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关键词： plasma cell leukaemia   multiple myeloma   plasma cell   flow cytometry   prognosis   phenotype  

摘要： Plasma cell leukaemia (PCL) is a rare and very aggressive plasma cell disorder. Preventing a dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Therefore, the investigation of 33 patients with primary and secondary PCL was done when the quantity of circulating plasma cells (PCs) using flow cytometry (FC) and morphology assessment was evaluated. The phenotypic profile of the PCs was also analysed to determine if there is an association with clinical outcomes and to evaluate the prognostic value of analysed markers. Our results revealed that FC is an excellent method for identifying circulating PCs as a significantly higher number was identified by FC than by morphology (26 center dot 7% vs. 13 center dot 5%, P = 0 center dot 02). None of secondary PCL cases expressed CD19 or CD20. A low level of expression with similar positivity of CD27, CD28, CD81 and CD117 was found in both PCL groups. A decrease of CD44 expression was detected only in secondary PCL. Expression of CD56 was present in more than half of PCL cases as well as cytoplasmic nestin. A decreased level of platelets, Eastern Cooperative Oncology Group score of 2-3 and lack of CD20(+) PC were associated with a higher risk of death. FC could be incorporated in PCL diagnostics not only to determine the number of circulating PCs, but also to assess their phenotype profile and this information should be useful in patients' diagnosis and possible prognosis.

关键词： Adaptation models   Computational modeling   Simulation   Dynamics   Force   Rotors   Real-time systems   Foundation motions   model   magnetic bearing   suspension force  

摘要： Conventional suspension forces modeling methods are usually only focused on the computation of the internal magnetic field of the magnetic bearing itself. However, the modeling accuracy is also affected by its actual application, especially for the magnetic bearing in moving situation, such as magnetic suspended flywheel battery system for electric vehicles. In this article, taking the centripetal force type-magnetic bearing as an example, a dynamic correction model considering influence of foundation motions is proposed, which has several submodels to cover as many driving conditions as possible. First, a universal static model based on spherical coordinate system is established. Then, the dynamic model is derived, which includes the control current, offset, and variables of foundation. Given the complexity and diversity of real-time operating conditions of vehicles will affect the calculation accuracy of variables of foundation, resulting in the increase of the error in single dynamic model. Therefore, the idea of foundational weight factor is brought up and fitted by analyzing the dynamic response laws of rotor under different foundation motions. Finally, the dynamic stiffness experiments and performance tests are carried out. The good experiment results show that the proposed model is more practical and has higher precision than traditional model.

关键词： Tumor Necrosis Factor-alpha   Cerebral Ischemia   Mesenchymal Stem Cell transplantation   Microglia   Astrocyte  

摘要： Recent studies report that inhibiting TNF-alpha might be a novel therapeutic strategy for managing brain ischemia. Our previous study reported that mesenchymal stem cell (MSC) transplantation could suppress TNF-alpha level in both serum and brain. However, the cell type(s) that contribute to the production of TNF-alpha during ischemia following MSC transplantation has not been well studied. In the present study, we found by fluorescent immunohistochemistry, that 7.95 +/- 6.17% of TNF-alpha(+) cells co-expressed Iba-1 in the infarct area of dMCAO rats, a majority of which were found to be CD68(+) (activated microglia), suggesting that resident microglial population were not the major source of TNF-alpha expression. 68.49 +/- 5.12% of the TNF-alpha(+) cells in the infarct area could be labeled by GFAP, a specific marker for astrocytes, indicating that resident GFAP(+) astrocytes might be the major source of TNF-alpha expression in the infarct area. In addition to the infarct area, the GFAP(+)/TNF-alpha(+) double-positive astrocytes accounted for 73.68 +/- 7.48% of the TNF-alpha(+) cells in striatum and corpus callosum. The infiltrating cells, including monocytes and lymphocytes, were not the main source of TNF-alpha either. In response to MSC transplantation, the total TNF-alpha(+) cells as well as the percentage of TNF-alpha-expressing astrocytes were significantly reduced in the infarct area, suggesting that MSC transplantation could suppress the expression of TNF-alpha by astrocytes. Taken together, the results demonstrated that resident astrocytes, but not microglia, were the major source of TNF-alpha expression and could be suppressed by MSC infusion.

