Frontiers in molecular medicine最新文献

{"title":"Editorial: CAR T-cells: novel therapeutic approaches in the new era of cancer immunotherapy.","authors":"Alice Turdo, Costanza Maria Cristiani, Niels Schaft","doi":"10.3389/fmmed.2023.1239013","DOIUrl":"10.3389/fmmed.2023.1239013","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1239013"},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43868769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Biomarkers to evaluate rare diseases.","authors":"Bridget E Bax, Dario Pacitti","doi":"10.3389/fmmed.2023.1237089","DOIUrl":"10.3389/fmmed.2023.1237089","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1237089"},"PeriodicalIF":0.0,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49507578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between astrocytes and extracellular matrix structures contribute to neuroinflammation-associated epilepsy pathology.","authors":"AnnaLin M Woo, Harald Sontheimer","doi":"10.3389/fmmed.2023.1198021","DOIUrl":"10.3389/fmmed.2023.1198021","url":null,"abstract":"<p><p>Often considered the \"housekeeping\" cells of the brain, astrocytes have of late been rising to the forefront of neurodegenerative disorder research. Identified as crucial components of a healthy brain, it is undeniable that when astrocytes are dysfunctional, the entire brain is thrown into disarray. We offer epilepsy as a well-studied neurological disorder in which there is clear evidence of astrocyte contribution to diseases as evidenced across several different disease models, including mouse models of hippocampal sclerosis, trauma associated epilepsy, glioma-associated epilepsy, and beta-1 integrin knockout astrogliosis. In this review we suggest that astrocyte-driven neuroinflammation, which plays a large role in the pathology of epilepsy, is at least partially modulated by interactions with perineuronal nets (PNNs), highly structured formations of the extracellular matrix (ECM). These matrix structures affect synaptic placement, but also intrinsic neuronal properties such as membrane capacitance, as well as ion buffering in their immediate milieu all of which alters neuronal excitability. We propose that the interactions between PNNs and astrocytes contribute to the disease progression of epilepsy vis a vis neuroinflammation. Further investigation and alteration of these interactions to reduce the resultant neuroinflammation may serve as a potential therapeutic target that provides an alternative to the standard anti-seizure medications from which patients are so frequently unable to benefit.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1198021"},"PeriodicalIF":0.0,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44271033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle-derived exosomes and exercise in cancer prevention.","authors":"Daniela Vitucci, Domenico Martone, Andreina Alfieri, Pasqualina Buono","doi":"10.3389/fmmed.2023.1202190","DOIUrl":"10.3389/fmmed.2023.1202190","url":null,"abstract":"<p><p>There are a lot of evidences on the beneficial effects mediated by exercise on the prevention of not communicable diseases (NCDs) including different type of cancer. The production of circulating exerkines transported in exosomes represents a novel pathway activated by exercise. However, the biological mechanisms that could explain the role of exosomes in cancer prevention have been not fully elucidated. The aim of this mini-review is to provide an update on the biological mechanisms bringing the release of muscle-derived exosomes during exercise and cancer prevention.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1202190"},"PeriodicalIF":0.0,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44931369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energy-based generative models for target-specific drug discovery.","authors":"Junde Li, Collin Beaudoin, Swaroop Ghosh","doi":"10.3389/fmmed.2023.1160877","DOIUrl":"10.3389/fmmed.2023.1160877","url":null,"abstract":"<p><p>Drug targets are the main focus of drug discovery due to their key role in disease pathogenesis. Computational approaches are widely applied to drug development because of the increasing availability of biological molecular datasets. Popular generative approaches can create new drug molecules by learning the given molecule distributions. However, these approaches are mostly not for target-specific drug discovery. We developed an energy-based probabilistic model for computational target-specific drug discovery. Results show that our proposed TagMol can generate molecules with similar binding affinity scores as <i>real</i> molecules. GAT-based models showed faster and better learning relative to Graph Convolutional Network baseline models.