Clinical and Translational Medicine最新文献

{"title":"Oropharyngeal cancer: Lack of human papillomavirus awareness and economic burden in the United States","authors":"Matt Lechner, Liam Masterson, Shiri Mermelstein, Jacklyn Liu, Umar Rehman, Michelle Chen, James O'Mahoney, F. Christopher Holsinger","doi":"10.1002/ctm2.70062","DOIUrl":"10.1002/ctm2.70062","url":null,"abstract":"<p>Both in the United States and the United Kingdom, with similar trends in continental Europe, the rates of male HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) have overtaken the incidence rates of cervical cancer in women. Persistent, oropharyngeal human papillomavirus (HPV) infection has been the major driver behind this rapid increase.<span><sup>1</sup></span> Despite these alarming numbers, the awareness of HPV has been extremely low, which may have implications on vaccine uptake. We conducted a survey of 4871 adults across the United States to ascertain the current levels of HPV awareness in relation to oropharyngeal cancer. The cohort was 49.9% female and 49.7% male, with patient age well distributed across the various age groups (see Supplemental Table 1). Regarding OPSCC risk, 43.3% and 78.5% identified alcohol and smoking as risk factors, respectively. 72.8%, 37.7%, 30.3% and 42.3% identified chewing tobacco, betel leaf, catechu/areca nut and marijuana use as additional risk factors, respectively.</p><p>Crucially, only one-third (31.3%) were aware that HPV is one of the most important risk factors of OPSCC. Indeed, only 62.3% of respondents had heard of HPV prior to taking the survey. Of these, 68.5% were aware that HPV can be sexually transmitted and 60.0% knew that it can be transmitted through oral sex. Of the entire cohort, less than two-thirds (62.7%) were aware that there is a vaccine against HPV.</p><p>Altogether, these results show that the awareness of HPV and its link to OPSCC is still limited in the United States, despite the introduction of gender-neutral vaccination and amid rapidly increasing rates of disease.</p><p>Indeed, it is expected that OPSCC rates will continue to rise over the next two decades. Several authors have attempted to assess the costs of OPSCC in the United States, using data from the early 2000s or based on a state-specific database. The most recent estimate of oropharyngeal cancer treatment cost in the United States was published by Wu et al.,<span><sup>2</sup></span> who used a large nationwide database (Truven MarketScan Commercial Claims and Encounter Database). They estimated that the average total lifetime treatment cost per newly diagnosed commercially insured patient would be $152 378 in 2015 prices, equivalent to $178 010 in 2020 prices (Medical Care Consumer Price Index, available from the US Bureau of Labor Statistics, 2020). The overall cost for OPSCC treatment in the United States was estimated by combining Wu et al.<span><sup>2</sup></span> treatment cost for commercially insured patients with the incidence rates of OPC<span><sup>3</sup></span> and the population projections (US Bureau, 2020), which gave a total direct cost of over $4.2 billion in 2020.</p><p>Broader societal costs of OPSCC were based on Pearce et al.<span><sup>4</sup></span> assessment of lost workplace productivity cost due to head and neck cancer in Ireland, equivalent to $311 926 per case diagnosed (in 20","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NDP-β-d-manno-heptoses are small molecule agonists sensed by the vertebrates to discriminate organisms of different kingdoms","authors":"Yue Tang, Zijian Zhong, Huijin Mao, Yihua Chen","doi":"10.1002/ctm2.70103","DOIUrl":"10.1002/ctm2.70103","url":null,"abstract":"<p>The mammalian innate immune system engages germline-encoded pattern recognition receptors (PRRs) to sense the agonists from invading organisms to discriminate ‘self’ and ‘nonself’.<span><sup>1</sup></span> Those agonists are usually large molecular signatures termed pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs), such as bacterial lipopolysaccharide (LPS) and fungal <i>β-</i>glucan recognized by toll-like receptor 4 or dectin-1, respectively.<span><sup>2, 3</sup></span> Notably, several recent works revealed that, besides the molecular patterns, specific small molecules can also act as agonists that elicit innate immune responses efficiently.<span><sup>4</sup></span> Several <i>β-</i><span>d</span>-<i>manno</i>-heptose metabolites involved in the biosynthesis of LPSs have been identified as small molecule agonists that can be recognized by host alpha-protein kinase 1 (ALPK1), with ADP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (ADP-heptose) and its C-6′′ epimer as the most potent ones.