摘要： Numerous processes occur simultaneously in the cell both for normal function and in response to changes in the environment. The ability of cells to segregate biochemical reactions into separate compartments is essential to ensure specificity and efficiency in cellular processes. The discovery of liquid-liquid phase separation as a mechanism of compartmentalization has revised our thinking regarding the intracellular organization of molecular pathways such as signal transduction. Here, we highlight recent studies that advance our understanding of how phase separation impacts the organization of biochemical processes, with a particular focus on the tools used to study the functional impact of phase separation. In addition, we offer some of our perspectives on the pathological consequences of dysregulated phase separation in biochemical pathways.

关键词： Cytotoxic cutaneous T cell lymphoma   primary cutaneous CD8+aggressive epidermotropic cytotoxic T cell lymphoma   JAK-STAT  

摘要： Background: Primary cytotoxic T cell lymphomas are a heterogenous collection of ill-defined diseases with aggressive disease course and poor response to conventional therapy. Of these, primary cutaneous CD8+ aggressive epidermotropic T cell lymphoma and cutaneous T cell lymphoma, not otherwise specified, have undergone few to no systematic analyses of its genetic landscape. In this study, we classify these lymphomas based on their histological and clinical features and perform systematic genomic analyses to find novel therapeutic targets. Methods: We clinically characterize 35 patients from 10 institutions with cytotoxic T cell lymphoma and performed integrative clinical, pathological, and genetic analyses. We perform Archer™ Heme Fusion on an initial 24 FFPE samples. In addition, we perform DNA and/or RNA sequencing on 11 cases. We functionally validate our genetic findings by transducing alterations into Ba/F3 cells and subsequently performing biochemical assays. In this setting, we assess sensitivity to FDA-approved small molecule inhibitors. We provide orthogonal evidence of transcriptional upregulation by geneset enrichment analysis. Results: We find kinase fusions impacting JAK-STAT signaling in all primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our cohort. Three of these fusions have not previously been described in cancer. Known fusions have been shown to upregulate JAK-STAT signaling. Upon each transduction, CAPRIN1-JAK2 and SELENOI-ABL1 cause increased phosphorylation and display IL-3-independent growth compared to control. Upon treatments to small molecule inhibitors, ruxolitinib and imatinib respectively, CAPRIN1-JAK2 and SELENOI-ABL1 expressing cells exhibit sensitivity. Cutaneous T cell lymphoma, not otherwise specified, harbor JAK-STAT hotspot mutations but not kinase fusions. Conclusions: All 9 primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our series harbor kinase fusions, while the majority of the cutaneo

关键词： Cutaneous B-cell lymphoma   primary cutaneous large B-cell lymphoma   leg-type   primary cutaneous follicle centre lymphoma   reverse transcriptase-multiplex ligation profiling assay   next generation sequencing  

摘要： Primary cutaneous large B-cell lymphomas (PCLBCL) correspond to either PCLBCL, leg type (PCLBCL, LT) or to primary cutaneous follicle centre lymphoma, large cell (PCFCL, LC). Patients with PCFCL, LC are mostly treated by local approaches such as radiotherapy or when multiple lesions by rituximab only. Alternatively, PCLBCL, LT have an aggressive course, requiring a combination of rituximab and polychemotherapy as first line therapy. The combination of clinico-pathological criteria according to WHO-EORTC guidelines permit to classify most cases but those with discordant findings may fall in a not otherwise specified (PLBCL, NOS) category without therapeutic guidelines. Moreover, the expected rate of the NOS diagnosis may vary between centers. We used an already well-characterized retrospective series with long-term follow-up data to evaluate the cell of origin classification of PCLBCL as either germinal center (GC)-type or non-germinal center (NGC)-type using either an immunohistochemical profiling or a reverse transcriptase multiplex ligation assay (RT-MLPA). This cohort contained 21 PCFCL, LC cases, 27 PCLBCL, LT cases and 7 PCLBCL, NOS cases for which the review of clinical data, morphology and immunophenotype could not achieve categorization. The Hans algorithm classified 21 PCFCL, LC cases as GC-type and 27 PCLBCL, LT as NGC-type. Accordingly, the RT-MLPA analysis classified 21 PCFCL, LC cases as GC-type and 25 out of 27 PCLBCL, LT as NGC-type with two undetermined or non-contributive cases containing less than 20% tumoral cells. A concordant profiling between the two techniques permitted to reclassify 4 of the 7 PCLBCL, NOS into either PCFCL, LC (n=2) or PCLBCL, LT (n=2). RT-MLPA profiling was also concordant with lymphopanel mutational analysis providing an integrative categorization of PCLBCL especially in 6 out of 7 NOS cases categorized as PCFCL, LC (n=3) or PCLBCL, LT (n=3). A single case with a discordant profiling remained as NOS and presented with leg i

