S. Jafri, Elizabeth A Burke, D. Adams, C. Evans, D. Bulas, S. Weinerman, Kristen S. Pan, M. Collins, T. Markello, G. Vezina, W. Gahl, C. Toro
The low-density lipoprotein receptor-related protein 5 gene (LRP5), which encodes a coreceptor within the canonical Wnt signaling pathway, plays a crucial role in bone mass regulation and has been associated with several bone disorders. Autosomal dominant osteopetrosis type I (ADO type I, OMIM 607634) is a rare disease caused by heterozygous, gain-of-function mutations in LRP5. Here we describe a 44-year-old female who presented with thickened calvarium, elevated bone density, torus palatinus, mandibular exostoses, enlarged mandible, and disabling headaches and bone pain. Exome sequencing revealed a previously reported heterozygous missense variant in the LRP5 gene (p.A242T). Post-diagnosis cranial vault volume measurement by computed tomography 3D reconstruction demonstrated decreasing intracranial volume over time. Off-label use of leuprolide acetate was associated with apparent stabilization of skull mineralization. This report documents a severe example of ADO type I and provides anecdotal evidence of the utility of therapy in need of formal evaluation.
{"title":"Potential therapeutic response in a severe case of autosomal dominant osteopetrosis type I","authors":"S. Jafri, Elizabeth A Burke, D. Adams, C. Evans, D. Bulas, S. Weinerman, Kristen S. Pan, M. Collins, T. Markello, G. Vezina, W. Gahl, C. Toro","doi":"10.20517/jtgg.2021.63","DOIUrl":"https://doi.org/10.20517/jtgg.2021.63","url":null,"abstract":"The low-density lipoprotein receptor-related protein 5 gene (LRP5), which encodes a coreceptor within the canonical Wnt signaling pathway, plays a crucial role in bone mass regulation and has been associated with several bone disorders. Autosomal dominant osteopetrosis type I (ADO type I, OMIM 607634) is a rare disease caused by heterozygous, gain-of-function mutations in LRP5. Here we describe a 44-year-old female who presented with thickened calvarium, elevated bone density, torus palatinus, mandibular exostoses, enlarged mandible, and disabling headaches and bone pain. Exome sequencing revealed a previously reported heterozygous missense variant in the LRP5 gene (p.A242T). Post-diagnosis cranial vault volume measurement by computed tomography 3D reconstruction demonstrated decreasing intracranial volume over time. Off-label use of leuprolide acetate was associated with apparent stabilization of skull mineralization. This report documents a severe example of ADO type I and provides anecdotal evidence of the utility of therapy in need of formal evaluation.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Chu, J. Fung, A. Tong, Sin Man Chow, Kelvin Y. K. Chan, Kit San Yeung, H. Lo, B. Chung
Genomic medicine and precision medicine initiatives have taken centre stage in scientific, clinical, as well as health economics and utility research on the global scene for the past decade. It is clear the important role genomic advancement has played in enhancing diagnostic rate, streamlining personalised treatment, and improving efficacy of the overall clinical management of undiagnosed, rare, and common diseases for humankind. The Hong Kong Genome Institute (HKGI) was established in May 2020 within the Food and Health Bureau, Hong Kong Special Administrative Region, to integrate genomic medicine into mainstream healthcare. The main goals of setting up HKGI are to (1) improve the diagnostic rate and future care for individuals affected by undiagnosed diseases and hereditary cancers using whole genome sequencing; (2) advance research in genomic science; (3) nurture talents in genomic medicine; and (4) enhance public genomic literacy and overall engagement through the launching of the Hong Kong Genome Project (HKGP). In this paper, we review the current landscape and specific challenges encountered during the construction of the infrastructure and implementation of the pilot phase of HKGP. Through reviewing what has been achieved and established to date, and the potentials and prospects that have emerged in the process, this paper will provide insights into planning the main phase of HKGP, and considerations for our international counterparts when building similar projects.
