Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of ...cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
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•The Rb tumor suppressor inhibits reprogramming of fibroblasts to iPSCs•The effect of Rb on reprogramming is independent of cell-cycle regulation•Rb promotes assembly of repressive chromatin at pluripotency network genes•Deletion of Sox2 prevents cancer initiation upon loss of Rb in mice
To investigate how the Rb tumor suppressor inhibits cellular dedifferentiation, Kareta et al. utilized iPSC reprogramming as a cellular system and observed that Rb restricts reprogramming by silencing pluripotency genes and networks. Rb repression of one pluripotency factor, Sox2, in particular, is critical to block cancer initiation in mice.
The clinical-radiographic distinction between idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) is challenging. We sought to investigate the gene expression profiles ...of IPF and NSIP vs. normal controls.
Gene expression from explanted lungs of patients with IPF (n = 22), NSIP (n = 10) and from normal controls (n = 11) was assessed. Microarray analysis included Significance Analysis of Microarray (SAM), Ingenuity Pathway, Gene-Set Enrichment and unsupervised hierarchical clustering analyses. Immunohistochemistry and serology of proteins of interest were conducted.
NSIP cases were significantly enriched for genes related to mechanisms of immune reaction, such as T-cell response and recruitment of leukocytes into the lung compartment. In IPF, in contrast, these involved senescence, epithelial-to-mesenchymal transition, myofibroblast differentiation and collagen deposition. Unlike the IPF group, NSIP cases exhibited a strikingly homogenous gene signature. Clustering analysis identified a subgroup of IPF patients with intermediate and ambiguous expression of SAM-selected genes, with the interesting upregulation of both NSIP-specific and senescence-related genes. Immunohistochemistry for p16, a senescence marker, on fibroblasts differentiated most IPF cases from NSIP. Serial serum levels of periostin, a senescence effector, predicted clinical progression in a cohort of patients with IPF.
Comprehensive gene expression profiling in explanted lungs identifies distinct transcriptional profiles and differentially expressed genes in IPF and NSIP, supporting the notion of NSIP as a standalone condition. Potential gene and protein markers to discriminate IPF from NSIP were identified, with a prominent role of senescence in IPF. The finding of a subgroup of IPF patients with transcriptional features of both NSIP and senescence raises the hypothesis that "senescent" NSIP may represent a risk factor to develop superimposed IPF.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Repetitive genomic regions include tandem sequence repeats and interspersed repeats, such as endogenous retroviruses and LINE-1 elements. Repressive heterochromatin domains silence expression of ...these sequences through mechanisms that remain poorly understood. Here, we present evidence that the retinoblastoma protein (pRB) utilizes a cell-cycle-independent interaction with E2F1 to recruit enhancer of zeste homolog 2 (EZH2) to diverse repeat sequences. These include simple repeats, satellites, LINEs, and endogenous retroviruses as well as transposon fragments. We generated a mutant mouse strain carrying an F832A mutation in Rb1 that is defective for recruitment to repetitive sequences. Loss of pRB-EZH2 complexes from repeats disperses H3K27me3 from these genomic locations and permits repeat expression. Consistent with maintenance of H3K27me3 at the Hox clusters, these mice are developmentally normal. However, susceptibility to lymphoma suggests that pRB-EZH2 recruitment to repetitive elements may be cancer relevant.
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•The retinoblastoma protein occupies repetitive sequences in somatic cells•RB-EZH2 is required for H3K27me3 deposition at repeats and repression•Loss of repeat repression by RB is associated with cancer susceptibility
Ishak et al. discover that the retinoblastoma protein extensively occupies and represses expression of tandem and interspersed genomic repeats in somatic cells. RB-EZH2 recruitment to repeats establishes H3K27me3-dependent repression, and its loss permits lymphomagenesis in gene-targeted mice.
ABSTRACT
Background and objective
Osteopontin (OPN) is a pleiotropic cytokine involved in the proliferation of pulmonary artery smooth muscle cells (PA‐SMC). OPN is upregulated in the lungs of ...patients with pulmonary hypertension (PH) associated with pulmonary fibrosis, suggesting that the lung is a source of OPN. We hypothesized that OPN lung expression is elevated in Group I pulmonary arterial hypertension (PAH) and is correlated to haemodynamics.
