Biomedicines最新文献

Background/Objectives: The incidence of acute kidney injury (AKI) has been steadily increasing. Despite its high prevalence, there is no pathogenetically rational therapy for AKI. This deficiency stems from the poor understanding of the pathogenesis of AKI. Renal ischemia/hypoxia is one of the leading causes of clinical AKI. This study investigates whether αMUPA mice, overexpressing the urokinase plasminogen activator (uPA) gene are protected against ischemic AKI, thus unraveling a potential renal damage treatment target. Methods: We utilized an in vivo model of I/R-induced AKI in αMUPA mice and in vitro experiments of uPA-treated HEK-293 cells. We evaluated renal injury markers, histological changes, mRNA expression of inflammatory, apoptotic, and autophagy markers, as compared with wild-type animals. Results: the αMUPA mice exhibited less renal injury post-AKI, as was evident by lower SCr, BUN, and renal NGAL and KIM-1 along attenuated adverse histological alterations. Notably, the αMUPA mice exhibited decreased levels pro-inflammatory, fibrotic, apoptotic, and autophagy markers like TGF-β, IL-6, STAT3, IKB, MAPK, Caspase-3, and LC3. By contrast, ACE-2, p-eNOS, and PGC1α were higher in the kidneys of the αMUPA mice. In vitro results of the uPA-treated HEK-293 cells mirrored the in vivo findings. Conclusions: These results indicate that uPA modulates key pathways involved in AKI, offering potential therapeutic targets for mitigating renal damage.

Introduction: Metastatic prostate cancer (PCa) presents a significant challenge in oncology due to its high mortality rate and the absence of effective biomarkers for predicting patient outcomes. Building on previous research that highlighted the critical role of the long noncoding RNA (lncRNA) H19 and cell adhesion molecules in promoting tumor progression under hypoxia and estrogen stimulation, this study aimed to assess the potential of these components as prognostic biomarkers for PCa at the biopsy stage.

Methods: This research utilized immunohistochemistry and droplet digital PCR to analyze formalin-fixed paraffin-embedded (FFPE) biopsies, focusing on specific markers within the H19/cell adhesion molecules pathway.

Results: A novel multivariate analysis led to a "BioScore", a composite biomarker score to predict disease progression. This score is based on evaluating five key markers: the expression levels of Hypoxia-Inducible Factor 2 Alpha (HIF-2α), endothelial Nitric Oxide Synthase (eNOS), β4 integrin, E-cadherin transcript (CDH1), and lncRNA H19. The criteria for the "BioScore" involve identifying three out of these five markers, combining elevated levels of HIF-2α, eNOS, β4 integrin, and CDH1 with reduced H19 expression.

Conclusions: This finding suggests the possibility of identifying, at the time of biopsy, PCa patients at higher risk of metastasis based on dysregulation in the H19/cell adhesion molecules circuitry. This study provides a valuable opportunity for early intervention in managing PCa, potentially contributing to personalized treatment strategies.

Background/Objectives: Less often employed as a rinsing solution for controlling oral biofilms, NaOCL was used in oral rinses at various concentrations in steps 1 and 4 of periodontal therapy. The aim of this study was to quantitatively evaluate the biofilm-disruptive properties of a 0.2% NaOCl solution in standardized oral rinses using dedicated plaque-disclosing agents and 3D scanning methods in patients undergoing the regular Guided Biofilm Therapy^® protocol. Methods: Eight patients with at least 20 teeth present evenly distributed between the two arches were included. After 24 h of refraining from oral hygiene, dental arches were stained with a disclosing agent, the subjects rinsed for 20 s, clinical photographs and 3D scans were performed, subjects rinsed again for 20 s, photographs and 3D scans were performed again, and then the GBT^® protocol was resumed as usual. Data representing areas covered with dental plaque were acquired using the "Medit Scan for Clinics" software and then underwent a post-processing and rendering process. The outcome variable was the percent reduction in the plaque-covered areas. Results: For the upper jaw, the estimated mean percent reduction in the biofilm-covered area was 39.65%, while for the mandible, it was 38.26%. The analysis of individual photographs revealed changes in the plaque-covered areas and reductions in the color intensity of the residual plaque-covered areas under identical lighting conditions. Conclusions: When analyzed using 3D intraoral scanning, the 0.2% NaOCl rinsing solution seems to be a clinically efficient disruptor/dissolvent of the oral biofilm, both when integrated into modern protocols of periodontal therapy like GBT^® and for home self-care.

Objectives: We aimed to study classical, publicly available convolutional neural networks (3D-CNNs) using a combination of several cine-MR orientation planes for the estimation of left ventricular ejection fraction (LVEF) without contour tracing.

Methods: Cine-MR examinations carried out on 1082 patients from our institution were analysed by comparing the LVEF provided by the CVI42 software (V5.9.3) with the estimation resulting from different 3D-CNN models and various combinations of long- and short-axis orientation planes.

