Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spin...Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.展开更多
The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA top...The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and preclinical development.展开更多
Acute gastric mucosal injury is a common disorder of the gastrointestinal tract and the search for new therapeutics is ongoing. The aim of this study is to update and expand the information related to the most widely ...Acute gastric mucosal injury is a common disorder of the gastrointestinal tract and the search for new therapeutics is ongoing. The aim of this study is to update and expand the information related to the most widely used rat models of acute gastric ulcer, the ethanol‐induced ulcer and the indomethacin‐induced ulcer. These two models are compared in terms of macroscopic and microscopic features. Experimentally, ethanol was given orally in a single dose and indomethacin was subcutaneously injected into male Wistar rats. After ulcerative challenges, the stomachs were removed and visually inspected. Anti‐ulcerative drugs were used to validate the models. Histological analysis of the stomachs determined the microscopic score. The methodology used for model evaluation applied to macroscopic and microscopic gastric lesions. With these methods it was possible to induce lesions in the gastric mucosa. Microscopic evaluation permitted assessment of the inflammatory and apoptotic impact in the mucosa not observable by macroscopic evaluation. Groups of animals were treated with two standard drugs: sulcralfate suspension or lansoprazole solution. Both drugs reduced macroscopic and microscopic lesions, particularly the hemorrhagic ones. Both models induced acute gastric mucosal injury and no single evaluation method can address all the aspects of the pathology of gastric lesions. As a complement to macroscopic evaluation, microscopy appears to be a relevant tool to selectively identify specific aspects of the development of mucosal injury, quantify the extent of lesions, and contribute to an appropriate interpretation of results. The score systems established here offer a reliable method for testing antiulcer drugs.展开更多
“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health pro...“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.展开更多
Background: Orthodontics is a dental specialty focusing on correcting dental irregularities and malocclusion. Knowledge and attitudes towards orthodontic treatment are crucial for promoting oral health and overall wel...Background: Orthodontics is a dental specialty focusing on correcting dental irregularities and malocclusion. Knowledge and attitudes towards orthodontic treatment are crucial for promoting oral health and overall well-being. Education and awareness play a vital role in ensuring optimal treatment outcomes and improving quality of life. Aim: This study aims to determine the knowledge and attitudes of Kwame Nkrumah University of Science and Technology (KNUST) pre-clinical dentistry students concerning orthodontic therapy. Methodology: This research is a quantitative descriptive cross-sectional study. The research used a non-random convenience sampling method to form the desired sample. For data collection, an interview-administered questionnaire was used over one month. The study set its sights on pre-clinical dental students in KNUST. A total of 150 questionnaires were printed to meet the sample size. Results: The results of the research showed that the knowledge level of KNUST pre-clinical students on orthodontic treatment and its nuances is quite limited. They however had a fair level of knowledge on the disease or ailment that orthodontic treatments solved (especially malocclusion). Their interest in orthodontic treatments on the other hand was quite significant, with a large number having interest in it. Conclusion: To conclude, KNUST pre-clinical students in Ghana although having a limited level of knowledge on orthodontic treatments have a keen interest in undergoing them regardless of the discomforts or the length of time.展开更多
A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in ...A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to accomplish.Herein,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug screening.The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo.As a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs.These PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors.Drugs,including cabazitaxel,oxaliplatin,and sorafenib,were tested in PDTOs.The sensitivity of PDTOs to these drugs differs between individuals.The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding patient.Therefore,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment.展开更多
