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1.
Circ Res ; 132(2): 238-250, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36656970

RESUMO

Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1+CD4+ T cells and the functional decline of NOTCH4+ T regulatory cells (Checkpoint 1). A defect in the endothelial cell barrier of adventitial vasa vasorum networks marks Checkpoint 2; the invasion of monocytes, macrophages and T cells into the arterial wall. Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). Eventually, the vascular lesions are occupied by self-renewing T cells that provide autonomy to the disease process and limit the therapeutic effectiveness of currently used immunosuppressants. The multi-step process deviating protective to pathogenic immunity offers an array of interception points that provide opportunities for the prevention and therapeutic management of this devastating autoimmune disease.


Assuntos
Arterite de Células Gigantes , Humanos , Inflamação/metabolismo , Artérias/metabolismo , Imunidade Inata , Células Gigantes/metabolismo
2.
Sci Rep ; 13(1): 419, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624105

RESUMO

Although polyploid giant cancer cells (PGCCs) are known as a key source of failure of current therapies, sufficient drugs to target these cells are not yet introduced. Considering the similarities of polyploid cells in regeneration and cancer, we hypothesized that zoledronic acid (ZA), an osteoclast-targeting agent, might be used to eliminate PGCCs. The 5637-bladder cancer cell line was treated with various doses of cisplatin to enrich polyploid cells and the efficacy of different concentrations of ZA in reducing this population was assessed. The metabolic profile of PGCCs was investigated with gas chromatography-mass spectrometry. Lipid profiles, mitochondrial density, and ROS content were also measured to assess the response of the cells to ZA. Cancer cells surviving after three days of exposure with 6 µM cisplatin were mainly polyploid. These cells demonstrated special morphological features such as fusion with diploid or other polyploid cells and originated in daughter cells through budding. ZA could substantially eradicate PGCCs with the maximal effect observed with 50 µM which resulted in the drop of PGCC fraction from 60 ± 7.5 to 19 ± 1.7%. Enriched PGCCs after cisplatin-treatment demonstrated a drastic metabolic shift compared to untreated cancer cells with an augmentation of lipids. Further assays confirmed the high content of lipid droplets and cholesterol in these cells which were reduced after ZA administration. Additionally, the mitochondrial density and ROS increased in PGCCs both of which declined in response to ZA. Taken together, we propose that ZA is a potent inhibitor of PGCCs which alters the metabolism of PGCCs. Although this drug has been successfully exploited as adjuvant therapy for some malignancies, the current evidence on its effects on PGCCs justifies further trials to assess its potency for improving the success of current therapies for tackling tumor resistance and relapse.


Assuntos
Cisplatino , Neoplasias , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Cisplatino/metabolismo , Ácido Zoledrônico/farmacologia , Ácido Zoledrônico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Células Gigantes/metabolismo , Poliploidia , Neoplasias/patologia
4.
Bone Joint J ; 104-B(12): 1352-1361, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36453049

RESUMO

AIMS: We performed a systematic literature review to define features of patients, treatment, and biological behaviour of multicentric giant cell tumour (GCT) of bone. METHODS: The search terms used in combination were "multicentric", "giant cell tumour", and "bone". Exclusion criteria were: reports lacking data, with only an abstract; papers not reporting data on multicentric GCT; and papers on multicentric GCT associated with other diseases. Additionally, we report three patients treated under our care. RESULTS: A total of 52 papers reporting on 104 patients were included in the analysis, with our addition of three patients. Multicentric GCT affected predominantly young people at a mean age of 22 years (10 to 62), manifesting commonly as metachronous tumours. The mean interval between the first and subsequent lesions was seven years (six months to 27 years). Synchronous lesions were observed in one-third of the patients. Surgery was curettage in 63% of cases (163 lesions); resections or amputation were less frequent. Systemic treatments were used in 10% (n = 14) of patients. Local recurrence and distant metastases were common. CONCLUSION: Multicentric GCT is rare, biologically aggressive, and its course is unpredictable. Patients with GCT should be followed indefinitely, and referred promptly if new symptoms, particularly pain, emerge. Denosumab can have an important role in the treatment.Cite this article: Bone Joint J 2022;104-B(12):1352-1361.


