Search Results (652)

Background and Objectives: Sodium butyrate (NaB) is a potent modulator of cancer-related gene networks. However, its precise mechanisms of action and effects at elevated doses remain insufficiently explored. This study investigated the impact of NaB at physiologically relevant doses on key cellular metrics (viability, confluence, cell number, morphology, nuclear integrity) and a comprehensive set of apoptosis and proliferation regulators (including underexplored genes) in colorectal cancer (CRC) cells. Materials and Methods: Human HCT-116 cells were treated with increasing NaB concentrations (0–20 mM). Cell viability, confluence, number, morphology, and nuclear integrity were assessed using MTT and imaging assays. RT-PCR was used to determine changes in the expression of critical pro-apoptotic players (BAX, CASP3, PUMA, TP53), anti-apoptotic facilitators (BCL-2, MCL-1), cell division regulators (PCNA, Ki-67, CDKN1), and inflammation genes (NF-κB). Results: This study provides the first exploration of MCL-1 and PCNA modulation by NaB in the context of CRC and HCT-116 cells, offering significant translational insights. All treatments reduced cell viability, confluence, and number in a dose-dependent manner (p < 0.0001). Gene expression revealed dose-related increases in most pro-apoptotic markers (BAX, CASP3, PUMA; p < 0.001), and decreases for the other genes (p < 0.001). BAX emerged as the most responsive gene to NaB, while TP53 showed minimal sensitivity, supporting NaB’s effectiveness in p53-compromised phenotypes. Nuclear condensation and fragmentation at higher NaB doses confirmed apoptotic induction. Conclusions: NaB can modulate critical apoptotic and cell cycle genes, disrupt tumor cell proliferation, and overcome resistance mechanisms associated with anti-apoptotic regulators such as MCL-1. By targeting both short-term and long-term anti-apoptotic defenses, NaB shows promise as a preventive and therapeutic agent in CRC, particularly in high-risk phenotypes with compromised p53 functionality. These findings support its potential for integration into combination therapies or dietary interventions aimed at enhancing colonic butyrate levels. Full article

Background/Objectives: In preparation for a potential pandemic caused by the H5N1 highly pathogenic avian influenza (HPAI) virus, pre-pandemic vaccines against several viral clades have been developed and stocked worldwide. Although these vaccines are well tolerated, their immunogenicity and cross-reactivity with viruses of different clades can be improved. Methods: To address this aspect, we generated recombinant influenza vaccines against H5-subtype viruses using two different strains of highly attenuated vaccinia virus (VACV) vectors. Results: rLC16m8-mcl2.2 hemagglutinin (HA) and rLC16m8-mcl2.3.4 HA consisted of a recombinant LC16m8 vector encoding the HA protein from clade 2.2 or clade 2.3.4 viruses (respectively); rDIs-mcl2.2 HA consisted of a recombinant DIs vector encoding the HA protein from clade 2.2. A single dose of rLC16m8-mcl2.2 HA showed rapid (1 week after vaccination) and long-term protection (20 months post-vaccination) in mice against the HPAI H5N1 virus. Moreover, cynomolgus macaques immunized with rLC16m8-mcl2.2 HA exhibited long-term protection when challenged with a heterologous clade of the HPAI H5N1 virus. Although the DIs strain is unable to grow in most mammalian cells, rDIs-mcl2.2 HA also showed rapid and long-lasting effects against HPAI H5N1 virus infection. Notably, the protective efficacy of rDIs-mcl2.2 HA was comparable to that of rLC16m8-mcl2.2 HA. Furthermore, these vaccines protected animals previously immunized with VACVs from a lethal challenge with the HPAI H5N1 virus. Conclusions: These results suggest that both rLC16m8-mcl2.2 HA and rDIs-mcl2.2 HA are effective in preventing HPAI H5N1 virus infection, and rDIs-mcl2.2 HA is a promising vaccine candidate against H5 HA-subtype viruses. Full article

