Search Results (112)

Lithium manganese iron phosphate [LiMn_xFe_1−xPO₄ (x ≤ 0.5)]-based cathode materials were synthesized via a hydrothermal method to investigate their composition effect on structure and electrochemical performance. The X-ray diffraction results confirmed a single-phase olivine structure (Pnma) for all the compositions, with minor lithium phosphate (Li₃PO₄) impurities detected at high manganese (Mn) contents (x ≥ 0.4). The morphological evolution from small particles with low Mn content to compact rod-like particles at x = 0.3 indicates optimized crystal growth and improved interparticle connectivity. Electrochemical testing revealed that the discharge capacity initially increased with the substituted Mn content to a maximum of 140 mAh g⁻¹ at 0.5 C for LiMn_0.3Fe_0.7PO₄/C with remarkable cycling stability. This high capacity is attributed to the activation of Fe²⁺/Fe³⁺ and Mn²⁺/Mn³⁺ redox couples and the minimal formation of electrochemically inactive phases. Further Mn incorporation (x > 0.3) caused structural distortion, Li₃PO₄ formation, and overall capacity loss. Codoping with Mg (LiMg_0.05Mn_xFe_1−xPO₄) improved stability but lowered discharge capacity owing to the electrochemical inactivity of Mg²⁺ and impurity formation. Notably, an optimal x value of ~0.3 exhibited an effective balance between high energy density, rate capability, and structural integrity in Mn-doped LiFePO₄ cathodes for next-generation lithium-ion batteries. Full article

Mammarenaviruses (MaAv) cause persistent infection in their natural rodent hosts across the world and, via zoonotic events, can cause severe disease in humans. Thus, the MaAv Lassa virus (LASV) in Western Africa and the Junin virus (JUNV) in the Argentinean Pampas cause hemorrhagic fever diseases with significant case fatality rates in their endemic regions. In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen of clinical significance capable of causing devastating infections in neonates and immunocompromised individuals. Despite their impact on human health, there are currently no FDA-approved vaccines or specific antiviral treatments for MaAv infections. Existing anti-MaAv therapies are limited to the off-label use of ribavirin, whose efficacy remains controversial; hence, the development of novel therapeutics to combat human pathogenic MaAv is vital. We employed a high-throughput cell-based infection assay to screen the Pandemic Response Box, a collection of 400 diverse compounds with established antimicrobial activity, for MaAv inhibitors. We identified Ro-24-7429, an antagonist of the HIV-1 Tat protein and RUNX family transcription factor 1 inhibitor; WO 2006118607 A2, a dihydroorotate dehydrogenase inhibitor; and verdinexor, a novel selective inhibitor of nuclear export (SINE) targeting the XPO1/CRM1, as potent anti-MaAv compounds. Consistent with their distinct validated targets, verdinexor and WO 2006118607 A2 exhibited very strong synergistic antiviral activity when used in combination therapy. Our findings pave the way for the development of verdinexor as a potent host-directed antiviral against MaAv, which could be integrated into the development of combination therapy with direct- or host-acting antivirals to combat human pathogenic MaAv. Full article

Background/Objectives: Aurora kinases (AURKs) are key regulators of mitosis, and their dysregulation contributes to plasma cell disorders, including multiple myeloma (MM) and plasma cell leukemia (PCL). Methods: The expression and prognostic relevance of AURK family members were examined, and the therapeutic potential of AURKA inhibition was evaluated. Results: Gene expression analysis demonstrated significant upregulation of AURKA in PCL. Treatment of MM cells with the selective AURKA inhibitor LY3295668 induced dose-dependent cytotoxicity, caspase-3/7 activation, and cellular senescence. Similarly, selinexor, a selective exportin-1 inhibitor, elicited dose-dependent cytotoxicity and apoptosis. Combined treatment with LY3295668 and selinexor significantly improved apoptosis compared with either agent alone, and AURKA knockdown further sensitized MM cells to selinexor, thereby increasing apoptosis. In bortezomib-resistant MM cells and primary PCL samples, the combination therapy induced cytotoxicity and caspase-3/7 activation. Conclusions: These findings underscore AURKA expression as a prognostic marker in plasma cell disorders and support the therapeutic potential of combining AURKA inhibition with selinexor for bortezomib-resistant MM and PCL. To explore biomarker-driven strategies for optimizing therapeutic outcomes, future studies are warranted. Full article

