Clinical and translational discovery最新文献

{"title":"Impact of prior coronavirus disease 2019 infection in females on assisted reproductive outcomes: A systematic review with meta-analysis","authors":"Yiqi Liu,&nbsp;Shen Chen,&nbsp;Mengyi Chen,&nbsp;Chutian Xing,&nbsp;Danjie Su,&nbsp;Lu Fan,&nbsp;Dingfei Xu,&nbsp;Lifeng Tian,&nbsp;Leizhen Xia,&nbsp;Ke Zhang,&nbsp;Qiongfang Wu,&nbsp;Zheng Fang,&nbsp;Jialyu Huang","doi":"10.1002/ctd2.251","DOIUrl":"https://doi.org/10.1002/ctd2.251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To investigate the relationship between prior coronavirus disease 2019 (COVID-19) infection in females and subsequent treatment outcomes of assisted reproductive technology (ART).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic literature review was carried out up to 16 December 2022, in PubMed, Web of Science, EMBASE, and Cochrane Library. Random-effect models were adopted to estimate the pooled effects as mean differences (MDs) or odds ratios (ORs). I2 statistic and Egger's test were applied to assess heterogeneity and publication bias, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After screening 1480 records, 15 cohort studies totalling 1905 cycles were included in this meta-analysis. In a comparison of previously COVID-19-infected versus uninfected women, no significant differences were observed in the primary outcomes of the retrieved oocytes number (MD = 0.06; 95% confidence interval [CI]: -0.75–0.88; I2 = 0) and clinical pregnancy rate (OR = 0.96; 95% CI: 0.74–1.24; I2 = 0). Pooled analyses of other predefined outcomes, which encompassed four cycle characteristics, six laboratory indicators and four pregnancy results, also showed no adverse effects of prior COVID-19 infection. Most outcomes remained consistent after further sensitivity and subgroup analyses, and no significant publication bias was observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our work provides the first systematic evidence that COVID-19 infection history in females may have no measurable detrimental impact on the subsequent ART cycle. More data are needed to assess the live birth outcome and the optimal time interval from infection to assisted reproduction.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"109168527","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":"The crossroads of RNA methylation and ferroptosis: Implications for disease pathogenesis","authors":"Masanori Yoshinaga","doi":"10.1002/ctd2.244","DOIUrl":"https://doi.org/10.1002/ctd2.244","url":null,"abstract":"<p>Post-transcriptional regulation constitutes an important mechanism for governing gene expression across diverse biological processes.<span>¹</span> It is now appreciated that multiple types of methylation in mRNA provide post-transcriptional regulation to control mRNA fates. <i>N</i>⁶-methyladenosine (m⁶A) methylation is one of the most prevalent internal RNA modifications.<span>²</span> m⁶A methylation is involved in various aspects of post-transcriptional regulation, such as the control of mRNA decay, translation and splicing. Accumulating evidence has shown that m⁶A methylation controls numerous biological processes, such as cell development, immune response and metabolic control.<span>^{3, 4}</span></p><p>The intricate interplay between RNA m⁶A methylation and programmed cell death or apoptosis, represents an expanding area of research in molecular biology. Studies have unveiled connections between m⁶A methylation and the regulation of apoptotic pathways. Specifically, m⁶A modifications have been found to modulate the expression of key genes involved in apoptosis, thereby exerting a regulatory influence on cell survival and death decisions. This regulatory role is particularly evident in the context of cancer biology, where dysregulation of m⁶A methylation can lead to aberrant apoptotic signaling, contributing to tumour progression.<span>⁵</span> Studying the precise mechanisms by which RNA methylation influences apoptotic pathways has the potential to reveal new therapeutic strategies for diseases with disrupted cell death regulation.</p><p>A new form of programmed cell death called ferroptosis adds a captivating dimension to the complex landscape of cell death regulation.<span>⁶</span> Unlike classical apoptosis, ferroptosis is a distinct form of regulated cell death, characterised by the iron-dependent accumulation of lipid peroxides, ultimately leading to membrane damage and cell death. Despite the growing recognition of ferroptosis as a significant cellular process with implications in various pathological conditions, such as neurodegenerative diseases and cancer, our understanding of the interplay between m⁶A methylation and ferroptosis remains in its infancy.</p><p>In a recent study by Zhang et al.,<span>⁷</span> a novel connection was established between RNA m⁶A modification, ferroptosis and the development of acute lung injury (ALI), a sudden and severe lung condition characterised by inflammation and increased lung tissue permeability.<span>⁸</span> ALI often results in impaired oxygen exchange and hypoxaemia, necessitating prompt medical intervention to prevent progression to acute respiratory distress syndrome (ARDS). Initially, the research explored the role of neutrophil extracellular traps (NETs) in the pathogenesis of sepsis-associated ALI (SI","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71953692","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}

