Treatment of multiple myeloma with selinexor: a review

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma. Selinexor may be useful for the treatment of refractory MM

Identification of a Novel Non-Canonical Splice-Site Variant in <i>ABCD1</i>

Cerebral adrenoleukodystrophy (CALD) is a fatal genetic disease characterized by rapid, devastating neurological decline, with a narrow curative treatment window in the early stage. Non-canonical splice-site (NCSS) variants can easily be missed during genomic DNA analyses, and only a few of them in ABCD1 have been explored. Here, we studied a Chinese patient with clinical features similar to those of early-stage CALD but with a negative molecular diagnosis and a sibling who had presumably died of CALD. Trio-based whole-exome sequencing (trio-WES) and RNA sequencing (RNA-Seq) revealed a novel hemizygote NCSS variant c.901-25_901-9 del in ABCD1 intron 1, resulting in a complex splicing pattern. The in vitro minigene assay revealed that the c.901-25_901-9 del construct contained two aberrant transcripts that caused skipping of exon 2 and a small 48-bp deletion on left of the same exon. We identified a novel NCSS variant, that extends the spectrum of the known ABCD1 variants, and demonstrated the pathogenicity of this gene variant. Our findings highlight the importance of combining RNA-Seq and WES techniques for prompt diagnosis of leukodystrophy with NCSS variants

Preparation of Polyethylene and Ethylene/Methacrylic Acid Copolymer Blend Films with Tunable Surface Properties through Manipulating Processing Parameters during Film Blowing

Polymer films based on polyethylene (PE) and ionomer ethylene/methacrylic acid (EMAA) copolymer blend were prepared by film blowing, whose surface properties were tuned by varying processing parameters, i.e., take up ratio (TUR). Blends of PE/EMAA copolymer were firstly prepared by the melt-mixing method, before being further blown to films. The wettability of the film was investigated by measuring the contact angle/water-film encounter time, and optical properties, i.e., the haze and transmittance. The wettability was found to be enhanced with the increase of TUR. So too was the haze, while the transmittance was found to be almost independent of TUR. The XPS and AFM results directly show the increasing polar functional groups (&ndash;COO&minus;) on the surface and roughness with increasing TUR. Further analysis of the 2D SAXS and WAXS unveiled the origin of the invariant transmittance, which resulted from the minor change of the crystallinity and the monotonic increase of the haze, with TUR resulting from the evolution of crystal orientation. In addition to other post-modification methods, the current study provides an alternative route to prepare large-scale PE films as the template for the advanced potential applications, i.e., covering in the layer of roof, the privacy of protective windows, and multitudes of packaging

Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation, Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts

Adiponectin, an adipocyte-derived hormone, exerts pleiotropic biological effects on metabolism, inflammation, vascular homeostasis, apoptosis and immunity. Recently, adiponectin has been suggested to attenuate the progression of human dermal fibrosis. Connective tissue growth factor (CTGF) is induced in keloids and is thought to be participated in the formation of keloid fibrosis. However, the roles played by adiponectin in keloids remain unclear. In this study, we explored the effects of adiponectin on CTGF-induced cell proliferation, migration and the deposition of extracellular matrix (ECM) and their associated intracellular signalling pathways in keloid fibroblasts (KFs). We also explored possible mechanisms of keloid pathogenesis. Primary fibroblast cultures were established from foreskin biopsies and skin biopsies from patients with keloids. The expression of adiponectin and adiponectin receptors (adipoRs) was evaluated by reverse transcription-PCR (RT-PCR), quantitative real-time RT-PCR, immunofluorescence staining, and immunohistochemical analysis. Next, KFs and normal dermal fibroblasts (NFs) were treated with CTGF in the presence or absence of adiponectin. A cell counting kit-8 (CCK-8) and the Transwell assay were used to examine cell proliferation and migration. The level of the collagen I, fibronectin (FN) and α-smooth muscle actin (α-SMA) mRNAs and proteins were determined by quantitative real-time RT-PCR and western blotting. The effects of RNA interference (RNAi) targeting the adipoR genes were detected. Phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase-protein kinase (PI3K-Akt) were examined by western blotting to further investigate the signalling pathways. Furthermore, inhibitors of signal transduction pathways were investigated. The expression levels of adiponectin and adipoRs were significantly decreased in keloids compared with those in normal skin tissue. Adiponectin suppressed the CTGF-induced KFs, but not NFs, proliferation, migration and ECM production. Moreover, adiponectin inhibited the phosphorylation of AMPK, p38 and extracellular-regulated kinase (ERK), but not that of Jun N-terminal kinase (JNK) or Akt, in CTGF-treated KFs. The activity of adiponectin-mediated signalling pathways was attenuated by small interfering RNAs (siRNAs) targeting adipoR1 (but not siRNAs targeting adipoR2, T-cadherin or calreticulin), AMPK (Compound C), p38 (SB203580) inhibitors, and mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059). Based on our results, adiponectin suppresses CTGF-induced KFs proliferation, migration and ECM overproduction. One of the underlying mechanisms is the activation of the adipoR1, AMPK, p38, and ERK signalling pathways. Therefore, adiponectin may play an important role in the progression of keloids, suggesting a potential novel target for keloid treatment

