Advances in Clinical and Experimental Medicine最新文献

Hematological malignancies encompass a diverse group of cancers affecting the blood, bone marrow and lymph nodes. The p16 gene, encoding the P16INK4A protein, plays a pivotal role in cell cycle regulation and tumor suppression. Understanding the involvement of p16 in the development and progression of hematological malignancies is crucial for advancing therapeutic strategies. This systematic review aims to elucidate the multifaceted roles of the p16 gene and P16INK4A protein in hematological malignancies, focusing on their impact on disease pathogenesis, prognostic significance and therapeutic implications. A comprehensive search was conducted across electronic databases, including PubMed, Scopus and Google Scholar, using predefined search terms related to p16, P16INK4A, hematological malignancies, and therapy. Studies published up to 2023 were included, encompassing clinical trials, observational studies, meta-analyses, and preclinical research. The review synthesizes evidence highlighting the dysregulation of the p16 pathway in various hematological cancers. Alterations in p16 expression levels, genetic mutations and epigenetic modifications contribute to disease initiation and progression. Moreover, the prognostic significance of p16 status in predicting therapeutic outcomes and patient survival is explored. The p16 gene and P16INK4A protein emerge as promising biomarkers and therapeutic targets in hematological malignancies. Integrating knowledge of p16 dysregulation into clinical practice holds the potential to optimize treatment strategies, enhance patient outcomes and pave the way for personalized medicine approaches in the management of these challenging diseases.

Background: Pyroptosis has been implicated in the progression of chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS).

Objectives: The present study was performed to explore the diagnostic value of the levels of the pyroptosis-related protein nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome in the expressed prostatic secretions (EPS) of patients with CP.

Material and methods: A total of 167 CP patients, including 85 National Institutes of Health (NIH)-IIIA CP patients and 82 NIH-IIIB CP patients, as well as 80 benign prostatic hyperplasia (BPH) patients and 80 healthy controls, were enrolled. The levels of NLRP3, interleukin 1 beta (IL-1β), and interleukin 18 (IL-18) in EPS were detected using an enzyme-linked immunosorbent assay (ELISA). Disease severity was assessed using the Bergman CP scale. Differences in EPS NLRP3 inflammasome levels between the groups were analyzed, and receiver operating characteristic (ROC) curves were used to investigate the clinical value of the NLRP3 inflammasome in the diagnosis of CP. The numerical rating scale (NRS), the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the Danish Prostatic Symptom Score (DAN-PSS-1) were applied to evaluate symptom severity. The cutoff value of NLRP3 expression was calculated using R language.

Results: NLRP3 inflammasome levels in EPS were significantly higher in CP patients of NIH-IIIA and NIH-IIIB compared to the BPH patients and controls. NLRP3 levels in EPS were positively associated with Bergman grade. In addition, NRS levels were in a positive relationship with NIH-CPSI and DAN-PSS-1. The ROC curve analysis demonstrated that NLRP3 in EPS may act as a decent indicator for the diagnosis of CP/CPPS. The cutoff value of EPS NLRP3 expression was ≥55.25 ng/mL.

Conclusions: NLRP3 levels in EPS were significantly higher in NIH-IIIA and NIH-IIIB patients compared to BPH patients and healthy controls. NLRP3 inflammasome levels in EPS may be valuable as diagnostic indicators, and targeting chemokines may present a promising approach to treatment for those suffering from CPPS.

Introduction: Proton pump inhibitors (PPIs) and histamine type-2 receptor antagonists (H2RAs) are generally effective in preventing delayed bleeding and healing artificial wounds after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). This study aimed to review the therapeutic effects of PPIs and H2RAs on damage caused by EMR and ESD.

