The Journal of Pathology最新文献

{"title":"Kisspeptin regulates airway hyperresponsiveness and remodeling in a mouse model of asthma","authors":"Niyati A Borkar,&nbsp;Nilesh Sudhakar Ambhore,&nbsp;Premanand Balraj,&nbsp;Yogaraj S Ramakrishnan,&nbsp;Venkatachalem Sathish","doi":"10.1002/path.6086","DOIUrl":"10.1002/path.6086","url":null,"abstract":"<p>Asthma is a multifactorial disease of origin characterized by airway hyperresponsiveness (AHR) and airway remodeling. Several pieces of evidence from other pathologies suggest that Kisspeptins (Kp) regulate cell proliferation, migration, and invasion, mechanisms that are highly relevant to asthma. Our recent <i>in vitro</i> studies show Kp-10 (active peptide of Kp), via its receptor, KISS1R, inhibits human airway smooth muscle cell proliferation. Here, we hypothesize a crucial role for Kp-10 in regulating AHR and airway remodeling <i>in vivo</i>. Utilizing C57BL/6J mice, we assessed the effect of chronic intranasal Kp-10 exposure on mixed allergen (MA)-induced mouse model of asthma. MA-challenged mice showed significant deterioration of lung function compared to those exposed to vehicle (DPBS); Kp-10 treatment significantly improved the MA-altered lung functions. Mice treated with Kp-10 alone did not show any notable changes in lung functions. MA-exposed mice showed a significant reduction in KISS1R expression as compared to vehicle alone. MA-challenged mice showed significant alterations in immune cell infiltration in the airways and remodeling changes. Proinflammatory cytokines were significantly increased upon MA exposure, an effect abrogated by Kp-10 treatment. Furthermore, biochemical and histological studies showed Kp-10 exposure significantly reduced MA-induced smooth muscle mass and soluble collagen in the lung. Overall, our findings highlight the effect of chronic Kp-10 exposure in regulating MA-induced AHR and remodeling. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"339-352"},"PeriodicalIF":7.3,"publicationDate":"2023-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6227031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spasmolytic polypeptide-expressing metaplasia (SPEM) cell lineages can be an origin of gastric cancer","authors":"James R Goldenring","doi":"10.1002/path.6089","DOIUrl":"10.1002/path.6089","url":null,"abstract":"<p>Intestinal-type gastric cancer arises in a field of precancerous metaplastic lineages. Two types of metaplastic glands are found in the stomachs of humans with the characteristics of pyloric metaplasia or intestinal metaplasia. While spasmolytic polypeptide-expressing metaplasia (SPEM) cell lineages have been identified in both pyloric metaplasia and incomplete intestinal metaplasia, it has been unclear whether SPEM lineages or intestinal lineages can give rise to dysplasia and cancer. A recent article published in <i>The Journal of Pathology</i> describes a patient with evidence of an activating <i>Kras</i>(G12D) mutation in SPEM that is propagated into adenomatous and cancerous lesions which manifest further oncogenic mutations. This case therefore supports the concept that SPEM lineages can serve as a direct precursor for dysplasia and intestinal-type gastric cancer. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 2","pages":"109-111"},"PeriodicalIF":7.3,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6138216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusion with type 2 macrophages induces melanoma cell heterogeneity that potentiates immunological escape from cytotoxic T lymphocytes","authors":"Tomoyuki Minowa,&nbsp;Yoshihiko Hirohashi,&nbsp;Kenji Murata,&nbsp;Kenta Sasaki,&nbsp;Toshiya Handa,&nbsp;Munehide Nakatsugawa,&nbsp;Yuka Mizue,&nbsp;Aiko Murai,&nbsp;Terufumi Kubo,&nbsp;Takayuki Kanaseki,&nbsp;Tomohide Tsukahara,&nbsp;Sadahiro Iwabuchi,&nbsp;Shinichi Hashimoto,&nbsp;Akemi Ishida-Yamamoto,&nbsp;Hisashi Uhara,&nbsp;Toshihiko Torigoe","doi":"10.1002/path.6083","DOIUrl":"10.1002/path.6083","url":null,"abstract":"<p>Evasion from immunity is a major obstacle to the achievement of successful cancer immunotherapy. Hybrids derived from cell–cell fusion are theoretically associated with tumor heterogeneity and progression by conferring novel properties on tumor cells, including drug resistance and metastatic capacity; however, their impact on immune evasion remains unknown. Here, we investigated the potency of tumor–macrophage hybrids in