Science Translational Medicine最新文献

{"title":"Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models","authors":"Alice Dejoux,&nbsp;Qianqian Zhu,&nbsp;Christelle Ganneau,&nbsp;Odile Richard-Le Goff,&nbsp;Ophélie Godon,&nbsp;Julien Lemaitre,&nbsp;Francis Relouzat,&nbsp;François Huetz,&nbsp;Aurélien Sokal,&nbsp;Alexis Vandenberghe,&nbsp;Cyprien Pecalvel,&nbsp;Lise Hunault,&nbsp;Thomas Derenne,&nbsp;Caitlin M. Gillis,&nbsp;Bruno Iannascoli,&nbsp;Yidan Wang,&nbsp;Thierry Rose,&nbsp;Christel Mertens,&nbsp;Pascale Nicaise-Roland,&nbsp;NASA Study Group,&nbsp;Patrick England,&nbsp;Matthieu Mahévas,&nbsp;Luc de Chaisemartin,&nbsp;Roger Le Grand,&nbsp;Hélène Letscher,&nbsp;Frederick Saul,&nbsp;Cédric Pissis,&nbsp;Ahmed Haouz,&nbsp;Laurent L. Reber,&nbsp;Pascal Chappert,&nbsp;Friederike Jönsson,&nbsp;Didier G. Ebo,&nbsp;Gaël A. Millot,&nbsp;Sylvie Bay,&nbsp;Sylvie Chollet-Martin,&nbsp;Aurélie Gouel-Chéron,&nbsp;Pierre Bruhns","doi":"10.1126/scitranslmed.ado4463","DOIUrl":"10.1126/scitranslmed.ado4463","url":null,"abstract":"<div >Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML","authors":"Bijender Kumar,&nbsp;Anand Singh,&nbsp;Rafet Basar,&nbsp;Nadima Uprety,&nbsp;Ye Li,&nbsp;Huihui Fan,&nbsp;Ana Karen Nunez Cortes,&nbsp;Mecit Kaplan,&nbsp;Sunil Acharya,&nbsp;Hila Shaim,&nbsp;Anna C Xu,&nbsp;Manrong Wu,&nbsp;Emily Ensley,&nbsp;Dexing Fang,&nbsp;Pinaki P. Banerjee,&nbsp;Luciana Melo Garcia,&nbsp;Silvia Tiberti,&nbsp;Paul Lin,&nbsp;Hind Rafei,&nbsp;Maliha Nuzhat Munir,&nbsp;Madison Moore,&nbsp;Mayra Shanley,&nbsp;Mayela Mendt,&nbsp;Lucila N. Kerbauy,&nbsp;Bin Liu,&nbsp;Alexander Biederstädt,&nbsp;Elif Gokdemir,&nbsp;Susmita Ghosh,&nbsp;Kiran Kundu,&nbsp;Francia Reyes-Silva,&nbsp;Xin Ru Jiang,&nbsp;Xinhai Wan,&nbsp;April L. Gilbert,&nbsp;Merve Dede,&nbsp;Vakul Mohanty,&nbsp;Jinzhuang Dou,&nbsp;Patrick Zhang,&nbsp;Enli Liu,&nbsp;Luis Muniz-Feliciano,&nbsp;Gary M. Deyter,&nbsp;Abhinav K. Jain,&nbsp;Juan Jose Rodriguez-Sevilla,&nbsp;Simona Colla,&nbsp;Guillermo Garcia-Manero,&nbsp;Elizabeth J. Shpall,&nbsp;Ken Chen,&nbsp;Hussein A. Abbas,&nbsp;Kunal Rai,&nbsp;Katayoun Rezvani,&nbsp;May Daher","doi":"10.1126/scitranslmed.adp0004","DOIUrl":"10.1126/scitranslmed.adp0004","url":null,"abstract":"<div >Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as <i>HAVCR2</i>, <i>LAG3</i>, <i>TIGIT</i>, and <i>CTLA4</i>. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories","authors":"João Da Silva Filho,&nbsp;Vanessa Herder,&nbsp;Matthew P. Gibbins,&nbsp;Monique Freire dos Reis,&nbsp;Gisely Cardoso Melo,&nbsp;Michael J. Haley,&nbsp;Carla Cristina Judice,&nbsp;Fernando Fonseca Almeida Val,&nbsp;Mayla Borba,&nbsp;Tatyana Almeida Tavella,&nbsp;Vanderson de Sousa Sampaio,&nbsp;Charalampos Attipa,&nbsp;Fiona McMonagle,&nbsp;Derek Wright,&nbsp;Marcus Vinicius Guimaraes de Lacerda,&nbsp;Fabio Trindade Maranhão Costa,&nbsp;Kevin N. Couper,&nbsp;Wuelton Marcelo Monteiro,&nbsp;Luiz Carlos de Lima Ferreira,&nbsp;Christopher Alan Moxon,&nbsp;Massimo Palmarini,&nbsp;Matthias Marti","doi":"10.1126/scitranslmed.adk9149","DOIUrl":"10.1126/scitranslmed.adk9149","url":null,"abstract":"<div >COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: “early death” (&lt;15 days until death) and “late