N6-methyladenosine (m6A) modification is a key methylation modification involved in reproductive processes. Myostatin gene editing (MT) in cattle is known to enhance muscle mass and productivity. However, the changes in m6A modification in MT bull sperm remain poorly understood. In the MT and wild-type (WT) groups, we identified 25,542 and 22,253 m6A peaks, respectively, mainly concentrated in the coding sequence (CDS) and 3′ untranslated region (UTR) of genes. The MT group showed an increase in gene transcription, but there was no significant difference in the overall m6A peaks pattern. There was also no significant difference in m6A motif and chromosome distribution between MT and WT groups. Most genes had less m6A modification sites. A total of 1120 m6A peaks were significantly different, corresponding to 1053 differentially m6A-methylated genes (DMMGs). These DMMGs are mainly associated with G protein-coupled receptor signaling pathways and the overall composition of the cell membrane. Furthermore, an MCL clustering analysis of 111 differentially m6A-methylated and expressed genes identified seven key genes (RHOA, DAAM1, EXOC4, GNA12, PRICKLE1, SCN1A, and STXBP5L), with the cytoskeleton and migration-related gene, RHOA, being the most important gene located at the center of the gene network. However, the analysis of sperm morphology and motility indicated no significant changes in semen volume, sperm count, sperm viability, plasma membrane integrity, acrosome membrane integrity, or mitochondrial membrane integrity. This study provides a map of m6A methylation in spermatozoa from MT and WT bulls, identifies key differential m6A genes that are affected by the myostatin gene but do not affect sperm morphology and viability in MT bulls, and provides a theoretical basis for the breeding quality of MT bulls. Full article

Background/Objectives: Multiligament knee injuries, involving damage to multiple stabilizing structures, present a significant challenge in orthopedic surgery, often resulting in knee instability and compromised function. While anatomic ligament reconstruction has been traditionally advocated, non-anatomic techniques may provide effective alternatives, particularly for patients with moderate functional demands who do not require high-level athletic performance. Material and methods: In this study, we assessed the outcomes of a non-anatomic, hybrid surgical approach involving combined arthroscopic and open non-anatomic ligament reconstruction in 60 patients with multiligament knee injuries. Using simplified reconstruction methods for the medial collateral ligament (MCL) and lateral collateral ligament (LCL), we tailored the procedures to the needs of active, non-professional patients. Functional outcomes were evaluated using the International Knee Documentation Committee (IKDC) Questionnaire, Lysholm Knee Scoring Scale, and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results: Postoperative improvements were significant, with the total IKDC score increasing from a median of 39.1 preoperatively to 75.9 postoperatively, Lysholm from 61.0 to 87.0, and KOOS from 47.6 to 85.7 (p < 0.01). The results demonstrated significant improvements across all scoring systems, with enhanced knee stability, reduced pain, and better quality of life. Conclusions: These findings support the feasibility of non-anatomic reconstructions as a practical solution for patients seeking a return to daily activities and recreational sports without the complexity of full anatomic reconstruction. Full article

Osteoarthritis (OA), particularly in the knee and hip, poses a significant global health challenge due to limited therapeutic options. To elucidate the molecular mechanisms of OA and identify potential biomarkers and therapeutic targets, we utilized genome-wide association studies (GWAS) and cis-miRNA expression quantitative trait loci (cis-miR-eQTL) datasets to identify miRNAs associated with OA, revealing 16 that were linked to knee OA and 21 to hip OA. Among these, hsa-miR-1303 was significantly upregulated in both knee and hip OA (IVW: p = $6.8164\times {10}^{-36}$ and $4.7919\times {10}^{-2}$ respectively, OR > 1) and identified as a key factor in disease progression. Hsa-miR-1303 potentially regulates 30 genes involved in critical signaling pathways, such as the neurotrophin signaling pathway, and interacts with competing endogenous RNAs (ceRNAs) like circ_0041843 and LINC01338, thereby influencing key regulatory proteins such as SUMO2 and PARP1. Pharmacologically, hsa-miR-1303 targets nine druggable genes, including NRAS, H2AZ1, and RPS3, which have implications for drugs like cantharidin and diindolylmethane, potentially critical for developing novel OA treatments. Conversely, hsa-miR-125a-5p and hsa-miR-125b-5p, which are downregulated in both knee and hip OA, are associated with pathways such as HIF-1 and JAK-STAT, which modulate apoptotic signaling and transcriptional regulation. These miRNAs also interact with ceRNAs such as circ_0000254 and SPACA6P-AS, impacting proteins like STAT3, MCL1, and TRAF6. A drug interaction analysis identified 47 potential treatments, including Resveratrol and Acetaminophen, suggesting new therapeutic possibilities for OA management. This study not only highlights the role of miRNAs like hsa-miR-1303 and hsa-miR-125 in OA but also opens avenues for miRNA-based therapeutic development. Full article

