RESUMO
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Assuntos
Bursite , Humanos , c-Mer Tirosina Quinase/metabolismo , Inflamação/metabolismo , Membrana Sinovial/metabolismo , FibroseRESUMO
The present study aimed to examine the prevalence of posttraumatic stress response in reaction to the COVID-19, including posttraumatic-stress-disorder-like symptoms (PTSD-like symptoms) and depressive symptoms, among patients with pre-existing psychiatric illness. The socio-demographic and psychological correlates of PTSD-like symptoms were also examined. A total of 193 participants were recruited. More than 45% of the respondents reported significant PTSD-like symptoms related to the COVID-19; this group of patients also had a high level of pandemic-related depressive symptoms. High level of PTSD-like symptoms were predicted by rumination on concerns about the outbreak of COVID-19 and feeling of social isolation. They were also associated with hypervigilance to cues related to the pandemic. Our results suggested that the pandemic had taken a psychological toll on people living with psychiatric illness. Further research is needed to understand the development and mechanism of traumatic stress reaction in response to a prolonged infectious disease outbreak among this vulnerable population. Clinical attention is also called to mitigate the psychiatric sequalae of the pandemic in this vulnerable group of people.
Assuntos
COVID-19 , Transtornos de Estresse Pós-Traumáticos , Surtos de Doenças , Humanos , Pandemias , SARS-CoV-2 , Transtornos de Estresse Pós-Traumáticos/epidemiologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.
Assuntos
Contratura de Dupuytren/imunologia , Contratura de Dupuytren/metabolismo , Fibrose/imunologia , Fibrose/metabolismo , Células Estromais/metabolismo , Actinas/metabolismo , Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Contratura de Dupuytren/patologia , Fibrose/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Molecular , Miofibroblastos/metabolismo , Tetraspaninas/metabolismo , Microambiente Tumoral/fisiologiaRESUMO
BACKGROUND & AIMS: An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in white individuals. METHODS: We genotyped 166 relatives of gastric cancer patients, including 43 Helicobacter pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based, case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. RESULTS: Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR], 1.5; 95% confidence interval [CI]: 1.1-1.9) and noncardia gastric cancer (OR, 1.9; 95% CI: 1.3-2.8). The association was strongest for the diffuse histologic type (OR, 3.2; 95% CI: 1.2-10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR, 0.5; 95% CI: 0.3-0.9), esophageal adenocarcinoma (OR, 0.5; 95% CI: 0.3-0.9), and esophageal squamous cell carcinoma (OR, 0.4; 95% CI: 0.2-0.9). CONCLUSIONS: The rs2294008 polymorphism in PSCA increases the risk of noncardia gastric cancer and its precursors in white individuals but protects against proximal cancers.
Assuntos
Adenocarcinoma/genética , Antígenos de Neoplasias/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Neoplasias Gastrointestinais/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adenocarcinoma/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Estudos de Casos e Controles , Neoplasias Esofágicas/epidemiologia , Feminino , Proteínas Ligadas por GPI/genética , Gastrite Atrófica/epidemiologia , Gastrite Atrófica/genética , Neoplasias Gastrointestinais/epidemiologia , Predisposição Genética para Doença , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/genética , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Risco , População Branca/genéticaRESUMO
Over recent years, genome-wide association studies have contributed to our understanding of genetic susceptibility to sporadic cancer. In this study, we assessed the association between upper gastrointestinal cancer risk and four genome-wide association studies-identified single nucleotide polymorphisms (SNPs), implicated earlier in prostate and colorectal cancer susceptibility. Genotyping for each SNP was performed in two independent Caucasian population-based case-control studies. The first study comprised 290 gastric cancer cases and 374 controls. The second study included 185 noncardia gastric cancers, 123 cardia cancers, 158 oesophageal cancers and 209 controls. Odds ratios (ORs) were computed from logistic models and adjusted for potential confounding variables. An inverse association was observed between the SNP rs1447295, located at 8q24, and gastric cancer risk in the first study population (OR=0.63; 95% confidence interval: 0.41-0.97). A positive association was observed for the same SNP and oesophageal squamous cell carcinoma in the second study population (OR=7.43; 95% confidence interval: 1.37-49.98). No significant associations were detected in either study for the three remaining SNPs (rs6983297, rs10505477 and rs719725). Our data represent novel findings on heritable susceptibility to gastric and oesophageal cancer and warrant validation in additional populations.