<span><sup>5</sup></span> Upon binding to ADP-heptose, ALPK1 will undergo conformational changes to phosphorylate TRAF-interacting protein with forkhead-associated domain (TIFA), and then triggers the activation of Nuclear factor kappa B (NF-κB) and inflammation.</p><p>ADP-heptose is synthesized from <span>d</span>-sedoheptulose 7-phosphate (S7P) via a four-step relay catalyzed by NDP-<span>h</span>eptose <span>b</span>iosynthetic <span>e</span>nzymes (HBEs) with isomerase, kinase, phosphatase, and nucleotidyltransferase activities (Figure 1). Three types of <span>H</span>B<span>E</span>s with <span>n</span>ucleotidyltransfer<span>ase</span> (HENase) activities were identified, including monodomain nucleotidyltransferase, didomain kinase/nucleotidyltransferase, and tridomain isomerase/kinase/nucleotidyltransferase.<span><sup>6</sup></span> Before our work, knowledge of HBEs is limited to bacteria. We expanded the understanding of HBEs repertoire beyond the territory of bacteria to viruses, archaea, and eukaryotes.<span><sup>7</sup></span> Enzymatic characterization of HBEs from different kingdoms verified that all of them could synthesize ADP-heptose and some HENases could also recognize CTP and UTP to generate two new heptose metabolites, CDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (CDP-heptose) and UDP-<span>d</span>-<i>glycero</i>-<i>β-</i><span>d</span>-<i>manno</i>-heptose (UDP-heptose). Systematic evaluation of the NTP substrate scopes of HENases identified a conserved (F/L)XXG<b>R</b>STT motif (STT<sub>R5</sub>) as a hallmark of HENases with high NTP substrate promiscuity (Figure 1). The fifth arginine residue of the STT<sub>R5</sub> motif may stabilize NTP in a reactive conformation by contributing cation-π interaction with its nucleotide base and hydrogen bonds with its phosphate groups, thereby enabling the HENases to take different NTPs t","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma","authors":"Benedikt Sauer,&nbsp;Jan Kueckelhaus,&nbsp;Nadja I. Lorenz,&nbsp;Süleyman Bozkurt,&nbsp;Dorothea Schulte,&nbsp;Jan-Béla Weinem,&nbsp;Mohaned Benzarti,&nbsp;Johannes Meiser,&nbsp;Hans Urban,&nbsp;Giulia Villa,&nbsp;Patrick N. Harter,&nbsp;Christian Münch,&nbsp;Johannes Rieger,&nbsp;Joachim P. Steinbach,&nbsp;Dieter Henrik Heiland,&nbsp;Michael W. Ronellenfitsch","doi":"10.1002/ctm2.70030","DOIUrl":"10.1002/ctm2.70030","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose.</p>\u0000 \u0000 <p>We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections.</p>\u0000 \u0000 <p>A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment.</p>\u0000 \u0000 <p>Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Points/Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity.</li>\u0000 \u0000 <li>PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma.</li>\u0000 \u0000 <li>PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Confirmation of previously identified plasma microRNA ratios for breast cancer detection in a nested case-control study within a screening setting","authors":"Emir Sehovic,&nbsp;Ilaria Gregnanin,&nbsp;Maurizia Mello-Grand,&nbsp;Paola Ostano,&nbsp;Viviana Vergini,&nbsp;Andrea Ortale,&nbsp;Angela Amoruso,&nbsp;Elisabetta Favettini,&nbsp;Nereo Segnan,&nbsp;Giovanna Chiorino,&nbsp;Livia Giordano,&nbsp;Elisabetta Petracci","doi":"10.1002/ctm2.70068","DOIUrl":"10.1002/ctm2.70068","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Circulating cell-free microRNAs (miRNAs) were rarely explored as biomarkers for early detection of breast cancer (BC) within a screening setting or in prospectively sampled cohorts.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In this study, we confirmed the discriminatory ability of a combination of novel and reliable circulating miRNA-ratio biomarkers, with and without nonmolecular predictors, that could be used for BC early detection in the context of mammographic screening using a standard, affordable, noninvasive and reproducible technique such as quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). The models were built on a discovery case-control set (&lt;i&gt;n&lt;/i&gt; = 131) nested within a large mammographic screening cohort,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; where more than 14 000 out of 26 640 enrolled women filled an extensive questionnaire on lifestyle habits, hormonal and reproductive history and familiarity for BC, underwent anthropometric measurements and blood sampling. A model with candidate predictors was obtained through penalised logistic regression, and the selected variables were seven plasma miRNA-ratios, breast density, lifestyle score, menopausal status (MS), body mass index (BMI) and their interaction (BMI × MS). Area under the receiver operating characteristic curve (ROC AUC) of .79 for the complete model and of .73 for the miRNA-only model were obtained.