Diagnostic value of peripheral blood miR-296 combined with vascular endothelial growth factor B on the degree of coronary artery stenosis in patients with coronary heart disease.
作者: Lei Xu ; Ting Fu ; Yu Wang ; Ningning Ji
Coronary heart disease (CHD) is a disorder resulting from organic and functional coronary artery stenosis (CAS), thus causing reduced oxygenated blood in the heart. miRNAs are useful biomarkers in the diagnosis of atherosclerosis, CHD, and acute coronary syndrome. Vascular endothelial growth factor (VEGF) is closely related to CHD. This study explored the correlation of miR-296 and VEGF-B expression levels in peripheral blood with CAS degree in CHD patients.
Totally 220 CHD patients were enrolled and classified into mild-(71 cases)/moderate-(81 cases)/severe-CAS (68 cases) groups, with another 80 healthy cases as controls. The serum miR-296 and VEGF-B expression levels were detected using reverse transcription quantitative polymerase chain reaction. The correlation between miR-296 and CAS-related indexes was assessed via Pearson analysis. The binding relationship of miR-296 and VEGF-B was first predicted and their correlation was further analyzed via the Pearson method. The clinical diagnostic efficacy of miR-296 or VEGF-B on CAS degree was evaluated by the receiver operating characteristic curve.
Serum miR-296 was downregulated in CHD patients and was the lowest in patients with severe-CAS. miR-296 was negatively-correlated with high-sensitivity C-reactive protein, brain natriuretic peptide, and cardiac troponin I. miR-296 targeted VEGF-B. VEGF-B was upregulated in CHD patients and inversely-related to miR-296. Low expression of miR-296 and high expression of VEGF-B both had high clinical diagnostic values on CAS degree in CHD patients. miR-296 combined with VEGF-B increased the diagnostic value on CAS.
Low expression of miR-296 combined with high expression of its target VEGF-B predicts CAS degree in CHD patients.
Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model.
作者: Raquel da Cruz ; Odalys Dominguez ; Elaine Chen ; Alexandra Gonsiewski ; Apsra Nasir ; M Idalia Cruz ; Xiaojun Zou ; Susana Galli ; Kepher Makambi ; Matthew McCoy ; Marcel Schmidt ; Lu Jin ; Ivana Peran ; Sonia de Assis
DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. It is becoming clear that environmentally induced epigenetic inheritance occurs and that the progeny's traits can be shaped by parental environmental experiences. In humans, epidemiological studies have implicated environmental toxicants, such as the pesticide DDT, in intergenerational cancer development, including breast and childhood tumors. Here, we show that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility to developing aggressive tumors in mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males, or synthetic miRNA-10b, recapitulated the tumor phenotypes observed in DDT offspring. Mechanistically, miR-10b injection altered the transcriptional profile in early embryos with enrichment of genes associated with cell differentiation, tissue and immune system development. In adult DDT-derived progeny, transcriptional and protein analysis of mammary tumors revealed alterations in stromal and in immune system compartments. Our findings reveal a causal role for sperm RNAs in environmentally induced inheritance of cancer predisposition and, if confirmed in humans, this could help partially explain some of the "missing heritability" of breast, and other, malignancies.
2023-02-05·Advanced healthcare materials
Enhancing the Management of Metastatic Tumors by Robust Co-delivery of 5-fluorouracil/microRNA-10b inhibitor Using EGFR-targeted Nanovehicles.
