Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMA...Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.展开更多
Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling ...Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.展开更多
Positron emission tomography （PET） is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes wh...Positron emission tomography （PET） is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically- engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.展开更多
A mathematical modeling of tumor therapy with oncolytic viruses is discussed. The model consists of two coupled, deterministic differential equations allowing for cell reproduction and death, and cell infection. The m...A mathematical modeling of tumor therapy with oncolytic viruses is discussed. The model consists of two coupled, deterministic differential equations allowing for cell reproduction and death, and cell infection. The model is one of the conceptual mathematical models of tumor growth that treat a tumor as a dynamic society of interacting cells. In this paper, we obtain an approximate analytical expression of uninfected and infected cell population by solving the non-linear equations using Homotopy analysis method (HAM). Furthermore, the results are compared with the numerical simulation of the problem using Matlab program. The obtained results are valid for the whole solution domain.展开更多
This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The mos...This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The most common primary brain tumors are gliomas, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Tumor portions were automatically segmented from 2D MR images using morphological filtering techniques. These segmented tumor slices were propagated and modeled with the software package. The 3D modeled tumor consists of gray level values of the original image with exact tumor boundary. Axial slices of FLAIR and T2 weighted images were used for extracting tumors. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process and is prone to error. These defects are overcome in this method. Authors verified the performance of our method on several sets of MRI scans. The 3D modeling was also done using segmented 2D slices with the help of medical software package called 3D DOCTOR for verification purposes. The results were validated with the ground truth models by the Radiologist.展开更多
Purpose: To generate parametric images of tumor hypoxia in a tumor-bearing rat model using voxel-based compartmental analysis of dynamic fluorine-18 labeled misonidazole (18F-FMISO) microPET? images, and to compare th...Purpose: To generate parametric images of tumor hypoxia in a tumor-bearing rat model using voxel-based compartmental analysis of dynamic fluorine-18 labeled misonidazole (18F-FMISO) microPET? images, and to compare the parametric images thus derived with static “late” 18F-FMISO microPET? images for the detection of tumor hypoxia. Materials and Methods: Nude rats bearing HT-29 colorectal carcinoma xenografts (≈1.5 - 2 cm in diameter) in the right hind limb were positioned in a custom-fabricated, animal-specific foam mold. Animals were injected via the tail vein with ≈55.5 MBq 18F-FMISO and continuously imaged for either 60 or 120 minutes, with additional late static images up to 3 hour post-injection. The raw list-mode data was reconstructed into 37 - 64 frames with earlier frames of shorter time durations (12 - 15 seconds) and later frames of longer durations (up to 300 seconds). Time activity curves (TACs) were generated over regions encompassing the tumor as well as an artery, the latter for use as an input function. A beta version of a compartmental modeling package (BioGuide?, Philips Healthcare) was used to generate parametric images of k3 and Ki, rate constants of entrapment and flux of 18F-FMISO, respectively. Results: Data for 7 HT-29 tumor xenografts were presented, 6 of which yielded clear areas of tumor hypoxia as defined by Ki/k3 maps. Importantly, intratumoral foci with high 18F-FMISO uptakes on the late images did not always exhibit high Ki/k3 values and may there- fore represent false-positives for radiobiologically significant hypoxia. Conclusions: This study attempts to quantify tumor hypoxia using compartmental analysis of dynamic 18F-FMISO PET images in rodent xenograft tumor models. The results demonstrate feasibility of the approach in small-animal imaging studies, and provide evidence for the possible unreliability of late-time static imaging of 18F-FMISO PET in identifying tumor hypoxia.展开更多
One of the best ways for better understanding of biological experiments is mathematical modeling. Modeling cancer is one of the complicated biological modeling that has uncertainty. Therefore, fuzzy models have studie...One of the best ways for better understanding of biological experiments is mathematical modeling. Modeling cancer is one of the complicated biological modeling that has uncertainty. Therefore, fuzzy models have studied because of their application in achievement uncertainty in modeling. Overall, the main purpose of this modeling is creating a new view of complex phenomena. In this paper, fuzzy differential equation model consisting of tumor, the immune system and normal cells has been studied. Model derived from a classical model DePillis in 2003, which some parameters from a clinical point of view can be described in the region. In this model, by considering fuzzy parameters from clinical point of view, the three-dimensional fuzzy tumor cells in terms of time and membership function are pictured and region of uncertainties are determined. To access the uncertainty area we use fuzzy differential inclusion method that is one of the including methods of solving differential equations. Also, different initial conditions on the model are inserted and the results of them are analyzed because tumor has different treatment in different initial conditions. Results show that fuzzy models in the best way justify what happens in the reality.展开更多
In an environment that is neither static nor in equilibrium, but is dynamic and changing, the kinetics of the reactions that cause the growth of a tumor, which depend on the state of the evolving environment, cannot b...In an environment that is neither static nor in equilibrium, but is dynamic and changing, the kinetics of the reactions that cause the growth of a tumor, which depend on the state of the evolving environment, cannot be parametrized in terms of constant rates. We propose a simple model for describing the growth on an untreated tumor in such environments, which is characterized by a minimal number of parameters and is generalizable to include the effects of various types of therapies. In the simplest version that we consider here, it consists of a linear equation with a time-dependent growth rate, which we interpret as the coupling of the system with a dynamic environment. A complete solution is given in terms of the integral of the growth rate. The essential features of the general solution are illustrated with a few examples, and comparison is made with the models that have been proposed to describe recent data.展开更多
文摘Atypical teratoid/rhabdoid tumor(ATRT)is a rare childhood malignancy that originates in the central nervous system.Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene SMARCB1.ATRT has no standard treatment,and a major limiting factor in therapeutic development is the lack of reliable ATRT models.We employed CRISPR/Cas9 gene-editing technology to knock out SMARCB1 and TP53 genes in human episomal induced pluripotent stem cells(Epi-iPSCs),followed by brief neural induction,to generate an ATRT-like model.The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers.High expression of OCT4 and NANOG in neurally induced knockout spheroids was comparable to that in two ATRT cell lines.Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids.Nucleophosmin,Osteopontin,and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids.In summary,the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels.Ribociclib,PTC-209,and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells.This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.