Patient-derived tumor organoids(PDOs)currently represent important modeling tools in pre-clinical investigation of malignancies.Organoid cultures conserve the genetic and phenotypic characteristics of the original tum...Patient-derived tumor organoids(PDOs)currently represent important modeling tools in pre-clinical investigation of malignancies.Organoid cultures conserve the genetic and phenotypic characteristics of the original tumor and maintain its heterogeneity,allowing their application in many research fields.PDOs derived from colorectal cancer(CRC)have been used for genetic modeling to investigate the function of driver genes.Some researchers have been exploring the value of CRC PDOs in chemotherapy,targeted therapy,and radiotherapy response prediction.The successful generation of PDOs derived from CRC could deepen our understanding of CRC biology and provide novel tools for cancer modeling,for realizing precision medicine by assessing specimens from individual patients ex vivo.The present review discusses recently reported advances in CRC PDOs and the challenges they face as pre-clinical models in CRC research.展开更多
Improving the osteogenic activity of BMP-2 in vivo has significant clinical application value.In this research,we use a clinical gelatin sponge scaffold loaded with BMP-2 and dexamethasone(Dex)to evaluate the osteogen...Improving the osteogenic activity of BMP-2 in vivo has significant clinical application value.In this research,we use a clinical gelatin sponge scaffold loaded with BMP-2 and dexamethasone(Dex)to evaluate the osteogenic activity of dual drugs via ectopic osteogenesis in vivo.We also investigate the mechanism of osteogenesis induced by BMP-2 and Dex with C2C12,a multipotent muscle-derived progenitor cell.The results show that the gelatin scaffold with Dex and BMP-2 can significantly accelerate osteogenesis in vivo.It is indicated that compared with the BMP-2 or Dex alone,100nM of Dex can dramatically enhance the BMP-2-induced alkaline phosphatase activity(ALP),ALP mRNA expression and mineralization.Further studies show that 100nM of Dex can maintain the secondary structure of BMP-2 and facilitate recognition of BMP-2 with its receptors on the surface of C2C12 cells.We also find that in C2C12,Dex has no obvious effect on the BMP-2-induced Smad1/5/8 protein expression and the STAT3-dependent pathway,but Runx2-dependent pathway is involved in the Dex-stimulated osteoblast differentiation of BMP-2 both in vitro and in vivo.Based on these results,a potential mechanism model about the synergistic osteoinductive effect of Dex and BMP-2 in C2C12 cells via Runx2 activation is proposed.This may provide a theoretical basis for the pre-clinical application of Dex and BMP-2 for bone regeneration.展开更多
The applications of two-photon microscopy （TPM） on pre-clinical and clinical study of human cancer and diseases are reviewed in this paper. First, the principle of two-photon excitation （TPE） is introduced. The re...The applications of two-photon microscopy （TPM） on pre-clinical and clinical study of human cancer and diseases are reviewed in this paper. First, the principle of two-photon excitation （TPE） is introduced. The resulting advantages of TPM for imaging studies of animal models and human samples are then elaborated. Subsequently, the applications of TPM on various aspects of tumor studies, including tumor angiogenesis, invasion and metastasis, tumor microenvironment and metabolism are introduced. Furthermore, studies of TPM on clinical human skin biopsy and the development of two-photon microendoscopy are reviewed. Finally, potential future directions are discussed.展开更多
The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an a...The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an anti-angiogenic therapy[an antibody against the vascular endothelial growth factor(bevacizumab;Avastin)],resulting in recurrent tumors.Several recurrent GBM tumors are commonly resistant to either TMZ,radiation or bevacizumab,which contributes to the low survival rate for GBM patients.This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance.One of these therapeutic options is a small molecule called OKlahoma Nitrone 007(OKN-007),which was discovered to inhibit the transforming growth factor β1 pathway,reduce TMZ-resistance and enhance TMZ-sensitivity.OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients.Another novel target is ELTD1(epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1;alternatively known as ADGRL4,Adhesion G protein-coupled receptor L4),which we used a monoclonal antibody against,where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model.Notch 1 is known to be associated with chemoresistance in GBM.Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway,nuclear factor-κB,the hepatocyte/scatter factor(c-MET),the epidermal growth factor receptor,and the tumor microenvironment.展开更多
Currently, there is an unmet need for treatments promoting post-stroke functional recovery.The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy(start...Currently, there is an unmet need for treatments promoting post-stroke functional recovery.The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy(starting on post-stroke day 5), coupled with limited physical exercise(2 hours daily voluntary wheel running;post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic stroke.These drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to stroke.The predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests.Additionally, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct volumes.Both sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after stroke.However, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent drug.This was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental groups.If further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity physiotherapy.Furthermore, in light of the recently completed Assessment o F Fluoxet INe In s Troke recover Y(AFFINITY) and Efficacy o F Fluoxetine-a randomis Ed Controlled Trial in Stroke(EFFECTS) trials, our observations call for newly designed studies where fluoxetine or atomoxetine pharmacotherapy is evaluated in combination w展开更多