{"title":"Inflammation and autonomic balance in cirrhosis: Association between sympathetic nervous system and osteopontin, interleukin-22, interleukin-6 and interleukin-1Ra concentrations according to portal hypertension and disease severity","authors":"Giuseppe Miceli,&nbsp;Grazia Pennisi,&nbsp;Luisa Agnello,&nbsp;Vincenza Calvaruso,&nbsp;Emanuele Amodio,&nbsp;Alessandra Casuccio,&nbsp;Chiara Pintus,&nbsp;Maria Grazia Basso,&nbsp;Rosaria Maria Pipitone,&nbsp;Mario Daidone,&nbsp;Rossella Zito,&nbsp;Giulia Lupo,&nbsp;Salvatore Petta,&nbsp;Giuseppe Cabibbo,&nbsp;Marcello Ciaccio,&nbsp;Stefania Grimaudo,&nbsp;Antonio CraxÌ,&nbsp;Antonino Tuttolomondo","doi":"10.1002/ctd2.215","DOIUrl":"https://doi.org/10.1002/ctd2.215","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The autonomic nervous system is linked to hyperdynamic circulation in cirrhosis and several studies have highlighted the crucial role that systemic inflammation elicits in altering sympathovagal equilibrium with the consequent reduction in heart rate variability (HRV).</p>\u0000 \u0000 <p>To investigate the correlation between time-domain HRV parameters, serum cytokines concentrations and portal hypertension, we studied a cohort of patients with cirrhosis, accounting for etiology and treatments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this cross-sectional, observational cohort study, 107 outpatients with non-alcoholic cirrhosis were assessed consecutively by abdominal ultrasound and by upper gastrointestinal endoscopy to search for esophagogastric varices. 24-h electrocardiogram Holter monitoring with time-domain HRV measurement (square root of the mean of successive differences of Normal-to-Normal [NN] [RMSSD], standard deviation or the square root of variance [SDNN] and standard deviation of the means of the NN intervals calculated over a 5-min period [SDANN]) was performed and serum concentrations of osteopontin (OPN), interleukin (IL)-22, IL-6, IL-1Ra and IL-17 were obtained in all patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>IL-6, OPN, IL-22 and IL-1Ra concentrations in cirrhotic patients were associated with disease severity expressed by Child-Pugh and MELD score, to some portal hypertension's indirect signs and some of its complications. A significant increase in systemic concentrations of OPN in patients with hepatocellular carcinoma was encountered. SDANN and SDNN values were indirectly related to serum levels of IL-6, OPN, IL-1Ra and IL-22.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study underlines the interaction between the alteration of the ANS and the activation of inflammatory pathways that characterize cirrhosis taking into account clinical characteristics and treatments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71953700","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}

{"title":"Identification of diagnostic markers of pancreatic ductal adenocarcinoma using transcriptomic tumour and blood sample data","authors":"Aristeidis Sionakidis,&nbsp;Panagiotis Nikolaos Lalagkas,&nbsp;Andigoni Malousi,&nbsp;Ioannis S. Vizirianakis","doi":"10.1002/ctd2.248","DOIUrl":"https://doi.org/10.1002/ctd2.248","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is the most frequently diagnosed form of pancreatic cancer worldwide. PDAC is associated with a poor survival rate mainly due to the disease being usually diagnosed at late stages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Publicly available gene expression data from 10 studies with tumour tissue (448 samples) and/or blood samples (128 samples) from PDAC patients were pooled together and analyzed for the identification of stage-specific and global diagnostic markers using differential gene expression analysis. The list of statistically significant (<math>\u0000 <semantics>\u0000 <mrow>\u0000 <msub>\u0000 <mi>p</mi>\u0000 <mrow>\u0000 <mi>a</mi>\u0000 <mi>d</mi>\u0000 <mi>j</mi>\u0000 </mrow>\u0000 </msub>\u0000 <mspace></mspace>\u0000 <mo>&lt;</mo>\u0000 <mspace></mspace>\u0000 <mn>0.05</mn>\u0000 </mrow>\u0000 <annotation>${p_{adj}}; &lt; ;0.05$</annotation>\u0000 </semantics></math>) differentially expressed genes were used to carry out enrichment analysis via active subnetworks and miRNA enrichment analysis. We then used the results from these analyses to identify the most significant genes and pathways and map these to marketed drugs’ pharmacological targets. The same process was replicated for studies with blood samples and results were compared to those from the tissue analysis. A set of consistently deregulated genes (pancreatic tumour signature, PTS) in both tissue and blood samples was derived and validated in