{"title":"Potentials and challenges of launching the pilot phase of Hong Kong Genome Project","authors":"A. Chu, J. Fung, A. Tong, Sin Man Chow, Kelvin Y. K. Chan, Kit San Yeung, H. Lo, B. Chung","doi":"10.20517/jtgg.2022.02","DOIUrl":"https://doi.org/10.20517/jtgg.2022.02","url":null,"abstract":"Genomic medicine and precision medicine initiatives have taken centre stage in scientific, clinical, as well as health economics and utility research on the global scene for the past decade. It is clear the important role genomic advancement has played in enhancing diagnostic rate, streamlining personalised treatment, and improving efficacy of the overall clinical management of undiagnosed, rare, and common diseases for humankind. The Hong Kong Genome Institute (HKGI) was established in May 2020 within the Food and Health Bureau, Hong Kong Special Administrative Region, to integrate genomic medicine into mainstream healthcare. The main goals of setting up HKGI are to (1) improve the diagnostic rate and future care for individuals affected by undiagnosed diseases and hereditary cancers using whole genome sequencing; (2) advance research in genomic science; (3) nurture talents in genomic medicine; and (4) enhance public genomic literacy and overall engagement through the launching of the Hong Kong Genome Project (HKGP). In this paper, we review the current landscape and specific challenges encountered during the construction of the infrastructure and implementation of the pilot phase of HKGP. Through reviewing what has been achieved and established to date, and the potentials and prospects that have emerged in the process, this paper will provide insights into planning the main phase of HKGP, and considerations for our international counterparts when building similar projects.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Werner (WRN) helicase belongs to the RECQL class of DNA helicases. Mutation in Werner (WRN) RECQL helicase leads to premature aging syndrome, Werner syndrome (WS), and predisposition to multiple cancers. WS patients exhibit heightened incidence of neoplasia, e.g., soft tissue sarcoma, osteosarcoma, malignant melanoma, meningioma, thyroid cancer, breast cancer, and leukemias. Extensive research on WRN helicase has revealed its important and diverse roles in DNA repair pathways, especially in double-strand break repair. Consequently, WRN deficiency is causally associated with genomic instability and cancer predispositions. In this review, we summarize recent studies unraveling the fundamental roles WRN helicase plays in DNA repair and genome stability and its implications in cancer therapy and resistance.
Werner (WRN)解旋酶属于RECQL类DNA解旋酶。Werner (WRN) RECQL解旋酶突变导致早衰综合征、Werner综合征(WS)和多种癌症易感性。WS患者表现出较高的肿瘤发病率，如软组织肉瘤、骨肉瘤、恶性黑色素瘤、脑膜瘤、甲状腺癌、乳腺癌和白血病。对WRN解旋酶的广泛研究揭示了其在DNA修复途径，特别是双链断裂修复中的重要和多样的作用。因此，WRN缺乏与基因组不稳定性和癌症易感性有因果关系。在这篇综述中，我们总结了最近的研究揭示了WRN解旋酶在DNA修复和基因组稳定性中的基本作用及其在癌症治疗和耐药中的意义。
{"title":"Enigmatic role of WRN-RECQL helicase in DNA repair and its implications in cancer","authors":"Pooja Gupta, A. G. Majumdar, B. Patro","doi":"10.20517/jtgg.2021.60","DOIUrl":"https://doi.org/10.20517/jtgg.2021.60","url":null,"abstract":"Werner (WRN) helicase belongs to the RECQL class of DNA helicases. Mutation in Werner (WRN) RECQL helicase leads to premature aging syndrome, Werner syndrome (WS), and predisposition to multiple cancers. WS patients exhibit heightened incidence of neoplasia, e.g., soft tissue sarcoma, osteosarcoma, malignant melanoma, meningioma, thyroid cancer, breast cancer, and leukemias. Extensive research on WRN helicase has revealed its important and diverse roles in DNA repair pathways, especially in double-strand break repair. Consequently, WRN deficiency is causally associated with genomic instability and cancer predispositions. In this review, we summarize recent studies unraveling the fundamental roles WRN helicase plays in DNA repair and genome stability and its implications in cancer therapy and resistance.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neurogenic dysphagia (ND) is characterized by a swallowing disorder where nervous system, muscle, and neuromuscular diseases are involved. DRD1, COMT, BDNF, and APOE are genes that may have a predictive role in the occurrence and evolution of ND. Many drugs that improve swallowing or can induce or exacerbate swallowing difficulties are related to dopamine metabolism and substance P. These pharmacological treatments for ND include dopamine precursors (levodopa), dopamine agonists (amantadine, apomorphine, cabergoline, and rotigotine), and TRP channel activators (capsaicin, piperine, and menthol). Since treatment outcomes are highly dependent on the genomic profiles of ND patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutic interventions. Knowledge of the pharmacogenetic profiles of these drugs would minimize the occurrence of adverse drug reactions (especially to antidopaminergic medications) that may induce dysphagia and optimize pharmacological treatment that can ameliorate it. This knowledge should also be applied to the use of medications that control symptoms associated with dysphagia, such as sialorrhea, xerostomia, reflux, or hiccups.