MS is a severe progressive autoimmune disease with slight short-term relapses in its course. Autoagression against vulnerable myelin-associated Ags results in multiple lesions throughout the CNS. Abnormal responses ag...MS is a severe progressive autoimmune disease with slight short-term relapses in its course. Autoagression against vulnerable myelin-associated Ags results in multiple lesions throughout the CNS. Abnormal responses against nervous issues are mainly affected by cell-mediated and humoral immunity. The first one plays a key role in the restructuring of myelin, while the last one is a biomarker of MS and does not participate in the gradation of the disease. Wide-scale autoimmune attack towards nervous tissues leads to a stepwise demyelination with concomitant release of myelin Ags (epitope spreading), formation of Abs and, consequently, systematization of pro-inflammatory responses. Monitoring of antimyelin-antibodies (Abs: OSP, MOBP, BMP, MOG, PLP) in peripheral blood and cerebrospinal fluid (CSF) is just a brick for making the preclinical diagnosis of MS and timely implementation of predictive measures and preventive treatment. Major autoAbs and their target antigens are discussed in this chapter with a special emphasize on the possibility of their impact for identification of pre-morbid stages and differential diagnosis of MS.展开更多
Surgical resection,chemotherapy,and radiation are the standard therapeutic modalities for treating cancer.These approaches are intended to target the more mature and rapidly dividing cancer cells.However,they spare th...Surgical resection,chemotherapy,and radiation are the standard therapeutic modalities for treating cancer.These approaches are intended to target the more mature and rapidly dividing cancer cells.However,they spare the relatively quiescent and intrinsically resistant cancer stem cells(CSCs)subpopulation residing within the tumor tissue.Thus,a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs'resistant features.Based on their unique expression profile,the identification,isolation,and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence.Yet,targeting CSCs is limited mainly by the irrelevance of the utilized cancer models.A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids(PDOs)as a tool for establishing pre-clinical tumor models.Herein,we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors.Additionally,we highlight the advantage and relevance of the threedimensional PDOs culture model as a platform for modeling cancer,evaluating the efficacy of CSC-based therapeutics,and predicting drug response in cancer patients.展开更多
Stroke management exerts insurmountable societal and economic burden on the patient as well as their caregivers. In the year 2010 alone, the direct and indirect costs of stroke care amounted to 36.5 billion dollars （...Stroke management exerts insurmountable societal and economic burden on the patient as well as their caregivers. In the year 2010 alone, the direct and indirect costs of stroke care amounted to 36.5 billion dollars （Go et al., 2014）. Despite concentrated efforts to develop a safe, effective drug for stroke, we have not discovered one since the introduction of recombinant tissue plasminogen activator （rtPA）--the standalone FDA-approved therapy for stroke. While rtPA is highly effective, it needs to be given within 3-4.5 hours of the onset of stroke symptoms （Zivin, 2009）. This is often complicated by the delay in the commencement of treatment due to preliminary inclusion parameters that are required to be ascertained before rtPA administration.展开更多
Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by t...Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by time-limited interventions such as traditional surgical resection,radiation therapy,and chemotherapy is short-lived.A new form of anti-cancer therapy called therapeutic alternating electric fields(AEFs)or tumor treating fields(TTFields)has been shown,either by itself or in combination with chemotherapy,to have anti-cancer effects that translate to improved survival outcomes in patients.Although the pre-clinical and clinical data are promising,the mechanisms of TTFields are not fully elucidated.Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation.The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies(both in vitro and in vivo).An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies,to further improve survival outcomes in patients with solid organ cancers.展开更多
文摘Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.