From Molecular Entanglement Network to Crystal-Cross-Linked Network and Crystal Scaffold during Film Blowing of Polyethylene: An in Situ Synchrotron Radiation Small- and Wide-Angle X‑ray Scattering Study

Combining a homemade film blowing machine and an in situ synchrotron radiation source with small- and wide-angle X-ray scattering (SAXS and WAXS) capability, an investigation of film blowing of polyethylene (PE) has been studied. From the die exit to the positions above the frost line, four zones defined with different structural features are observed with SAXS and WAXS measurements. In zone I, precursor and crystal structures emerge from the polymer entanglement network during cooling and extension, which lead to the formation of a deformable crystal-cross-linked network at the boundary between zones I and II. The occurrence of the crystal-cross-linked network enhances the effective chain stretching during further deformation in zone II. Crystallization is largely accelerated, which generates crystals with high orientation. Further increasing the crystallinity results in the deformable crystal-cross-linked network transforming into a nondeformable crystal scaffold at the frost line (the boundary between zones II and III), which stabilizes the bubble and prevents further deformation. In zones III and IV, the scaffold and the entire sample are gradually filled up by crystals, respectively. Interestingly, increasing the take-up ratio (TUR) does not influence the critical crystallinity (χ_I–II) for the formation of the deformable crystal-cross-linked network, while the crystallinity (χ_f) at the frost line or for the formation of nondeformable scaffold does vary with TUR. This suggests that the former (χ_I–II) is mainly controlled by molecular parameters, while the latter (χ_f) is determined by both processing and molecular parameters of PE material

Endoplasmic reticulum stress mediates nickel chloride-induced epithelial‑mesenchymal transition and migration of human lung cancer A549 cells through Smad2/3 and p38 MAPK activation

Background: The endoplasmic reticulum (ER) is a cellular membrane-bound organelle whereby proteins are synthesized, folded and glycosylated. Due to intrinsic (e.g., genetic) and extrinsic (e.g., environmental stressors) perturbations, ER proteostasis can be deregulated within cells which triggers unfolded protein response (UPR) as an adaptive stress response that may impact the migration and invasion properties of cancer cells. However, the mechanisms underlying the nickel compounds on lung cancer cell migration and invasion remain uncertain. Objective: We aimed to study whether Nickel chloride (NiCl2) induces ER stress in lung cancer cells, and whether ER stress is involved in modulating epithelial-mesenchymal transition (EMT) and migration by Smads and MAPKs pathways activation following NiCl2 treatment. Methods: A549 cells were treated with NiCl2 to determine the cell viability using MTT assay. The wound healing assay was used to evaluate cell migration ability. ER ultrastructure was observed by transmission electron microscopy. Western blotting assay was performed to evaluate the protein levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 for ER stress and UPR, E-cadherin and Vimentin for EMT, p-Smad2/3, p-ERK, p-JNK, and p-P38 for activation of Smads and MAPKs signaling pathways. Results: The expression levels of BIP, PERK, IRE-1α, XBP-1 s, and ATF6 were significantly increased following treatment with NiCl2 in time- and dose-effect relationship. The ER stress inhibitor 4-PBA downregulated the expression levels of the above five proteins, and reversed the decrease in E-cadherin protein level and the increase in vimentin protein expression and cell migration abilities caused by NiCl2. Furthermore, 4-PBA significantly reduced nickel chloride-induced Smad2/3 and p38 MAPK pathway activation, while not affected ERK and JNK MAPK pathways. Conclusion: NiCl2 triggers ER stress and UPR in A549 cells. Moreover, 4-PBA alleviates NiCl2-induced EMT and migration ability of A549 cells possibly through the Smad2/3 and p38 MAPK pathways activation, rather than ERK and JNK MAPK pathways