Purpose
The blood–brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver ...anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (
Danio rerio
) model.
Materials and Methods
Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model.
Results
Four exosomes in 30–100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker.
Conclusions
Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.
The symmetry of the wavefunction describing the Cooper pairs is one of the most fundamental quantities in a superconductor, but for iron-based superconductors it has proved to be problematic to ...determine, owing to their complex multi-band nature. Here we use a first-principles many-body method, including the two-particle vertex function, to study the spin dynamics and the superconducting pairing symmetry of a large number of iron-based compounds. Our results show that these high-temperature superconductors have both dispersive high-energy and strong low-energy commensurate or nearly commensurate spin excitations, which play a dominant role in Cooper pairing. We find three closely competing types of pairing symmetries, which take a very simple form in the space of active iron 3d orbitals, and differ only in the relative quantum mechanical phase of the xz, yz and xy orbital components of the Cooper pair wavefunction. The extensively discussed s+- symmetry appears when contributions from all orbitals have equal sign, whereas a novel orbital-antiphase s+- symmetry emerges when the xy orbital has an opposite sign to the xz and yz orbitals. This orbital-antiphase pairing symmetry agrees well with the angular variation of the superconducting gaps in LiFeAs (refs , ).
The iron pnictide and chalcogenide compounds are a subject of intensive investigations owing to their surprisingly high temperature superconductivity. They all share the same basic building blocks, ...but there is significant variation in their physical properties, such as magnetic ordered moments, effective masses, superconducting gaps and transition temperature (T(c)). Many theoretical techniques have been applied to individual compounds but no consistent description of the microscopic origin of these variations is available. Here we carry out a comparative theoretical study of a large number of iron-based compounds in both their magnetic and paramagnetic states. Taking into account correlation effects and realistic band structures, we describe well the trends in all of the physical properties such as the ordered moments, effective masses and Fermi surfaces across all families of iron compounds, and find them to be in good agreement with experiments. We trace variation in physical properties to variations in the key structural parameters, rather than changes in the screening of the Coulomb interactions. Our results also provide a natural explanation of the strongly Fermi-surface-dependent superconducting gaps observed in experiments.
Histiocytic sarcoma, a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes, is characterized typically by extranodal presentation and a dismal clinical course, ...particularly in patients with disseminated disease. A history of hematolymphoid disorder can be identified in a subset of patients, suggesting transdifferentiation of a preexisting hematolymphoid neoplasm in its pathogenesis. The differential diagnosis of histiocytic sarcoma includes various lymphomas, other histiocytic and dendritic cell neoplasms, carcinomas, melanomas, and pleomorphic sarcomas. Given its rarity and histologic overlap with diverse mimics, the diagnosis of histiocytic sarcoma can be extremely challenging. Recognition of morphologic clues, as well as judicious application of immunohistochemical markers to confirm its histiocytic lineage and to exclude mimics, is crucial for the diagnosis. Recent molecular studies by targeted next-generation sequencing identified recurrent alterations in the mitogen-activated protein (MAP) kinase pathway and chromatin regulators in the pathogenesis of histiocytic sarcoma and may suggest possible therapeutic targets.
Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a distinctive vascular neoplasm of intermediate biological potential with a predilection for young adults and frequent multifocal ...presentation. Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindled and epithelioid cells with abundant eosinophilic cytoplasm and coexpression of keratins and endothelial markers. Recently, a SERPINE1-FOSB fusion has been identified as a consistent genetic alteration in pseudomyogenic hemangioendothelioma. FOSB gene fusions have also been reported in a subset of epithelioid hemangiomas. The purpose of this study was to assess the potential diagnostic utility of FOSB immunohistochemistry for pseudomyogenic hemangioendothelioma compared with other endothelial neoplasms and histologic mimics. We evaluated whole-tissue sections from 274 cases including 50 pseudomyogenic hemangioendotheliomas, 84 other vascular tumors (24 epithelioid hemangiomas including 6 cases with angiolymphoid hyperplasia with eosinophilia histology, 20 epithelioid angiosarcomas, 20 epithelioid hemangioendotheliomas 17 CAMTA1 positive, 2 TFE3 positive, 10 spindle-cell angiosarcomas, and 10 epithelioid angiomatous nodules), and 140 other histologic mimics (20 each epithelioid sarcoma, proliferative fasciitis, nodular fasciitis, cellular benign fibrous histiocytoma, spindle-cell squamous cell carcinoma, spindle-cell rhabdomyosarcoma, and leiomyosarcoma). Immunohistochemistry for FOSB was performed following pressure cooker antigen retrieval using a rabbit monoclonal antibody. Diffuse nuclear immunoreactivity for FOSB (>50% of cells) was observed in 48 of 50 (96%) pseudomyogenic hemangioendotheliomas and 13 of 24 (54%) epithelioid hemangiomas (including all angiolymphoid hyperplasia with eosinophilia type). Both FOSB-negative pseudomyogenic hemangioendothelioma cases were decalcified bone tumors. Only 7 other tumors showed diffuse FOSB expression: 2 proliferative fasciitis, 2 nodular fasciitis, 1 epithelioid angiosarcoma, 1 spindle-cell angiosarcoma, and 1 epithelioid hemangioendothelioma. Of note, the FOSB-positive epithelioid hemangioendothelioma was negative for CAMTA1 and TFE3. Focal weak FOSB staining was observed in a subset of histologic mimics and is therefore not diagnostically meaningful. In conclusion, FOSB is a highly sensitive and diagnostically useful marker for pseudomyogenic hemangioendothelioma. Immunohistochemistry for FOSB may be helpful to distinguish pseudomyogenic hemangioendothelioma from histologic mimics including epithelioid sarcoma and other vascular neoplasms. As expected, a subset of epithelioid hemangiomas expresses FOSB, including angiolymphoid hyperplasia with eosinophilia. Although occasional cases of nodular and proliferative fasciitis are positive for FOSB, distinction between these tumor types and pseudomyogenic hemangioendothelioma is usually straightforward based on morphology and other immunophenotypic findings.
A distinct subset of round cell sarcomas harbors capicua transcriptional repressor (CIC) rearrangement. Diagnosing these sarcomas can be difficult owing to their resemblance to Ewing sarcoma and ...other 'small round blue cell tumors'; molecular techniques are generally required. Recent gene expression studies of CIC-rearranged sarcomas identified the upregulation of ETV4. We assessed the sensitivity and specificity of ETV4 and WT1 immunohistochemistry for CIC-rearranged sarcoma. We evaluated whole-tissue sections from 40 CIC-rearranged sarcomas, 40 Ewing sarcomas, 4 BCOR-CCNB3 sarcomas, 6 unclassified round cell sarcomas, and 150 histologic mimics. Moderate-to-strong nuclear immunoreactivity for ETV4 in at least 50% of cells was observed in 36 (90%) CIC-rearranged sarcomas and 10 (5%) other tumors, including 5 unclassified round cell sarcomas, 2 Wilms tumors, and 1 each desmoplastic small round cell tumor, melanoma, and small cell carcinoma. Thirty-eight (95%) CIC-rearranged sarcomas showed nuclear staining for WT1, and 34 (85%) were positive for both ETV4 and WT1. Of 182 other tumors evaluated, 34 (19%) showed nuclear WT1 positivity, including all Wilms tumors and desmoplastic small round cell tumors, 5 unclassified round cell sarcomas, and a subset of lymphoblastic lymphomas, rhabdomyosarcomas, mesenchymal chondrosarcomas, carcinomas, and melanomas. In summary, diffuse moderate-to-strong ETV4 expression is present in most CIC-rearranged sarcomas and unclassified round cell sarcomas. More limited expression is seen in small subsets of various other round cell neoplasms. Nuclear WT1 expression is also present in most CIC-rearranged sarcomas and unclassified round cell sarcomas, along with Wilms tumors and desmoplastic small round cell tumors, and subsets of various histologic mimics. The sensitivity and specificity of diffuse ETV4 expression for CIC-rearranged sarcomas are 90% and 95%, respectively, whereas the sensitivity and specificity of WT1 are 95% and 81%, respectively. Diffuse ETV4 along with at least focal WT1 expression is helpful to distinguish CIC-rearranged sarcoma from Ewing sarcoma and other histologic mimics.