基金supported by faculty development program funding from University of Tennessee Health Science Center (UTHSC) College of Pharmacy to Kirk E. HevenerChimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, USA (supported by U.S. National Institute of General Medical Sciences (NIGMS) P41GM103311)
文摘The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and preclinical development.
基金Agencia de Inovacao, Grant/Award Number: XILOGASTRO/AdI/2003Fundacao para a Ciencia e Tecnologia, Grant/Award Number: UID/DTP/04138/2013+1 种基金FAIR, Grant/Award Number: FAIR-PI97 3811JABA Recordati
文摘Acute gastric mucosal injury is a common disorder of the gastrointestinal tract and the search for new therapeutics is ongoing. The aim of this study is to update and expand the information related to the most widely used rat models of acute gastric ulcer, the ethanol‐induced ulcer and the indomethacin‐induced ulcer. These two models are compared in terms of macroscopic and microscopic features. Experimentally, ethanol was given orally in a single dose and indomethacin was subcutaneously injected into male Wistar rats. After ulcerative challenges, the stomachs were removed and visually inspected. Anti‐ulcerative drugs were used to validate the models. Histological analysis of the stomachs determined the microscopic score. The methodology used for model evaluation applied to macroscopic and microscopic gastric lesions. With these methods it was possible to induce lesions in the gastric mucosa. Microscopic evaluation permitted assessment of the inflammatory and apoptotic impact in the mucosa not observable by macroscopic evaluation. Groups of animals were treated with two standard drugs: sulcralfate suspension or lansoprazole solution. Both drugs reduced macroscopic and microscopic lesions, particularly the hemorrhagic ones. Both models induced acute gastric mucosal injury and no single evaluation method can address all the aspects of the pathology of gastric lesions. As a complement to macroscopic evaluation, microscopy appears to be a relevant tool to selectively identify specific aspects of the development of mucosal injury, quantify the extent of lesions, and contribute to an appropriate interpretation of results. The score systems established here offer a reliable method for testing antiulcer drugs.
基金supported by the Key Research and Development Project of Hubei Province of China,2022BCA028(to HC)。
文摘“Peripheral nerve injury”refers to damage or trauma affecting nerves outside the brain and spinal cord.Peripheral nerve injury results in movements or sensation impairments,and represents a serious public health problem.Although severed peripheral nerves have been effectively joined and various therapies have been offered,recovery of sensory or motor functions remains limited,and efficacious therapies for complete repair of a nerve injury remain elusive.The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function.Mesenchymal stem cells,as large living cells responsive to the environment,secrete various factors and exosomes.The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins,microRNA,and messenger RNA derived from parent mesenchymal stem cells.Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function,offering solutions to changes associated with cell-based therapies.Despite ongoing investigations,mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage.A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation.This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury,exploring the underlying mechanisms.Subsequently,it provides an overview of the current status of mesenchymal stem cell and exosomebased therapies in clinical trials,followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes.Finally,the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes,offering potential solutions and guiding future directions.
