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The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED 50 <200 n M ), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom’s macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3′UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC -dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.

In the present study, an adsorbent material for removal of organic contaminants in wastewater is synthetized by a green and facile mechanochemical method. It is composed of Ti3C2Tx MXene layers (obtained by mechanochemical etching of MAX phase with concentrated HF) pillared with terephthalate by rapid direct reaction. Such material shows high specific surface area (135.7 m2 g−1) and excellent adsorption capability of methylene blue (209 mg g−1) because of the larger interlayer space among MXene sheets and free carboxylate groups of terephthalate. The spent adsorbent is reutilized (with addition of sole aluminum) to synthetize the MAX phase by mechanochemical procedure, where the terephthalate and the pollutant are carbonized into the carbide. In this way, new MXene-based adsorbent can be re-synthetized for further use.

Fluorinated organic chemicals have a wide variety of industrial and consumer applications. For long time perfluorooctane sulfonate and perfluorooctanoic acid have been used as precursors for manufacture of such chemicals. However, these C 8 chain compounds have been demonstrated to be toxic, persistent, and bioaccumulative, thus inducing their phase-out. Currently, C 6 telomer based fluorocarbon surfactants are considered better alternatives to C 8 products because of their low bioaccumulability. But, their high persistency suggests that in the near future their concentrations will increase in the environment and in industrial waste. Being a solid state non-thermal technology, mechanochemical treatment is a good candidate for the destruction of emerging C 6 fluorotelomers in solid waste. In the present study, 6:2 fluorotelomer sulfonate is effectively destroyed (~100%) in rapid manner (<1 h) by high energy ball milling with KOH. Stoichiometric fluoride formation confirms its entire mineralization, assuring that no toxic by-products are generated. Reaction mechanism and kinetics indicate that effective mineralization of the perfluorinated moiety is obtained thanks to a rapid CF 2 “flake-off” process through radical mechanism.

● Application of the MOF-composite membranes in adsorption was discussed. ● Recent application of MOFs-membranes for separation was summarized. ● Separation and degradation for emerging organic contaminants were described. Presence of emerging organic contaminants (EOCs) in water is one of the major threats to water safety. In recent decades, an increasing number of studies have investigated new approaches for their effective removal. Among them, metal-organic frameworks (MOFs) have attracted increasing attention since their first development thanks to their tunable metal nodes and versatile, functional linkers. However, whether or not MOFs have a promising future for practical application in emerging contaminants-containing wastewater is debatable. This review summarizes recent studies about the removal of EOCs using MOFs-related material. The synthesis strategies of both MOF particles and composites, including thin-film nanocomposite and mixed matrix membranes, are critically reviewed, as well as various characterization technologies. The application of the MOF-based composite membranes in adsorption, separation (nanofiltration and ultrafiltration), and catalytic degradation are discussed. Overall, literature survey shows that MOFs-based composite could play a crucial role in eliminating EOCs in the future. In particular, modified membranes that realize separation and degradation might be the most promising materials for such application.

Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.

In transplant-ineligible patients with multiple myeloma (MM), disease relapse represents a critical step in the therapeutic pathway. The increasingly early use of frontline regimens containing anti-CD38 monoclonal antibodies has led to significant improvements in clinical outcomes, while simultaneously increasing the complexity of treatment selection in subsequent lines, particularly in elderly and frail patients. Current guidelines recommend the use of combination regimens based on triplets in the second-line setting, preferably incorporating mechanisms of action different from those previously employed. In this context, selinexor, an oral selective inhibitor of exportin-1 (XPO1), represents an innovative therapeutic option due to its ability to restore tumor suppressor protein activity and enhance the efficacy of other antimyeloma agents, including proteasome inhibitors. Data from the phase III BOSTON trial demonstrated that the selinexor-bortezomib-dexamethasone (SVd) combination is associated with a clinically meaningful benefit in terms of progression-free survival and overall survival in patients with relapsed MM, with a particularly relevant advantage in patients treated in the second-line setting who were not previously exposed to bortezomib. Overall, the SVd regimen may represent an effective and sustainable second-line therapeutic strategy, capable of combining antitumor activity with manageable tolerability, and addressing the clinical needs of a patient population increasingly representative of contemporary hematologic practice.