external cohorts and The Cancer Genome Atlas (TCGA) data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Notable gene expression deregulation was found in all tumour stages with significant overlap. We identified 820 consistently deregulated genes (PTS) in tissue samples of all stages and blood samples. Active subnetwork analysis revealed enriched ribosome, proteasome, adherens junction and cell cycle pathways across all stages and blood samples. Our findings suggest that microRNA (miRNA) contribution to PDAC pathology plays a significant role and is probably mediated by distinct miRNAs across stages of PDAC. Stage-specific enriched miRNAs with diagnostic potential included miR-21, miR-29, miR-124 and miR-30, for stages 1–4, respectively. By investigating the pharmacogenetic interactions of the i","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50119754","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":"Lp(a) and inflammation: a new insight into atherosclerosis","authors":"Hangyu Pan,&nbsp;Kexin Hu,&nbsp;Qiao Wu,&nbsp;Yan Tu,&nbsp;Zhigang Guo","doi":"10.1002/ctd2.247","DOIUrl":"https://doi.org/10.1002/ctd2.247","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lipid-lowering therapy is of utmost importance in both primary and secondary prevention of atherosclerotic cardio vascular disease (ASCVD). However, the presence of residual risk allows cardiovascular events to occur even when low-density lipoprotein cholesterol (LDL-C) levels are very low. A large number of clinical studies have provided evidence confirming the association between elevated plasma Lp(a) and the development of ASCVD. Clinical studies have also suggested that reducing Lp(a) may help decrease the occurrence of cardiovascular events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main</h3>\u0000 \u0000 <p>Lp(a) consists of LDL-like particles, apo(a) and OxPL. The level of Lp(a) in thehuman body is predominantly determined by genetics, with external factorshaving minimal impact. Additionally, Lp(a) levels have been found to vary among different ethnicities. There is a notable correlation between elevated levels of Lp(a) and coronary artery disease (CAD), which is independent of other lipoproteins. Furthermore, there exists a linear relationship between Lp(a) levels and the risk of developing ASCVD. It is now wildly believed that Lp(a) primarily contributes to the development of cardiovascular events through pro-inflammation, pro-thrombosis and pro-atherosclerosis. From the perspective of Lp(a) influencing inflammation, it primarily promotes the release of inflammatoryfactors. This, in turn, increases levels of vascular inflammation and facilitates the recruitment of monocytes-macrophages. Moreover, it also affects the function of endothelial cells during the development process of atherosclerosis. All these aspects complement each other and contribute to the progression of at herosclerosis. Currently, the lipid-lowering treatment used inclinical practice can partially reduce the levels of Lp(a), but its impact on inflammation is not significant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Lp(a) is an independent risk factor for CAD, as it promotes inflammation in the body and accelerates theprogression of atherosclerosis. Further research on effective methods to reduce Lp(a) levels can provide new insights for the treatment of atherosclerosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50130429","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":"Mesenchymal stem cell-derived extracellular vesicles in treatment against renal fibrosis","authors":"Jiantao Wang,&nbsp;Jianxin Cui,&nbsp;Shengqiang Yu,&nbsp;Shujie Xia","doi":"10.1002/ctd2.211","DOIUrl":"https://doi.org/10.1002/ctd2.211","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Renal fibrosis (RF) is the main pathological pathway of acute kidney injury and chronic kidney disease. Its main pathological feature is extracellular matrix aggregation in the renal stroma and glomerulus. There is currently no effective treatment to delay or treat RF. Mesenchymal stem cells (MSCs) are multipotent somatic stem cells that can direct differentiation, direct cell-cell interactions and have secretory activity. The most important secretory activity of MSCs is mediated by extracellular vesicles (EVs). At present, there is increasing evidence that EVs produced by MSCs may be used in regenerative methods of tissue repair.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The goal of this review is to present the latest efficacy of MSC-EVs in the prevention, treatment and improvement of RF caused by acute and chronic kidney injury and reveals the molecular mechanism of MSCs in various models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and discussion</h3>\u0000 \u0000 <p>MSC-EVs show potential for RF by regulating autophagy, inhibiting apoptosis, countering oxidation, suppressing inflammation, reducing EMT and modulating angiogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>MSC-EVs show potential for treating RF. However, more studies establishing their safety, efficiency and specific mechanisms in the context of RF are still needed before further clinical application.