(1) This cross-sectional study aims to elucidate the association between the XPO5 gene polymorphism (rs11544382) and colon cancer (CC). (2) Genotyping of XPO5 (rs11544382) was performed in 120 individuals (60 CC patients and 60 controls) using real-time PCR (qPCR). Logistic regression and Chi-square (χ²) tests were used for statistical analysis. (3) Evaluation of the XPO5 gene polymorphism in CC and control groups revealed no statistically significant association between the mutant (GG) genotype and either the wild-type (AA) or heterozygous (AG) genotypes (χ² = 2.07, p = 0.151). The AG genotype was predominant in both patients (86.7%) and controls (91.7%). Smoking and alcohol consumption showed significant associations with CC (p < 0.05). Although the rs11544382 polymorphism was not associated with CC risk, this is a cross-sectional study. In light of these findings, larger and more comprehensive studies with increased sample size are required to clarify the relationship between the XPO5 gene polymorphism (rs11544382) and CC. Full article

This study investigates phase formation in the Sr–Zn–Eu³⁺ orthophosphate system, focusing on double- and triple-phosphates. The isomorphisms and phase formation in Sr_3–1.5xEu_1+x(PO₄)₃, Sr_9–1.5xZn_1.5Eu_x(PO₄)₇, Sr_9.5–1.5xZnEu_x(PO₄)₇, Sr_3–xZn_xEu(PO₄)₃, and Sr_3–xZn_x(PO₄)₂ series were studied using powder X-ray diffraction and Rietveld refinement. A ternary phase diagram was constructed, identifying concentration limits for pure phases and multi-phase regions as well as areas of stabilization of strontiowhitlockite-, palmierite-, eulytite-, and strontiohurlbutite-type phases. The combinatorial complexity of Sr-based phosphates is discussed. The β-Sr₃(PO₄)₂ isostructural to whitlockite was found to exhibit the highest isomorphic capacity for Eu³⁺ cations, which is advantageous for its application as a red-emitting phosphor. Photoluminescence properties were studied, and analyzed based on structural data. Photoluminescence studies confirmed intense red-emission dominated by the ⁵D₀ → ⁷F₂ transition of Eu³⁺, with the β-Sr₃(PO₄)₂-based phosphor showing the highest emission intensity. Full article

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, with therapeutic resistance continuing to limit long-term responses. Among emerging resistance mechanisms, dysregulation of nucleocytoplasmic transport has gained attention for its ability to inactivate tumor suppressor pathways. Exportin 1 (XPO1), the primary nuclear export protein, is frequently overexpressed in NSCLC and promotes the cytoplasmic mislocalization of proteins involved in cell cycle control, apoptosis, and DNA repair. This includes key regulators such as p53, FOXO, and RB, whose inactivation supports tumor progression and therapy resistance. Inhibition of XPO1 with selective inhibitors of nuclear export (SINE) compounds, including selinexor, has demonstrated the ability to restore nuclear localization and function of these proteins, thereby enhancing cellular sensitivity to DNA-damaging agents, kinase inhibitors, and immunotherapies. In preclinical NSCLC models, XPO1 inhibition has shown efficacy both as monotherapy and in combination strategies, with particular promise in KRAS- and EGFR-driven tumors. This review explores the role of XPO1 in NSCLC biology and therapy resistance, the rationale for targeting nuclear export, and the current landscape of XPO1-directed clinical development in lung cancer. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive and antiangiogenic therapies, yet its molecular mechanisms remain poorly defined. The present study employed an analysis of microarray data (GSE7116) from peripheral blood mononuclear cells of patients with multiple myeloma, myeloma patients with MRONJ, and healthy controls. Differentially expressed genes were identified using the limma package, followed by functional enrichment analysis, weighted gene co-expression network analysis, and LASSO regression and CytoHubba network ranking. The predictive performance was validated by means of nested cross-validation, Firth logistic regression, and safe stratified 0.632+ bootstrap ridge regression. The profiling revealed distinct gene expression patterns between the groups: the upregulation of ribosomal and translational pathways, as well as the suppression of neutrophil degranulation and antimicrobial defense mechanisms, and identified key candidate genes, including PDE4B, JAK1, ETS1, EIF4A2, FCMR, IGKV4-1, and XPO7. These genes demonstrated substantial discriminatory capability, with an area under the curve ranging from 0.95 to 0.99, and were found to be functionally linked to immune system dysfunction, cytokine signaling, NF-κB activation, and a maladaptive stress response. These findings link MRONJ to systemic immune-inflammatory imbalance and translational stress disruption, offering novel insights and potential biomarkers for diagnosis and risk evaluation. Full article