immune evasion. Hybrids were established by co-culture of a melanoma cell line (A375 cells) and type 2 macrophages. The hybrids showed greater migration ability and greater tumorigenicity than the parental melanoma cells. The hybrids showed heterogeneous sensitivity to New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T-cell receptor-transduced T (TCR-T) cells and two out of four hybrid clones showed less sensitivity to TCR-T compared with the parental cells. An <i>in vitro</i> tumor heterogeneity model revealed that the TCR-T cells preferentially killed the parental cells compared with the hybrids and the survival rate of the hybrids was higher than that of the parental cells, indicating that the hybrids evade killing by TCR-T cells efficiently. Analysis of a single-cell RNA sequencing dataset of patients with melanoma revealed that a few macrophages expressed RNA encoding melanoma differentiation antigens including melan A, tyrosinase, and premelanosome protein, which indicated the presence of hybrids in primary melanoma. In addition, the number of potential hybrids was correlated with a poorer response to immune checkpoint blockade. These results provide evidence that melanoma–macrophage fusion has a role in tumor heterogeneity and immune evasion. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"304-316"},"PeriodicalIF":7.3,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6052833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutational landscape of primary spinal cord astrocytoma","authors":"Lei Cheng,&nbsp;Fan Zhang,&nbsp;Xingang Zhao,&nbsp;Leiming Wang,&nbsp;Wanru Duan,&nbsp;Jian Guan,&nbsp;Kai Wang,&nbsp;Zhenlei Liu,&nbsp;Xingwen Wang,&nbsp;Zuowei Wang,&nbsp;Hao Wu,&nbsp;Zan Chen,&nbsp;Lianghong Teng,&nbsp;Yifei Li,&nbsp;Fei Xiao,&nbsp;Tao Fan,&nbsp;Fengzeng Jian","doi":"10.1002/path.6084","DOIUrl":"10.1002/path.6084","url":null,"abstract":"<p>Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, <i>H3F3A</i> (47.1%), <i>TP53</i> (29.4%), <i>NF1</i> (19.6%), <i>ATRX</i> (17.6%), and <i>PPM1D</i> (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: <i>HNRNPC</i>, <i>SYNE1</i>, and <i>RBM10</i>. Several germline mutations, including three variants (<i>SLC16A8</i> rs2235573, <i>LMF1</i> rs3751667, <i>FAM20C</i> rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene <i>CDK4</i> was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"317-328"},"PeriodicalIF":7.3,"publicationDate":"2023-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6078329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFN-γ and androgens disrupt mitochondrial function in murine myocytes","authors":"John M Fenimore,&nbsp;Danielle A Springer,&nbsp;Maria E Romero,&nbsp;Elijah F Edmondson,&nbsp;Dan W McVicar,&nbsp;Sudhirkumar Yanpallewar,&nbsp;Michael Sanford,&nbsp;Thea Spindel,&nbsp;Elizabeth Engle,&nbsp;Thomas J Meyer,&nbsp;Julio C Valencia,&nbsp;Howard A Young","doi":"10.1002/path.6081","DOIUrl":"10.1002/path.6081","url":null,"abstract":"<p>The effect of cytokines on non-traditional immunological targets under conditions of chronic inflammation is an ongoing subject of study. Fatigue is a symptom often associated with autoimmune diseases. Chronic inflammatory response and activated cell-mediated immunity are associated with cardiovascular myopathies which can be driven by muscle weakness and fatigue. Thus, we hypothesize that immune dysfunction-driven changes in myocyte mitochondria may play a critical role in fatigue-related pathogenesis. We show that persistent low-level expression of IFN-γ in designated IFN-γ AU-Rich Element deletion mice (ARE mice) under androgen exposure resulted in mitochondrial and metabolic deficiencies in myocytes from male or castrated ARE mice. Most notably, echocardiography unveiled that low ejection fraction in the left ventricle post-stress correlated with mitochondrial deficiencies, explaining how heart function decreases under stress. We report that inefficiencies and structural changes in mitochondria, with changes to expression of mitochondrial genes, are linked to male-biased fatigue and acute cardiomyopathy under stress. Our work highlights how male androgen hormone backgrounds and active autoimmunity reduce mitochondrial function and the ability to cope with stress and how pharmacological blockade of stress signal protects heart function. These studies provide new insight into the diverse actions of IFN-γ in fatigue, energy