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Here, we applied the two models to a new set of women (validation set, &lt;i&gt;n&lt;/i&gt; = 159) nested within the same cohort, including cases diagnosed up to four years after blood collection. Table 1 shows the main characteristics of the sample, with a similar distribution of factors between cases and controls except for the number of previous breast biopsies, breastfeeding and waist circumference. The flowchart of the validation study is visualised in Figure 1 and the methods are detailed in the Supplementary Information. Investigating associations between sample characteristics and studied miRNAs, we found weak correlations between BMI and three miRNA-ratios and between WCRF lifestyle score and one miRNA-ratio (Figure S1).&lt;/p&gt;&lt;p&gt;The cancer characteristics in the discovery and validation sets were similar. However, in the discovery set the diagnosis occurred earlier relative to blood sampling (average 3 months vs. average 25 months), and the proportion of ki-67 positive tumours was lower (23 .5% vs. 82%) (Table S1). Moreover, unlike the discovery set, the validation set included 31 controls that underwent second-level investigation after a suspicious mammogram but then had a negative biopsy. The variables selected in the discovery model were comparable between the two control subgroups (Table S2). Two miRNA-ratios (miR-199a-3p/let-7a-5p and miR-26b-5p/miR-142-5p) were associated with ER status, with &lt;i&gt;p&lt;/i&gt;-values of .049 and .027, respectively. Additionally, miR-93-5p/miR-19b-3p was associated with PgR status (&lt;i&gt;p&lt;/i&gt; = .036) and let-7b-5p/miR","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistence of activated anti-mesothelin hYP218 chimeric antigen receptor T cells in the tumour is associated with efficacy in gastric and colorectal carcinomas","authors":"Sameer Mir,&nbsp;Abhilash Venugopalan,&nbsp;Jingli Zhang,&nbsp;Nishanth Ulhas Nair,&nbsp;Manjistha Sengupta,&nbsp;Manakamana Khanal,&nbsp;Chaido Stathopoulou,&nbsp;Qun Jiang,&nbsp;Raffit Hassan","doi":"10.1002/ctm2.70057","DOIUrl":"10.1002/ctm2.70057","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Patients with advanced gastric and colorectal cancers have limited treatment options. Since mesothelin is highly expressed in these tumour types, we evaluated the therapeutic benefits of anti-mesothelin hYP218 CAR T cells alone, and in combination with anti-PD1 antibody, pembrolizumab.&lt;/p&gt;\u0000 \u0000 &lt;p&gt;GEPIA analysis was performed using human gastric (&lt;i&gt;n&lt;/i&gt; = 408) and colon cancer tumours (&lt;i&gt;n&lt;/i&gt; = 275) in TCGA database, to evaluate mRNA expression of mesothelin, compared to normal tissues. Mesothelin expression in gastric and colorectal cancer cell-lines (&lt;i&gt;n&lt;/i&gt; = 5) was analysed using flow cytometry. In vitro efficacy by hYP218 CAR T cells was tested by cytotoxicity and cytokine release assays. In vivo anti-tumour efficacy of hYP218 CAR T cells alone, and in combination with pembrolizumab, was evaluated in NSG mice bearing human gastric (HGC27) and colorectal (SW48) tumour xenografts. Additionally, hYP218 CAR-T cell persistence, activation and exhaustion marker-expression were studied.&lt;/p&gt;\u0000 \u0000 &lt;p&gt;Mesothelin expression was significantly higher in gastric and colon cancer biopsies compared to normal tissues (&lt;i&gt;p&lt;/i&gt; &lt; .005). Mesothelin expression in gastric and colon cancer cell lines ranged from 10 000 to 70 000 molecules per cell. hYP218 CAR T cells demonstrated strong cytotoxic activity at low effector to target ratio, ranging from 0.24 to 1.0. In NSG mouse-models, hYP218 CAR T cells demonstrated anti-tumour efficacy and persisted in the tumour microenvironment in a functional state at day 40 posttreatment with expression of activation markers CD39 and CD69, increased production of IFN-γ and TNF-α and ability to kill tumour cells in vitro when isolated from tumours. There was increased PD1 expression. In combination with pembrolizumab, hYP218 CAR T cells led to slower tumour growth in NSG mice bearing large but not small HGC27 tumours. Anti-tumour efficacy of hYP218 CAR T cells is due to increased accumulation of activated CAR T cells in the tumour and combination with pembrolizumab resulted in improvement in anti-tumour activity of large established tumours.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Mesothelin expression is significantly higher in gastric and colorectal cancers than normal tissues.