ABSTRACT
Erk1/2 activation contributes to mouse ES cell pluripotency. We found a direct role of Erk1/2 in modulating chromatin features required for regulated developmental gene expression. Erk2 binds to specific DNA sequence motifs typically accessed by Jarid2 and PRC2. Negating Erk1/2 activation leads to increased nucleosome occupancy and decreased occupancy of PRC2 and poised RNAPII at Erk2-PRC2-targeted developmental genes. Surprisingly, Erk2-PRC2-targeted genes are specifically devoid of TFIIH, known to phosphorylate RNA polymerase II (RNAPII) at serine-5, giving rise to its initiated form. Erk2 interacts with and phosphorylates RNAPII at its serine 5 residue, which is consistent with the presence of poised RNAPII as a function of Erk1/2 activation. These findings underscore a key role for Erk1/2 activation in promoting the primed status of developmental genes in mouse ES cells and suggest that the transcription complex at developmental genes is different than the complexes formed at other genes, offering alternative pathways of regulation.
Subject(s)
Mitogen-Activated Protein Kinase 1/metabolism , Promoter Regions, Genetic , RNA Polymerase II/metabolism , Transcription Factor TFIIH/metabolism , Animals , Chromatin/metabolism , Embryonic Stem Cells/metabolism , Enzyme Activation , Gene Expression Regulation, Developmental , Mice , Mitogen-Activated Protein Kinase 3/metabolism , Nucleosomes/metabolism , Phosphorylation , Polycomb Repressive Complex 2/metabolismABSTRACT
Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
Subject(s)
Cell Cycle Proteins/metabolism , F-Box Proteins/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Cycle Proteins/genetics , Disease Models, Animal , F-Box Proteins/genetics , F-Box-WD Repeat-Containing Protein 7 , Hematopoietic Stem Cells/metabolism , Humans , Mice , Mice, Knockout , Mutation, Missense , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Proto-Oncogene Proteins c-myc/antagonists & inhibitors , Receptor, Notch1/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/genetics , UbiquitinationABSTRACT
The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/virology , SARS-CoV-2/physiology , Viral Tropism , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , COVID-19/genetics , Epithelium/immunology , Epithelium/virology , Humans , Interferons/genetics , Interferons/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lung/immunology , Lung/virology , SARS-CoV-2/drug effects , Viral Tropism/drug effects , Virus Replication/drug effects , COVID-19 Drug TreatmentABSTRACT
Polycomb-repressive complex 2 (PRC2) facilitates the maintenance and inheritance of chromatin domains repressive to transcription through catalysis of methylation of histone H3 at Lys27 (H3K27me2/3). However, through its EZH2 subunit, PRC2 also binds to nascent transcripts from active genes that are devoid of H3K27me2/3 in embryonic stem cells. Here, biochemical analyses indicated that RNA interaction inhibits SET domain-containing proteins, such as PRC2, nonspecifically in vitro. However, CRISPR-mediated truncation of a PRC2-interacting nascent RNA rescued PRC2-mediated deposition of H3K27me2/3. That PRC2 activity is inhibited by interactions with nascent transcripts supports a model in which PRC2 can only mark for repression those genes silenced by transcriptional repressors.
Subject(s)
Polycomb Repressive Complex 2/metabolism , RNA/metabolism , Animals , Clustered Regularly Interspaced Short Palindromic Repeats/physiology , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Enzyme Activation , Gene Expression Regulation , Gene Silencing , Histones/metabolism , Mice , Polycomb Repressive Complex 2/genetics , Protein Binding , Sf9 CellsABSTRACT
As COVID-19 pandemic approaching its third year, more data have shown that obesity and hypertriglyceridemia are the high-risk factors for the major complications such as acute respiratory distress syndrome, thromboembolism, coagulopathy and cytokine storm, which are responsible for the majority of disease severity and mortality. In this review article, we have analyzed the public available clinical reports and laboratory research results of the COVID-19 studies by researchers and clinicians of many nations around the world. Many of these reports covered COVID-19 patients of different ethnic groups. We suggested that obesity and high triglycerides are high risks for severe COVID-19 and death. We also summarized the possible underlying molecular mechanism likely connecting the severe COVID-19 with obesity and hypertriglyceridemia. From public health perspective, we highlight the importance of the healthy diet and lifestyle in fighting against SARS-CoV-2 virus in long period of time.