Assuntos
Neoplasias , Encaminhamento e Consulta , Humanos , Adolescente , Adulto Jovem , Adulto , Seguimentos , Projetos de Pesquisa , Células Gigantes
5.
Biomolecules ; 12(12)2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36551240

RESUMO

The interest in astrocytes, the silent brain cells that accumulate polyamines (PAs), is growing. PAs exert anti-inflammatory, antioxidant, antidepressant, neuroprotective, and other beneficial effects, including increasing longevity in vivo. Unlike neurons, astrocytes are extensively coupled to others via connexin (Cx) gap junctions (GJs). Although there are striking modulatory effects of PAs on neuronal receptors and channels, PA regulation of the astrocytic GJs is not well understood. We studied GJ-propagation using molecules of different (i) electrical charge, (ii) structure, and (iii) molecular weight. Loading single astrocytes with patch pipettes containing membrane-impermeable dyes, we observed that (i) even small molecules do not easily permeate astrocytic GJs, (ii) the ratio of the charge to weight of these molecules is the key determinant of GJ permeation, (iii) the PA spermine (SPM) induced the propagation of negatively charged molecules via GJs, (iv) while no effects were observed on propagation of macromolecules with net-zero charge. The GJ uncoupler carbenoxolone (CBX) blocked such propagation. Taken together, these findings indicate that SPM is essential for astrocytic GJ communication and selectively facilitates intracellular propagation via GJs for negatively charged molecules through glial syncytium.


Assuntos
Poliaminas , Espermina , Espermina/farmacologia , Poliaminas/farmacologia , Astrócitos , Junções Comunicantes , Células Gigantes
6.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 57(11): 1097-1101, 2022 Nov 09.
Artigo em Chinês | MEDLINE | ID: mdl-36379887

RESUMO

Cartilage and giant cell-related neoplastic lesions originating in the temporomandibular joint region have similar clinical, imaging and pathological manifestations, making the diagnosis of these disorders challenging to varying degrees. Diagnostic findings can influence treatment procedures and a definitive pathological diagnosis is important for the prognosis of these conditions. In this article, we discuss the pathological diagnosis and differentiation of four benign cartilage and giant cell related tumors and tumor-like lesions that occur in the temporomandibular joint, namely synovial chondromatosis, tumoral calcium pyrophosphate deposition disease, pigmented villonodular synovitis and chondroblastoma, taking into account their clinical features and histological manifestations, with a view to providing a basis for clinical management.


Assuntos
Condromatose Sinovial , Sinovite Pigmentada Vilonodular , Humanos , Articulação Temporomandibular/patologia , Condromatose Sinovial/diagnóstico , Condromatose Sinovial/patologia , Sinovite Pigmentada Vilonodular/diagnóstico , Sinovite Pigmentada Vilonodular/patologia , Células Gigantes/patologia , Cartilagem
7.
Biochem Biophys Res Commun ; 636(Pt 1): 205-212, 2022 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-36335871

RESUMO

The placenta plays various roles in a healthy pregnancy, and abnormalities in the placenta result in adverse outcomes. Adequate differentiation of trophoblast subtypes is necessary for placental function, but the molecular mechanisms that determine trophoblast cell fate remain unclear. Here, we screened small molecular compound (SMC) libraries (1904 SMCs) to identify particular SMCs which regulate trophoblast differentiation in mouse trophoblast stem cells (mTSCs) to understand the molecular mechanisms underlying cell fate decision in trophoblast cells. The two-step screening revealed a novel effect of N-oleoyldopamine (OLDA), an endogenic vanilloid, to promote differentiation into parietal trophoblast giant cells (P-TGCs) and repress them into spongiotrophoblast cells in mTSCs. Analyses by gene deletion and inhibitor treatments indicated that transient receptor potential cation channel subfamily V member 3 (Trpv3), one of the candidates for targeting by OLDA, was involved in maintaining stem status and P-TGC differentiation in mTSCs. Finally, transcriptome analysis revealed that Fosl1, a key regulatory factor in differentiation into P-TGCs, was upregulated by OLDA treatment, suggesting that OLDA promoted the differentiation of mTSCs into P-TGCs via regulation of Fosl1 expression.