Methods
Microarray analysis (Affymetrix) was performed after RNA was extracted from explanted lungs in 15 patients with Group I PAH who underwent lung transplantation (LTx) and 11 normal controls. PA pressure levels were recorded intraoperatively, immediately before starting LTx. Serum OPN levels were measured in subjects with PAH, Group II PH and normal controls on the day of right heart catheterization.
Results
OPN was among the top five upregulated genes in PAH compared to normal controls, which was confirmed by reverse transcription polymerase chain reaction (RT‐PCR). OPN expression was similar and equally elevated in different subtypes of PAH. A strong significant correlation was observed between mean pulmonary arterial pressure and OPN gene expression. Ingenuity pathway analysis showed the involvement of OPN in functions and networks relevant to angiogenesis, cell death and proliferation of PA‐SMC. OPN serum levels did not differ in subjects with Group I PAH and Group II PH.
Conclusion
In the lungs of patients with severe PAH, OPN is highly expressed and the level of expression is significantly correlated to disease severity. OPN may play an important role in the vascular remodelling process of PAH.
See related Editorial
Osteopontin (OPN), a pleiotropic cytokine, was identified among the top five upregulated genes in the lung explants from patients with Group I pulmonary arterial hypertension, compared to normal controls. Its expression correlated strongly to haemodynamic severity. Ingenuity pathway analysis showed the involvement of OPN in functions and networks relevant to vascular remodelling.
Pathology of Vaping-Associated Lung Injury Butt, Yasmeen M; Smith, Maxwell L; Tazelaar, Henry D ...
New England journal of medicine/The New England journal of medicine,
10/2019, Letnik:
381, Številka:
18
Journal Article
Recenzirano
Odprti dostop
This letter describes findings in 17 patients with a history of vaping who had lung biopsies after presenting with symptoms and bilateral pulmonary opacities that led to a clinical diagnosis of ...vaping-associated lung injury. The lung histopathology is described, along with some preliminary insights into the pathogenesis of acute lung injury.
Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct ...entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.
Social media is a powerful tool in pathology education and professional networking that connects pathologists and pathology trainees from around the world. Twitter (X) appears to be the most popular ...social media platform pathologists use to share pathology-related content and connect with other pathologists. Although there has been some published research on pathology-related activity on Twitter during short time frames, to date there has not been published research examining pathology-related Twitter activity in totality from its earliest days of activity to recently.
To comprehensively evaluate the use of pathology on Twitter (X) during the last 10 years.
Pathology-related tweets were systematically scraped from Twitter from January 2012 to January 2023 using pathology hashtags as a surrogate measure for all pathology content on Twitter. COVID-related tweets were approximated by tweets containing the term "COVID."
There were 591 812 unique pathology-related tweets identified during the time period, with #pathology being the most common hashtag used and #PathTwitter becoming more popular since 2020. There has been positive annual growth of pathology Twitter, with peaks in use during major pathology conferences. During the initial phases of the COVID-19 pandemic a sustained increase in pathology tweets was observed.
Pathology Twitter has grown during the last 10 years and has become increasingly popular for pathology education and networking. With the changing landscape of social media platforms this study provides an understanding of how pathology medical education and professional networking uses of social media are used and evolve over time.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
10.
Pathways to Precision Cecchini, Matthew J
Archives of pathology & laboratory medicine (1976),
07/2024, Letnik:
148, Številka:
7
Journal Article
Recenzirano
In this issue, a collaborative group from the College of American Pathologists, the Association for Molecular Pathology, the International Association for the Study of Lung Cancer, the Pulmonary ...Pathology Society, and the LUNGevity Foundation release a comprehensive guideline on PD-L1 and TMB testing in lung cancer.16 After an extensive systematic review of the literature and the use of a comprehensive tool for grading, the group has developed 6 evidence-based recommendations for the use of PD-L1 and TMB testing in lung cancer to direct the selection of patients for immunotherapy. There is a correlation between PD-L1 tumor proportion score (IPS) and patient response and survival following immunotherapy.17 However, multiple studies have demonstrated a lack of benefit for patients with driver alterations in EGFR and ALK, and studies have demonstrated that combined therapy with EGFR and immune checkpoint inhibitors has high rates of interstitial pneumonitis.18 These findings underscore the need for comprehensive testing in lung cancer patients for both PD-L1 and molecular drivers. By ensuring accurate, clinically validated, and timely biomarker testing, pathologists directly influence treatment decisions, and consequently patient outcomes. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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