Subject(s)
COVID-19 , Hypertriglyceridemia , Humans , Pandemics , SARS-CoV-2 , Obesity , Severity of Illness IndexABSTRACT
Pleomorphic giant cell carcinoma (PGCC) of the prostate is a rare entity categorized as a variant of prostatic acinar adenocarcinoma in the 2016 World Health Organization (WHO) classification system. PGCC differs from conventional prostatic adenocarcinoma by having bizarre, markedly enlarged, and pleomorphic cells. It differs from high grade urothelial carcinoma by negativity for urothelial differentiation markers, and can be distinguished from sarcomatoid carcinoma by lack of spindle cells. Including two new cases described herein, there have been 51 cases of prostate PGCC reported in the English literature. Clinical features shared by cases of prostate PGCC include poor prognosis, occurrence in older patients, and frequent association with prior therapy. Pathologic features common to cases of prostate PGCC include admixture with a high-grade conventional prostate carcinoma component and absent or reduced expression of prostate differentiation markers. More recent studies have begun to elucidate the molecular characteristics of PGCC, detecting specific mutations and chromosomal translocations, and showing evidence of a high degree of molecular instability in these tumors. We report novel findings in two cases of PGCC including a PIK3CA p.His1047Arg mutation not previously described. One of our cases is the first to clearly demonstrate chronological loss of prostate markers during dedifferentiation from prior conventional prostate carcinoma to PGCC. Herein, we present our two new cases and comprehensively review the literature on all reported cases of PGCC with critical commentary on findings in cases of this rare tumor.
Subject(s)
Carcinoma, Giant Cell/diagnosis , Carcinoma, Giant Cell/metabolism , Prostatic Neoplasms/pathology , Urinary Bladder Neoplasms/pathology , Adult , Aged , Biomarkers, Tumor/analysis , Carcinoma, Acinar Cell/pathology , Cell Dedifferentiation , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Diagnosis, Differential , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Immunohistochemistry/methods , Male , Middle Aged , Mutation , Neoplasm Grading/methods , Prognosis , Transcription Factors/genetics , Transcription Factors/metabolism , Urothelium/pathologyABSTRACT
Polycomb-repressive complex 2 (PRC2) comprises specific members of the Polycomb group of epigenetic modulators. PRC2 catalyzes methylation of histone H3 at Lys 27 (H3K27me3) through its Enhancer of zeste (Ezh) constituent, of which there are two mammalian homologs: Ezh1 and Ezh2. Several ancillary factors, including Jarid2, modulate PRC2 function, with Jarid2 facilitating its recruitment to target genes. Jarid2, like Ezh2, is present in poorly differentiated and actively dividing cells, while Ezh1 associates with PRC2 in all cells, including resting cells. We found that Jarid2 exhibits nucleosome-binding activity that contributes to PRC2 stimulation. Moreover, such nucleosome-binding activity is exhibited by PRC2 comprising Ezh1 (PRC2-Ezh1), in contrast to PRC2-Ezh2. The presence of Ezh1 helps to maintain PRC2 occupancy on its target genes in myoblasts where Jarid2 is not expressed. Our findings allow us to propose a model in which PRC2-Ezh2 is important for the de novo establishment of H3K27me3 in dividing cells, whereas PRC2-Ezh1 is required for its maintenance in resting cells.