{"title":"Neurogenic dysphagia: current pharmacogenomic perspectives","authors":"J. Guerra, V. Naidoo, R. Cacabelos","doi":"10.20517/jtgg.2022.08","DOIUrl":"https://doi.org/10.20517/jtgg.2022.08","url":null,"abstract":"Neurogenic dysphagia (ND) is characterized by a swallowing disorder where nervous system, muscle, and neuromuscular diseases are involved. DRD1, COMT, BDNF, and APOE are genes that may have a predictive role in the occurrence and evolution of ND. Many drugs that improve swallowing or can induce or exacerbate swallowing difficulties are related to dopamine metabolism and substance P. These pharmacological treatments for ND include dopamine precursors (levodopa), dopamine agonists (amantadine, apomorphine, cabergoline, and rotigotine), and TRP channel activators (capsaicin, piperine, and menthol). Since treatment outcomes are highly dependent on the genomic profiles of ND patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutic interventions. Knowledge of the pharmacogenetic profiles of these drugs would minimize the occurrence of adverse drug reactions (especially to antidopaminergic medications) that may induce dysphagia and optimize pharmacological treatment that can ameliorate it. This knowledge should also be applied to the use of medications that control symptoms associated with dysphagia, such as sialorrhea, xerostomia, reflux, or hiccups.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Chambers, J. Foote, R. T. Bentley, D. Botta, D. Crossman, D. D. Manna, D. Estevez-Ordonez, J. Koehler, C. Langford, Michael A. Miller, J. Markert, A. Olivier, N. Omar, S. Platt, D. Rissi, A. Shores, D. Sorjonen, E. Yang, A. B. Yanke, G. Gillespie
Aim: To molecularly characterize the tumor microenvironment and evaluate immunologic parameters in canine glioma patients before and after treatment with oncolytic human IL-12-expressing herpes simplex virus (M032) and in treatment naïve canine gliomas. Methods: We assessed pet dogs with sporadically occurring gliomas enrolled in Stage 1 of a veterinary clinical trial that was designed to establish the safety of intratumoral oncoviral therapy with M032, a genetically modified oncolytic herpes simplex virus. Specimens from dogs in the trial and dogs not enrolled in the trial were evaluated with immunohistochemistry, NanoString, Luminex cytokine profiling, and multi-parameter flow cytometry. Results: Treatment-naive canine glioma microenvironment had enrichment of Iba1 positive macrophages and minimal numbers of T and B cells, consistent with previous studies identifying these tumors as immunologically “cold”. NanoString mRNA profiling revealed enrichment for tumor intrinsic pathways consistent with suppression of tumor-specific immunity and support of tumor progression. Oncolytic viral treatment induced an intratumoral mRNA transcription signature of tumor-specific immune responses in 83% (5/6) of canine glioma patients. Changes included mRNA signatures corresponding with interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. Multiplexed protein analysis identified a subset of oligodendroglioma subjects with increased concentrations of IL-2, IL-7, IL-6, IL-10, IL-15, TNFα, GM-CSF between 14 and 28 days after treatment, with evidence of CD4+ T cell activation and modulation of IL-4 and IFNγ production in CD4+ and CD8+ T cells isolated from peripheral blood. Conclusion: These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model.