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"3 1","pages":"1160877"},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44410354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase I-II study using DeltaRex-G, a tumor-targeted retrovector encoding a cyclin G1 inhibitor for metastatic carcinoma of breast.","authors":"Howard W Bruckner, Sant P Chawla, Nadezhda Omelchenko, Don A Brigham, Erlinda M Gordon","doi":"10.3389/fmmed.2023.1105680","DOIUrl":"10.3389/fmmed.2023.1105680","url":null,"abstract":"<p><p><b>Background:</b> Metastatic breast cancer is associated with a poor prognosis and therefore, innovative therapies are urgently needed. Here, we report on the results of a Phase I-II study using DeltaRex-G for chemotherapy resistant metastatic carcinoma of breast. <b>Patients and Methods:</b> <i>Endpoints:</i> Dose limiting toxicity; Antitumor activity. <i>Eligibility</i>: ≥18 years of age, pathologic diagnosis of breast carcinoma, adequate hematologic and organ function. <i>Treatment</i>: Dose escalation of DeltaRex-G 1-4 x 10¹¹cfu intravenously thrice weekly x 4 weeks with 2-week rest period. Treatment cycles repeated if there is ≤ Grade 1 toxicity until disease progression or unacceptable toxicity. <i>Safety:</i> NCI CTCAE v3 for adverse events reporting, vector related testing. <i>Efficacy:</i> RECIST v1.0, International PET criteria and Choi criteria for response, progression free and overall survival. <b>Results:</b> Twenty patients received escalating doses of DeltaRex-G from 1 × 10¹¹ cfu to 4 × 10¹¹ cfu thrice weekly for 4 weeks with a 2-week rest period. <i>Safety</i>: ≥ Grade 3 treatment-related adverse event: pruritic rash (<i>n</i> = 1), no dose limiting toxicity, no replication-competent retrovirus, nor vector-neutralizing antibodies detected. No vector DNA integration was observed in peripheral blood lymphocytes evaluated. <i>Efficacy</i>: by RECIST v1.0: 13 stable disease, 4 progressive disease; tumor control rate 76%; by PET and Choi Criteria: 3 partial responses, 11 stable disease, 3 progressive disease; tumor control rate 82%. Combined median progression free survival by RECIST v1.0, 3.0 months; combined median overall survival, 20 months; 1-year overall survival rate 83% for Dose Level IV. Biopsy of residual tumor in a participant showed abundant CD8⁺ killer T-cells and CD45⁺ macrophages suggesting an innate immune response. Two patients with pure bone metastases had >12-month progression free survival and overall survival and are alive 12 years from the start of DeltaRex-G therapy. These patients further received DeltaRex-G + DeltaVax for 6 months. <b>Conclusion:</b> Taken together, these data indicate that 1) DeltaRex-G has a distinctively high level of safety and exhibits anti-cancer activity, 2) PET/Choi provide a higher level of sensitivity in detecting early signs of tumor response to DeltaRex-G, 3) DeltaRex-G induced 12- year survival in 2 patients with pure bone metastases who subsequently received DeltaVax immunotherapy, and 4) DeltaRex-G may prove to be a biochemical and/or immune modulator when combined with other cancer therapy/immunotherapy.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1105680"},"PeriodicalIF":0.0,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46372698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into cancer stem cells targeting: CAR-T therapy and epigenetic drugs as new pillars in cancer treatment.","authors":"Veronica Veschi, Alice Turdo, Giorgio Stassi","doi":"10.3389/fmmed.2023.1120090","DOIUrl":"10.3389/fmmed.2023.1120090","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) represent the most aggressive subpopulation present in the tumor bulk retaining invasive capabilities, metastatic potential and high expression levels of drug efflux pumps responsible for therapy resistance. Cancer is still an incurable disease due to the inefficacy of standard regimens that spare this subpopulation. Selective targeting of CSCs is still an unmet need in cancer research field. Aberrant epigenetic reprogramming promotes the initiation and maintenance of CSCs, which are able to escape the immune system defense. Promising therapeutic approaches able to induce the selective inhibition of this stem-like small subset include immunotherapy alone or in combination with epigenetic compounds. These strategies are based on the specific expression of epitopes and/or epigenetic alterations present only in the CSC and not in the other cancer cells or normal cells. Thus, the combined approach utilizing CAR-T immunotherapy along with epigenetic probes may overcome the barriers of treatment ineffectiveness towards a more precision medicine approach in patients with known specific alterations of CSCs. In this perspective article we will shed new lights on the future applications of epi-immunotherapy in tumors enriched in CSCs, along with its potential side-effects, limitations and the development of therapy resistance.