Subject(s)
Chromatin/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Nucleosomes/metabolism , Polycomb Repressive Complex 2/metabolism , Animals , Cell Line , Gene Knockdown Techniques , Histone-Lysine N-Methyltransferase/genetics , Histones/metabolism , Mice , Myoblasts/metabolism , Myoblasts/pathology , NIH 3T3 Cells , Polycomb Repressive Complex 2/deficiency , Polycomb Repressive Complex 2/genetics , Protein Binding , Protein Structure, TertiaryABSTRACT
The 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system subdivides prostatic pT3 tumors into pT3a, which includes cases with extraprostatic extension (EPE) and pT3b, which is defined by the presence of seminal vesicle invasion (SVI) with or without EPE. Yet, it is not established whether combined SVI and EPE impart a worse prognosis compared to SVI alone. We studied a cohort of 69 prostatectomy patients with SVI with or without EPE. Patient age at the time of radical prostatectomy was documented and Gleason score and presence or absence of EPE and/or SVI were determined. Biochemical recurrence (BCR) was defined as a PSA rise >0.2 ng/mL. The frequency of BCR was 33.9% in cases with combined EPE and SVI versus 12.5% in cases with SVI alone (relative risk = 2.71). An additional cohort of 88 patients also showed a higher frequency of lymph node metastasis of 29% in patients with combined SVI and EPE at the time of radical prostatectomy versus a 10% frequency of lymph node metastasis in patients with SVI alone (relative risk = 2.9). Based on our data, we propose further subdividing pT3 prostate cancers into three groups: EPE alone (pT3a), SVI alone (pT3b), and combined EPE and SVI (pT3c). This classification system would more accurately identify patients with pT3 prostate cancer who are more likely to experience worse outcomes and provide clinicians with additional information to aid in follow-up and postoperative treatment decisions.
Subject(s)
Adenocarcinoma/pathology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging/methods , Prostatic Neoplasms/pathology , Seminal Vesicles/pathology , Adenocarcinoma/classification , Aged , Aged, 80 and over , Humans , Lymphatic Metastasis/pathology , Male , Middle Aged , Neoplasm Invasiveness/pathology , Prostate-Specific Antigen/blood , Prostatic Neoplasms/classificationABSTRACT
Histone post-translational modifications impact many aspects of chromatin and nuclear function. Histone H4 Lys 20 methylation (H4K20me) has been implicated in regulating diverse processes ranging from the DNA damage response, mitotic condensation, and DNA replication to gene regulation. PR-Set7/Set8/KMT5a is the sole enzyme that catalyzes monomethylation of H4K20 (H4K20me1). It is required for maintenance of all levels of H4K20me, and, importantly, loss of PR-Set7 is catastrophic for the earliest stages of mouse embryonic development. These findings have placed PR-Set7, H4K20me, and proteins that recognize this modification as central nodes of many important pathways. In this review, we discuss the mechanisms required for regulation of PR-Set7 and H4K20me1 levels and attempt to unravel the many functions attributed to these proteins.
Subject(s)
Cell Cycle/physiology , Chromosomes/metabolism , Gene Expression Regulation , Genome , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Animals , DNA Damage , Humans , Lysine/metabolism , MethylationABSTRACT
The value of histochemical analysis in the diagnosis of medical renal diseases has long been known, and its use continues currently. Depending on the particular disorder in question, a variety of "special" stains may be applied to renal biopsies. These include the periodic acid-Schiff, Masson trichrome, Jones, von Kossa, Verhoeff-van Gieson, Congo Red, and toluidine blue methods, among others. This review considers the application of such techniques in the assessment of vascular, glomerular, and tubulointerstitial lesions of the kidney.
Subject(s)
Histocytochemistry , Kidney Diseases/pathology , Kidney/pathology , Biopsy , Humans , Predictive Value of Tests , Prognosis , Staining and LabelingABSTRACT
Sarcoid-like (SL) granulomas have been previously described in association with malignant tumors. These granulomas appear to be tumor-related but are not indicative of systemic sarcoidosis, and hence are referred to as SL reactions. These SL reactions can be seen within the primary tumor, its vicinity, or in uninvolved sites such as the spleen, bone marrow, skin, and/or regional lymph nodes draining the tumor. It is a widely held view that SL granulomas are caused by soluble antigenic factors, shed by tumor cells or released due to tumor necrosis. SL reactions reported in Hodgkin lymphoma have been associated with a better prognosis. SL granulomas are thought to play an important role in the host's defenses against metastatic extension. SL granulomas have been reported in approximately 4.4% of carcinomas. Isolated cases of renal cell carcinoma (RCC) with SL granulomas have been reported with questionable prognostic significance. We identified 11 cases of RCCs with SL granulomas. Interestingly, all cases had abundant clear cell cytoplasm (10 clear cell RCC cases and 1 clear cell papillary RCC). We propose that this clear, abundant cytoplasm of the tumor cells with high content of glycogen and lipids may trigger granuloma formation akin to that seen in seminomas with SL granulomas. To date, this is the largest case series of RCCs with SL granulomas.