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50118531","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":"Understanding the interplay between N6-methyladenine RNA methylation and noncoding RNAs in kidney disease","authors":"Saiya Zhu,&nbsp;Dong Zhou","doi":"10.1002/ctd2.246","DOIUrl":"https://doi.org/10.1002/ctd2.246","url":null,"abstract":"<p>First discovered in 1974,<span>¹</span> N6-methyladenosine (m⁶A) is the most prevalent epigenetic modification in eukaryotic mRNAs at the posttranscriptional level under pathophysiological conditions. The m⁶A modification entails methylation of adenine at the nitrogen 6 (N6) position. Three classes of enzymes mediate the process of m⁶A modification, including RNA methyltransferases (writers), demethylases (erasers), and methylation recognition proteins (readers).<span>²</span> Writers can form a multicomponent m⁶A methyltransferase complex (MTC) that catalyzes RNA modification by transferring methyl groups to RNA. In MTC, METTL3, METTL14 and WTAP are core components. Serving as erasers, as the name implies, demethylases (FTO and ALKBH5) are responsible for removing S-adenosyl methionine from adenines in RNA. At the same time, readers (YTHDF, YTHDC and eIF3) can recognize m⁶A-modified RNAs and bind the m⁶A modification, subsequently determining the fate of the RNA. Therefore, m⁶A RNA modification is considered invertible and dynamic. In recent years, the advent of advanced high-throughput sequencing has facilitated the identification of m⁶A.</p><p>In general, m⁶A presents 0.4%−0.6% of all cellular RNAs, including mRNAs, noncoding RNAs (ncRNAs), and circular RNAs (circRNAs).<span>³</span> In a recent publication in <i>Clinical and Translational Medicine</i>, Ni et al. reported that METTL3 promoted the m⁶A modification of Ena/VASP-like (EVL) mRNA and subsequently activated the transforming growth factor-beta 1 (TGF-β1) signalling pathway, which ultimately aggravated kidney fibrosis.<span>⁴</span> Beyond regulating mRNA-coding genes, m⁶A modification exhibited remarkable capacity in modulating the function of ncRNAs to dictate kidney fate after various insults, especially in kidney carcinoma. Conversely, ncRNAs also participate in the regulation of m⁶A modification amid kidney disease progression. Therefore, fully understanding the crosstalk between m⁶A modification and ncRNAs will supplement a piece of the puzzle of the pathogenesis of non-tumour kidney diseases and shed light on developing effective therapeutic strategies for these medical catastrophes.</p><p>ncRNAs, mainly comprised of micro RNAs (miRNAs), long noncoding RNAs (lncRNAs), and circRNAs, account for a large class of transcripts in mammalian genomes without protein-coding potential. Despite this, they are crucial regulators of diverse physiological and pathological processes. The m⁶A modification of ncRNAs controls RNA stability, processing, and transport. As illustrated in Figure 1, accumulating studies have shown that m⁶A-modified ncRNAs cause kidney disorders through multiple dysregulated signalling pathways in diseased kidneys. Because the evidence of m⁶A modific","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50148264","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":"Commentary: All models are wrong, but some are useful: understanding cognitive decline and dementia in atrial fibrillation through vascular computational modelling","authors":"Brian Zenger,&nbsp;T. Jared Bunch","doi":"10.1002/ctd2.243","DOIUrl":"https://doi.org/10.1002/ctd2.243","url":null,"abstract":"<p>Atrial fibrillation (AF) has been clearly shown to be an independent risk factor for cognitive decline and dementia.<span>^{1, 2}</span> However, the exact mechanism that causes this precipitous cognitive decline is unknown.<span>¹</span> Some of the most unmistakable evidence comes from the SWISS-AF trial, where adequately anticoagulated patients had serial brain imaging before and after starting anticoagulation therapy.<span>³</span> In this study, patients were shown to have an increased prevalence of brain injury compared to healthy controls that correlated with cognitive decline. A striking finding was that nearly all patients (99%) had white matter disease. The exact mechanisms for brain injury patterns beyond overt thrombotic or haemorrhagic mechanisms have been speculated to include many different hypotheses, including biochemical, drug side effects, vascular injury, or physiologic flow-related.<span>^{1, 2, 4}</span> This region of brain vulnerability is supplied by the lenticulostriate arteries that have a perpendicular origin that is a potential vulnerable region to the haemodynamic perturbations of AF. Focal wall stress may result in vascular disease and dysfunction underlying what is traditionally described as “findings of chronic microvascular disease.” However, these mechanisms are hard to measure or test in humans and require advanced translational models for direct measurements. Computational modeling provides a unique avenue to test these hypotheses in a simulated setting with explicit parameter modulation based on patient-specific models.