文摘Background: Orthodontics is a dental specialty focusing on correcting dental irregularities and malocclusion. Knowledge and attitudes towards orthodontic treatment are crucial for promoting oral health and overall well-being. Education and awareness play a vital role in ensuring optimal treatment outcomes and improving quality of life. Aim: This study aims to determine the knowledge and attitudes of Kwame Nkrumah University of Science and Technology (KNUST) pre-clinical dentistry students concerning orthodontic therapy. Methodology: This research is a quantitative descriptive cross-sectional study. The research used a non-random convenience sampling method to form the desired sample. For data collection, an interview-administered questionnaire was used over one month. The study set its sights on pre-clinical dental students in KNUST. A total of 150 questionnaires were printed to meet the sample size. Results: The results of the research showed that the knowledge level of KNUST pre-clinical students on orthodontic treatment and its nuances is quite limited. They however had a fair level of knowledge on the disease or ailment that orthodontic treatments solved (especially malocclusion). Their interest in orthodontic treatments on the other hand was quite significant, with a large number having interest in it. Conclusion: To conclude, KNUST pre-clinical students in Ghana although having a limited level of knowledge on orthodontic treatments have a keen interest in undergoing them regardless of the discomforts or the length of time.
基金the Key Research and Development Plan of Zhejiang Province(No.2020C04003)the National Natural Science Foundation of China(No.82070652,No.81870434,NO.T2125009,NO.92048302,NO.11822207 and NO.12102388)+1 种基金the Natural Science Foundation of Zhejiang Province(NO.LR18A020001)the Research Project of Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022007B).
文摘A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening.The economical and high-efficiency simulation of the liver tumor microenvironment(TME)in a drug-screening model has high value yet challenging to accomplish.Herein,we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters,and the culture of patient-derived tumor organoids(PDTOs)for personalized pre-clinical drug screening.The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo.As a result,18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs.These PDTOs,along with hepatocyte growth factor(HGF)of non-cellular components,preserve stromal cells,including cancer-associated fibroblasts(CAFs)and vascular endothelial cells(VECs).They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors.Drugs,including cabazitaxel,oxaliplatin,and sorafenib,were tested in PDTOs.The sensitivity of PDTOs to these drugs differs between individuals.The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging(MRI)and biochemical tests after oxaliplatin clinical treatment of the corresponding patient.Therefore,this approach is promising for economical,accurate,and high-throughput drug screening for personalized treatment.
基金Supported by a grant from the National Natural Science Foundation(No.81773214).
文摘Patient-derived tumor organoids(PDOs)currently represent important modeling tools in pre-clinical investigation of malignancies.Organoid cultures conserve the genetic and phenotypic characteristics of the original tumor and maintain its heterogeneity,allowing their application in many research fields.PDOs derived from colorectal cancer(CRC)have been used for genetic modeling to investigate the function of driver genes.Some researchers have been exploring the value of CRC PDOs in chemotherapy,targeted therapy,and radiotherapy response prediction.The successful generation of PDOs derived from CRC could deepen our understanding of CRC biology and provide novel tools for cancer modeling,for realizing precision medicine by assessing specimens from individual patients ex vivo.The present review discusses recently reported advances in CRC PDOs and the challenges they face as pre-clinical models in CRC research.
基金supported by the Natural Science Foundation of China for Innovative Research Groups(No.51621002)the National Natural Science Foundation of China(No.32071337)+2 种基金Shanghai Pujiang Program(20PJ1402600)the 111 Project(B14018)supported by‘the Fundamental Research Funds for the Central Universities’.
文摘Improving the osteogenic activity of BMP-2 in vivo has significant clinical application value.In this research,we use a clinical gelatin sponge scaffold loaded with BMP-2 and dexamethasone(Dex)to evaluate the osteogenic activity of dual drugs via ectopic osteogenesis in vivo.We also investigate the mechanism of osteogenesis induced by BMP-2 and Dex with C2C12,a multipotent muscle-derived progenitor cell.The results show that the gelatin scaffold with Dex and BMP-2 can significantly accelerate osteogenesis in vivo.It is indicated that compared with the BMP-2 or Dex alone,100nM of Dex can dramatically enhance the BMP-2-induced alkaline phosphatase activity(ALP),ALP mRNA expression and mineralization.Further studies show that 100nM of Dex can maintain the secondary structure of BMP-2 and facilitate recognition of BMP-2 with its receptors on the surface of C2C12 cells.We also find that in C2C12,Dex has no obvious effect on the BMP-2-induced Smad1/5/8 protein expression and the STAT3-dependent pathway,but Runx2-dependent pathway is involved in the Dex-stimulated osteoblast differentiation of BMP-2 both in vitro and in vivo.Based on these results,a potential mechanism model about the synergistic osteoinductive effect of Dex and BMP-2 in C2C12 cells via Runx2 activation is proposed.This may provide a theoretical basis for the pre-clinical application of Dex and BMP-2 for bone regeneration.