Subject(s)
Carcinoma, Renal Cell/pathology , Granuloma/pathology , Kidney Neoplasms/pathology , Sarcoidosis/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
PURPOSE: We determined the likelihood that transurethral resection biopsy of the prostatic urethra adjacent to the verumontanum would detect prostatic involvement of urothelial carcinoma in patients with bladder carcinoma. MATERIALS AND METHODS: We compared precystectomy transurethral resection biopsy specimens of the prostatic urethra with those of the matched radical cystoprostatectomy in 272 patients with urothelial carcinoma of the bladder. All prostates were evaluated by whole mount step sections. RESULTS: Prostatic involvement by urothelial carcinoma was detected by transurethral resection biopsy or radical cystoprostatectomy in 101 patients (37.1%). Transurethral resection biopsy detected urothelial carcinoma in 72 cases with 71.3% sensitivity and 100% specificity. The overall accuracy of transurethral resection biopsy to detect urothelial carcinoma of the prostate was 89% (positive and negative predictive values 100% and 86%, respectively). Invasive prostatic urothelial carcinoma arising from the prostatic urethra was detected by transurethral resection biopsy in 21 of 26 patients (81%) while prostatic carcinoma in situ was detected in 39 of 52 (75%). Transurethral resection biopsy detected prostatic invasive urothelial carcinoma resulting from transmural invasion of a bladder tumor in 4 of 15 patients. CONCLUSIONS: Prostatic involvement by urothelial carcinoma of the bladder was found in 37.1% of patients. Transurethral resection biopsy missed most tumors resulting from transmural invasion of the bladder primary lesion. Carcinoma in situ and invasive urothelial carcinoma arising from the prostatic urethra were detected in most cases. Transurethral resection biopsy of the prostatic urethra can complement staging and support clinical decision making with respect to neoadjuvant chemotherapy and planning for an orthotopic neobladder.
Subject(s)
Carcinoma, Transitional Cell/surgery , Cystectomy , Neoplasms, Multiple Primary/pathology , Preoperative Care , Prostate/pathology , Urinary Bladder Neoplasms/surgery , Biopsy/methods , Cystectomy/methods , Humans , Male , Neoplasm Staging , UrethraABSTRACT
The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining.
Subject(s)
Bronchi/drug effects , Cell Transformation, Neoplastic/chemically induced , Epithelial Cells/drug effects , Hydraulic Fracking , Lung Neoplasms/chemically induced , Oil and Gas Fields , Wastewater/analysis , Water Pollutants, Chemical/toxicity , Animals , Bronchi/metabolism , Bronchi/pathology , Cell Line , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Dose-Response Relationship, Drug , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Nude , Neoplasm Transplantation , Risk Assessment , Time Factors , Transcription, Genetic/drug effectsABSTRACT
AIMS: The study of haemangiomas in end-stage renal disease (ESRD). METHODS AND RESULTS: Twenty ESRD nephrectomies from 16 patients (aged 9 months-68 years) were due to hypertension (four), focal segmental glomerulosclerosis (four), lupus nephritis (three), diabetes (one), IgA nephropathy (one), hereditary nephritis (one), congenital nephrotic syndrome (one) and unknown cause (one). Haemangiomas appeared as a single mass (15), two masses (one), three masses (one), four masses (two) and eight masses (one) per kidney. Tumours measured 0.2-3.5 cm. Four patients had bilateral haemangiomas. All tumours were in the medulla and often abutted renal sinus fat. All except one of the tumours were anastomosing haemangiomas, showing isolated or interconnected sinusoidal capillary-sized vascular channels lined by a single layer of benign cuboidal CD34(+) , CD31(+) , D2-40(-) endothelial cells, separated by loose stroma with spindle cells. One tumour was a cellular capillary haemangioma. Intravascular growth was seen in nine specimens. All haemangiomas had extramedullary haematopoiesis. Acquired cystic kidney disease (ACKD) was seen in 11 kidneys (nine patients), renal cell carcinoma (RCC) in five, ACKD-associated RCC precursors in three, Wilms' tumour in one and papillary adenomas in five. CONCLUSIONS: Anastomosing haemangioma appears as a distinctive clinicopathological entity developing in kidneys with ESRD, with or without ACKD.