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;hYP218 CAR T cells demonstrate strong anti-tumour activity against mesothelin-positive gastric and colorectal carcinomas.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Activated hYP218 CAR T cells persist in the tumour microenvironment and retain their cytotoxic activity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Addition of pembrolizumab in larger tumours en","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive mapping of somatotroph pituitary neuroendocrine tumour heterogeneity using spatial and single-cell transcriptomics","authors":"Jialin Wang,&nbsp;Xuejing Li,&nbsp;Jing Guo,&nbsp;Zan Yuan,&nbsp;Xinyu Tong,&nbsp;Zehao Xiao,&nbsp;Meng Liu,&nbsp;Changxiaofeng Liu,&nbsp;Hongyun Wang,&nbsp;Lei Gong,&nbsp;Chuzhong Li,&nbsp;Yazhuo Zhang,&nbsp;Weiyan Xie,&nbsp;Chunhui Liu","doi":"10.1002/ctm2.70090","DOIUrl":"10.1002/ctm2.70090","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pituitary neuroendocrine tumours (PitNETs) are common intracranial tumours that are highly heterogeneous with unpredictable growth patterns. The driver genes and mechanisms that are crucial for tumour progression in somatotroph PitNETs are poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we performed integrative spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) analysis on somatotroph tumours and normal pituitary samples to comprehensively characterize the differences in cellular characteristics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>By analyzing combined copy number variations (CNVs), tumour tissues were divided into two regions, which included the CNV_high and CNV_low areas. The protumour genes DLK1 and RCN1 were highly expressed in the CNV_high area, which might be related to tumour progression and could be targeted for precision therapy. We also found that the transforming growth factor beta signalling pathway participated in tumour progression and identified heterogeneity in the expression profiles of key genes. We assessed the intertumoral and intratumoral heterogeneity in somatotroph PitNETs and emphasized the importance of individualized treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, we visualized the cellular distribution and transcriptional differences in normal pituitary and somatotroph PitNETs by ST and scRNA-seq for the first time. This study provides a strong theoretical foundation to comprehensively understand the crucial mechanisms involved in tumour progression and develop new strategies to treat somatotroph PitNETs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The first-ever visualization of cellular distributions in normal and tumor pituitary tissues.</li>\u0000 \u0000 <li>The inter- and intra-tumoral transcriptomic heterogeneity of somatotroph PitNETs was comprehensively revealed.</li>\u0000 \u0000 <li>Identification of potential protumor factors and critical signaling pathways, opening new avenues for therapeutic intervention.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The generation of a neuronal phase code for space","authors":"Eran Stark,&nbsp;Hadas E. Sloin","doi":"10.1002/ctm2.70092","DOIUrl":"10.1002/ctm2.70092","url":null,"abstract":"&lt;p&gt;Neurons are thought to represent information by spikes, but which specific aspect of spiking activity represents information is debated. Place coding in the mammalian hippocampus provides a useful system for studying forms of neuronal coding. Individual pyramidal cells in the hippocampal CA1 region spike when an exploring rodent is at a particular part of the environment, the “place field” of the cell.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Place cell firing is a “rate code”, where the rate profile is independent of the millisecond timing of individual spikes.&lt;/p&gt;&lt;p&gt;During locomotion, local field potentials in the rodent hippocampus exhibit rhythmic theta (4–11 Hz) oscillations. In many place fields, the spikes follow a specific temporal pattern: when the animal enters the field, spikes occur at the peak of the theta wave, and subsequent spikes occur at progressively earlier phases.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Knowing the phase in which a spike occurs can indicate where the animal is within the place field. This “phase precession” is an example of a “phase code”, in which the phase of the individual spike with respect to the ongoing theta may carry information beyond the firing rate.