death” (&gt;15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2⁺ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2⁺ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (T_H17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, T_H2 responses, and anti-inflammatory–mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis","authors":"Ishtiaq Jeelani,&nbsp;Jae-Su Moon,&nbsp;Flavia Franco da Cunha,&nbsp;Chanond A. Nasamran,&nbsp;Seokhyun Jeon,&nbsp;Xinhang Zhang,&nbsp;Gautam K. Bandyopadhyay,&nbsp;Katarzyna Dobaczewska,&nbsp;Zbigniew Mikulski,&nbsp;Mojgan Hosseini,&nbsp;Xiao Liu,&nbsp;Tatiana Kisseleva,&nbsp;David A. Brenner,&nbsp;Seema Singh,&nbsp;Rohit Loomba,&nbsp;Minkyu Kim,&nbsp;Yun Sok Lee","doi":"10.1126/scitranslmed.adi0284","DOIUrl":"10.1126/scitranslmed.adi0284","url":null,"abstract":"<div >Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow–derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)– and extracellular signal–regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α–dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage–specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α–specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype–specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adi0284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170428","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":"A skin-interfaced microfluidic platform supports dynamic sweat biochemical analysis during human exercise","authors":"Soongwon Cho,&nbsp;Samy M. Shaban,&nbsp;Ruihao Song,&nbsp;Haohui Zhang,&nbsp;Dasom Yang,&nbsp;Min-Jae Kim,&nbsp;Yirui Xiong,&nbsp;Xiuyuan Li,&nbsp;Kenneth Madsen,&nbsp;Sarena Wapnick,&nbsp;Shifan Zhang,&nbsp;Ziyu Chen,&nbsp;Jiwon Kim,&nbsp;Gianna Guinto,&nbsp;Michelle Li,&nbsp;Minkyu Lee,&nbsp;Ravi F. Nuxoll,&nbsp;Shaghayegh Shajari,&nbsp;Jin Wang,&nbsp;Seongeun Son,&nbsp;Jihoon Shin,&nbsp;Alexander J. Aranyosi,&nbsp;Donald E. Wright,&nbsp;Tae-il Kim,&nbsp;Roozbeh Ghaffari,&nbsp;Yonggang Huang,&nbsp;Dong-Hwan Kim,&nbsp;John A. Rogers","doi":"10.1126/scitranslmed.ado5366","DOIUrl":"10.1126/scitranslmed.ado5366","url":null,"abstract":"<div >Blood lactate concentration is an established circulating biomarker for measuring muscle acidity and can be evaluated for monitoring endurance, training routines, or athletic performance. Sweat is an alternative biofluid that may serve similar purposes and offers the advantage of noninvasive collection and continuous monitoring. The relationship between blood lactate and dynamic sweat biochemistry for wearable engineering applications in physiological fitness remains poorly defined. Here, we developed a microfluidic wearable band with an integrated colorimetric timer and biochemical assays that temporally captures sweat and measures pH and lactate concentration. A colorimetric silver nanoplasmonic assay was used to measure the concentration of lactate, and dye-conjugated SiO₂ nanoparticle–agarose composite materials supported dynamic pH analysis. We evaluated these sweat biomarkers in relation to blood lactate in human participant studies during cycling exercise of varying intensity. Iontophoresis-generated sweat pH from regions of actively working muscles decreased with increasing heart rate during exercise and was negatively correlated with blood lactate concentration. In