关键词： Primary adenosquamous carcinoma of the liver   Small cell carcinoma   Chemotherapy  

摘要： Primary adenosquamous carcinoma (ASC) of the liver is a rare subtype of cholangiocarcinoma that comprises both adenocarcinoma and squamous cell carcinoma components. We report a 48-year-old woman with advanced primary ASC and small cell carcinoma of the liver who had extrahepatic metastasis and received multiple chemotherapy regimens. After first presenting with upper abdominal pain, imaging revealed a 10.2 x 9.5 cm mass in the right lobe of the liver with lymph node and lung metastases. A liver tumor biopsy revealed adenocarcinoma and squamous cell carcinoma components, leading to a diagnosis of advanced primary ASC of the liver. The tumor shrank with gemcitabine/cisplatin therapy;however, neuron-specific enolase (NSE) and CYFRA levels were increased and the tumor grew. Next, hepatic arterial infusion chemotherapy using 5-fluorouracil and cisplatin decreased NSE and CYFRA levels and suppressed tumor growth. However, due to tumor growth, she died 14 months post-initial diagnosis. Post-autopsy pathology revealed a mixture of CD56- and synaptophysin-positive small cell carcinoma component in addition to ASC. We report a rare advanced primary ASC with small cell carcinoma of the liver diagnosed at autopsy.

关键词： Shear stress   Cilium   Nrf2   Elastase   FGF-2   Endothelial cells  

摘要： Endothelial cells are sensitive to mechanical stress and respond differently to oscillatory flow versus unidirectional flow. This review highlights the mechanisms by which a wide range of unidirectional laminar shear stress induces activation of the redox sensitive antioxidant transcription factor nuclear factor-E2-related factor 2 (Nrf2) in cultured endothelial cells. We propose that fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor (BDNF) and 15-Deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) are potential Nrf2 activators induced by laminar shear stress. Shear stress-dependent secretion of FGF-2 and its receptor-mediated signaling is tightly controlled, requiring neutrophil elastase released by shear stress, alpha v beta 3 integrin and the cell surface glycocalyx. We speculate that primary cilia respond to low laminar shear stress ( 10 dyn/cm2), resulting in secretion of insulin-like growth factor 1 (IGF-1), which facilitates alpha v beta 3 integrin-dependent FGF-2 secretion. Shear stress induces generation of heparan-binding epidermal growth factor-like growth factor (HB-EGF), which contributes to FGF-2 secretion and gene expression. Furthermore, HB-EGF signaling modulates FGF-2-mediated NADPH oxidase 1 activation that favors casein kinase 2 (CK2)-mediated phosphorylation/activation of Nrf2 associated with caveolin 1 in caveolae. Higher shear stress ( 15 dyn/cm2) induces vesicular exocytosis of BDNF from endothelial cells, and we propose that BDNF via the p75NTR receptor could induce CK2-mediated Nrf2 activation. Unidirectional laminar shear stress upregulates gene expression of FGF-2 and BDNF and generation of 15d-PGJ2, which cooperate in sustaining Nrf2 activation to protect endothelial cells against oxidative damage.

关键词： cancer/malignancy/neoplasia: hematogenous/leukemia/lymphoma   complication: malignant   dialysis: hemodialysis   hematology/oncology   immunobiology   infection and infectious agents - viral: Epstein-Barr Virus (EBV)   translational research/science  

摘要： Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission >= 34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).