Search Results (720)

Since its discovery, the BTK inhibitor ibrutinib has redefined the standard treatments for hematological cancers, such as chronic lymphocytic leukemia (CLL). However, concerns exist regarding its secondary effects in humans and its occasional lack of efficacy in certain malignancies. Therefore, combined therapies with ibrutinib have emerged as promising new approaches. In this study, we aimed to explore its therapeutic potential through different approaches. For this purpose, we combined this drug with the BH3 mimetics ABT-199 and ABT-737, which inhibit anti-apoptotic members of the Bcl-2 family, and with the PDK1 inhibitor dichloroacetate (DCA), respectively. As cell models, we used ex vivo samples from patients and also selected the in vitro CLL cell line Mec-1, generating two sub-lines overexpressing Bcl-XL and Mcl-1, a common feature in this cancer. Results demonstrated a synergistic effect for both approaches, in all tumor cells tested, for both cytostatic and cytotoxic effects. Mechanistically, the expression of Bcl-2-family proteins was explored, exhibiting increases in pro-apoptotic, but also in anti-apoptotic, proteins upon ibrutinib treatment and a relative increase in the amount of the pro-apoptotic protein PUMA after treatment with DCA. Our data provides new insights into combined therapies with ibrutinib for CLL, which further expands our knowledge and the potential of this drug for cancer treatment. Full article

Pyridyl-thiourea complexes of formula [(Cym)MCl(κ²N_py,S-H₂NNS)][SbF₆] (Cym = η⁶-p-MeC₆H₄iPr; H₂NNS = N-(p-tolyl)-N′-(2-pyridylmethyl)thiourea); M = Ru (1), Os (2)) were synthesized by reacting the corresponding metal dimers [{(Cym)MCl}₂(μ-Cl)₂] with H₂NNS in the presence of NaSbF₆. Subsequent chloride abstraction with AgSbF₆, followed by NH deprotonation using NaHCO₃, afforded the cationic complexes [(Cym)M(κ³N_py,N_amide,S-HNNS)][SbF₆] (M = Ru (5a), (5c); M = Os (6a, 6c)) and [(Cym)M(κ²N_amide,S-HNNS)][SbF₆] (M = Ru (5b); M = Os (6b)). The proposed structures for the prepared compounds are based on NMR data. Complexes 5a, 5b, and 6a, 6b evolve to the thermodynamically more stable species 5c and 6c, respectively, in which the deprotonated ligand HNNS adopts a κ³N_py,N_amide,S coordination mode. Complexes 5c and 6c activate H₂, behaving as frustrated Lewis pair (FLP) species, and catalyze (5c and/or 6c) the hydrogenation of polar multiple bonds, including the C=N bonds of N-benzylideneaniline and quinoline, the C=C bond of methyl acrylate, and the C=O bond of 2,2,2-trifluoroacetophenone. Full article

Cardiovascular diseases remain a leading cause of mortality in the United States, driving the need for advanced cardiovascular devices and pharmaceuticals. Mock Circulatory Loops (MCLs) have emerged as essential tools for in vitro testing, replicating pulsatile pressure and flow to simulate various physiological and pathological conditions. While many studies focus on custom MCL designs tailored to specific applications, few have systematically reviewed their use in device testing, and none have assessed their broader utility across diverse biomedical domains. This comprehensive review categorizes MCL designs into three types: mechanical, computational, and hybrid. Applications are classified into four major areas: Cardiovascular Devices Testing, Clinical Training and Education, Hemodynamics and Blood Flow Studies, and Disease Modeling. Most existing MCLs are complex, highly specialized, and difficult to reproduce, highlighting the need for simplified, standardized, and programmable hybrid systems. Improved validation and waveform fidelity—particularly through incorporation of the dicrotic notch and other waveform parameters—are critical for advancing MCL reliability. Furthermore, integration of machine learning and artificial intelligence holds significant promise for enhancing waveform analysis, diagnostics, predictive modeling, and personalized care. In conclusion, the development of MCLs should prioritize standardization, simplification, and broader accessibility to expand their impact across biomedical research and clinical translation. Full article