文摘The applications of two-photon microscopy （TPM） on pre-clinical and clinical study of human cancer and diseases are reviewed in this paper. First, the principle of two-photon excitation （TPE） is introduced. The resulting advantages of TPM for imaging studies of animal models and human samples are then elaborated. Subsequently, the applications of TPM on various aspects of tumor studies, including tumor angiogenesis, invasion and metastasis, tumor microenvironment and metabolism are introduced. Furthermore, studies of TPM on clinical human skin biopsy and the development of two-photon microendoscopy are reviewed. Finally, potential future directions are discussed.
基金This work was supported by the Oklahoma Medical Research Foundation,and Oblato,Inc.,as reported in published manuscripts.
文摘The poor prognosis of glioblastoma multiforme(GBM)patients is in part due to resistance to current standard-of-care treatments including chemotherapy[predominantly temozolomide(TMZ;Temodar)],radiation therapy and an anti-angiogenic therapy[an antibody against the vascular endothelial growth factor(bevacizumab;Avastin)],resulting in recurrent tumors.Several recurrent GBM tumors are commonly resistant to either TMZ,radiation or bevacizumab,which contributes to the low survival rate for GBM patients.This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance.One of these therapeutic options is a small molecule called OKlahoma Nitrone 007(OKN-007),which was discovered to inhibit the transforming growth factor β1 pathway,reduce TMZ-resistance and enhance TMZ-sensitivity.OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients.Another novel target is ELTD1(epidermal growth factor,latrophilin and seven transmembrane domain-containing protein 1;alternatively known as ADGRL4,Adhesion G protein-coupled receptor L4),which we used a monoclonal antibody against,where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model.Notch 1 is known to be associated with chemoresistance in GBM.Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway,nuclear factor-κB,the hepatocyte/scatter factor(c-MET),the epidermal growth factor receptor,and the tumor microenvironment.
基金partly supported by a National Institutes of Health Research Grant to VTK (1R01NS106879)。
文摘Currently, there is an unmet need for treatments promoting post-stroke functional recovery.The aim of this study was to evaluate and compare the dose-dependent effect of delayed atomoxetine or fluoxetine therapy(starting on post-stroke day 5), coupled with limited physical exercise(2 hours daily voluntary wheel running;post-stroke days 9 to 42), on motor recovery of adult male mice after photothrombotic stroke.These drugs are selective norepinephrine or serotonin reuptake inhibitors indicated for disorders unrelated to stroke.The predetermined primary end-point for this study was motor function measured in two tasks of spontaneous motor behaviors in grid-walking and cylinder tests.Additionally, we quantified the running distance and speed throughout the study, the number of parvalbumin-positive neurons in the medial agranular cortex and infarct volumes.Both sensorimotor tests revealed that neither limited physical exercise nor a drug treatment alone significantly facilitated motor recovery in mice after stroke.However, combination of physical exercise with either of the drugs promoted restoration of motor function by day 42 post-stroke, with atomoxetine being a more potent drug.This was accompanied by a significant decrease in parvalbumin-positive inhibitory interneurons in the ipsilateral medial agranular cortex of mice with recovering motor function, while infarct volumes were comparable among experimental groups.If further validated in larger studies, our observations suggest that add-on atomoxetine or fluoxetine therapy coupled with limited, structured physical rehabilitation could offer therapeutic modality for stroke survivors who have difficulty to engage in early, high-intensity physiotherapy.Furthermore, in light of the recently completed Assessment o F Fluoxet INe In s Troke recover Y(AFFINITY) and Efficacy o F Fluoxetine-a randomis Ed Controlled Trial in Stroke(EFFECTS) trials, our observations call for newly designed studies where fluoxetine or atomoxetine pharmacotherapy is evaluated in combination w