Assuntos
Placenta , Trofoblastos , Camundongos , Animais , Feminino , Gravidez , Trofoblastos/metabolismo , Placenta/metabolismo , Células Gigantes , Diferenciação Celular/genética , Células-Tronco
8.
Exp Cell Res ; 421(2): 113403, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36336028

RESUMO

Vascular mimicry (VM) is defined as a vascular channel-like structure composed of tumor cells that correlates with the growth of cancer cells by providing blood circulation. However, whether VM can be formed in dormant cancer cells remains unclear. Our previous research revealed that polyploid giant cancer cells (PGCCs) are specific dormant cells related to the poor prognosis of head and neck cancer. Here, we demonstrated that EBV could promote VM formation by PGCCs in vivo and in vitro. Furthermore, we revealed that the activation of the ERK pathway partly mediated by LMP2A is responsible for stemness, and the acquisition of the stemness phenotype is crucial to the malignant biological behavior of PGCCs. The epithelial-to-mesenchymal transition (EMT) process plays a considerable role in PGCCs, and EMT progression is vital for EBV-positive PGCCs to form VM. This is the first study to reveal that EBV creates plasticity in PGCC-VM and provide a new strategy for targeted anti-tumor therapy.


Assuntos
Herpesvirus Humano 4 , Neoplasias , Humanos , Herpesvirus Humano 4/genética , Transição Epitelial-Mesenquimal/genética , Células Gigantes/metabolismo , Linhagem Celular Tumoral , Neovascularização Patológica/metabolismo , Neoplasias/patologia
9.
Diagn Pathol ; 17(1): 88, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36320082

RESUMO

BACKGROUND: Tenosynovial giant cell tumor (TSGCT) is a benign fibrohistiocytic tumor that affects the synovium of joints, bursa, and tendon sheaths and is categorized into localized TSGCT (LTSGCT) and diffuse TSGCT (DTSGCT). LTSGCT and DTSGCT are characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and its translocation partner collagen type VI alpha 3 chain. The fusion gene induces intratumoral overexpression of CSF1 mRNA and CSF1 protein. CSF1 expression is a characteristic finding of TSGCT and detection of CSF1 mRNA and CSF1 protein may be useful for the pathological diagnosis. Although there have been no effective anti-CSF1 antibodies to date, in situ hybridization (ISH) for CSF1 mRNA has been performed to detect CSF1 expression in TSGCT. We performed CSF1 immunohistochemistry (IHC) using anti-CSF1 antibody (clone 2D10) in cases of TSGCT, giant cell-rich tumor (GCRT), and GCRT-like lesion and verified its utility for the pathological diagnosis of TSGCT. METHODS: We performed CSF1 IHC in 110 cases including 44 LTSGCTs, 20 DTSGCTs, 1 malignant TSGCT (MTSGCT), 10 giant cell tumors of bone, 2 giant cell reparative granulomas, 3 aneurysmal bone cysts, 10 undifferentiated pleomorphic sarcomas, 10 leiomyosarcomas, and 10 myxofibrosarcomas. We performed fluorescence ISH (FISH) for CSF1 rearrangement to confirm CSF1 expression on IHC in TSGCTs. We considered the specimens to have CSF1 rearrangement if a split signal was observed in greater than 2% of the tumor cells. RESULTS: Overall, 50 of 65 TSGCT cases, including 35 of the 44 LTSGCTs and 15 of the 20 DTSGCTs, showed distinct scattered expression of CSF1 in the majority of mononuclear tumor cells. MTSGCT showed no CSF1 expression. Non-TSGCT cases were negative for CSF1. FISH revealed CSF1 rearrangement in 6 of 7 CSF1-positive cases on IHC. On the other hand, FISH detected no CSF1 rearrangement in all CSF1-negative cases on IHC. Thus, the results of IHC corresponded to those of FISH. CONCLUSION: We revealed characteristic CSF1 expression on IHC in cases of TSGCT, whereas the cases of non-TSGCT exhibited no CSF1 expression. CSF1 IHC may be useful for differentiating TSGCTs from histologically mimicking GCRTs and GCRT-like lesions.


Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Tumores de Células Gigantes , Humanos , Adulto , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Imuno-Histoquímica , Tumor de Células Gigantes de Bainha Tendinosa/diagnóstico , Tumor de Células Gigantes de Bainha Tendinosa/genética , Tumor de Células Gigantes de Bainha Tendinosa/patologia , Células Gigantes/patologia , RNA Mensageiro
10.
Diagn Cytopathol ; 50(12): 543-556, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36317760

RESUMO

BACKGROUND: Localized tenosynovial giant cell tumor (GCT) or giant cell tumor of tendon sheath (GCTTS), is a benign nodular lesion that arises from the synovium of the tendon sheath of the hands and foot. GCTTS is characterized by the presence of multinucleated giant cells and proliferation of synovial-like mononuclear cells. A clinical diagnosis of GCTTS is kept as a differential when a firm, nodular mass shows decreased signal intensity on both T1-and T2-weighted MR imaging. Treatment is usually marginal excision of the mass. MATERIAL AND METHODS: It is a retrospective study, observed in the past 3 years at a tertiary care hospital. Those cases were included in the study in which histopathological confirmation was available or if clinico-radiological features were confirmatory of the diagnosis of GCTTS when correlated with cytological features. RESULTS: There was a total of 24 cases, out of which 16 were females and 8 males. The tumor was located in the upper limb in 21 cases and in 3 cases the tumor was present in the lower limb. In the upper limb, 18 cases were on the right side and three cases were on the left side. In the lower limb, 1 case was present on the left and 2 on the right side. The cytomorphology consisted of mononuclear stromal cells, multinucleated giant cells, and hemosiderin-laden macrophages in variable numbers. CONCLUSION: It is important to accurately diagnose and categorize giant cell-containing lesions because their prognosis depends on the exact categorization of the tumor.


Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Tumores de Células Gigantes , Masculino , Feminino , Humanos , Estudos Retrospectivos , Tumor de Células Gigantes de Bainha Tendinosa/diagnóstico por imagem , Tumor de Células Gigantes de Bainha Tendinosa/patologia , Radiografia , Células Gigantes/patologia , Imageamento por Ressonância Magnética , Tumores de Células Gigantes/diagnóstico por imagem , Tumores de Células Gigantes/patologia
11.
Am J Dermatopathol ; 44(11): 834-836, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36240499

RESUMO

ABSTRACT: Multinucleate cell angiohistiocytoma (MCAH) is a benign vascular and fibrohistiocytic (probably reactive) proliferation with peculiar multinucleate cells which most authors interpret as degenerated macrophages. Several clinical variants of MCAH have been described, some of them with brownish-appearing lesions clinically. However, no histologically identified pigment has been described in the cytoplasm of the multinucleate cells so far. We present a pigmented MCAH with cytoplasmic brownish pigment, which was positive with a Masson-Fontana stain and negative with an iron stain, consistent with melanin, in a 33-year-old woman with multiple papules and plaques on the right elbow, right jawline, and left flank.


