Search Results (40,885)

Background: Cognitive behavioral therapy (CBT) has shown consistent efficacy in individuals with psychosis, as supported by many trials. One classical distinction is that between affective and non-affective psychosis. Few studies have specifically examined the possible moderating role of substantial affective elements. In this systematic review and meta-regression analysis, we assess how CBT response differs across the affective spectrum in psychosis. Methods: We included studies assessing various CBT modalities, including third-wave therapies, administered in people with psychosis. The study protocol is published in the Open Science Framework. Meta-regression was conducted to assess whether the proportion of participants with affective psychosis (AP), as proxied by a documented diagnosis of schizoaffective (SZA) disorder, moderated CBT efficacy across positive, negative, and depressive symptom domains. Results: The literature search identified 4457 records, of which 39 studies were included. The median proportion of SZA disorder participants was 17%, with a total of 422 AP participants represented. Meta-regression showed a trend toward lower CBT efficacy for positive symptoms with a higher SZA disorder proportion (β = +0.10 SMD per 10% increase in AP; p = 0.12), though it was not statistically significant. No significant associations were found for negative (β = +0.05; p = 0.73) or depressive symptoms (β = −0.02; p = 0.78). Heterogeneity was substantial across all models (I² ranging from 54% to 80%), and funnel plot asymmetry was observed in negative and depressive symptoms, indicating possible publication bias. Risk of bias assessment showed the anticipated inherent difficulty of psychotherapies in blinding and possibly dropout rates affecting some studies. Conclusions: Affective symptoms may reduce the effectiveness of CBT for positive symptoms in psychotic disorders, although the findings did not reach statistical significance. Other patient-level characteristics in psychosis could indicate which patients can benefit most from CBT modalities. Full article

Despite the widespread accessibility of vaccines and antivirals, seasonal influenza virus epidemics continue to pose a threat to public health. In this study, we constructed a recombinant replication-deficient simian adenovirus type 25 vector carrying the full-length hemagglutinin (HA) of the H1N1 influenza virus, named rSAd25-H1. Both systemic and mucosal humoral immune responses, as well as the protective efficacy, were assessed in mice immunized via the intramuscular (IM) or intranasal (IN) route. A single-dose IM or IN administration of rSAd25-H1 elicited a robust systemic IgG antibody response, including hemagglutination inhibition antibodies. As expected, only IN immunization was able to induce IgA production in serum and respiratory mucosa. Notably, a single dose of rSAd25-H1 at the highest dose (10¹⁰ viral particles) conferred complete protection against lethal homologous H1N1 challenge in mice despite the route of administration. These findings demonstrate the potential of simian adenovirus type 25-based vectors as a promising candidate for intranasal vaccine development targeting respiratory pathogens. Full article

Background/Objectives: The diminished efficacy of azoles in treating fungal infections is attributed to the emergence of resistance among pathogenic fungi. Employing a synergistic approach with other compounds to enhance the antifungal activity of azoles has shown promise, yet the availability of clinically valuable adjuvants for azoles and allylamines remains limited. Studies have demonstrated that the human host environment provides multiple carbon sources, which can influence the susceptibility of C. albicans to antifungal agents. Therefore, a comprehensive investigation into the mechanisms by which carbon sources modulate the susceptibility of C. albicans to azoles may uncover a novel pathway for enhancing the antifungal efficacy of azoles. Methods: This study explored the impact of various carbon sources on the antifungal efficacy of azoles through methodologies including minimum inhibitory concentration (MIC) assessments, super-MIC growth (SMG) assays, disk diffusion tests, and spot assays. Additionally, the mechanism by which galactose augments the antifungal activity of azoles was investigated using a range of experimental approaches, such as gene knockout and overexpression techniques, quantitative real-time PCR (qRT-PCR), Western blot analysis, and cycloheximide (CHX) chase experiments. Results: This study observed that galactose enhances the efficacy of azoles against C. albicans by inhibiting the translation of Erg1. This results in the suppression of Erg1 protein levels and subsequent inhibition of ergosterol biosynthesis in C. albicans. Conclusions: In C. albicans, the translation of Erg1 is inhibited when galactose is utilized as a carbon source instead of glucose. This novel discovery of galactose’s inhibitory effect on Erg1 translation is expected to enhance the antifungal efficacy of azoles. Full article