The MIM1-BH3 mimetic, which inhibits the Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MXFL) is able to modulate Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of the MXFL, MIM1, and MXFL/MIM1 mixtures on viability and apoptosis in amelanotic A375 and melanotic G361 melanoma cells. The obtained results showed that MXFL and MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of the MIM1 and MXFL mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity, shown as a modulatory effect on the early and late phases of apoptosis toward the analyzed melanoma cells when compared with MIM1 or MXFL alone. We report, for the first time, the high proapoptotic activity of MIM1 and MXFL applied in a two-component model toward melanoma cells, pointing to the Mcl-1 protein as an important molecular target. The observed potential synergistic mode of action—expressed as cytotoxic and proapoptotic activity enhancement, detected for MIM1 and MXFL—may represent a new direction for further in vitro and in vivo experiments concerning the role of the Mcl-1 protein in the treatment of melanoma. Moreover, the presented results certainly contribute to expanding the knowledge of the pharmacology of both fluoroquinolones and BH3 mimetics, and also enable a better understanding of melanoma cell biology. Full article

Our purpose is to evaluate the binocular contrast sensitivity function (CSF) in a presbyopic population and compare the results obtained with four different simultaneous-vision center-near multifocal contact lens (MCL) designs for distance vision under two illumination conditions. Additionally, chromatic CSF (red-green and blue-yellow) was evaluated. A randomized crossover pilot study was conducted. Four daily disposable lens designs, based on simultaneous-vision and center-near correction, were compared. The achromatic contrast sensitivity function (CSF) was measured binocularly using the CSV1000e test under two lighting conditions: room light on and off. Chromatic CSF was measured using the OptoPad-CSF test. Comparison of achromatic results with room lighting showed a statistically significant difference only for 3 cpd (p = 0.03) between the baseline visit (with spectacles) and all MCLs. Comparison of achromatic results without room lighting showed no statistically significant differences between the baseline and all MCLs for any spatial frequency (p > 0.05 in all cases). Comparison of CSF-T results showed a statistically significant difference only for 4 cpd (p = 0.002). Comparison of CSF-D results showed no statistically significant difference for all frequencies (p > 0.05 in all cases). The MCL designs analyzed provided satisfactory achromatic contrast sensitivity results for distance vision, similar to those obtained with spectacles, with no remarkable differences between designs. Chromatic contrast sensitivity for the red-green and blue-yellow mechanisms revealed some differences from the baseline that should be further investigated in future studies. Full article

Background/Objectives: Moschus (musk) has long been used in traditional Tibetan medicine to prevent and treat epidemic febrile illnesses. However, its antiviral mechanisms remain poorly understood. Given the urgent need for effective treatments against viral respiratory tract infections (VRTIs), this study aimed to systematically investigate the molecular targets and pharmacological pathways through which Moschus may exert therapeutic effects. Methods: Based on the identification of bioactive compounds with favorable pharmacokinetics, we applied integrated network pharmacology and multi-omics analyses to systematically identify key therapeutic targets involved in VRTIs. Gene Set Enrichment Analysis (GSEA) and immune infiltration further revealed strong associations with multiple immune cell subsets, reflecting their pivotal roles in immunomodulatory mechanisms during viral infections. Molecular docking confirmed the strong binding affinities between Moschus compounds and these key targets. Results: Notably, testosterone exhibited the strongest and most consistent binding across key targets, suggesting its potential as a pivotal bioactive compound. Importantly, the antiviral effects of Moschus may be mediated in part by the downregulation of the key genes MCL1, MAPK3, and CDK2, which are involved in the regulation of viral replication, apoptosis, and host immune responses. Conclusions: This study provides a comprehensive mechanistic framework supporting the multi-target antiviral potential of Moschus, offering a scientific basis for its further development as a therapeutic agent against VRTIs. Full article