Primary mesenchymal tumours of the pleura are uncommon and can be diagnostically challenging due to their overlapping histopathologic and immunophenotypic features. Herein we discuss selected ...mesenchymal tumours of the pleura, including solitary fibrous tumour, calcifying fibrous tumour, desmoid fibromatosis, synovial sarcoma, schwannoma, malignant peripheral nerve sheath tumour, inflammatory myofibroblastic tumour, follicular dendritic cell sarcoma, epithelioid hemangioendothelioma, and desmoplastic small round cell tumour. We review their clinicopathologic characteristics, along with an update on the relevant immunohistochemical and molecular features.
We show that the numerical renormalization group is a viable multi-band impurity solver for dynamical mean-field theory (DMFT), offering unprecedented real-frequency spectral resolution at ...arbitrarily low energies and temperatures. We use it to obtain a numerically exact DMFT solution to the Hund metal problem for a three-band model on a Bethe lattice at 1/3 filling. The ground state is a Fermi liquid. The one-particle spectral function undergoes a coherence-incoherence crossover with increasing temperature, with spectral weight being transferred from low to high energies. Further, it exhibits a strong particle-hole asymmetry. In the incoherent regime, the self-energy displays approximate power-law behavior for positive frequencies only. The spin and orbital spectral functions show "spin-orbital separation": spin screening occurs at much lower energies than orbital screening. The renormalization group flows clearly reveal the relevant physics at all energy scales.
Malignant peritoneal mesothelioma is a rare aggressive tumor that arises from the peritoneal lining. While recurrent BAP1 mutations have been identified in a subset of mesotheliomas, molecular ...characteristics of peritoneal mesotheliomas, including those lacking BAP1 alterations, remain poorly understood. Using targeted next-generation sequencing, we examined the molecular features of 26 diffuse malignant peritoneal mesotheliomas. As part of an exploratory analysis, we analyzed an additional localized peritoneal mesothelioma and one well-differentiated papillary mesothelioma with invasive foci. Genomic characterization identified categories of diffuse malignant peritoneal mesotheliomas: The first group included 18 (69%) tumors with recurrent BAP1 alterations, with eight (31%) having more than one BAP1 alterations, and concomitant alterations in PBRM1 (46%) and SETD2 (35%). All tumors with complete loss of BAP1 expression by immunohistochemistry harbored BAP1 molecular alterations. PBRM1 alterations were significantly enriched in the BAP1-altered cohort. Frequent copy number loss of BAP1, ARID1B, PRDM1, PBRM1, SETD2, NF2, and CDKN2A was noted. The second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published. One TP53-mutant biphasic mesothelioma showed evidence of genomic near-haploidization showing loss of heterozygosity of all chromosomes except 5, 7, 16, and 20. The localized peritoneal mesothelioma harbored a nonsense CHEK2 mutation, and the well-differentiated papillary mesothelioma with invasive foci harbored no reportable variants. In conclusion, we described the genetic categories of diffuse malignant peritoneal mesotheliomas, with BAP1-mutant and BAP1-wild-type groups. Our findings implicated DNA repair, epigenetics, and cell cycle regulation in the pathogenesis of peritoneal mesotheliomas, with identification of potential therapeutic targets.
Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic ...kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion.
To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions.
We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions.
Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.
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