Conessine is a steroidal alkaloid found in many plants. The pharmacological efficacies of conessine on various ailments, including antiviral effects against Zika, Herpes, and Coronavirus, were reported. However, the effect of conessine on the influenza virus was still unknown. In this study, conessine exhibited a strong inhibitory effect against influenza A virus (IAV) infection. We examined the effect of conessine on IAV using green fluorescent protein (GFP)-expressing Influenza A/PR8/34 and wild-type A/PR8/34. The fluorescence-activated cell sorting, fluorescence microscopy, cytopathic effect analysis, and plaque assay demonstrated that conessine significantly inhibits IAV infection. Consistently, immunofluorescence results showed that conessine strongly reduces the expression of IAV proteins. The time-of-drug-addition assay revealed that conessine could affect the viral attachment and entry into the cells upon IAV infection. Further, conessine eradicated the virus before binding to the cells in the early stage of viral infection. Our results suggest that conessine has strong anti-viral efficacy against IAV infection and could be developed as an anti-influenza viral agent. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with limited therapeutic options and increasing global incidence, with a median survival of only 2–5 years. The clinical utility of macrophage polarization to regulate the progression of pulmonary fibrosis remains understudied. This study determined the efficacy of nintedanib and pexidartinib (PLX3397) combination therapy for treating IPF. Combination treatment effectively inhibited the progression of radiation-induced pulmonary fibrosis (RIPF) and prolonged survival in bleomycin-treated mice. Micro-CT analysis revealed a significant tissue repair efficacy. The therapy significantly normalized the abnormal vascular structure observed during RIPF and bleomycin-induced pulmonary fibrosis progression and was accompanied by a decrease in the M2 population. Polarized M1 macrophages enhanced normalized tube formation of irradiated endothelial cells (ECs) in vitro; M2 macrophages increased adhesion in irradiated ECs and abnormal tube formation. Single-cell RNA sequencing data from patients with IPF further supports colony stimulating factor (CSF) 1 upregulation in macrophages and downregulation of capillary EC markers. This study highlights a promising combination strategy to overcome the therapeutic limitations of monotherapy with nintedanib for the treatment of IPF. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal dysfunction. It is driven by the accumulation of amyloid-beta (Aβ) plaques, Tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Resveratrol (RSV) is a natural polyphenolic compound found in grapes, berries, and red wine that has garnered attention for its potential neuroprotective properties in combating AD. The neuroprotective effects of RSV are mediated through the activation of sirtuins (SIRT1), inhibition of Aβ aggregation, modulation of Tau protein phosphorylation, and the attenuation of oxidative stress and inflammatory responses. RSV also enhances mitochondrial function and promotes autophagy, which are important processes for maintaining neuronal health. Preclinical studies have demonstrated its efficacy in reducing Aβ burden, improving cognitive performance, and mitigating synaptic damage; however, challenges such as poor bioavailability, rapid metabolism, and limited blood–brain barrier penetration restrict its clinical applicability. Recent technological advances and selected modifications are being explored to overcome these limitations and enhance its therapeutic efficacy. This review summarizes the multifaceted neuroprotective mechanisms of RSV, the synergistic potential of natural compounds in enhancing neuroprotection, and the advancements in formulation strategies aimed at mitigating AD pathology. Leveraging the therapeutic potential of natural compounds represents a compelling paradigm shift for AD management, paving the way for future clinical applications. Full article

Although PD-1/PD-L1 inhibitors have transformed cancer immunotherapy, a substantial proportion of patients derive no clinical benefit due to resistance driven by the tumour microenvironment (TME). Transforming growth factor-β (TGF-β) is a key immunosuppressive cytokine implicated in this resistance. Several bifunctional antibodies that co-target PD-1 and TGF-β signalling have entered clinical trials and shown encouraging efficacy, but the mechanistic basis of their synergy is not fully understood. Here, we engineered 015s, a bifunctional fusion antibody that simultaneously targets murine PD-1 and TGF-β and evaluated its antitumour efficacy and mechanistic impact in pre-clinical models. Antibody 015s exhibited high affinity, dual target binding, and the effective inhibition of PD-1 and TGF-β signalling. In vivo, 015s significantly suppressed tumour growth compared with anti-mPD-1 or TGF-β receptor II (TGF-βRII) monotherapy. When combined with the CD24-targeted ADC, 015s produced even greater antitumour activity and achieved complete tumour regression. Mechanistic studies demonstrated that 015s significantly reduced tumour cell migration and invasion, reversed epithelial–mesenchymal transition (EMT), decreased microvascular density, and attenuated collagen deposition within the TME. Antibody 015s also decreased bioactive TGF-β1 and increased intratumoural IFN-γ, creating a more immunostimulatory milieu. These findings support further development of PD-1/TGF-β bifunctional antibodies for cancers with high TGF-β activity or limited response to immune checkpoint blockade. Full article