Assuntos
Histiocitoma Fibroso Benigno , Neoplasias Cutâneas , Adulto , Feminino , Células Gigantes/patologia , Histiocitoma Fibroso Benigno/patologia , Humanos , Ferro , Melaninas , Neoplasias Cutâneas/patologia
13.
J Vet Med Sci ; 84(12): 1579-1584, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36261364

RESUMO

A 12-year-old female Himalayan cat underwent an ovariohysterectomy to remove an intra-abdominal mass. Histologic examination using immunohistochemical staining revealed that the mass was comprised of epithelial and mesenchymal components. Within the lesion, multinucleated giant cells (MGCs) were observed diffusely. MGCs were positive for vimentin and Iba-1 and negative for cytokeratin AE1/AE3 and CD204. In addition, MGCs were negative for Ki-67, indicating nonneoplastic cells. Osteoclast-like MGC (OLMGC) phenotype with tartrate-resistant acid phosphatase positivity was also seen. These findings suggested that the uterine tumor was carcinosarcoma with OLMGCs. Uterine tumors in humans, such as leiomyosarcoma and carcinosarcoma, with OLMGC infiltration, are well-known pathologic entities; however, they are rare in animals and to our knowledge, have not been previously reported in cats.


Assuntos
Carcinossarcoma , Doenças do Gato , Leiomiossarcoma , Neoplasias Uterinas , Animais , Gatos , Feminino , Carcinossarcoma/veterinária , Carcinossarcoma/patologia , Doenças do Gato/cirurgia , Doenças do Gato/patologia , Células Gigantes/patologia , Leiomiossarcoma/patologia , Leiomiossarcoma/veterinária , Osteoclastos , Neoplasias Uterinas/cirurgia , Neoplasias Uterinas/veterinária , Neoplasias Uterinas/patologia
14.
Antiviral Res ; 208: 105428, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36252824

RESUMO

The continuous emergence of SARS-CoV-2 variants prolongs COVID-19 pandemic. Although SARS-CoV-2 vaccines and therapeutics are currently available, there is still a need for development of safe and effective drugs against SARS-CoV-2 and also for preparedness for the next pandemic. Here, we discover that astersaponin I (AI), a triterpenoid saponin in Aster koraiensis inhibits SARS-CoV-2 entry pathways at the plasma membrane and within the endosomal compartments mainly by increasing cholesterol content in the plasma membrane and interfering with the fusion of SARS-CoV-2 envelope with the host cell membrane. Moreover, we find that this functional property of AI as a fusion blocker enables it to inhibit the infection with SARS-CoV-2 variants including the Alpha, Beta, Delta, and Omicron with a similar efficacy, and the formation of syncytium, a multinucleated cells driven by SARS-CoV-2 spike protein-mediated cell-to-cell fusion. Finally, we claim that the triterpene backbone as well as the attached hydrophilic sugar moieties of AI are structurally important for its inhibitory activity against the membrane fusion event. Overall, this study demonstrates that AI is a natural viral fusion inhibitor and proposes that it can be a broad-spectrum antiviral agent against current COVID-19 pandemic and future outbreaks of novel viral pathogens.


Assuntos
SARS-CoV-2 , Saponinas , Humanos , Vacinas contra COVID-19 , Células Gigantes , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Asteraceae/química , Saponinas/farmacologia
15.
Front Cell Infect Microbiol ; 12: 953785, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211967

RESUMO

Leishmaniasis is caused by infection with protozoan parasites of the genus Leishmania. In both clinical and experimental visceral leishmaniasis, macrophage multinucleation is observed in parasitized tissues. However, the feature and the mechanism of macrophage multinucleation remained unclear. Here, we report that infection of Leishmania donovani, a causative agent of visceral leishmaniasis, induces multinucleation of bone marrow-derived macrophages (BMDMs) in vitro. When these infection-induced multinucleated macrophages were compared with cytokine-induced multinucleated giant cells, the former had higher phagocytic activity on red blood cells but no apparent changes on phagocytosis of latex beads. BMDMs infected with L. donovani had increased expression of ATP6V0D2, one of the components of V-ATPase, which was also upregulated in the spleen of infected mice. Infection-induced ATP6V0D2 localized in a cytoplasmic compartment, which did not overlap with the mitochondria, endoplasmic reticulum, or lysosomes. When ATP6V0D2 expression was recombinantly induced in BMDMs, the formation of multinucleated macrophages was induced as seen in the infected macrophages. Taken together, L. donovani infection induces multinucleation of macrophages via ATP6V0D2 upregulation leading to a unique metamorphosis of the macrophages toward hemophagocytes.


