to docetaxel (DTX), that is, cell death. Collectively, this resistance‐acquired cell model displayed presumed genotypic and phenotypic profiles of chemoresistance providing a viable option for testing new therapeutic strategies for restoring tumor sensitivity to DTX.
{"title":"Establishment of a chemoresistant laryngeal cancer cell model to study chemoresistance and chemosensitization responses via transcriptomic analysis and a tumor‐on‐a‐chip platform","authors":"Christian R. Moya‐Garcia, Meghana Munipalle, Alain Pacis, Nader Sadeghi, Maryam Tabrizian, Nicole Y. K. Li‐Jessen","doi":"10.1002/btm2.10741","DOIUrl":"https://doi.org/10.1002/btm2.10741","url":null,"abstract":"Tumor resistance to chemotherapy is a common cause of cancer recurrence in patients with head and neck squamous cell carcinoma. The goal of this study is to establish and characterize a chemoresistant laryngeal cancer cell model and test its potential utility for chemosensitizing therapy. At the genotypic level, RNA sequencing confirmed that the cells acquired putative resistance with upregulated docetaxel‐resistant (DR) genes (e.g., TUBB3, CYP24A1) and signaling pathways (e.g., PI3K/mTOR, autophagy). For phenotypic analysis, DR cells were co‐cultured with laryngeal fibroblasts in a 2‐channel microfluidic chip that mimics a hypoxic tumor core in vivo. A drug sensitivity test with a chemosensitizer, metformin (MTF), was performed on the laryngeal tumor‐on‐a‐chip. Compared to non‐treated controls, MTF‐primed cancer cells exhibit higher sensitivity to docetaxel (DTX), that is, cell death. Collectively, this resistance‐acquired cell model displayed presumed genotypic and phenotypic profiles of chemoresistance providing a viable option for testing new therapeutic strategies for restoring tumor sensitivity to DTX.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020087","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}
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