基金This work was supported by the National Natural Science Foundation of China(82173682,China)Shenzhen Science and Technology Program(JCYJ20210324133213037,China)Innovation Capability Support Program of Shaanxi(2021KJXX-92,China)。
文摘Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.
文摘Positron emission tomography （PET） is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically- engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.
文摘A mathematical modeling of tumor therapy with oncolytic viruses is discussed. The model consists of two coupled, deterministic differential equations allowing for cell reproduction and death, and cell infection. The model is one of the conceptual mathematical models of tumor growth that treat a tumor as a dynamic society of interacting cells. In this paper, we obtain an approximate analytical expression of uninfected and infected cell population by solving the non-linear equations using Homotopy analysis method (HAM). Furthermore, the results are compared with the numerical simulation of the problem using Matlab program. The obtained results are valid for the whole solution domain.
文摘This work presents an efficient method for volume rendering of glioma tumors from segmented 2D MRI Datasets with user interactive control, by replacing manual segmentation required in the state of art methods. The most common primary brain tumors are gliomas, evolving from the cerebral supportive cells. For clinical follow-up, the evaluation of the preoperative tumor volume is essential. Tumor portions were automatically segmented from 2D MR images using morphological filtering techniques. These segmented tumor slices were propagated and modeled with the software package. The 3D modeled tumor consists of gray level values of the original image with exact tumor boundary. Axial slices of FLAIR and T2 weighted images were used for extracting tumors. Volumetric assessment of tumor volume with manual segmentation of its outlines is a time-consuming process and is prone to error. These defects are overcome in this method. Authors verified the performance of our method on several sets of MRI scans. The 3D modeling was also done using segmented 2D slices with the help of medical software package called 3D DOCTOR for verification purposes. The results were validated with the ground truth models by the Radiologist.
文摘Purpose: To generate parametric images of tumor hypoxia in a tumor-bearing rat model using voxel-based compartmental analysis of dynamic fluorine-18 labeled misonidazole (18F-FMISO) microPET? images, and to compare the parametric images thus derived with static “late” 18F-FMISO microPET? images for the detection of tumor hypoxia. Materials and Methods: Nude rats bearing HT-29 colorectal carcinoma xenografts (≈1.5 - 2 cm in diameter) in the right hind limb were positioned in a custom-fabricated, animal-specific foam mold. Animals were injected via the tail vein with ≈55.5 MBq 18F-FMISO and continuously imaged for either 60 or 120 minutes, with additional late static images up to 3 hour post-injection. The raw list-mode data was reconstructed into 37 - 64 frames with earlier frames of shorter time durations (12 - 15 seconds) and later frames of longer durations (up to 300 seconds). Time activity curves (TACs) were generated over regions encompassing the tumor as well as an artery, the latter for use as an input function. A beta version of a compartmental modeling package (BioGuide?, Philips Healthcare) was used to generate parametric images of k3 and Ki, rate constants of entrapment and flux of 18F-FMISO, respectively. Results: Data for 7 HT-29 tumor xenografts were presented, 6 of which yielded clear areas of tumor hypoxia as defined by Ki/k3 maps. Importantly, intratumoral foci with high 18F-FMISO uptakes on the late images did not always exhibit high Ki/k3 values and may there- fore represent false-positives for radiobiologically significant hypoxia. Conclusions: This study attempts to quantify tumor hypoxia using compartmental analysis of dynamic 18F-FMISO PET images in rodent xenograft tumor models. The results demonstrate feasibility of the approach in small-animal imaging studies, and provide evidence for the possible unreliability of late-time static imaging of 18F-FMISO PET in identifying tumor hypoxia.
文摘One of the best ways for better understanding of biological experiments is mathematical modeling. Modeling cancer is one of the complicated biological modeling that has uncertainty. Therefore, fuzzy models have studied because of their application in achievement uncertainty in modeling. Overall, the main purpose of this modeling is creating a new view of complex phenomena. In this paper, fuzzy differential equation model consisting of tumor, the immune system and normal cells has been studied. Model derived from a classical model DePillis in 2003, which some parameters from a clinical point of view can be described in the region. In this model, by considering fuzzy parameters from clinical point of view, the three-dimensional fuzzy tumor cells in terms of time and membership function are pictured and region of uncertainties are determined. To access the uncertainty area we use fuzzy differential inclusion method that is one of the including methods of solving differential equations. Also, different initial conditions on the model are inserted and the results of them are analyzed because tumor has different treatment in different initial conditions. Results show that fuzzy models in the best way justify what happens in the reality.
文摘In an environment that is neither static nor in equilibrium, but is dynamic and changing, the kinetics of the reactions that cause the growth of a tumor, which depend on the state of the evolving environment, cannot be parametrized in terms of constant rates. We propose a simple model for describing the growth on an untreated tumor in such environments, which is characterized by a minimal number of parameters and is generalizable to include the effects of various types of therapies. In the simplest version that we consider here, it consists of a linear equation with a time-dependent growth rate, which we interpret as the coupling of the system with a dynamic environment. A complete solution is given in terms of the integral of the growth rate. The essential features of the general solution are illustrated with a few examples, and comparison is made with the models that have been proposed to describe recent data.