Assuntos
Leishmania donovani , Leishmaniose Visceral , ATPases Vacuolares Próton-Translocadoras , Adenosina Trifosfatases , Animais , Citocinas , Células Gigantes , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Regulação para Cima
16.
Cesk Patol ; 58(3): 161-165, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36224038

RESUMO

Giant cell fibroblastoma is a rare locally aggressive tumor of subcutaneous mesenchymal tissue, occurring mostly on the trunk in young individuals with maximal incidence in the first decade of life. Local recurrences of giant cell fibroblastoma are common if marginally excised, however, distant metastases do not occur. Giant cell fibroblastoma was labelled as a juvenile variant of dermatofibrosarcoma protuberans (DFSP) due to quite frequent combination of both lesions, morphological similarities, identical immunoprofile, and shared gene fusion t(17;22) COL1A1-PDGFB. In this paper, we report a case of a young man with a slowly growing subcutaneous tumor in the groin. The tumor was excised and histological examination identified a mesenchymal tumor with variable cellularity, presence of multinucleated giant cells and pleomorphic spindle cells, which lined pseudovascular or angiectoid spaces. The CD34 immunohistochemistry showed strong positivity in all of these cells, whereas ERG was positive only in endothelial cells in true vessels. These findings led to a suspicion on giant cell fibroblastoma. Because of its borderline malignant behaviour and positive surgical margins, the lesion was subsequently reexcised. The molecular analysis identified the transcription product of gene fusion COL1A1-PDGFB and thus, final diagnosis was confirmed. The article includes review of the literature and brief historical overview of giant cell fibroblastoma concept as an unique entity.


Assuntos
Dermatofibrossarcoma , Neoplasias Cutâneas , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Células Endoteliais/patologia , Células Gigantes/patologia , Humanos , Masculino , Proteínas Proto-Oncogênicas c-sis/genética , Neoplasias Cutâneas/patologia
18.
Nihon Shokakibyo Gakkai Zasshi ; 119(10): 961-968, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36216547

RESUMO

In this study, a 76-year-old man initially diagnosed with branch-duct pancreatic intraductal papillary mucinous tumor is presented. During follow-up, stenosis was discovered in the main pancreatic duct of the tail. A nodular lesion was found in the pancreatic duct consistent with the stenosis. Distal pancreatectomy was performed since it was suspected to be malignant. Histopathology revealed polymorphic mononuclear cells proliferated with osteoclast-like giant cells in the nodule. The patient was finally diagnosed with anaplastic pancreatic cancer with osteoclast-like giant cells, a relatively rare tumor. It is reported herein with a review of the literature.


Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/cirurgia , Idoso , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Constrição Patológica , Seguimentos , Células Gigantes/patologia , Humanos , Masculino , Osteoclastos/patologia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia
19.
mBio ; 13(5): e0254322, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36197088