Backgroud: The introduction of highly active immunotherapies has changed the outcome of B-cell non-Hodgkin lymphomas (B-NHLs) in the last two decades. Since then, important progress has been shown using newer and more active immunotherapies, including chimeric antigen receptor T-cell therapy (CAR-T), conjugated monoclonal antibodies, and bispecific antobodies, which currently plays a significant role in the treatment of diffuse large B-cell (DLBCL), follicular (FL), and mantle cell (MCL) lymphoma. Purpose: In this review, we provide an updated overview of recently completed and ongoing BsAb trials in patients with relapsed/refractory(R/R) B-NHL and Hodgkin’s lymphoma, including single-agent results, emerging combinations, safety data, and novel constructs. Conclusions: Bispecific antibodies (BsAbs) are a novel class of “off-the-shelf” T-cell-redirecting drugs capable of targeting various cell-surface antigens. New antigen targets are currently under investigation, such as CD19 × CD3 and CD30 × CD3 or CD30 × CD16, in different settings. BsAbs are among the most promising therapeutic options for lymphoma today since they have demonstrated significant single-agent activity, along with a manageable toxicity profile, in patients with heavily pretreated B-NHL. Full article

Background/Objectives: Aurora (AK) A/B are oncogenic mitotic kinases that when over-expressed are poor prognostic markers in mantle cell lymphoma (MCL). Methods and Results: Alisertib, an AK-A inhibitor, has anti-tumor activity in relapsed/refractory (r/r) MCL patients. We evaluated alisertib plus ibrutinib in MCL to abrogate ibrutinib resistance. Alisertib plus ibrutinib was therapeutically synergistic on both Granta-519 insensitive to ibrutinib and JeKo-1 cells sensitive to ibrutinib. Alisertib decreased PI-3K, BTK, p38, HCK, and RSK kinases, indicative of its multipotent effect on cellular proliferation and growth. A mouse xenograft model of Granta-519 demonstrated that alisertib plus ibrutinib had a comparable anti-tumor response to ibrutinib plus rituximab. However, alisertib plus ibrutinib plus rituximab demonstrated significantly stronger tumor growth inhibition than the doublets. Conclusions: Both double and triple combinations showed enhanced survival versus ibrutinib alone. Ibrutinib insensitivity can be disrupted by alisertib plus ibrutinib in MCL. Full article

Background: Assessment of bone marrow infiltration (BMI) is part of the initial staging of mantle cell lymphoma (MCL), although BMI evaluated by biopsy (BMB) is not considered significant in the MIPI scales, and standardized recommendations remain lacking. Objectives: To evaluate the accuracy and prognostic impact of BMI assessed by PET/CT and BMB in a large series of MCL patients. Methods: We deconstructed the IPI-NCCN, MIPI, and MIPI-c indices and considered BMI as positive if indicated by a BMB, PET/CT scan, or a combination of both. Results: In the total cohort (n = 148), 110 patients had BMI detected by BMB and 33 by PET/CT. The sensitivity of BMB was higher than that of PET/CT (94.8% vs. 28.4%), as were its negative predictive value (84.2% vs. 27.8%) and accuracy (95.9% vs. 43.9%). In the total cohort, BMI detected by PET/CT showed a significant predictive value for PFS (p = 0.027), while BMB demonstrated independent prognostic value only in combination with PET/CT (p = 0.025). Among intensively treated patients (n = 128), PET/CT had significant clinical impact on PFS (p = 0.030), and when combined with BMB, it provided independent prognostic value for both PFS and OS (p = 0.026 and p = 0.033, respectively). Based on these findings, we propose a prognostic model (MCL-PET-I) that incorporates BMI by PET/CT, allowing for the identification of three groups with distinct clinical outcomes (p < 0.0001 for PFS and p = 0.00025 for OS). Conclusions: In the upfront work of MCL, PET/CT-based BMI has greater prognostic impact, while BMB remains essential for staging. We propose the MCL-PET-I prognostic index, which effectively differentiates between clinical risk groups. Full article