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The observation that both rate and phase codes may carry information about the same parameter in the same neuron provides an opportunity for understanding how these codes are generated. A priori, there are at least three options (Figure 1): a rate code might be somehow converted into a phase code&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;; a phase code may be converted into a rate code&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;; or a third, “progenitor” code could generate both.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Work in the past three decades provided evidence for all three possibilities and for various combinations thereof, and numerous models were proposed for generating phase precession.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We combined electrophysiological recordings with optogenetic manipulations in freely-moving mice to approach the problem of the generation of rate and phase codes in CA1 pyramidal cells. We reasoned that imposing one code on the system may determine whether the codes are interdependent, and possibly constrain the generative mechanisms. Because multiple prior studies suggested that the phase precession observed in CA1 is inherited from other regions,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; we chose to impose a rate code on individual pyramidal cells in CA1.&lt;/p&gt;&lt;p&gt;The induction of an artificial rate code presents several technical challenges. First, we developed hardware to manipulate the activity of individual neurons deep in the brain of freely-moving subjects.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; We invented multi-site/multi-colour optoelectronic devices called “diode-probes” in which light from multiple miniature sources is emitted near the recording electrodes. Second, we coupled the activation of CA1 pyramidal cell spiking with the actual kinematics of the mouse. We developed a system called “Spotter","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiling reveals the dynamics of fibrotic progression-related gene expression into post-coronavirus disease 2019 pulmonary fibrosis","authors":"Sabrina Setembre Batah,&nbsp;Andrea Jazel Rodriguez-Herrera,&nbsp;Maria Júlia Faci do Marco,&nbsp;Juliana Rocha Souza Chiappetto,&nbsp;Mariana Gatto,&nbsp;Simone Alves do Vale,&nbsp;Robson Aparecido Prudente,&nbsp;Amanda Piveta Schnepper,&nbsp;Robson Francisco Carvalho,&nbsp;João Paulo Facio Almeida,&nbsp;Tales Rubens de Nadai,&nbsp;Marcel Konigkam Santos,&nbsp;Li Siyuan Wada,&nbsp;José Baddini-Martinez,&nbsp;Danilo Tadao Wada,&nbsp;Andrea Antunes Cetlin,&nbsp;Vera Luiza Capelozzi,&nbsp;Bruno Guedes Baldi,&nbsp;Suzana Tanni,&nbsp;Rosane Duarte Achcar,&nbsp;Alexandre Todorovic Fabro","doi":"10.1002/ctm2.70088","DOIUrl":"10.1002/ctm2.70088","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Our study has identified a gene expression profile associated with the progression of coronavirus disease 2019 (COVID-19) to pulmonary fibrosis in a pro-fibrotic environment similar to that found in fibrosing interstitial lung diseases (f-ILDs). Briefly, we noted the common expression of 86 genes in post-COVID-19 pulmonary fibrosis (post-CPF) and f-ILDs, indicating their likely involvement in perpetuating pulmonary fibrosis through shared fibrotic pathways—confirmed by the in-situ expression of MUC5ac and WNT10a. Furthermore, an additional set of 31 genes exhibited common expression patterns between subacute COVID-19, the so-called organizing diffuse alveolar damage (ODAD), and CPF, as well as f-ILDs. Among those genes, MUC4 and KRT5 were confirmed by immunohistochemistry, suggesting their role as potential predictors for the early outcome of possible pulmonary fibrosis.&lt;/p&gt;&lt;p&gt;Post-CPF is a long-term complication diagnosed by clinical setting, pulmonary function tests and/or image examinations.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Initially, some COVID-19-infected patients develop acute respiratory distress syndrome (ARDS) during the exudative phase of DAD, marked by cytokine storm and immune cell recruitment.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Following the inflammatory peak and pneumocyte injury, myofibroblast activation triggers extracellular matrix (ECM) deposition, leading to ODAD-phase which typically restores to typical lung architecture. However, some patients progress to pulmonary fibrosis&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; with morphological changes that are driven by a complex pathophysiological sequence and dynamic gene expression shifts. In the end, the fibrotic outcome can resemble other f-ILDs. Identifying gene expression levels linked to the progression from ODAD to CPF is crucial for finding biomarkers for early diagnosis. Our study aimed to identify potential biomarkers in gene expression associated with fibrotic progression to CPF by analyzing the transcriptome of patients with ODAD, CPF, f-ILDs and controls.