Current systemic therapies for advanced colorectal cancer (CRC) have limited efficacy, so more effective strategies for the treatment and prevention of CRC are needed. The majority of colorectal cancers are initiated by mutations in Wnt signalling pathway genes, including mutations in the APC gene, which result in a truncated APC protein and lead to excess signalling from β-catenin and the formation of pre-cancerous adenomas. The aim of this study was to determine if targeting the Wnt pathway in combination with pro-apoptotic mimetics altered the proliferative capacity or viability of human colorectal adenoma cells. Patient-derived colorectal adenoma organoid cultures were established from colon adenoma tissue collected by colonoscopy and recapitulated the histopathology of primary colorectal adenoma tissue. The growth of colorectal adenoma organoids is inhibited by the Wnt-signalling antagonist pyrvinium pamoate (PP) and a pro-apoptotic inhibitor of BCL-XL but not BCL-2 (venetoclax) or MCL-1 inhibitors. At low concentrations, the PP and the BCL-XL inhibitor combination demonstrated potent synergy and induced apoptosis in APC-defective patient-derived adenoma organoids, even in the presence of oncogenic KRAS or BRAF mutations, providing a new strategy for colon cancer prevention. Full article

Arsenic (As) contamination in groundwater represents a major global public health threat, particularly in alluvial aquifer systems where redox-sensitive geochemical processes facilitate the mobilization of naturally occurring trace elements. This study investigates groundwater quality, particularly focusing on the origin of arsenic contamination in shallow and deep alluvial aquifers of the Lower Sakarya River Basin, which are crucial for drinking, domestic, and agricultural uses. Groundwater samples were collected from 34 wells—7 tapping the shallow aquifer (<60 m) and 27 tapping the deep aquifer (>60 m)—during wet and dry seasons for the hydrogeochemical characterization of groundwater. Environmental isotope analysis (δ¹⁸O, δ²H, ³H) was conducted to characterize origin and groundwater residence times, and the possible hydraulic connection between shallow and deep alluvial aquifers. Mineralogical and geochemical characterization of the sediment core samples were carried out using X-ray diffraction and acid digestion analyses to identify mineralogical sources of As and other metals. Pearson correlation coefficient analyses were also applied to the results of the chemical analyses to determine the origin of metal enrichments observed in the groundwater, as well as related geochemical processes. The results reveal that 33–41% of deep groundwater samples contain arsenic concentrations exceeding the WHO and Turkish drinking water standard of 10 µg/L, with maximum values reaching 373 µg/L. Manganese concentrations exceeded the 50 µg/L limit in up to 44% of deep aquifer samples, reaching 1230 µg/L. On the other hand, iron concentrations were consistently low, remaining below the detection limit in nearly all samples. The co-occurrence of As and Mn above their maximum contaminant levels was observed in 30–33% of the wells, exhibiting extremely low sulfate concentrations (0.2–2 mg/L), notably low dissolved oxygen concentration (1.45–3.3 mg/L) alongside high bicarbonate concentrations (450–1429 mg/L), indicating localized varying reducing conditions in the deep alluvial aquifer. The correlations between molybdenum and As (rdry = 0.46, rwet = 0.64) also indicate reducing conditions, where Mo typically mobilizes with As. Arsenic concentrations also showed significant correlations with bicarbonate (HCO₃⁻) (rdry = 0.66, rwet = 0.80), indicating that alkaline or reducing conditions are promoting arsenic mobilization from aquifer materials. All these correlations between elements indicate that coexistence of As with Mn above their MCLs in deep alluvial aquifer groundwater result from reductive dissolution of Mn/Fe(?) oxides, which are primary arsenic hosts, thereby releasing arsenic into groundwater under reducing conditions. In contrast, the shallow aquifer system—although affected by elevated nitrate, sulfate, and chloride levels from agricultural and domestic sources—exhibited consistently low arsenic concentrations below the maximum contaminant level. Seasonal redox fluctuations in the shallow zone influence manganese concentrations, but the aquifer’s more dynamic recharge regime and oxic conditions suppress widespread As mobilization. Mineralogical analysis identified that serpentinite, schist, and other ophiolitic/metamorphic detritus transported by river processes into basin sediments were identified as the main natural sources of arsenic and manganese in groundwater of deep alluvium aquifer. Full article