Background: Peripheral nerve injuries, especially involving the facial nerve, present unique reconstructive challenges due to their complex functional demands and limited regenerative potential. While autografts remain the gold standard, their drawbacks—such as donor-site morbidity and limited availability—have driven interest in processed nerve allografts. Acellular grafts, in particular, offer promising off-the-shelf alternatives without the need for immunosuppression. Methods: We conducted a narrative review of the literature (1990–2023), identifying 55 peer-reviewed studies via PubMed, Embase, and Cochrane Library. The studies included clinical and preclinical work on motor nerve regeneration using processed nerve allografts, with particular attention to outcomes in facial nerve repair. Two independent reviewers conducted abstract screening, full-text review, and data extraction. Results: Processed nerve allografts show encouraging motor recovery in gaps under 50 mm, with recovery rates of up to 85% reported. Outcomes decrease significantly in longer gaps (>50–60 mm) and in complex cases, including facial nerve repairs, where evidence remains sparse and largely extrapolated from broader motor nerve data. Registry data (e.g., RANGER) support their use but are limited by heterogeneity and lack of randomization. Conclusions: Processed nerve allografts represent a viable alternative to autografts in selected cases—especially short to mid-length motor nerve defects. However, their role in facial nerve reconstruction remains insufficiently studied. Further trials are needed to address specific anatomical and functional challenges in this subgroup and to clarify long-gap efficacy. Full article

Background and Objectives: Discrimination between various causes of exudative pleural effusion (PE) remains a major clinical challenge, and to date, definitive biochemical markers for this discrimination remain lacking. An increasing number of studies have reported that serum C-reactive protein (CRPs), pleural fluid CRP (CRPpf), and CRPpf/CRPs ratio (CRPr) are useful for the differential diagnosis of exudative PE; however, their efficacy rate is not similar in these studies. The majority of these studies were conducted on small groups of subjects, and the efficacy of the gradient between CRPs and CRPpf (CRPg—calculated as CRPs—CRPpf) in this differentiation has not been previously investigated. This study aims to evaluate the efficacy rate of CRPs, CRPpf, CRPg, and CRPr in the differential diagnoses of various causes of exudative PE in a relatively large cohort of patients. Materials and Methods: The research group included 282 subjects with exudative PE—146 had parapneumonic effusion (PPE), 126 had malignant pleural effusion (MPE), and 10 had tuberculous pleural effusion (TPE). The values are presented as mean ± SD. Results: The mean CRPs level was significantly higher in the PPE group compared to the MPE group (p < 0.0001) and the TPE group (p < 0.001), and also significantly higher in the TPE group than in the MPE group (p = 0.0009). Similarly, the mean CRPpf level was significantly higher in the PPE group than in the MPE group (p < 0.0001) and the TPE group (p = 0.04), and also significantly higher in the TPE group than in the MPE group (p < 0.0001). The mean CRPg level was significantly higher in the PPE group than in both the MPE group (p < 0.0001) and the TPE group (p < 0.002). The mean CRPr level did not differ significantly among these groups of exudate. Conclusions: CRPs, CRPpf, and CRPg are effective in the differential diagnosis of exudative PE, while CRPr was not effective in this regard. The main limitation of this study is that the sample size of the TPE group is very small. Full article