RESUMO

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on global public health, emphasizing the importance of understanding innate immune mechanisms and cellular restriction factors that cells can harness to fight viral infections. The multimembrane-spanning zinc metalloprotease ZMPSTE24 is one such restriction factor. ZMPSTE24 has a well-characterized proteolytic role in the maturation of prelamin A, precursor of the nuclear scaffold protein lamin A. An apparently unrelated role for ZMPSTE24 in viral defense involves its interaction with the interferon-inducible membrane proteins (IFITMs), which block virus-host cell fusion by rigidifying cellular membranes and thereby prevent viral infection. ZMPSTE24, like the IFITMs, defends cells against a broad spectrum of enveloped viruses. However, its ability to protect against coronaviruses has never been examined. Here, we show that overexpression of ZMPSTE24 reduces the efficiency of cellular infection by SARS-CoV-2 Spike-pseudotyped lentivirus and that genetic knockout or small interfering RNA-mediated knockdown of endogenous ZMPSTE24 enhances infectivity. We further demonstrate a protective role for ZMPSTE24 in a Spike-ACE2-dependent cell-cell fusion assay. In both assays, a catalytic dead version of ZMPSTE24 is equally as protective as the wild-type protein, indicating that ZMPSTE24's proteolytic activity is not required for defense against SARS-CoV-2. Finally, we demonstrate by plaque assays that Zmpste24-/- mouse cells show enhanced infection by a genuine coronavirus, mouse hepatitis virus (MHV). This study extends the range of viral protection afforded by ZMPSTE24 to include coronaviruses and suggests that targeting ZMPSTE24's mechanism of viral defense could have therapeutic benefit. IMPORTANCE The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has underscored the importance of understanding intrinsic cellular components that can be harnessed as the cell's first line of defense to fight against viral infection. Our paper focuses on one such protein, the integral membrane protease ZMPSTE24, which interacts with interferon-inducible transmembrane proteins (IFITMs). IFITMs interfere with virus entry by inhibiting fusion between viral and host cell membranes, and ZMPSTE24 appears to contribute to this inhibitory activity. ZMPSTE24 has been shown to defend cells against several, but not all, enveloped viruses. In this study, we extend ZMPSTE24's reach to include coronaviruses, by showing that ZMPSTE24 protects cells from SARS-CoV-2 pseudovirus infection, Spike protein-mediated cell-cell fusion, and infection by the mouse coronavirus MHV. This work lays the groundwork for further studies to decipher the mechanistic role of ZMPSTE24 in blocking the entry of SARS-CoV-2 and other viruses into cells.


Assuntos
COVID-19 , Vírus da Hepatite Murina , Humanos , Camundongos , Animais , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2 , Pandemias , Lamina Tipo A , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , RNA Interferente Pequeno , Internalização do Vírus , Vírus da Hepatite Murina/genética , Antivirais/farmacologia , Células Gigantes , Metaloproteases , Interferons , Zinco
20.
Viruses ; 14(10)2022 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-36298738

RESUMO

The viral envelope is essential for virus maturation. Virus-mediated syncytium formations are induced by viral envelope proteins that cause membrane fusion of the infected cells. Polydnaviridae (Polydnavirus) are enveloped viruses with multiple nucleocapsids, and virions mature in symbiotic parasitoid wasp ovaries. However, the mechanism governing the envelope packaging of multiple nucleocapsids remains unclear. In this study, we used transmission electron microscopy to examine the process whereby multiple nucleocapsids of Microplitis bicoloratus bracovirus are packaged into an envelope and observed envelope-fusion-syncytium formation in symbiotic wasp calyx cells during virus maturation. The virus maturation process in calyx cells comprised four stages: pre-virogenic stroma, virogenic stroma, assembly, and fusion. Each virus contained a single envelope with one nucleocapsid in the assembly stage; multiple envelopes then fused to form a viral envelope with multiple nucleocapsids (i.e., the envelope-fusion-syncytium) around the envelope fusion core in the fusion stage. The envelope-fusion-syncytium then stabilized the virions that were released into the lumen of the ovary across the calyx epithelial layer. The phagocytic calyx epithelial cells on the border of the calyx and ovary lumen cleared the majority of non-enveloped nucleocapsids. In contrast, non-phagocytic calyx epithelial cells with microvilli and a cuticular line between the ovary wall and the lumen remained intact in the ovary lumen. These results indicate that envelope-fusion-syncytium formation is important for packaging multiple nucleocapsids in bracovirus maturation.


Assuntos
Polydnaviridae , Vespas , Animais , Feminino , Polydnaviridae/genética , Proteínas do Envelope Viral , Nucleocapsídeo , Células Gigantes
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