After spinal cord injury (SCI), patients face many physical and psychological issues including intestinal dysfunction and comorbidities, strongly affecting quality of life. The gut microbiota has recently been suggested to influence the course of the disease in these patients. However, to date only two studies have profiled the gut microbiota in SCI patients, months after a traumatic injury. Here we characterized the gut microbiota in a large Italian SCI population, within a short time from a not only traumatic injury. Feces were collected within the first week at the rehabilitation center (no later than 60 days after SCI), and profiled by 16S rRNA gene-based next-generation sequencing. Microbial profiles were compared to those publicly available of healthy age- and gender-matched Italians, and correlated to patient metadata, including type of SCI, spinal unit location, nutrition and concomitant antibiotic therapies. The gut microbiota of SCI patients shows distinct dysbiotic signatures, i.e. increase in potentially pathogenic, pro-inflammatory and mucus-degrading bacteria, and depletion of short-chain fatty acid producers. While robust to most host variables, such dysbiosis varies by lesion level and completeness, with the most neurologically impaired patients showing an even more unbalanced microbial profile. The SCI-related gut microbiome dysbiosis is very likely secondary to injury and closely related to the degree of completeness and severity of the lesion, regardless of etiology and time interval. This microbial layout could variously contribute to increased gut permeability and inflammation, potentially predisposing patients to the onset of severe comorbidities.

Chitosan is a promising adsorbent for removing a wide range of pollutants from wastewater. However, its practical application is hindered by instability in acidic environments, which significantly impairs its adsorption capacity and limits its utilization in water purification. While cross-linking can enhance the acid stability of chitosan, current solvent-based methods are often costly and environmentally unfriendly. In this study, a solvent-free mechanochemical process was developed using high-energy ball milling to cross-link chitosan with various polyanionic linkers, including dextran sulfate (DS), poly[4-styrenesulfonic acid-co-maleic acid] (PSSM), and tripolyphosphate (TPP). The mechanochemically cross-linked (MCCL) chitosan products exhibited superior adsorption capacity and stability in acidic solutions compared to pristine chitosan. Chitosan cross-linked with DS (Cht-DS) showed the highest Reactive Red 2 (RR2) adsorption capacity, reaching 1559 mg·g−1 at pH 3, followed by Cht-PSSM (1352 mg·g−1) and Cht-TPP (1074 mg·g−1). The stability of MCCL chitosan was visually confirmed by the negligible mass loss of Cht-DS and Cht-PSSM tablets in pH 3 solution, unlike the complete dissolution of the pristine chitosan tablet. The MCCL significantly increased the microhardness of chitosan, with the order Cht-DS > Cht-PSSM > Cht-TPP, consistent with the RR2 adsorption capacity. When tested on simulated rinsing wastewater from chromium electroplating, Cht-DS effectively removed Cr(VI) (98.75% removal) and three per- and polyfluoroalkyl substances (87.40–95.87% removal), following pseudo-second-order adsorption kinetics. This study demonstrates the potential of the cost-effective and scalable MCCL approach to produce chitosan-based adsorbents with enhanced stability, mechanical strength, and adsorption performance for treating highly acidic industrial wastewater containing a mixture of toxic pollutants.

The brain responds to experience through modulation of synaptic transmission, that is synaptic plasticity. An increase in the strength of synaptic transmission is manifested as long-term potentiation (LTP), while a decrease in the strength of synaptic transmission is expressed as long-term depression (LTD). Most of the studies of synaptic plasticity have been carried out by induction via electrophysiological stimulation. It is largely unknown in which behavioural tasks such synaptic plasticity occurs. Moreover, some stimuli can induce both LTP and LTD, thus making it difficult to separately study the different forms of synaptic plasticity. Two studies have shown that an aversive memory task – inhibitory avoidance learning and contextual fear conditioning – physiologically and selectively induce LTP and an LTP-like molecular change, respectively, in the hippocampus in vivo. Here, we show that a non-aversive behavioural task – exploration of new space – physiologically and selectively elicits a biochemical change in the hippocampus that is a hallmark of LTP. Specifically, we found that exploration of new space induces an increase in the phosphorylation of GluA1(Ser831), without affecting the phosphorylation of GluA1(Ser845), which are biomarkers of early-LTP and not NMDAR-mediated LTD. We also show that exploration of new space engenders the phosphorylation of the translational regulator S6K and the expression of Arc, which are features of electrophysiologically-induced late-LTP in the hippocampus. Therefore, our results show that exploration of new space is a novel non-aversive behavioural paradigm that elicits molecular changes in vivo that are analogous to those occurring during early- and late-LTP, but not during NMDAR-mediated LTD.