contrast, sweat pH from nonworking muscles did not correlate with blood lactate concentration. Changes in sweat pH and blood lactate were observed in participants who did not regularly exercise but not in individuals who regularly exercised, suggesting a relationship to physical fitness and supporting further development for noninvasive, biochemical fitness evaluations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision adjuvants for pediatric vaccines","authors":"Anjali Singh,&nbsp;César Boggiano,&nbsp;Dwight E. Yin,&nbsp;Laura Polakowski,&nbsp;Sai P. Majji,&nbsp;Wolfgang W. Leitner,&nbsp;Ofer Levy,&nbsp;Kristina De Paris","doi":"10.1126/scitranslmed.abq7378","DOIUrl":"10.1126/scitranslmed.abq7378","url":null,"abstract":"<div >Elucidating optimal vaccine adjuvants for harnessing age-specific immune pathways to enhance magnitude, breadth, and durability of immunogenicity remains a key gap area in pediatric vaccine design. A better understanding of age-specific adjuvants will inform precision discovery and development of safe and effective vaccines for protecting children from preventable infectious diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer","authors":"Zhuo Chen,&nbsp;Wenxiang Ji,&nbsp;Wenxin Feng,&nbsp;Jingchuan Cui,&nbsp;Yuchen Wang,&nbsp;Fan Li,&nbsp;Jiachen Chen,&nbsp;Ziheng Guo,&nbsp;Liliang Xia,&nbsp;Xiaokuan Zhu,&nbsp;Xiaomin Niu,&nbsp;Yanshuang Zhang,&nbsp;Ziming Li,&nbsp;Alice S. T. Wong,&nbsp;Shun Lu,&nbsp;Weiliang Xia","doi":"10.1126/scitranslmed.adl3598","DOIUrl":"10.1126/scitranslmed.adl3598","url":null,"abstract":"<div >With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adl3598","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133635","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":"Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months","authors":"Xue Zhang,&nbsp;Adam Pines,&nbsp;Patrick Stetz,&nbsp;Andrea N. Goldstein-Piekarski,&nbsp;Lan Xiao,&nbsp;Nan Lv,&nbsp;Leonardo Tozzi,&nbsp;Philip W. Lavori,&nbsp;Mark B. Snowden,&nbsp;Elizabeth M. Venditti,&nbsp;Joshua M. Smyth,&nbsp;Trisha Suppes,&nbsp;Olusola Ajilore,&nbsp;Jun Ma,&nbsp;Leanne M. Williams","doi":"10.1126/scitranslmed.adh3172","DOIUrl":"10.1126/scitranslmed.adh3172","url":null,"abstract":"<div >Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of CCL7 improves endothelial dysfunction and vasculopathy in mouse models of diabetes mellitus","authors":"Ting-Ting Chang,&nbsp;You-Zhen Li,&nbsp;Hsiao-Wei Mo,&nbsp;Ching Chen,&nbsp;Liang-Yu Lin,&nbsp;Chia-Chi Chang,&nbsp;Jaw-Wen Chen","doi":"10.1126/scitranslmed.adn1507","DOIUrl":"10.1126/scitranslmed.adn1507","url":null,"abstract":"<div >Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. <i>Ccl7</i> knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in <i>db/db</i> mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific <i>Ccl7</i>-knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 763","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum for the Research Article “MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells” by S. Perrin et al.","authors":"","doi":"10.1126/scitranslmed.ads3171","DOIUrl":"10.1126/scitranslmed.ads3171","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 762","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}