Subject(s)
Hemangioma/complications , Hemangioma/pathology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/pathology , Kidney Neoplasms/complications , Kidney Neoplasms/pathology , Adenoma/complications , Adenoma/pathology , Adolescent , Adult , Aged , Carcinoma, Renal Cell/complications , Carcinoma, Renal Cell/pathology , Female , Hemangioma/blood supply , Hemangioma, Capillary/blood supply , Hemangioma, Capillary/complications , Hemangioma, Capillary/pathology , Hematopoiesis, Extramedullary , Humans , Infant , Kidney Diseases, Cystic/complications , Kidney Diseases, Cystic/pathology , Kidney Neoplasms/blood supply , Male , Middle Aged , Retrospective Studies , Wilms Tumor/complications , Wilms Tumor/pathologyABSTRACT
The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.
Subject(s)
Carcinoma, Intraductal, Noninfiltrating/pathology , Prostatic Neoplasms/pathology , Diagnosis, Differential , Health Surveys , Humans , Male , Neoplasm Grading , Observer Variation , Physicians , Prognosis , Prostatic Intraepithelial Neoplasia/pathology , Reproducibility of ResultsABSTRACT
Aim: This study aims to elucidate the involvement of triple-negative breast cancer (TNBC)-derived extracellular vesicles in metastasis. The loss of components in the type 1 interferon (IFN1) signaling pathway has been linked to the promotion of metastasis. However, IFN1 signaling induces immunological dormancy and promotes tumorigenesis. Our hypothesis was that TNBC cells release tumor-derived extracellular vesicles (TEVs) that promote metastasis in an IFN1-independent manner. Methods: Two murine TNBC models and transgenic mice were used to examine the role of IFN1 in TNBC progression to metastasis. Reserpine was employed to determine the effect of TEV education on TNBC progression and overall survival. EVs from cancer cells treated with vehicle and reserpine and from the serum of tumor-bearing mice receiving reserpine were examined to determine changes in EV release and EV content. Results: TNBC cells progress to metastasis in mice lacking the IFN1-induced gene cholesterol-25 hydroxylase (CH25H) or expressing the IFNAR1S526 knock-in that cannot be downregulated. Reserpine suppresses EV release from TNBC cells in vitro and in vivo. Western blot analysis demonstrated reserpine decreased NUPR1 protein levels in EVs. RNAseq analysis demonstrated that endothelial cells lacking CH25H treated with TEVs exhibited increased NUPR1 expression that was decreased by adding reserpine with the TEVs. NUPR1 overexpression upregulated genes that mediate TEV biogenesis and incorporation. Knockdown of NUPR1 with shRNA decreased the release of TEVs. Conclusion: In conclusion, our study suggests that TNBC is driven by aberrant packaging of NUPR1 into TEVs which were transferred into recipient cells to activate pro-metastatic transcription driven by NUPR1.
ABSTRACT
Nephrogenic adenoma is a benign lesion of the urinary tract, particularly the urinary bladder. It is a gross and microscopic mimicker of urothelial neoplasm or metastatic carcinoma. Several histological patterns (tubular, tubulocystic, polypoid, papillary, fibromyxoid) have been recognized, but a flat pattern has not been described. Histologically, nephrogenic adenoma consists of tubules, cysts or papillae lined by flat to polygonal cells with frequent hobnail appearance. The stroma is often edematous or has a granulation tissue-like appearance with acute or chronic inflammation. By immunohistochemistry, nephrogenic adenomas are positive for renal epithelial markers CK7, CD10 and alpha-methylacyl-coenzyme A racemase, and negative for bladder urothelium or prostate markers. Recent studies have shown that nephrogenic adenomas are positive for PAX2 and PAX8. We encountered an interesting case of tubular nephrogenic adenoma with adjacent areas suspicious of flat urothelial atypia. Immunohistochemistry for PAX2 and PAX8 were positive in these areas, unveiling a flat pattern of nephrogenic adenoma. This case prompted us to study 15 cases of nephrogenic adenoma to determine additional instances of flat pattern and to assess the value of PAX2 and PAX8 immunoreactivity to diagnose nephrogenic adenoma. PAX2 and PAX8 immunostaining was positive in 14/15 and 15/15 cases, respectively. The flat pattern was present at least focally adjacent to tubular, polypoid and papillary areas, in 8/15 cases of nephrogenic adenoma. In conclusion, the flat pattern is a common finding in nephrogenic adenomas, but easily under recognized by morphologic examination and may be confused with flat urothelial lesions with atypia. Immunostains for PAX2 and PAX8 are useful in the detection of nephrogenic adenomas and particularly unveil those nephrogenic adenomas with flat pattern.