Background: The prognostic value of the comprehensive geriatric assessment (CGA) is recognized by many in hematology. However, there is no consensus on the utilization of alternative abbreviated methods to assess disabilities in elderly patients with B-cell non-Hodgkin’s lymphomas (B-NHLs). Aim: The aim of this study was to prospectively analyze the prognostic value of selected CGA tools in predicting adverse events (AEs) and outcomes of R-CHOP or R-CHOP-like treatment in elderly patients with diffuse large B-cell lymphomas (DLBCLs) or mantle cell lymphomas (MCLs). Methods: All patients who participated in this study underwent the Katz Index of Independence in Activities of Daily Living (ADL), the Lawton Instrumental Activities of Daily Living (iADL) scale, the Vulnerable Elders Survey-13 (VES-13), the Groningen Frailty Index (GFI), and the Mini Nutritional Assessment Short Form (MNA-SF) before starting anticancer treatment. Selected clinical predictors were also included in the study. Results: A total of 62 patients with newly diagnosed DLBCLs or MCLs, treated with R-CHOP in the Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation of Wroclaw University Hospital between 1 July 2018, and 1 July 2020, were included in the study. The median age upon initiation of the treatment was 72 years (range: 61–68). Multinomial logistic regression and Cox proportional hazard regression analysis demonstrated that the iADL scale was significantly associated with response to treatment (OR = 1.21, 95% CI: 1.02–1.44, p = 0.03), was inversely related to non-hematological AEs (OR = 0.81, 95% CI: 0.71–0.92, p = 0.001), and was a statistically significant predictor of longer overall survival (OS) (HR = 0.83, 95% CI: 0.79–0.89, p < 0.001) and longer progression-free survival (PFS) (HR = 0.91, 95% CI: 0.83–0.99, p = 0.03). Conclusions: These results underscore the effectiveness of the iADL scale as a quick, easy-to-use, and universal CGA tool for evaluating crucial functional status before treatment in elderly hematological patients with DLBCLs or MCLs. Full article

The Annona genus contains some species used in Mexican traditional medicine for the treatment cancer, including Annona macroprophyllata (A. macroprophyllata). The present study aimed to investigate the anticancer activity of caryophyllene oxide (CO) isolated from A. macroprophyllata using in vivo, in vitro, and in silico approaches. The identification of CO was performed using gas chromatography-mass spectroscopy and NMR methods. Antilymphoma activity was evaluated in male and female Balb/c mice inoculated with U-937 cells. Cytotoxic activity was evaluated using the WST method and flow cytometry was used to determine the type of cell death. Acute oral toxicity was determined, and a molecular docking study was performed using target proteins associated with cancer, including, HMG-CoA, Bcl-2, Mcl-1, and VEGFR-2. Results showed that CO exhibited significant antilymphoma and cytotoxic activities, and its effects were comparable to MTX. In addition, flow cytometry showed that the anticancer activity of CO could be mediated by the induction of late apoptosis and necrosis. The result for the acute oral toxicity of CO was classified in category 4, suggesting it is low risk. Finally, molecular coupling studies showed that CO had more affinity for the enzymes HMG-CoA reductase and Bcl-2. Our study provides evidences that CO is a potential anticancer agent for the treatment of histiocytic lymphoma. Full article