Results: The 3D-Resnet18 architecture appeared to be the most favourable, and the results gradually and significantly improved as several long-axis and short-axis planes were combined. Simply pasting multiple orientation views into composite frames increased performance. Optimal results were obtained by pasting two long-axis views and six short-axis views. The best configuration provided an R² = 0.83, a mean absolute error (MAE) = 4.97, and a root mean square error (RMSE) = 6.29; the area under the ROC curve (AUC) for the classification of LVEF < 40% was 0.99, and for the classification of LVEF > 60%, the AUC was 0.97. Internal validation performed on 149 additional patients after model training provided very similar results (MAE 4.98). External validation carried out on 62 patients from another institution showed an MAE of 6.59. Our results in this area are among the most promising obtained to date using CNNs with cardiac magnetic resonance.

Conclusion: (1) The use of traditional 3D-CNNs and a combination of multiple orientation planes is capable of estimating LVEF from cine-MRI data without segmenting ventricular contours, with a reliability similar to that of traditional methods. (2) Performance significantly improves as the number of orientation planes increases, providing a more complete view of the left ventricle.

Background: Irritable bowel syndrome (IBS) has a major negative influence on quality of life, causing cramps, stomach pain, bloating, constipation, etc. Antispasmodics have varying degrees of efficacy. Mebeverine, for example, works by controlling bowel movements and relaxing the muscles of the intestines but has side effects. Therefore, more efficient medication is required. Methods: In the current study, we investigated the synthesis of novel mebeverine analogs and determined ex vivo their spasmolytic and in vitro and ex vivo anti-inflammatory properties. The ability to influence both contractility and inflammation provides a dual-action approach, offering a comprehensive solution for the prevention and treatment of both conditions. Results: The results showed that all the compounds have better spasmolytic activity than mebeverine and good anti-inflammatory potential. Among the tested compounds, 3, 4a, and 4b have been pointed out as the most active in all the studies conducted. To understand their mechanism of activity, molecular docking simulation was investigated. The docking analysis explained the biological activities with their calculated Gibbs energies and possibilities for binding both centers of albumin. Moreover, the calculations showed that molecules can bind also the two muscarinic receptors and interleukin-β, hence these structures would exert a positive therapeutic effect owed to interaction with these specific receptors/cytokine. Conclusions: Three of the tested compounds have emerged as the most active and effective in all the studies conducted. Future in vivo and preclinical experiments will contribute to the establishment of these novel mebeverine derivatives as potential drug candidates against inflammatory diseases in the gastrointestinal tract.

Background: Rosette-Forming Glioneuronal Tumors (RGNTs) are rare, typically benign central nervous system tumors primarily located in the fourth ventricle and pineal region. Despite being classified as WHO grade I with generally favorable prognoses, RGNTs present complexities in their molecular mechanisms, occasional malignant transformation, and epidemiological characteristics that require further investigation.

Method: This study systematically reviews the existing literature to analyze the epidemiological patterns, MRI characteristics, pathological features, diagnostic challenges, and molecular mechanisms associated with RGNTs, aiming to provide a comprehensive theoretical foundation for clinical practice and future research.

Results: Through an in-depth review of recent studies, key molecular mechanisms, including mutations in FGFR1, PIK3CA, TERT, and IDH1/2, are highlighted. Additionally, the challenges in accurate diagnosis and the potential for misdiagnosis are discussed, emphasizing the importance of thorough molecular analysis in clinical settings. The literature indicates that RGNTs predominantly affect young adults and adolescents, with a slight female predominance. MRI typically reveals mixed cystic-solid lesions, often accompanied by hydrocephalus. Pathologically, RGNTs are characterized by a combination of neuronal and glial components, with immunohistochemical staining showing positivity for Synaptophysin and GFAP. High frequencies of FGFR1 and PIK3CA mutations underscore the significance of these pathways in RGNT pathogenesis and progression. Although RGNTs generally exhibit low malignancy, the TERT mutations identified in some cases suggest a risk of malignant transformation.

Conclusions: This study concludes that while current treatment strategies focus on surgical resection, integrating molecular diagnostics and targeted therapies may be essential for managing recurrent or refractory RGNTs. Future research should explore the impact of various gene mutations on tumor behavior and their correlation with clinical outcomes, to optimize individualized therapeutic strategies and improve patient survival and quality of life.

Background/objectives: Myocardial involvement has been observed in athletes following SARS-CoV-2 infection. It is unclear if these changes are due to myocardial damage per se or to an interruption in training. The aim of this study was to assess cardiac function and structure in elite athletes before and after infection (INFAt) and compare them to a group of healthy controls (CON).

Methods: Transthoracic echocardiography was performed in 32 elite athletes, including 16 INFAt (median 21.0 (19.3-21.5) years, 10 male) before (t₀) and 52 days after (t₁) mild SARS-CoV-2 infection and 16 sex-, age- and sports type-matched CON. Left and right ventricular global longitudinal strain (LV/RV GLS), RV free wall longitudinal strain (RV FWS) and left atrial strain (LAS) were assessed by an investigator blinded to patient history.