Subject(s)
Adenoma/chemistry , Biomarkers, Tumor/analysis , Immunohistochemistry , PAX2 Transcription Factor/analysis , Paired Box Transcription Factors/analysis , Urologic Neoplasms/chemistry , Adenoma/pathology , Adult , Aged , Aged, 80 and over , Biopsy , Female , Humans , Male , Middle Aged , PAX8 Transcription Factor , Predictive Value of Tests , Urologic Neoplasms/pathology , Young AdultABSTRACT
Interstitial cystitis (IC) is a disease of undetermined etiology and pathogenesis. Inflammation is thought to play a key role in many patients, characteristically with an increase in mast cells within the detrusor muscle of the bladder. We observed that some patients with IC had prominent plasma cells in bladder tissue, which elicited our interest in their possible pathogenic role in patients with IC. A total of 44 cases of IC were collected, including 42 bladder biopsies and 2 cystectomies. Patient age ranged from 18 to 92 years (average age of 49.5 years) and included 7 male and 37 female patients. The histology and immunostains for IgG, IgG4 and tryptase were examined, and the results were correlated with clinical and cystoscopic findings. Four cases showed a significant increase in IgG4-positive plasma cells, with greater than 30 IgG4 plasma cells per high-power field and an IgG4/IgG ratio greater than 0.5. In addition, statistically significant differences were found between IC with IgG4-positive plasma cells vs IgG4-negative cases. The IgG4-positive patients were of older age and had increased severe inflammation and decreased bladder capacity as compared with the IgG4-negative patients. We propose that a subset of patients with IC may have an IgG4-related disease, and further study including serum IgG4 measurement is required to better define this relationship.
Subject(s)
Autoimmune Diseases/immunology , Cystitis, Interstitial/immunology , Cystitis, Interstitial/pathology , Immunoglobulin G/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Autoimmune Diseases/pathology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Plasma Cells/pathology , Urinary Bladder/pathology , Young AdultABSTRACT
BACKGROUND: The World Health Organization Classification (WHO) of Urinary and Male Genital Tumors has recently been updated to its 5th edition. The new edition presents a comprehensive approach to the classification of urinary and male genital tumors with an incorporation of morphologic, clinical, and genomic data. OBJECTIVE: This review aims to update the new classification of bladder cancer in the 5th edition and to highlight important changes in nomenclatures, diagnostic criteria, and molecular characterization, as compared to the 4th edition. METHODS: The pathologic classification of bladder cancer in the 5th edition of WHO Classification of Urinary and Male Genital Tumours was compared to that in the 4th edition. PubMed was searched using key words, including bladder cancer, WHO 1973, WHO 1998, WHO 2004, WHO 2016, histology, pathology, genomics, and molecular classification in the time frame from 1973 to August of 2022. Other relevant papers were also consulted, resulting in the selection of 81 papers as references. RESULTS: The binary grading of papillary urothelial carcinoma (UC) is practical, but it may be oversimplified and contribute to "grade migration" in recent years. An arbitrary cutoff (5%) has been proposed for bladder cancers with mixed grades. The diagnosis of papillary urothelial neoplasm with low malignant potential has been dramatically reduced in recent years because of overlapping morphology and treatment with low-grade papillary UC. An inverted growth pattern should be distinguished from true (or destructive) stromal invasion in papillary UC. Several methods have been proposed for pT1 tumor substaging, but it is often challenging to substage pT1 tumors in small biopsy specimens. Bladder UC shows a high tendency for divergent differentiation, leading to several distinct histologic subtypes associated with an aggressive clinical behavior. Molecular classification based on the genomic analysis may be a useful tool in the stratification of patients for optimal treatment. CONCLUSIONS: The 5th edition of WHO Classification of Urinary and Male Genital Tumours has made several significant changes in the classification of bladder cancer. It is important to be aware of these changes and to incorporate them into routine clinical practice.
ABSTRACT
CONTEXT.: Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. OBJECTIVE.: To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. DATA SOURCES.: The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. CONCLUSIONS.: The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.