{"title":"Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus","authors":"M. Chambers, J. Foote, R. T. Bentley, D. Botta, D. Crossman, D. D. Manna, D. Estevez-Ordonez, J. Koehler, C. Langford, Michael A. Miller, J. Markert, A. Olivier, N. Omar, S. Platt, D. Rissi, A. Shores, D. Sorjonen, E. Yang, A. B. Yanke, G. Gillespie","doi":"10.20517/jtgg.2021.31","DOIUrl":"https://doi.org/10.20517/jtgg.2021.31","url":null,"abstract":"Aim: To molecularly characterize the tumor microenvironment and evaluate immunologic parameters in canine glioma patients before and after treatment with oncolytic human IL-12-expressing herpes simplex virus (M032) and in treatment naïve canine gliomas. Methods: We assessed pet dogs with sporadically occurring gliomas enrolled in Stage 1 of a veterinary clinical trial that was designed to establish the safety of intratumoral oncoviral therapy with M032, a genetically modified oncolytic herpes simplex virus. Specimens from dogs in the trial and dogs not enrolled in the trial were evaluated with immunohistochemistry, NanoString, Luminex cytokine profiling, and multi-parameter flow cytometry. Results: Treatment-naive canine glioma microenvironment had enrichment of Iba1 positive macrophages and minimal numbers of T and B cells, consistent with previous studies identifying these tumors as immunologically “cold”. NanoString mRNA profiling revealed enrichment for tumor intrinsic pathways consistent with suppression of tumor-specific immunity and support of tumor progression. Oncolytic viral treatment induced an intratumoral mRNA transcription signature of tumor-specific immune responses in 83% (5/6) of canine glioma patients. Changes included mRNA signatures corresponding with interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. Multiplexed protein analysis identified a subset of oligodendroglioma subjects with increased concentrations of IL-2, IL-7, IL-6, IL-10, IL-15, TNFα, GM-CSF between 14 and 28 days after treatment, with evidence of CD4+ T cell activation and modulation of IL-4 and IFNγ production in CD4+ and CD8+ T cells isolated from peripheral blood. Conclusion: These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 1","pages":"423 - 442"},"PeriodicalIF":0.0,"publicationDate":"2021-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45720425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Yashin, Deqing Wu, K. Arbeev, A. Yashkin, I. Akushevich, Olivia Bagley, Matt Duan, S. Ukraintseva
Aim: Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods: Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results: Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion: Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.
{"title":"Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans","authors":"A. Yashin, Deqing Wu, K. Arbeev, A. Yashkin, I. Akushevich, Olivia Bagley, Matt Duan, S. Ukraintseva","doi":"10.20517/jtgg.2021.26","DOIUrl":"https://doi.org/10.20517/jtgg.2021.26","url":null,"abstract":"Aim: Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods: Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results: Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion: Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 1","pages":"357 - 379"},"PeriodicalIF":0.0,"publicationDate":"2021-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45808839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prostate cancer (PCa) is the most commonly diagnosed malignancy among men, and the progression of this disease results in fewer treatment options available to clinical patients. It highlights the vital necessity for discovering novel therapeutic approaches and expanding the current understanding of molecular mechanisms. Epigenetic alternations such as DNA methylation models and histone modifications have been associated as key drivers in the development and advancement of PCa. Several studies have been conducted and demonstrated that targeting these epigenetic enzymes or regulatory proteins has been strongly associated with the regulation of cancer cell growth. Due to the success rate of these therapeutic routes in pre-clinical settings, many drugs have now advanced to clinical testing, where efficacy will be measured. This review will discuss the role of epigenetic modifications in PCa development and its function in the progression of the disease to resistant forms and introduce therapeutic strategies that have demonstrated successful results as PCa treatment.