Background/Objectives: The functionalization of various forms of graphene, such as graphene nanoplatelets, graphene oxide, and reduced graphene oxide, in biomaterials is a promising strategy in dentistry, particularly regarding their antimicrobial potential. However, conclusive studies on the toxicity and biocompatibility of graphene-based materials remain limited, and standardized guidelines for their production, handling, and dental applications are still lacking. This scoping review aims to map the available studies on various types of graphene, synthesize evidence on their antimicrobial effectiveness, and describe the main biological responses when functionalized in dental biomaterials. Methods: An electronic search was conducted in the Clarivate, PubMed, and Scopus databases using the descriptors as follows: ‘graphene’ AND ‘antimicrobial effect’ AND ‘bactericidal effect’ AND (‘graphene oxide’ OR ‘dental biofilm’ OR ‘antibacterial properties’ OR ‘dental materials’). Article screening and eligibility assessment were performed based on predefined inclusion and exclusion criteria, following the PRISMA-ScR guidelines. Results: The search identified 793 articles. After removing duplicates, applying the eligibility criteria, and performing a full-text analysis of 64 articles, 21 studies were included in the review. Graphene oxide, particularly at low concentrations, was the most commonly studied graphene variant, demonstrating significant antimicrobial efficacy against S. mutans, S. faecalis, E. coli, P. aeruginosa, and C. albicans. Both mechanical and chemical mechanisms have been linked to the biological responses of graphene-doped biomaterials. The biocompatibility and cytotoxicity of these compounds remain controversial, with some studies reporting favorable outcomes, while others raise significant concerns. Conclusions: Graphene shows great promise as an antimicrobial agent in dental biomaterials. Despite encouraging results, more in vitro and in vivo studies are needed to better understand its biocompatibility and cytotoxicity in dental applications. Additionally, standardized production protocols, clearly defined clinical applications in dentistry, and regulatory guidelines from the World Health Organization concerning handling procedures and occupational risks remain necessary. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article

Background/Objectives: Leukemia is associated with high recurrence rates and cancer vaccines are emerging as a promising immunotherapy against the disease. Here, we investigate the mechanism of action by which a personalized vaccine made from leukemia cells infected with an oncolytic virus (ICV) induces anti-tumor immunity. Methods: Using the L1210 murine model, leukemia cells were infected and irradiated to create the ICV. The CRISPR-Cas9 system was used to engineer knockout cells to test in treatment efficacy studies. Results: We found that pro-inflammatory interferons (IFNs) that are produced by infected vaccine cells induce the immunoproteasome (ImP), a specialized proteasome subtype that is found in immune cells. Interestingly, we show that while a vaccine using the oncolytic vesicular stomatitis virus (oVSV) completely protects against tumor challenge, the wild-type (wt) virus, which does not induce the ImP, is not as effective. To delineate the contribution of the ImP for vaccine efficacy, we generated ImP-knockout cell lines and found no differences in treatment efficacy compared to wild-type cells. Furthermore, an ICV using another murine leukemia model that expresses the ImP only when infected by an IFN gamma-encoding variant of the virus demonstrated similar efficacy as the parental virus. Conclusions: Taken together, our data show that ImP expression by vaccine cells was not required for the efficacy of leukemia ICVs. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-stranded positive-sense RNA virus, poses a significant threat to global swine production. Despite the availability of modified live virus and inactivated vaccines, their limited efficacy and safety concerns highlight the urgent need for novel antiviral therapeutics. This study aimed to investigate the molecular mechanisms by which lycopene inhibits PRRSV replication. Initial assessments confirmed that lycopene did not adversely affect cellular viability, cell cycle progression, or apoptosis. Using fluorescence microscopy, flow cytometry, immunoblotting, quantitative real-time PCR (qRT-PCR), and viral titration assays, lycopene was shown to exhibit potent antiviral activity against PRRSV. Mechanistic studies revealed that lycopene suppresses reactive oxygen species (ROS) production, which is critical for PRRSV proliferation. Additionally, lycopene attenuated PRRSV-induced inflammatory responses, as demonstrated by immunoblotting, ELISA, and qRT-PCR assays. These findings suggest that lycopene inhibits PRRSV replication by modulating ROS levels and mitigating inflammation, offering a promising avenue for the development of antiviral therapeutics. This study provides new insights and strategies for combating PRRSV infections, emphasizing the potential of lycopene as a safe and effective antiviral agent. Full article

Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy. Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases. Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis. Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy. Full article

The objective of this study was to evaluate the efficacy of selected herbicides permitted for use in sustainable agriculture, specifically targeting spring rye and spring barley in a no-till farming system. The application of chemical herbicide protection in the cultivation of spring rye and barley significantly increased the yield and improved the quality parameters of the harvested grain, with the most pronounced effect observed in spring barley. The effectiveness of the herbicide treatment in reducing the number of weeds was 99.4% for spring rye and 82.39% for spring barley. The study demonstrated that the application of chemical herbicide protection had a positive impact on the quality parameters of spring barley grain. Both the thousand-grain weight and protein content were significantly higher in the grain collected from protected plots compared to the control plots. By utilizing herbicides permitted for use in integrated production (IP) in a sustainable manner, we protect the environment while minimizing the impact on crop yields and maintaining the quality of the harvested produce. Full article