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1120090"},"PeriodicalIF":0.0,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48907548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomechanical and biochemical assessment of YB-1 expression in A375 melanoma cell line: Exploratory study.","authors":"Anna Cykowska, Ulf Krister Hofmann, Aadhya Tiwari, Corinna Kosnopfel, Rosa Riester, Marina Danalache","doi":"10.3389/fmmed.2023.1050487","DOIUrl":"10.3389/fmmed.2023.1050487","url":null,"abstract":"<p><p>Malignant melanoma is the most lethal form of skin cancer. Y-box binding protein 1 (YB-1) plays a prominent role in mediating metastatic behavior by promoting epithelial-to-mesenchymal transition (EMT). Migratory melanoma cells exhibit two major migration modes: elongated mesenchymal or rounded amoeboid. Using A375 melanoma cell line and the YB-1 knock-out model, we aimed to elucidate biochemical and biomechanical changes in migration signaling pathways in the context of melanoma metastases. We subjected A375 YB-1 knock-out and parental cells to atomic force microscopy (stiffness determination), immunolabelling, and proteome analysis. We found that YB-1 expressing cells were significantly stiffer compared to the corresponding YB-1 knock-out cell line. Our study demonstrated that the constitutive expression of YB-1 in A375 melanoma cell line appears to be closely related to known biomarkers of epithelial-to-mesenchymal transition, nestin, and vimentin, resulting in a stiffer phenotype, as well as a wide array of proteins involved in RNA, ribosomes, and spliceosomes. YB-1 knock-out resulted in nestin depletion and significantly lower vimentin expression, as well as global upregulation of proteins related to the cytoskeleton and migration. YB-1 knock-out cells demonstrated both morphological features and biochemical drivers of mesenchymal/ameboid migration. Melanoma is a highly plastic, adaptable, and aggressive tumor entity, capable of exhibiting characteristics of different migratory modes.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"3 1","pages":"1050487"},"PeriodicalIF":0.0,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41871372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene transfer and genome editing for familial hypercholesterolemia.","authors":"Cesare Canepari, Alessio Cantore","doi":"10.3389/fmmed.2023.1140997","DOIUrl":"10.3389/fmmed.2023.1140997","url":null,"abstract":"<p><p>Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by high circulating low-density lipoprotein (LDL) cholesterol. High circulating LDL cholesterol in FH is due to dysfunctional LDL receptors, and is mainly expressed by hepatocytes. Affected patients rapidly develop atherosclerosis, potentially leading to myocardial infarction and death within the third decade of life if left untreated. Here, we introduce the disease pathogenesis and available treatment options. We highlight different possible targets of therapeutic intervention. We then review different gene therapy strategies currently under development, which may become novel therapeutic options in the future, and discuss their advantages and disadvantages. Finally, we briefly outline the potential applications of some of these strategies for the more common acquired hypercholesterolemia disease.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1140997"},"PeriodicalIF":0.0,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46393260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy and genome editing for type I glycogen storage diseases.","authors":"Janice Y Chou, Brian C Mansfield","doi":"10.3389/fmmed.2023.1167091","DOIUrl":"10.3389/fmmed.2023.1167091","url":null,"abstract":"<p><p>Type I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT are functionally co-dependent. Together, the G6Pase-α/G6PT complex catalyzes the translocation of G6P from the cytoplasm into the endoplasmic reticulum lumen and its subsequent hydrolysis to glucose that is released into the blood to maintain euglycemia. Consequently, all GSD-I patients share a metabolic phenotype that includes a loss of glucose homeostasis and long-term risks of hepatocellular adenoma/carcinoma and renal disease. A rigorous dietary therapy has enabled GSD-I patients to maintain a normalized metabolic phenotype, but adherence is challenging. Moreover, dietary therapies do not address the underlying pathological processes, and long-term complications still occur in metabolically compensated patients. Animal models of GSD-Ia and GSD-Ib have delineated the disease biology and pathophysiology, and guided development of effective gene therapy strategies for both disorders. Preclinical studies of GSD-I have established that recombinant adeno-associated virus vector-mediated gene therapy for GSD-Ia and GSD-Ib are safe, and efficacious. A phase III clinical trial of rAAV-mediated gene augmentation therapy for GSD-Ia (NCT05139316) is in progress as of 2023. A phase I clinical trial of mRNA augmentation for GSD-Ia was initiated in 2022 (NCT05095727). Alternative genetic technologies for GSD-I therapies, such as gene editing, are also being examined for their potential to improve further long-term outcomes.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1167091"},"PeriodicalIF":0.0,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46794582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}