metabolism, and autoimmunity. © 2023 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"276-288"},"PeriodicalIF":7.3,"publicationDate":"2023-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5828257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Receptor for hyaluronan-mediated motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients","authors":"Sarah E Tarullo,&nbsp;Yuyu He,&nbsp;Claire Daughters,&nbsp;Todd P Knutson,&nbsp;Christine M Henzler,&nbsp;Matthew A Price,&nbsp;Ryan Shanley,&nbsp;Patrice Witschen,&nbsp;Cornelia Tolg,&nbsp;Rachael E Kaspar,&nbsp;Caroline Hallstrom,&nbsp;Lyubov Gittsovich,&nbsp;Megan L Sulciner,&nbsp;Xihong Zhang,&nbsp;Colleen L Forster,&nbsp;Carol A Lange,&nbsp;Oleg Shats,&nbsp;Michelle Desler,&nbsp;Kenneth H Cowan,&nbsp;Douglas Yee,&nbsp;Kathryn L Schwertfeger,&nbsp;Eva A Turley,&nbsp;James B McCarthy,&nbsp;Andrew C Nelson","doi":"10.1002/path.6082","DOIUrl":"10.1002/path.6082","url":null,"abstract":"<p>Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant synthesis, processing, and signaling of hyaluronan (HA). Hyaluronan-mediated motility receptor (RHAMM, CD168; <i>HMMR</i>) is an HA receptor enabling tumor cells to sense and respond to this aberrant TME during breast cancer progression. Previous studies have associated RHAMM expression with breast tumor progression; however, cause and effect mechanisms are incompletely established. Focused gene expression analysis of an internal breast cancer patient cohort confirmed that increased <i>RHAMM</i> expression correlates with aggressive clinicopathological features. To probe mechanisms, we developed a novel 27-gene RHAMM-related signature (RRS) by intersecting differentially expressed genes in lymph node (LN)-positive patient cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validated in an independent cohort. We demonstrate that the RRS predicts for poor survival and is enriched for cell cycle and TME-interaction pathways. Further analyses using CRISPR/Cas9-generated <i>RHAMM</i>^−/− breast cancer cells provided direct evidence that RHAMM promotes invasion <i>in vitro</i> and <i>in vivo</i>. Immunohistochemistry studies highlighted heterogeneous RHAMM protein expression, and spatial transcriptomics associated the RRS with RHAMM-high microanatomic foci. We conclude that RHAMM upregulation leads to the formation of ‘invasive niches’, which are enriched in RRS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"289-303"},"PeriodicalIF":7.3,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/path.6082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6046516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer","authors":"Rafael Mena-Osuna,&nbsp;Ana Mantrana,&nbsp;Silvia Guil-Luna,&nbsp;María Teresa Sánchez-Montero,&nbsp;Carmen Navarrete-Sirvent,&nbsp;Teresa Morales-Ruiz,&nbsp;Aurora Rivas-Crespo,&nbsp;Marta Toledano-Fonseca,&nbsp;María Victoria García-Ortíz,&nbsp;Gema García-Jurado,&nbsp;María Auxiliadora Gómez-España,&nbsp;Rafael González-Fernández,&nbsp;Carlos Villar,&nbsp;Francisco Javier Medina-Fernández,&nbsp;José Manuel Villalba,&nbsp;Enrique Aranda,&nbsp;Antonio Rodríguez-Ariza","doi":"10.1002/path.6080","DOIUrl":"10.1002/path.6080","url":null,"abstract":"<p>S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR-low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8⁺ T cells. Notably, GSNOR-low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR-Cas9-mediated generation of GSNOR gene knockout (KO) CRC cells confirmed <i>in vitro</i> and <i>in vivo</i> that GSNOR-deficiency conferred higher tumorigenic and tumor-initiating capacities. Moreover, GSNOR-KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR-KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2-deoxyglucose (2DG), and a fragmented mitochondrial network. Real-time metabolic analysis revealed that GSNOR-KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient-derived xenografts and organoids from clinical GSNOR-low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"261-275"},"PeriodicalIF":7.3,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5705318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative analysis of transcriptomic and metabolomic profiles reveals abnormal phosphatidylinositol metabolism in follicles from endometriosis-associated infertility patients","authors":"Yongdong Dai,&nbsp;Xiang Lin,&nbsp;Na Liu,&nbsp;Libing Shi,&nbsp;Feng Zhuo,&nbsp;Qianmeng