Results: INFAt showed no significant changes in echocardiographic parameters between t₀ and t₁, including LV GLS (-21.8% vs. -21.7%, p = 0.649) and RV GLS (-29.1% vs. -28.7%, p = 0.626). A significant increase was observed in LA reservoir strain (LASr) (35.7% vs. 47.8%, p = 0.012). Compared to CON, INFAt at t₁ had significantly higher RV FWS (-33.0% vs. -28.2%, p = 0.011), LASr (47.8% vs. 30.5%, p < 0.001) and LA contraction strain (-12.8% vs. -4.9%, p = 0.050) values.

Conclusions: In elite athletes, mild SARS-CoV-2 infection does not significantly impact LV function when compared to their pre-SARS-CoV-2 status and to healthy controls. However, subtle changes in RV and LA strain may indicate temporary or training-related adaptions. Further research is needed, particularly focusing on athletes with more severe infections or prolonged symptoms.

Purpose: This study aimed to characterize the association between microbial dynamics and excessive exercise. Methods: Swabbed fecal samples, body composition (percent body fat), and swimming logs were collected (n = 94) from a single individual over 107 days as he swam across the Pacific Ocean. The V4 region of the 16S rRNA gene was sequenced, generating 6.2 million amplicon sequence variants. Multivariate analysis was used to analyze the microbial community structure, and machine learning (random forest) was used to model the microbial dynamics over time using R statistical programming. Results: Our findings show a significant reduction in percent fat mass (Pearson; p < 0.01, R = -0.89) and daily swim distance (Spearman; p < 0.01, R = -0.30). Furthermore, the microbial community structure became increasingly similar over time (PERMANOVA; p < 0.01, R = -0.27). Decision-based modeling (random forest) revealed the genera Alistipes, Anaerostipes, Bifidobacterium, Butyricimonas, Lachnospira, Lachnobacterium, and Ruminococcus as important microbial biomarkers of excessive exercise for explaining variations observed throughout the swim (OOB; R = 0.893). Conclusions: We show that microbial community structure and composition accurately classify outcomes of excessive exercise in relation to body composition, blood pressure, and daily swim distance. More importantly, microbial dynamics reveal the microbial taxa significantly associated with increased exercise volume, highlighting specific microbes responsive to excessive swimming.

Objectives: Parkinson's disease psychosis (PDP) is a prevalent non-motor symptom associated with Parkinson's disease. The treatment options for PDP are limited, and its pharmacological management remains ambiguous. This study aimed to evaluate the existing evidence in relation to clinical practice.

Methods: This multi-methods study consisted of a systematic review of reviews, adhering to the PRISMA guidelines. The review was registered with PROSPERO. Following data extraction and assessment using the AMSTAR 2 tool, a narrative synthesis was performed. In the second phase of the study, a questionnaire was developed, validated, piloted, and distributed to the heads of specialized PD clinics in Germany and Austria.

Results: The search resulted in the inclusion of eleven reviews. The quality of eight of these reviews was rated as high (n = 7) or moderate (n = 1). The reviews indicated that clozapine and pimavanserin demonstrated the highest efficacy and tolerability. Other antipsychotic medications either failed to alleviate PDP symptoms or resulted in distinct motor complications. The survey findings also favored clozapine for its efficacy in managing PDP and improving quality of life, although quetiapine was regarded as effective and pimavanserin was not available. Clinicians reported initiating antipsychotic treatment at various stages of PDP, with a tendency to reduce the dosage or discontinue D2 agonists or anticholinergics.

Conclusions: The reviewed literature and the survey results consistently favored clozapine for its efficacy and tolerability in treating PDP. It may be considered the first-line treatment, with pimavanserin as an alternative option.

Objectives: To evaluate the long-term anatomical and functional prognosis of patients with retinal detachment (RD) secondary to acute retinal necrosis (ARN) treated with pars plana vitrectomy (PPV). Methods: This retrospective case series included 21 eyes from 21 patients with RD secondary to ARN. The study analyzed vitreous or aqueous biopsy results, the impact of antiviral therapy, time to retinal detachment, changes in visual acuity (VA), and anatomical and surgical outcomes. All cases underwent 23-gauge PPV with silicone oil tamponade, and an episcleral encircling band was used in 11 cases. All patients received systemic antiviral therapy at diagnosis. Results: Retinal reattachment was achieved in 91% of cases during follow-up, with an average follow-up period of 39.5 ± 36.8 months. The average time from ARN diagnosis to RD onset was 33.3 ± 27.5 days. VZV was detected in 10 eyes through PCR analysis. Significant differences in visual prognosis were found between macula-off and macula-on RD (p = 0.048). Eyes with optic nerve head inflammation had worse final VA (p = 0.010). No significant difference was observed between preoperative VA and VA at the end of follow-up (p = 0.665). Conclusions: VZV was the primary virus associated with ARN-related RD. Early involvement of the macula and optic nerve in retinitis negatively impacted the final visual prognosis.