&lt;/p&gt;&lt;p&gt;As previously described by Batah et al.,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; autopsies from the ODAD group revealed ODAD-phase with bronchiolar metaplasia, myxoid fibrosis, myofibroblastic activation and extensive alveolar septal thickening with collagen types I and III deposition (Table S1; Figure 1A–C). Meanwhile, after an average of 324.6 days following the initial positive nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients from the CPF group developed pulmonary fibrosis with bronchiolar metaplasia and parenchymal remodelling with increased collagen deposition, especially type I (suppinfo1; Figure 1D–F). Although the common remodelling profile, the differential gene expression (DGE) analysis between ODAD and CPF revealed distinct gene signatures (Figure S1A,B), Some of the top 20 DGEs reflect the manifestation of ARDS in ODAD patients (Figure S1C,D and Table S2). For example, the upregulatio","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization of human HSPCs with different cell fates in vivo using single-cell transcriptome analysis and lentiviral barcoding technology","authors":"Junnan Hua,&nbsp;Ke Wang,&nbsp;Yue Chen,&nbsp;Xiaojing Xu,&nbsp;Guoyi Dong,&nbsp;Yue Li,&nbsp;Rui Liu,&nbsp;Yecheng Xiong,&nbsp;Jiabin Ding,&nbsp;Tingting Zhang,&nbsp;Xinru Zeng,&nbsp;Yuxi Li,&nbsp;Haixi Sun,&nbsp;Ying Gu,&nbsp;Sixi Liu,&nbsp;Wenjie Ouyang,&nbsp;Chao Liu","doi":"10.1002/ctm2.70085","DOIUrl":"10.1002/ctm2.70085","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Hematopoietic stem and progenitor cells (HSPCs) possess the potential to produce all types of blood cells throughout their lives. It is well recognized that HSPCs are heterogeneous, which is of great significance for their clinical applications and the treatment of diseases associated with HSPCs. This study presents a novel technology called Single-Cell transcriptome Analysis and Lentiviral Barcoding (SCALeBa) to investigate the molecular mechanisms underlying the heterogeneity of human HSPCs in vivo. The SCALeBa incorporates a transcribed barcoding library and algorithm to analyze the individual cell fates and their gene expression profiles simultaneously. Our findings using SCALeBa reveal that HSPCs subset with stronger stemness highly expressed &lt;i&gt;MYL6B&lt;/i&gt;, &lt;i&gt;ATP2A2&lt;/i&gt;, &lt;i&gt;MYO19&lt;/i&gt;, &lt;i&gt;MDN1&lt;/i&gt;, &lt;i&gt;ING3&lt;/i&gt;, and so on. The high expression of &lt;i&gt;COA3&lt;/i&gt;, &lt;i&gt;RIF1&lt;/i&gt;, &lt;i&gt;RAB14&lt;/i&gt;, and &lt;i&gt;GOLGA4&lt;/i&gt; may contribute to the pluripotent-lineage differentiation of HSPCs. Moreover, the roles of the representative genes revealed in this study regarding the stemness of HPSCs were confirmed with biological experiments. HSPCs expressing &lt;i&gt;MRPL23&lt;/i&gt; and &lt;i&gt;RBM4&lt;/i&gt; genes may contribute to differentiation bias into myeloid and lymphoid lineage, respectively. In addition, transcription factor (TF) characteristics of lymphoid and myeloid differentiation bias HSPCs subsets were identified and linked to previously identified genes. Furthermore, the stemness, pluripotency, and differentiation-bias genes identified with SCALeBa were verified in another independent HSPCs dataset. Finally, this study proposes using the SCALeBa-generated tracking trajectory to improve the accuracy of pseudo-time analysis results. In summary, our study provides valuable insights for understanding the heterogeneity of human HSPCs in vivo and introduces a novel technology, SCALeBa, which holds promise for broader applications.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;SCALeBa and its algorithm are developed to study the molecular mechanism underlying human HSPCs identity and function.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The human HSPCs expressing &lt;i&gt;MYL6B, MYO19, ATP2A2, MDN1, ING3&lt;/i&gt;, and &lt;i&gt;PHF20&lt;/i&gt; may have the capability for high stemness.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The human HSPCs expressing &lt;i&gt;COA3, RIF1, RAB14&lt;/i&gt;, and &lt;i&gt;GOLGA4&lt;/i&gt; may have the capability for pluripotent-lineage differentiation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The human HSPCs expressing &lt;i&gt;MRPL23&lt;/i&gt; and &lt;i&gt;RBM4&lt;/i&gt; genes may have the capability to differentiate into myeloid and lymphoid lineage respectively in vivo.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The legit","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70083","DOIUrl":"https://doi.org/10.1002/ctm2.70083","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}