This study investigated proteomic differences in nasopharyngeal swabs of SARS-CoV-2-infected patients from Manaus (Brazil) who were hospitalized during the devastating first wave of the COVID-19 pandemic, before the emergence of the deadly P1 SARS-CoV-2 strain. LC-MS/MS proteomic analysis compared 16 matched COVID-19 patient profiles: eight survivors and eight fatalities. A total of 1604 proteins were identified in fatality swabs, and 981 in the swabs of survivors. Our study provides new insights into the cellular mechanisms underlying first-wave COVID-19 deaths from Manaus and identifies hypoxia-related HYOU1, endothelial injury-associated S100A10, and some viral replication proteins (DDX1/17, XPO1) as potential biomarkers of fatal infections. The proteomic profiles of the swabs taken from patients that died collectively suggest that many of the first wave COVID-19 fatalities in Manaus suffered immune-system collapse. Survivor patient swabs showed elevated levels of immune defense proteins (FN1, C4BPA, IGKV1-5), indicating effective antiviral responses. Gene ontology analysis revealed dysregulated secretory pathways in fatalities and did not detect the defense-response pathways in fatality-group datasets that were observed in survivor protein datasets. Interestingly, the NOS2 protein, previously associated with first-wave fatalities, was found exclusively in our fatality swabs. Full article

Background/Objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis. Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared with SPEN wild type CLL patients, SPEN mutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%, p = 0.004), CD38 positivity (73.3% vs. 52.4%, p = 0.01), ZAP70 positivity (77.3% vs. 58.3%, p = 0.01) and trisomy 12 (43.5% vs. 13.7%, p < 0.001). The most common gene mutations co-occurring with SPEN mutations were as follows: NOTCH1 (43.7%), TP53 (22.9%), BIRC3 (12.5%), SF3B1 (10.4%), XPO1 (8.3%), MUC2 (6.2%), ATM (4.2%), FBXW7 (4.2%), and BTK (4.2%). Patients with SPEN mutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild type SPEN (2.5 vs. 4.07 years, p = 0.01). The finding of shorter time-to-first treatment in SPEN mutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status, TP53 disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis. Conclusions: These data show that SPEN mutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients. Full article

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer with limited treatment options. Our previous work explored repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. To enhance its efficacy, this study aimed to identify beneficial combination therapies with selinexor and experimentally evaluate their effects in TNBC. Using the computational tool IDACombo, we nominated drugs predicted to improve the efficacy of XPO1 inhibition. The top candidate, parthenolide, was tested in vitro using three transcriptionally distinct TNBC cell lines. Fluorescently labeled cells were co-cultured and treated with selinexor, parthenolide, or their combination. Growth inhibition was assessed across the mixed population and by individual cell line after 96 h, and potential synergy was evaluated using Combenefit. While selinexor and parthenolide monotherapy inhibited the growth of TNBC subtypes, the combination was more effective in suppressing the overall cell population. Synergistic interactions between the two agents were observed in specific TNBC lines but not all, reflecting the combination effect in heterogeneous TNBC patients. Our findings suggest the selinexor–parthenolide combination as a potential therapeutic strategy for TNBC, warranting further investigation. Our study also demonstrates the value of integrative computational–experimental approaches in guiding heterogeneity-informed drug combinations for preclinical evaluation. Full article

NASICON-type Li_1+XFe_XTi_2-X(PO₄)₃ (x = 0.1, 0.3, 0.4) solid electrolytes for all-solid-state Li-ion batteries were synthesized using a sol–gel method. This study investigated the impact of substituting Fe³⁺ (0.645 Å), a trivalent cation, for Ti⁴⁺ (0.605 Å) on ionic conductivity. Li_1+XFe_XTi_2-X(PO₄)₃ samples, subjected to various sintering temperatures, were characterized using TG-DTA, XRD with Rietveld refinement, XPS, FE-SEM, and AC impedance to evaluate composition, crystal structure, fracture-surface morphology, densification, and ionic conductivity. XRD analysis confirmed the formation of single-crystalline NASICON-type Li_1+XFe_XTi_2-X(PO₄)₃ at all sintering temperatures. However, impurities in the secondary phase emerged owing to the high sintering temperature above 1000 °C and increased Fe content. Sintered density increased with the densification of Li_1+XFe_XTi_2-X(PO₄)₃, as evidenced by FE-SEM observations of sharper edges of larger quasi-cubic grains at elevated sintering temperatures. At 1000 °C, with Fe content exceeding 0.4, grain coarsening resulted in additional grain boundaries and internal cracks, thereby reducing the sintered density. Li_1.3Fe_0.3Ti_1.7(PO₄)₃ sintered at 900 °C exhibited the highest density among the other conditions and achieved the maximum total ionic conductivity of 1.51 × 10⁻⁴ S/cm at room temperature, with the lowest activation energy for Li-ion transport at 0.37 eV. In contrast, Li_1.4Fe_0.4Ti_1.6(PO₄)₃ sintered at 1000 °C demonstrated reduced ionic conductivity owing to increased complex impedance associated with secondary phases and grain crack formation. Full article