</p><p>In the most recent issue of the Journal of Clinical and Translational Medicine, Saglietto et al.<span>⁵</span> described their computational approach to showing how changes in wall shear stress in the lacunar brain vasculature during AF could contribute to the development of brain infarct outside of embolic events. The authors used well-established fluid dynamic simulation methods to show that during simulated episodes of AF, the wall shear stress range at the lacunar vessels junction is significantly increased compared to normal sinus rhythm. The authors show increased peak and trough wall shear stress localised to the vessel junctions. Importantly, changes in wall shear stress have been shown to have significant adverse downstream effects. In vitro data have shown that decreases in wall stress can lead to plaque buildup on the endothelium.<span>⁶</span> Furthermore, increased wall shear stress increases the likelihood of plaque rupture.<span>⁶</span> The authors postulate that increasing the dynamic range of sheer stress in the lacunar vessels during AF could create a vicious cycle of plaque buildup and rupture, leading to downstream brain infarction. Furthermore, the authors also highlight that increased wall stress alone can lead to long-term vessel damage, including atheroma formation, that could further devel","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50140311","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":"Targeting deubiquitinases for cancer therapy","authors":"Qian Xue,&nbsp;Daolin Tang,&nbsp;Xin Chen,&nbsp;Jinbao Liu","doi":"10.1002/ctd2.242","DOIUrl":"https://doi.org/10.1002/ctd2.242","url":null,"abstract":"<p>The ubiquitin-proteasome system assumes a critical role in numerous cellular processes, and among its components, deubiquitinases (DUBs) have emerged as essential regulators. With roughly 100 DUBs encoded within the human genome, these enzymes can be categorized into two main types: cysteine protease DUBs and metalloproteinase DUBs, based on the catalytic mechanism of the active site. DUBs exert significant influence over specific substrates implicated in cancer progression, establishing them as closely associated with various malignancies, including breast carcinoma, prostate cancer, and chronic myeloid leukemia. Consequently, the targeted inhibition of DUBs presents an enticing therapeutic strategy for cancer treatment. Here, we delve into the functional roles of DUBs in different cancer types and provide a thorough overview of the anticancer properties exhibited by DUB inhibitors. This knowledge will propel the development and clinical application of DUB inhibitors, opening promising avenues for tumor treatment.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50130978","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":"Challenges of clinical translation from single-cell sequencing to measures in clinical biochemistry of haematology: Definition of immune cell identities","authors":"Xuanqi Liu,&nbsp;Xiangdong Wang,&nbsp;Charles A. Powell,&nbsp;Diane C. Wang","doi":"10.1002/ctd2.239","DOIUrl":"https://doi.org/10.1002/ctd2.239","url":null,"abstract":"<p>Peripheral immune cells play important roles in the maintenance of systemic and microenvironmental hemostasis. Measurements of circulating blood cells by single-cell RNA sequencing (scRNA-seq) were proposed as one of the routine measures in the clinical biochemistry of haematology. Out of translational challenges, defining precise identities of cell subsets and states is more difficult, due to the complexity of immune cell development, location, regulation, function, and metabolism. It is also a challenge to precisely interpret the clinical significance and impact of each cell identity marker gene panel (ciMGPs). ciMGPs have the potential to advance the understanding of systemic responses to the disease, identify disease-specific biomarkers and define cell heterogeneity. Recently, a large number of peripheral cell subsets and expanding/activating states have been identified and validated for use in the fast developments in clinical single-cell biomedicine. Defining the specificity, measurability and repeatability of cell subsets/states is important for the translation of peripheral scRNA-seq in clinical haematology and biochemistry. The development of standard operating procedures and the performance of clinical trials in large populations of various ages, diseases, and therapies will promote the clinical translation of ciMGPs to measures. Thus, defining cell subset/state identities will provide the multi-dimensional and comprehensive readouts of systemic immune cells, the precision monitoring of immune dynamics, and a deeper understanding of the disease and response to therapy.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50130991","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}