Journal of Clinical Investigation最新文献_第7页

Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis. 诱导性 CCR2+ 非典型单核细胞介导癌症转移的消退。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI179527

Xianpeng Liu, Ziyou Ren, Can Tan, Félix L Núñez-Santana, Megan E Kelly, Yuanqing Yan, Haiying Sun, Hiam Abdala-Valencia, Wenbin Yang, Qiang Wu, Takahide Toyoda, Marija Milisav, S Marina Casalino-Matsuda, Emilia Lecuona, Emily Jeong Cerier, Lena J Heung, Mohamed E Abazeed, Harris Perlman, Ruli Gao, Navdeep S Chandel, G R Scott Budinger, Ankit Bharat

{"title":"Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis.","authors":"Xianpeng Liu, Ziyou Ren, Can Tan, Félix L Núñez-Santana, Megan E Kelly, Yuanqing Yan, Haiying Sun, Hiam Abdala-Valencia, Wenbin Yang, Qiang Wu, Takahide Toyoda, Marija Milisav, S Marina Casalino-Matsuda, Emilia Lecuona, Emily Jeong Cerier, Lena J Heung, Mohamed E Abazeed, Harris Perlman, Ruli Gao, Navdeep S Chandel, G R Scott Budinger, Ankit Bharat","doi":"10.1172/JCI179527","DOIUrl":"10.1172/JCI179527","url":null,"abstract":"A major limitation of immunotherapy is the development of resistance resulting from cancer-mediated inhibition of host lymphocytes. Cancer cells release CCL2 to recruit classical monocytes expressing its receptor CCR2 for the promotion of metastasis and resistance to immunosurveillance. In the circulation, some CCR2-expressing classical monocytes lose CCR2 and differentiate into intravascular nonclassical monocytes that have anticancer properties but are unable to access extravascular tumor sites. We found that in mice and humans, an ontogenetically distinct subset of naturally underrepresented CCR2-expressing nonclassical monocytes was expanded during inflammatory states such as organ transplant and COVID-19 infection. These cells could be induced during health by treatment of classical monocytes with small-molecule activators of NOD2. The presence of CCR2 enabled these inducible nonclassical monocytes to infiltrate both intra- and extravascular metastatic sites of melanoma, lung, breast, and colon cancer in murine models, and they reversed the increased susceptibility of Nod2-/- mutant mice to cancer metastasis. Within the tumor colonies, CCR2+ nonclassical monocytes secreted CCL6 to recruit NK cells that mediated tumor regression, independent of T and B lymphocytes. Hence, pharmacological induction of CCR2+ nonclassical monocytes might be useful for immunotherapy-resistant cancers.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 22","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638912","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}

引用次数: 0

IFN-γ and YAP lead epithelial cells astray after severe respiratory infection. 严重呼吸道感染后，IFN-γ 和 YAP 将上皮细胞引入歧途。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI185072

Bradley E Hiller, Joseph P Mizgerd

引用次数: 0

The expanding application of antisense oligonucleotides to neurodegenerative diseases. 扩大反义寡核苷酸在神经退行性疾病中的应用。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI186116

Charlotte J Sumner, Timothy M Miller

引用次数: 0

Toward a better understanding of chronic hepatitis B virus infection. 更好地了解慢性乙型肝炎病毒感染。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI185568

Barbara Rehermann

引用次数: 0

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation. 有神经症状的 HIV-1 CSF 逸出与中枢神经系统 T 细胞的复制和炎症有关。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI176358

Laura P Kincer, Ameet Dravid, Mattia Trunfio, Andrea Calcagno, Shuntai Zhou, Riccardo Vercesi, Serena Spudich, Magnus Gisslen, Richard W Price, Paola Cinque, Sarah B Joseph

{"title":"Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation.","authors":"Laura P Kincer, Ameet Dravid, Mattia Trunfio, Andrea Calcagno, Shuntai Zhou, Riccardo Vercesi, Serena Spudich, Magnus Gisslen, Richard W Price, Paola Cinque, Sarah B Joseph","doi":"10.1172/JCI176358","DOIUrl":"10.1172/JCI176358","url":null,"abstract":"During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 19","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347637","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}

引用次数: 0

Clonal hematopoiesis and atherosclerosis. 克隆造血与动脉粥样硬化

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI180066

Ohad Oren, Aeron M Small, Peter Libby

{"title":"Clonal hematopoiesis and atherosclerosis.","authors":"Ohad Oren, Aeron M Small, Peter Libby","doi":"10.1172/JCI180066","DOIUrl":"10.1172/JCI180066","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 19","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347630","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}

引用次数: 0

Distinct landscape and clinical implications of therapy-related clonal hematopoiesis. 与治疗相关的克隆性造血的独特景观和临床意义。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI180069

Koichi Takahashi, Daisuke Nakada, Margaret Goodell

{"title":"Distinct landscape and clinical implications of therapy-related clonal hematopoiesis.","authors":"Koichi Takahashi, Daisuke Nakada, Margaret Goodell","doi":"10.1172/JCI180069","DOIUrl":"10.1172/JCI180069","url":null,"abstract":"Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 19","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347632","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}

引用次数: 0

The arc of discovery, from the description of cystic fibrosis to effective treatments. 从囊肿性纤维化的描述到有效治疗方法的发现历程。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI186231

Michael J Welsh

引用次数: 0

Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma. 双重靶向巨噬细胞和小胶质细胞是PTEN缺陷胶质母细胞瘤模型的治疗漏洞。

IF 4.1 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI178628

Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen

{"title":"Dual targeting macrophages and microglia is a therapeutic vulnerability in models of PTEN-deficient glioblastoma.","authors":"Yang Liu, Junyan Wu, Hinda Najem, Yiyun Lin, Lizhi Pang, Fatima Khan, Fei Zhou, Heba Ali, Amy B Heimberger, Peiwen Chen","doi":"10.1172/JCI178628","DOIUrl":"10.1172/JCI178628","url":null,"abstract":"Tumor-associated macrophages and microglia (TAMs) are critical for tumor progression and therapy resistance in glioblastoma (GBM), a type of incurable brain cancer. We previously identified lysyl oxidase (LOX) and olfactomedin like-3 (OLFML3) as essential macrophage and microglia chemokines, respectively, in GBM. Here, single-cell transcriptomics and multiplex sequential immunofluorescence followed by functional studies demonstrate that macrophages negatively correlate with microglia in the GBM tumor microenvironment. LOX inhibition in PTEN-deficient GBM cells upregulates OLFML3 expression via the NF-κB-PATZ1 signaling pathway, inducing a compensatory increase of microglia infiltration. Dual targeting macrophages and microglia via inhibition of LOX and the CLOCK-OLFML3 axis generates potent antitumor effects and offers a complete tumor regression in more than 60% of animals when combined with anti-PD1 therapy in PTEN-deficient GBM mouse models. Thus, our findings provide a translational triple therapeutic strategy for this lethal disease.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365423","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}

引用次数: 0

Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation. 在过敏性气道炎症中，雄性激素信号限制谷氨酰胺酵解，从而驱动具有性别特异性的 Th17 新陈代谢。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2024-10-01 DOI: 10.1172/JCI177242

Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb

{"title":"Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.","authors":"Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb","doi":"10.1172/JCI177242","DOIUrl":"https://doi.org/10.1172/JCI177242","url":null,"abstract":"Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466684","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}

引用次数: 0