{"title":"Epigenetics in prostate cancer treatment","authors":"Katelyn Jones, Yanquan Zhang, Yifan Kong, Elia Farah, Ruixin Wang, Chaohao Li, Xinyi Wang, Zhuangzhuang Zhang, Jianlin Wang, Fengyi Mao, Xiaoqi Liu, Jinghui Liu","doi":"10.20517/jtgg.2021.19","DOIUrl":"https://doi.org/10.20517/jtgg.2021.19","url":null,"abstract":"Prostate cancer (PCa) is the most commonly diagnosed malignancy among men, and the progression of this disease results in fewer treatment options available to clinical patients. It highlights the vital necessity for discovering novel therapeutic approaches and expanding the current understanding of molecular mechanisms. Epigenetic alternations such as DNA methylation models and histone modifications have been associated as key drivers in the development and advancement of PCa. Several studies have been conducted and demonstrated that targeting these epigenetic enzymes or regulatory proteins has been strongly associated with the regulation of cancer cell growth. Due to the success rate of these therapeutic routes in pre-clinical settings, many drugs have now advanced to clinical testing, where efficacy will be measured. This review will discuss the role of epigenetic modifications in PCa development and its function in the progression of the disease to resistant forms and introduce therapeutic strategies that have demonstrated successful results as PCa treatment.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"5 1","pages":"341 - 356"},"PeriodicalIF":0.0,"publicationDate":"2021-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43798566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patricia Berber, Andrea Milenkovic, Lisa Michaelis, B. Weber
methods determine Abstract Aim: We aimed to compare the quantity and quality of aging retinal organoids generated by applying three distinct differentiation protocols for human-derived induced pluripotent stem cells (hiPSC). Methods: hiPSC were differentiated to retinal organoids using a 3D technique (Method 1) and a 3D-2D-3D technique (Method
{"title":"Retinal organoid differentiation methods determine organoid cellular composition","authors":"Patricia Berber, Andrea Milenkovic, Lisa Michaelis, B. Weber","doi":"10.20517/jtgg.2021.35","DOIUrl":"https://doi.org/10.20517/jtgg.2021.35","url":null,"abstract":"methods determine Abstract Aim: We aimed to compare the quantity and quality of aging retinal organoids generated by applying three distinct differentiation protocols for human-derived induced pluripotent stem cells (hiPSC). Methods: hiPSC were differentiated to retinal organoids using a 3D technique (Method 1) and a 3D-2D-3D technique (Method","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44989675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiaxin Jiang, Zhaohui Ruan, Qianyu Wang, Li Jiang, Roujun Peng
and of extranodal natural killer/T cell lymphoma: from etiology to treatment. J Transl Abstract Extranodal natural killer/T cell lymphoma (NKTCL) is a heterogenous and unique epidemiological non-Hodgkin’s lymphoma, which is strongly associated with Epstein-Barr virus (EBV) infection. Based on the development of various sequencing methods and molecular biology technologies, genome- and transcriptome-wide association studies of NKTCL have provided insight into the etiology and pathogenesis of NKTCL. Comparative genomic hybridization detected variations in tumor suppressor genes such as PRDM1 , RUNX3 , and EZH2 . Whole-exome sequencing identified pathogenic variant such as DDX3X , and TP53 . Signal pathways such as the Janus kinase/signal transduction and activator of transcription pathway and nuclear factor kappaB pathway are frequently abnormal in NKTCL. In addition, programmed death-1, programmed death ligand-1, and the human leukocyte antigen risk alleles are significantly associated with NKTCL pathogenesis. Meanwhile, epigenetics analysis has also exposited changes such as PTPRK , HACE1 , microRNAs, and long non-coding RNAs, which play important role on the development and biology of NKTCL. EBV infection is tightly correlated with NKTCL. Viral genomic alterations and lytic genes of EBV are reported to have pathogenic effects on host cells that contribute to the etiology of NKTCL. We summarize the genomic and genetic alterations during the pathogenesis and development of NKTCL and exhibit the potential therapeutic targets that are worth exploring in future research and clinical trials. (2/7) [98] Sanger sequencing revealed that LMP1 gene contained a 30 bp deletion, which may be related to the poor prognosis of NKTCL patients [99] . Analyzing the EBV genome and transcriptome derived from NKTCL, in addition to the 30 bp deletion in LMP1 , small deletions