Introduction: Acceptable Noise Level (ANL) is defined as the most comfortable level (MCL) intensity for speech and is calculated by subtracting the maximum noise tolerable by an individual. The ANL test has been used over time to predict hearing aid use and the impact of digital noise reduction. This study analyzes this impact by using different masker babble spectra when performing the ANL test in both hearing-impaired and healthy subjects in three different languages (Dutch, French, and Italian). Materials and Methods: A total of 198 patients underwent the ANL test in their native language using a standardized protocol. The babble file was speech-weighted to match the long-term spectrum of the specific ANL language version. ANL was proposed in three different masking conditions: with multitalker Matched babble speech noise, with the same masking signal with the spectrum reduced from 2 kHz onwards (High Cut), and with the spectrum increased from 2 kHz onwards (High Boost). Results: In all of the comparisons among the three languages, ANL with High Boost noise gave significantly higher (worse) scores than ANL with Matched noise (p-value S1: <0.0001, S2: <0.0001, S3: 0.0003) and ANL with High Cut noise (p-value S1: 0.0002, S2: <0.0001, S3: <0.0001). The ANL values did not show any significant correlation with age and gender. In French, a weak correlation was found between ANL with High Cut noise and the Fletcher index of the worst ear. In Italian, a weak correlation was found between both ANL with Matched and High Boost noise and the Fletcher index of the best ear. Conclusions: ANL with High Boost added to noise stimuli was less acceptable for all patients in all of the languages. The ANL results did not vary in relation to the patients’ characteristics. This study confirms that the ANL test has potential application for clinical use regardless of the native language spoken. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, disabling disorder of unknown etiology, poor prognosis, and limited therapeutic options. Previously, 3′5-dimaleamylbenzoic acid (3′5-DMBA) was shown to exert resolving effects in IPF, offering a promising alternative for treating this disease; however, the molecular mechanisms associated with this effect have not been explored. Objetive: We evaluated the potential antifibrotic mechanisms of 3′5-DMBA by network pharmacology (NP) and molecular docking (MD). Methods: 3′5-DMBA-associated targets were identified by screening in SwissTargetPrediction. IPF-associated targets were identified using lung tissue meta-analysis and public databases. Common targets were identified, and a protein–protein interaction (PPI) network was constructed; we ranked the proteins in the PPI network by topological analysis. MD validated the binding of 3′5-DMBA to the main therapeutic targets. Results: A total of 57 common targets were identified between 3′5-DMBA and IPF; caspase 8, 9, 3, and 7; myeloid leukemia-induced cell differentiation protein Mcl-1; and poly [ADP-ribose] polymerase 1 are primary targets regulating PPI networks. Functional analysis revealed that the common targets are involved in the pathological features of tissue fibrosis and primarily in the apoptotic process. MD revealed favorable interaction energies among the three main targets regulating PPI networks. Conclusions: NP results suggest that the antifibrotic effect of 3′5-DMBA is due to its regulation of the pathological features of IPF, mainly by modulating signaling pathways leading to apoptosis, suggesting its therapeutic potential to treat this disease. Full article

Our previous studies have demonstrated that pegcrisantaspase (PegC), a long-acting Erwinia asparaginase, synergizes with the BCL-2 inhibitor Venetoclax (Ven) in vitro and in vivo; however, the anti-leukemic activity of E. coli-derived asparaginases in combination with BCL-2 inhibition, and potential synergy with inhibitors of MCL-1, a key resistance factor of BCL-2 inhibition, has yet to be determined. Using a combination of human AML cells lines, primary samples, and in vivo xenograft mouse models, we established the anti-leukemic activity of the BCL-2 inhibitor S55746 and the MCL-1 inhibitor S63845, alone and in combination with the long-acting E. coli asparaginase calaspargase pegol-mknl (CalPegA). We report that CalPegA enhances the anti-leukemic effect of S55746 but does not impact the activity of S63845. The S55746-CalPegA combination inhibited protein synthesis and increased eIF4E/4EBP1 interaction, suggesting an inhibition of translational complex formation. These results support the clinical evaluation of CalPegA in combination with BCL-2 inhibition for AML. Full article

Background/Objectives: Mantle cell lymphoma (MCL) represents a rare B-cell lymphoma subtype with rather high relapse rates. Somatic mutations in the PPM1D gene were shown to be associated with adverse outcomes in patients with diffuse large B-cell lymphoma (DLBCL) who received CD19 CAR-T-cell therapy with tisa-cel, which may also apply to mantle cell lymphoma receiving brexu-cel CAR-T-cells. Methods: In this study, we determined the prevalence of PPM1D mutations in peripheral blood cells of MCL patients before CAR-T-cell infusion and analyzed the impact of low-frequency PPM1D mutations on efficacy and safety aspects of brexu-cel CAR-T-cell treatment in the first 16 r/r MCL patients enrolled at Inselspital Bern. Results: The prevalence of low-frequency PPM1D gene mutations was 25%, with variant allele frequencies (VAF) of 0.011 to 0.099. Clinical response was analyzed in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild-type (PPM1Dwt) groups with median progression-free survival of 1 versus 32 months (p = 0.07) and median overall survival of 1.5 vs. 27 months (p = 0.001). Conclusions: Our data suggest that low-frequency PPM1D gene mutations in peripheral blood cells may predict inferior outcomes in patients with mantle cell lymphoma treated with CAR-T-cell therapy. Full article