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, underscoring the need for continuous innovation in diagnostics and treatment. Mock circulation loops (MCLs) systems have recently emerged as new research platforms capable of replicating the hemodynamics of the human cardiovascular system. This review explores the expanding applications of MCLs to cardiovascular diseases beyond their traditional role in testing ventricular assist devices and heart failure management. We focus on their versatility in simulating various cardiovascular conditions, particularly arterial diseases such as atherosclerosis, stenosis, and aneurysms. This review traces the evolution of MCLs and their integration with computational simulations and real-time data acquisition systems. MCLs provide detailed insights into hemodynamic responses under diverse conditions, enhancing the precision and safety of cardiovascular interventions. This comprehensive review emphasizes the critical role of MCLs in advancing cardiovascular research, refining clinical interventions, and improving patient outcomes. Full article

Introducing small-sized metal nanoparticles directly into biopolymers susceptible to thermal and chemical stimulations remains a significant challenge. Recently, we showed a novel approach to fabricating gold nanoparticles through pulsed laser ablation in liquid (PLAL) using a microchip laser (MCL). Despite its lower pulse energy compared to conventional lasers, this technique demonstrates high ablation efficiency, offering the potential to produce composites without compromising the distinctive structure of biopolymers. As a proof of concept, we successfully generated gelatin-stabilized gold nanoparticles with a smaller size (average diameter of approximately 4 nm), while preserving the unchanged circular dichroism (CD) spectra, indicating the retention of gelatin’s unique structure. Extending this technique to the preparation of type I collagen-stabilized gold nanoparticles yielded non-aggregated nanoparticles, although challenges in yield still persist. These results highlight the potential of the microchip laser ablation technique for producing metal nanoparticles within a vulnerable matrix. Full article

Arsenic in drinking water poses a threat to public health world-wide. In March 2001, the EPA revised the maximum contaminant level (MCL) for arsenic in drinking water downward from 50 µg/L to 10 µg/L and required all U.S. small community water systems (CWSs) and non-community water systems (NCWSs) to comply by 23 January 2006. Much of the financial burden associated with complying with and maintaining this new drinking water MCL was shouldered by local community governments. For example, the Walker River Paiute Tribe operated a CWS on the Walker River Paiute Indian Reservation that needed upgrading to meet the new arsenic MCL. In collaboration with the Walker River Paiute Tribe, we conducted a study to assess whether reducing the arsenic concentration in drinking water to meet the new MCL reduced the arsenic body burden in local community members who drank the water. Installing a drinking water treatment to remove arsenic dramatically reduced both the drinking water concentrations (to below the current EPA MCL of 10 µg/L) and the community members’ urinary concentrations of total As, AsIII, and AsV within a week of its full implementation. Additional assistance to small water systems to sustain new drinking water treatments may be warranted. Full article

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

Robotic cadaveric testing provides a controlled approach to studying knee ligament biomechanics under continuous motion, addressing limitations in static or mechanical loading testing. Our study describes an alternative method for soft-tissue strain measurement, followed by an investigation of this method on knee ligament strain and joint kinematics using a six-degree-of-freedom robotic system equipped with force and torque sensors. Six cadaveric knee specimens underwent controlled 90° flexion cycles, with uniaxial strain gauges sutured to the ACL, PCL, MCL, and LCL for strain measurement. Results indicate that the LCL exhibited the highest extension at 1.63 mm, while the ACL showed minimal extension at 0.09 mm. The MCL were at −0.76 mm and PCL at −1.76 mm contraction, suggesting a stabilizing function under flexion. Varus torque at 2.18 Nm at 90° flexion correlated with LCL strain, and PCL translation variability reflected its multi-planar engagement. These findings confirm ligament-specific strain responses under dynamic loading, highlighting that the LCL and PCL undergo the most significant length changes. Full article