Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in ...transgenic mice with Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis.
Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway ...in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling.
Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM ...cells through constitutively active β-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115-584, which disrupt the interaction of the transcriptionally active β-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115-584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115-584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the β-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM.
Custom-designed zinc finger nucleases (ZFNs) are becoming powerful tools in gene targeting—the process of replacing a gene within a genome by homologous recombination. Here, we have studied the DNA ...cleavage by one such ZFN, ΔQNK-FN, in order to gain insight into how ZFNs cleave DNA and how two inverted sites promote double-strand cleavage. DNA cleavage by ΔQNK-FN is greatly facilitated when two ΔQNK-binding sites are close together in an inverted orientation. Substrate cleavage was not first order with respect to the concentration of ΔQNK-FN, indicating that double-strand cleavage requires dimerization of the FokI cleavage domain. Rates of DNA cleavage decrease as the substrate concentrations increase, suggesting that the ΔQNK-FN molecules are effectively “trapped” in a 1:1 complex on DNA when the DNA is in excess. The physical association of two ZFN monomers on DNA was monitored by using the biotin-pull-down assay, which showed that the formation of ΔQNK-FN active complex required both binding of the two ΔQNK-FN molecules to specific DNA sites and divalent metal ions.
is a rare, opportunistic fungal infection that affects immune-compromised hosts. When involving the PNS, it can be Rhino-orbital or Rhinocerebral and may rapidly prove fatal. We present a ...retrospective case series analysis of 48 patients from the COVID-19 pandemic, our management of them, and our takeaways. Out of 48, 12 had a previous history of oxygen therapy, 32 had tested positive for COVID-19 recently,8 had a history of ICU admission, and the most common occupations affected were homemakers and housewives. Grade 2 and 3 of rhino-orbital cerebral (ROCM)were most commonly found, and 28 developed type 2 diabetes before and after ROCM and 4 in the aftermath of the disease. A high degree of suspicion should be maintained in all patients with nasal, orbital, or neuro complaints with a previous history of COVID-19 infection and with or without co-morbid conditions.
Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved ...difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of β-catenin with B cell lymphoma 9 (BCL9), a co-activator for β-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives β-catenin signaling through direct binding mediated by its α-helical homology domain 2. We developed a stabilized α helix of BCL9 (SAH-BCL9), which we show targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-β-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.
Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and ...proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.
The purpose of this study was to assess the effect of the inclined outer velocity on heat and flow transportation in boundary layer Casson fluid over a stretching sheet. The flow is adopted to have ...non-orthogonal magnetic field with heat generation in the uniform manner on stretching surface. It has been taken that in both the directions along the x-axis, the sheet is stretched. By applying similarity transformations, the governing equations representing the heat and flow transportation are converted to ordinary differential equations. Runge-Kutta Fehlberg approach was adopted to solve numerically the moulded differential equations with the help of shooting technique. The flow is also governed by the heat source parameter, Casson fluid parameter, magnetic parameter, Prandtl number, aligned angle of magnetic field and the impinging angle parameter. The results revealed that velocity decreases with an increase in Casson fluid parameter, magnetic parameter and aligned angle of magnetic field for the case of outer velocity parameter less than one while velocity increases for the case of outer velocity parameter greater than one because of the inverted boundary layer formation for velocity profile in second case. Also, the fluid temperature increases (for the case of outer velocity parameter less than one) and temperature decreases (for the case of outer velocity parameter greater than one) with an increase in Casson fluid parameter, impinging angle parameter and aligned angle parameter. The results indicate that outer velocity and aligned magnetic field has a significant impact on fluid temperature and velocity. The behaviour of emerging fluid parameters on fluid temperature and velocity are depicted graphically and their effect on local Nusselt number (〖Nu〗_x ) and skin friction coefficient (C_f ) are represented by tables. The finding of this study may serve as to control the rate of heat transportation and fluid velocity in many manufacturing processes and industrial applications to make the desired quality of final product. Acceptance of the extant technique used in current study is correlated with the existing outcomes in the literature.
Custom-designed zinc finger nucleases (ZFNs), proteins designed to cut at specific DNA sequences, are becoming powerful tools in gene targeting—the process of replacing a gene within a genome by ...homologous recombination (HR). ZFNs that combine the non-specific cleavage domain (N) of FokI endonuclease with zinc finger proteins (ZFPs) offer a general way to deliver a site-specific double-strand break (DSB) to the genome. The development of ZFN-mediated gene targeting provides molecular biologists with the ability to site-specifically and permanently modify plant and mammalian genomes including the human genome via homology-directed repair of a targeted genomic DSB. The creation of designer ZFNs that cleave DNA at a pre-determined site depends on the reliable creation of ZFPs that can specifically recognize the chosen target site within a genome. The (Cys2His2) ZFPs offer the best framework for developing custom ZFN molecules with new sequence-specificities. Here, we explore the different approaches for generating the desired custom ZFNs with high sequence-specificity and affinity. We also discuss the potential of ZFN-mediated gene targeting for ‘directed mutagenesis’ and targeted ‘gene editing’ of the plant and mammalian genome as well as the potential of ZFN-based strategies as a form of gene therapy for human therapeutics in the future.
Ameloblastomas are odontogenic tumours that arise from the maxilla and mandible. They are mostly benign but can seldom turn malignant. Their low incidence (<1-3%) and ambiguous presentation can often ...pose a diagnostic dilemma for the clinician. They are mostly diagnosed with the help of contrast-enhanced computed tomography scans and confirmed by characteristic findings on histopathological examination. We present a case of a 14-year-old boy presenting with a firm to hard external swelling on the right side of his face and extensive intraoral mass, which showed features of a bony malignancy but was subsequently diagnosed with ameloblastoma.
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