Huang,&nbsp;Weijia Gu,&nbsp;Fanxuan Zhao,&nbsp;Yi Zhang,&nbsp;Yinli Zhang,&nbsp;Yinbin Pan,&nbsp;Songying Zhang","doi":"10.1002/path.6079","DOIUrl":"10.1002/path.6079","url":null,"abstract":"<p>Endometriosis is a common gynecological disorder that causes female infertility. Our recent research found that excessive oxidative stress in ovaries of endometriosis patients induced senescence of cumulus granulosa cells. Here, we analyzed the transcriptomic and metabolomics profiles of follicles in a mouse model of endometriosis and in patients with endometriosis and investigated the potential function of changed metabolites in granulosa cells. RNA-sequencing indicated that both endometriosis lesions and oxidative stress in mice induced abnormalities of reactive oxidative stress, steroid hormone biosynthesis, and lipid metabolism. The mouse model and women with endometriosis showed altered lipid metabolism. Nontargeted metabolite profiling of follicular fluid from endometriosis and male-factor infertility patients by liquid chromatography mass spectrometry identified 55 upregulated and 67 downregulated metabolites. These differential metabolites were mainly involved in steroid hormone biosynthesis and glycerophospholipid metabolism. Phosphatidylinositol (PI 16:0/18:2) was significantly elevated in follicular fluid from endometriosis patients compared with controls (<i>p</i> &lt; 0.05), while lysophosphatidylinositol (LPI 18:2, 20:2, 18:1, 20:3 and 18:3) was reduced (<i>p</i> &lt; 0.05). Upregulated PI and downregulated LPI correlated with oocyte retrieval number and mature oocyte number. LPI inhibited cellular reactive oxidative stress induced by hemin in granulosa cells. Cell proliferation inhibition, senescence, and apoptosis induced by hemin were partially reversed by LPI. Moreover, LPI administration rescued hemin blocking of cumulus-oocyte complex expansion and stimulated expression of ovulation-related genes. Transcriptomic Switching mechanism at 5' end of the RNA transcript sequencing and western blot revealed that LPI effects on granulosa cells were associated with its regulation of MAPK-ERK1/2 signaling, which was suppressed in the presence of hemin. In conclusion, our results revealed the dysregulation of lipid metabolism in endometriotic follicles. LPI may represent a novel agent for <i>in vitro</i> follicular culture that reverses the excessive oxidative stress from endometriotic lesions. © 2023 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"248-260"},"PeriodicalIF":7.3,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5773606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea","authors":"Jinnan Xiang,&nbsp;Haoyu Wang,&nbsp;Qianqian Tao,&nbsp;Wenxi Li,&nbsp;Yanfei Huang,&nbsp;Yushuo Zhang,&nbsp;Linan Yang,&nbsp;Shiyi Zhang","doi":"10.1002/path.6078","DOIUrl":"10.1002/path.6078","url":null,"abstract":"<p>Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with <i>in vivo</i> results, we determined that palbociclib enhanced intestinal organoid and <i>ex vivo</i> tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 3","pages":"235-247"},"PeriodicalIF":7.3,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6086783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MIF inhibition alleviates vitiligo progression by suppressing CD8+ T cell activation and proliferation","authors":"Jianru Chen,&nbsp;Weinan Guo,&nbsp;Pengran Du,&nbsp;Tingting Cui,&nbsp;Yuqi Yang,&nbsp;Yinghan Wang,&nbsp;Pan Kang,&nbsp;Zhe Zhang,&nbsp;Qi Wang,&nbsp;Zhubiao Ye,&nbsp;Ling Liu,&nbsp;Zhe Jian,&nbsp;Tianwen Gao,&nbsp;Huijie Bian,&nbsp;Shuli Li,&nbsp;Chunying Li","doi":"10.1002/path.6073","DOIUrl":"10.1002/path.6073","url":null,"abstract":"<p>In vitiligo, autoreactive CD8⁺ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8⁺ T cells remains ill-defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8⁺ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, <i>in vitro</i> experiments indicated that MIF-inhibition suppressed the activation and proliferation of CD8⁺ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8⁺ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8⁺ T cells derived from MIF-inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8⁺ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"260 1","pages":"84-96"},"PeriodicalIF":7.3,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5846648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}