The XPO1 (exportin 1) gene encodes exportin 1 protein responsible for transporting proteins and RNA from the nucleus to the cytoplasm. It has been used as a biomarker for lymphoma detection. XPO1^E571K mutation has been frequently observed and identified as a good prognostic indicator for lymphoma patients. The detection of a target molecule released by lymphoma cells into blood circulation (cell-free circulating tumor DNA, cfDNA) is a better method than tissue biopsy. However, cfDNA concentration in blood circulation is very low in cancer patients. Therefore, a precise and sensitive method is needed. In this study, cfDNA was extracted, and then the XPO1 gene was detected and amplified using conventional PCR. Sanger sequencing was employed to verify the DNA sequences. FAST-COLD-PCR was developed to detect XPO1^E571K gene mutation using a CFX96 Touch Real-Time PCR System. The optimal critical temperature (Tc) was 73.3 °C, allowing selective amplification of XPO1^E571K mutant DNA while wild-type XPO1 could not be amplified. XPO1^E571K gene mutation can be detected by this method with high specificity and sensitivity in lymphoma patients. This approach facilitates rapid and straightforward detection in a timely manner after the diagnosis. Accordingly, the optimized FAST-COLD-PCR conditions can be used as a prototype for XPO1^E571K mutant detection in lymphoma patients. Full article

Lymphoma is the most common neoplasm of lymphoid tissues in dogs. Exportin 1 (XPO1) is an important major nuclear receptor for exporting proteins and RNA species. The XPO1 upregulation can eliminate some tumor suppressor proteins (TSPs) function upon their nuclear–cytoplasmic export. The XPO1 inhibitor, KPT-335, blocks the translocation of TSPs and restores their function to induce cell cycle arrest, apoptosis, and cell proliferation. This in vitro study aimed to evaluate the XPO1 mRNA and protein expression in canine lymphoma cell lines and confirm the relevance with KPT-335. XPO1 mRNA and protein levels were quantified, and the effect of KPT-335 was assessed by a cell proliferation assay. The results indicated that XPO1 mRNA and protein were highly expressed in 17-71, CLBL-1, CLC, CLGL-90, and UL-1, and were moderately expressed in GL-1, Ema, and Nody-1. All canine lymphoma cell lines showed dose-dependent growth inhibition and decreased cell viability in response to KPT-335, with IC₅₀ concentrations ranged from 89.8–418 nM. The expression levels of XPO1 mRNA and protein were related; however, no correlation was found between those expression levels and the efficacy of KPT-335. These findings suggest that XPO1 may represent a promising target for therapeutic intervention in canine lymphoma. Full article

There have been multiple approved agents for relapsed/refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) over the last 8 years. The majority of these therapies act on specific signaling pathways in malignant B-cells. These signaling pathways stem from the B-cell receptor (BCR), Toll-Like Receptor (TLR), PI3K/AKT/mTOR, BCL-2, and XPO-1. In addition, novel therapies that target extracellular proteins (CD19, CD20, CD30, ROR1, and PD-1) have been developed. The purpose of this review is to discuss the various therapies that target these pathways and highlight the success and shortcomings of these novel agents. Full article

The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes for a protein that normally shuttles between the nucleus and the cytoplasm of the normal hematopoietic cells. Patients harboring NPM1 mutations are diagnosed as having NPM1-mutated AMLs, which are types of leukemia with distinct clinical and laboratory characteristics. The essential diagnostics for investigating NPM1-mutated AMLs, the interactions with concomitant mutations affecting prognosis and the therapeutic interventions that the treatment of such patients requires are discussed in this review. Novel investigational agents in current clinical trials are also highlighted, along with the roles of exportin 1 (XPO1), menin-KMT2A inhibitors and immunotherapy in NPM1-mutated AMLs. This review focuses on critically evaluating the available data and aims to reveal the secrets of NPM1-mutated AMLs. Full article