文摘MS is a severe progressive autoimmune disease with slight short-term relapses in its course. Autoagression against vulnerable myelin-associated Ags results in multiple lesions throughout the CNS. Abnormal responses against nervous issues are mainly affected by cell-mediated and humoral immunity. The first one plays a key role in the restructuring of myelin, while the last one is a biomarker of MS and does not participate in the gradation of the disease. Wide-scale autoimmune attack towards nervous tissues leads to a stepwise demyelination with concomitant release of myelin Ags (epitope spreading), formation of Abs and, consequently, systematization of pro-inflammatory responses. Monitoring of antimyelin-antibodies (Abs: OSP, MOBP, BMP, MOG, PLP) in peripheral blood and cerebrospinal fluid (CSF) is just a brick for making the preclinical diagnosis of MS and timely implementation of predictive measures and preventive treatment. Major autoAbs and their target antigens are discussed in this chapter with a special emphasize on the possibility of their impact for identification of pre-morbid stages and differential diagnosis of MS.
文摘Surgical resection,chemotherapy,and radiation are the standard therapeutic modalities for treating cancer.These approaches are intended to target the more mature and rapidly dividing cancer cells.However,they spare the relatively quiescent and intrinsically resistant cancer stem cells(CSCs)subpopulation residing within the tumor tissue.Thus,a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs'resistant features.Based on their unique expression profile,the identification,isolation,and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence.Yet,targeting CSCs is limited mainly by the irrelevance of the utilized cancer models.A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids(PDOs)as a tool for establishing pre-clinical tumor models.Herein,we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors.Additionally,we highlight the advantage and relevance of the threedimensional PDOs culture model as a platform for modeling cancer,evaluating the efficacy of CSC-based therapeutics,and predicting drug response in cancer patients.
文摘Stroke management exerts insurmountable societal and economic burden on the patient as well as their caregivers. In the year 2010 alone, the direct and indirect costs of stroke care amounted to 36.5 billion dollars （Go et al., 2014）. Despite concentrated efforts to develop a safe, effective drug for stroke, we have not discovered one since the introduction of recombinant tissue plasminogen activator （rtPA）--the standalone FDA-approved therapy for stroke. While rtPA is highly effective, it needs to be given within 3-4.5 hours of the onset of stroke symptoms （Zivin, 2009）. This is often complicated by the delay in the commencement of treatment due to preliminary inclusion parameters that are required to be ascertained before rtPA administration.
基金supported by the McNair Medical Institute at The Robert and Janice McNair Foundation.
文摘Despite improved survival outcomes across many cancer types,the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer.Invariably in these cancers,the control achieved by time-limited interventions such as traditional surgical resection,radiation therapy,and chemotherapy is short-lived.A new form of anti-cancer therapy called therapeutic alternating electric fields(AEFs)or tumor treating fields(TTFields)has been shown,either by itself or in combination with chemotherapy,to have anti-cancer effects that translate to improved survival outcomes in patients.Although the pre-clinical and clinical data are promising,the mechanisms of TTFields are not fully elucidated.Many investigations are underway to better understand how and why TTFields is able to selectively kill cancer cells and impede their proliferation.The purpose of this review is to summarize and discuss the reported mechanisms of action of TTFields from pre-clinical studies(both in vitro and in vivo).An improved understanding of how TTFields works will guide strategies focused on the timing and combination of TTFields with other therapies,to further improve survival outcomes in patients with solid organ cancers.