in BARTs , EBNA2 , EBNA3s , BLLF1/2 , and other regions were also detected, which disclosed the heterogeneity in EBV cloning in NKTCL patients [17] . Interestingly, this study also clarified an insertion of EBV fragments into the human nonhomologous end-joining 1 ( NHEJ1 ) gene region, which may lead to changes in the expression and function of NHEJ1 . The NHEJ1 gene is vital in repairing DNA damage and maintaining genome stability [100] . Thus, integration of the EBV genome and human genome might have crucial impact on the pathogenesis and development of NKTCL. The molecular mechanism of this integration affecting NKTCL tumorigenesis and whether indeed contributes to clinical treatment of NKTCL need
{"title":"Genetics and genomics of extranodal natural killer/T cell lymphoma: from etiology to treatment","authors":"Jiaxin Jiang, Zhaohui Ruan, Qianyu Wang, Li Jiang, Roujun Peng","doi":"10.20517/jtgg.2021.21","DOIUrl":"https://doi.org/10.20517/jtgg.2021.21","url":null,"abstract":"and of extranodal natural killer/T cell lymphoma: from etiology to treatment. J Transl Abstract Extranodal natural killer/T cell lymphoma (NKTCL) is a heterogenous and unique epidemiological non-Hodgkin’s lymphoma, which is strongly associated with Epstein-Barr virus (EBV) infection. Based on the development of various sequencing methods and molecular biology technologies, genome- and transcriptome-wide association studies of NKTCL have provided insight into the etiology and pathogenesis of NKTCL. Comparative genomic hybridization detected variations in tumor suppressor genes such as PRDM1 , RUNX3 , and EZH2 . Whole-exome sequencing identified pathogenic variant such as DDX3X , and TP53 . Signal pathways such as the Janus kinase/signal transduction and activator of transcription pathway and nuclear factor kappaB pathway are frequently abnormal in NKTCL. In addition, programmed death-1, programmed death ligand-1, and the human leukocyte antigen risk alleles are significantly associated with NKTCL pathogenesis. Meanwhile, epigenetics analysis has also exposited changes such as PTPRK , HACE1 , microRNAs, and long non-coding RNAs, which play important role on the development and biology of NKTCL. EBV infection is tightly correlated with NKTCL. Viral genomic alterations and lytic genes of EBV are reported to have pathogenic effects on host cells that contribute to the etiology of NKTCL. We summarize the genomic and genetic alterations during the pathogenesis and development of NKTCL and exhibit the potential therapeutic targets that are worth exploring in future research and clinical trials. (2/7) [98] Sanger sequencing revealed that LMP1 gene contained a 30 bp deletion, which may be related to the poor prognosis of NKTCL patients [99] . Analyzing the EBV genome and transcriptome derived from NKTCL, in addition to the 30 bp deletion in LMP1 , small deletions in BARTs , EBNA2 , EBNA3s , BLLF1/2 , and other regions were also detected, which disclosed the heterogeneity in EBV cloning in NKTCL patients [17] . Interestingly, this study also clarified an insertion of EBV fragments into the human nonhomologous end-joining 1 ( NHEJ1 ) gene region, which may lead to changes in the expression and function of NHEJ1 . The NHEJ1 gene is vital in repairing DNA damage and maintaining genome stability [100] . Thus, integration of the EBV genome and human genome might have crucial impact on the pathogenesis and development of NKTCL. The molecular mechanism of this integration affecting NKTCL tumorigenesis and whether indeed contributes to clinical treatment of NKTCL need","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48501589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the Abstract Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53 mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart. This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-SCNC have contributed to improving the diagnosis and treatment of this aggressive disease.
{"title":"Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the prostate","authors":"I. Kouchkovsky, D. Quigley, E. Small, R. Aggarwal","doi":"10.20517/jtgg.2021.32","DOIUrl":"https://doi.org/10.20517/jtgg.2021.32","url":null,"abstract":"Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the Abstract Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53 mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart. This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-SCNC have contributed to improving the diagnosis and treatment of this aggressive disease.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42204570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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