作者: Di Wang ; Liwei Wang ; Liming Zheng ; Jiaxin Chen ; Wei Zhang ; Wei Zhou ; Xiaobo Yang ; Lifeng Jiang ; Xiaoqiang Jin ; Xiaohua Yu ; Xin Liu ; Heng Chen ; Jianbin Xu
Invasion and metastasis of colorectal cancer (CRC) are the leading causes of death of patients with CRC. 5-fluorouracil (5-FU) has been widely used in clinic practice as the basic chemotherapy drug for CRC. However, it is inefficient in inhibiting tumor metastasis. microRNA-10b (miR-10b) is uninvolved in regulating the growth of primary tumors; however, it could induce early tumor metastases and is a key regulator of chemotherapeutic resistance to 5-FU. We previously developed a multifunctional nanovehicle that can carry small molecule drugs not only through the hydrophobic pockets of conjugated β-cyclodextrin (β-CD) but also through electrostatic interaction between the conjugated peptides and cargo siRNA to target functional genes. In this study, we employed a nanovehicle, named GCD, with EGFR-targeted characteristics to simultaneously deliver chemotherapeutic (5-FU) and nucleotide (miR-10b inhibitor) drugs to distinct targets in CRC. Our data showed that the co-delivery of 5-FU and anti-miR-10b can be effectively applied to the targeted EGFR-overexpressed CRC, particularly inhibiting the metastasis of CRC in vitro and in vivo. Furthermore, we evaluated the therapeutic effect of this combination on a tumor xenograft model derived from patients with CRC. Taken together, this study may provide insights into the inhibition of tumor growth and metastasis simultaneously. This article is protected by copyright. All rights reserved.
Further Supporting TTX-MC138 Application in Metastatic CancerBOSTON, July 31, 2023 (GLOBE NEWSWIRE) -- TransCode Therapeutics, Inc. (NASDAQ: RNAZ), the RNA oncology company committed to more effectively treating cancer using RNA therapeutics, announced today positive results with its lead therapeutic candidate, TTX-MC138, in non-human primates (NHPs), showing that the therapeutic effectively engaged its target and showed favorable pharmacokinetics and tissue distribution. In the study, non-human primates (n = 4) were injected with a microdose of radiolabeled TTX-MC138 and imaged by positron emission tomography-magnetic resonance imaging (PET-MRI) to determine the pharmacokinetics and tissue distribution of the therapeutic. In addition, the pharmacodynamic activity of radiolabeled TTX-MC138 following a microdose injection was determined by measuring inhibition of the therapeutic target, miRNA-10b, using qRT-PCR. TTX-MC138 demonstrated a long circulation half-life and tissue distribution consistent with hepatic clearance. Importantly, even at a microdose, the therapeutic showed lasting activity and significantly inhibited its target, miRNA-10b, known to be a driver of metastatic progression in a number of cancers. Data from the NHP study were incorporated into a Drug Metabolism and Pharmacokinetics (DMPK) model, intended to model human exposure to TTX-MC38. The model predicted a long circulation and tissue distribution in humans, similar to results seen in preclinical studies of cancer in which complete regressions of metastatic disease were seen. TTX-MC138 consists of an iron oxide nanocarrier conjugated to a nucleic acid designed to inhibit the oncogenic RNA, microRNA-10b. MiRNA-10b is described as the master regulator of cancer progression in a number of advanced solid tumors. TransCode believes that TTX-MC138 could become a treatment for many of these cancers. Administration of TTX-MC138 has resulted in complete regression of metastatic disease in mouse models of pancreatic and breast cancer. In addition, TTX-MC138 was successfully delivered and demonstrated preliminary efficacy in a case study of spontaneous feline mammary carcinoma. TransCode’s Chief Technology Officer, Zdravka Medarova, commented, “The latest data obtained in non-human primates support the application of TTX-MC138 for the treatment of metastatic cancer. The wealth of pre-clinical evidence pointing towards miRNA-10b’s critical role in metastatic progression across most major cancer types suggests that being able to inhibit miRNA-10b in patients with advanced disease could have a dramatic impact on their disease.” “The success of the non-human primate study further de-risks our TTX-MC138 program. Our Phase 0 trial also involves a single microdose of radiolabeled TTX-MC138 followed by noninvasive PET-MRI. Given the similarities between humans and non-human primates relative to anatomy, physiology, and molecular biology, we anticipate comparable results in trial patients to those predicted by the DMPK model in the NHP studies,” added Michael Dudley, Chief Executive Officer of TransCode. The study was done in collaboration with Dr. Peter Caravan, co-director of the Institute for Innovation in Imaging (I3) at Massachusetts General Hospital and a Professor of Radiology at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital and Harvard Medical School. TransCode is enrolling patients in a first-in-human clinical trial with TTX-MC138 in patients with advanced solid cancers (https://clinicaltrials.gov/study/NCT05908773?spons=transcode&rank=1). In this clinical trial, up to 12 patients will be given a single microdose of radiolabeled TTX-MC138 followed by noninvasive PET-MRI. The trial is intended to quantify the amount of TTX-MC138 delivered to metastatic lesions and the pharmacokinetics of the therapeutic candidate in cancer patients. The trial could yield important data regarding TTX-MC138 delivery to clinical metastases that could inform dose selection, dosing frequency, and patient selection to expedite the path to success in later stage clinical trials. This trial is not intended to have therapeutic efficacy. About TransCode Therapeutics TransCode is an RNA oncology company created on the belief that cancer can be more effectively treated using RNA therapeutics. Using its iron oxide nanoparticle delivery platform, the Company has created a portfolio of drug candidates designed to target a variety of tumor types with the objective of significantly improving patient outcomes. The Company’s lead therapeutic candidate, TTX-MC138, is focused on treating metastatic cancer, which is believed to cause approximately 90% of all cancer deaths totaling over nine million per year worldwide. The Company believes that TTX-MC138 has the potential to dramatically improve clinical outcomes in a range of cancers, including breast, pancreatic, ovarian and colon cancer, glioblastomas and others. Another of the Company’s drug candidates, TTX-siPDL1, focuses on treating tumors by targeting a protein called Programmed death-ligand 1 (PD-L1). TransCode also has three cancer-agnostic programs: TTX-RIGA, an RNA–based agonist of the retinoic acid-inducible gene I designed to drive an immune response in the tumor microenvironment; TTX-CRISPR, a CRISPR/Cas9–based therapy platform for the repair or elimination of cancer-causing genes inside tumor cells; and TTX-mRNA, an mRNA-based platform for the development of cancer vaccines designed to activate cytotoxic immune responses against tumor cells. Forward-Looking Statements This release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements concerning the results of preclinical studies of TTX-MC138 in breast cancer and other tumor types, statements concerning expected clinical results of TransCode’s therapeutic candidates, statements concerning the results of RNA research, statements concerning the potential for treating cancer with RNA therapeutics, statements concerning the timing and outcome of expected regulatory filings and clinical trials, including the planned first-in-human study of TTX-MC138, and whether this study will demonstrate proof-of-mechanism, and statements concerning TransCode’s portfolio of drug candidates and TTX technology platform generally. Of note, a Phase 0 clinical trial is an exploratory study, conducted under an exploratory Investigational New Drug (eIND) application. Exploratory IND studies usually involve very limited human exposure to a therapeutic candidate to evaluate mechanism of action in order to inform potential clinical evaluation in future clinical studies, but otherwise have no therapeutic intent. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the risk associated with drug discovery and development; the risk that the results of our planned clinical trials will not be consistent with our pre-clinical studies or expectations; risks associated with the timing and outcome of TransCode’s planned regulatory submissions; risks associated with TransCode’s planned clinical trials for its product candidates; risks associated with obtaining, maintaining and protecting intellectual property; risks associated with TransCode’s ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties; the risk of competition from other companies developing products for similar uses; risks associated with TransCode’s financial condition and its need to obtain additional funding to support its business activities, including TransCode’s ability to continue as a going concern; risks associated with TransCode’s dependence on third parties; and risks associated with the COVID-19 coronavirus. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause TransCode’s actual results to differ from those contained in or implied by the forward-looking statements, see the section entitled “Risk Factors” in TransCode’s Annual Report on Form 10-K for the year ended December 31, 2022, as well as discussions of potential risks, uncertainties and other important factors in any subsequent TransCode filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release; TransCode undertakes no duty to update this information unless required by law. For more information, please contact: TransCode Therapeutics, Inc.Alan Freidman, VP Investor Relationsalan.firstname.lastname@example.org