Material and methods: Thirteen articles were collected between 2002 and 2022 by searching Medlib, ScienceDirect, PubMed, International Scientific Indexing (ISI), Embase, and Scopus databases using valid keywords. The main inclusion criteria were delayed wound healing, bleeding, epigastric pain, intraoperative bleeding, and perforation. The odds ratio (OR) and 95% confidence interval (95% CI) were evaluated using a random or fixed effects model. Data analysis was performed using Stata v. 14.2.

Results: A total of 13 articles including 1,483 patients were analyzed. The results showed that delayed bleeding was significantly less frequent in the PPI group than in the H2RA group (OR = 0.6; 95% CI: 0.39-0.92). Subgroup analysis showed that PPI was more effective in preventing delayed bleeding than H2RA for ESD wounds (OR = 0.65; 95% CI: 0.44-1.08). There was no statistically significant difference between both groups regarding the incidence of epigastric pain, intraoperative bleeding, wound healing, and perforation after endoscopic treatments.

Conclusion: The meta-analysis results reveal that PPI is more effective than H2RA in preventing delayed bleeding after endoscopic treatment, particularly in patients treated with ESD. However, there was no significant difference between PPI and H2RA in terms of intraoperative bleeding, epigastric pain, wound healing, and perforation from endoscopic therapy.

Ceramic is a commonly used material in dentistry for reconstructing missing teeth or their tissues due to its biocompatibility, durability and excellent esthetic properties. Despite these advantages, the ceramic restoration damage remains a significant clinical problem. Its causes can be divided into clinical and laboratory factors. The most known include uneven occlusion, improper preparation, trauma, or parafunctions. This study focuses on characterizing less known laboratory causes of ceramic restoration damage. We reviewed the current literature available in the PubMed and Scopus databases. On the basis of 63 selected studies, 3 basic causes of damage were identified: excessive stresses between the framework and ceramic veneering, poor quality of the connection between the facing layer and the substructure, and defects resulting from the nature of the ceramic material such as defects in the ceramic layer, brittleness and lack of flexibility. The stages of the manufacturing process of various permanent ceramic restorations were presented. By controlling these procedures, we can eliminate the errors, resulting in long-term effective functioning of the ceramic restorations.

Venetoclax, a BH3 mimetic, is a novel targeted anti-cancer drug with a unique mechanism of action leading to the execution of apoptosis through inhibition of the Bcl-2 protein. The development of venetoclax has revolutionized the treatment paradigm of several hematologic malignancies, including treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML) in unfit patients. However, despite the high effectiveness of venetoclax in these diseases, some patients, as in the case with other targeted therapies, develop primary or secondary resistance to the drug. Various mechanisms contributing to the resistance to venetoclax have been elucidated, including selection of mutations in the BCL-2 binding groove which decrease affinity to venetoclax, or compensatory overexpression of anti-apoptotic proteins such as MCL-1. Moreover, alterations in cell metabolism and signaling pathways like MAPK or ERK activation have also been reported, suggesting the resistance to venetoclax is highly complex and involves multiple pathways. This review aimed to describe the mechanisms of resistance to venetoclax in AML, CLL, multiple myeloma, and other hematologic malignancies, as well as to propose a perspective to circumvent it.

Background: Establishing a robust signature for prognostic prediction and precision treatment is necessary due to the heterogeneous prognosis and treatment response of clear cell renal cell carcinoma (ccRCC).

Objectives: This study set out to elucidate the biological functions and prognostic role of ferroptosis-related long non-coding RNAs (lncRNAs) based on a synthetic analysis of competing endogenous RNA networks in ccRCC.

Material and methods: Ferroptosis-related genes were obtained from the FerrDb database. The expression data and matched clinical information of lncRNAs, miRNAs and mRNAs from The Cancer Genome Atlas (TCGA) database were obtained to identify differentially expressed RNAs. The lncRNA-miRNA-mRNA ceRNA network was established utilizing the common miRNAs that were predicted in the RNAHybrid, StarBase and TargetScan databases. Then, using progressive univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis of gene expression data and clinical information, a ferroptosis-related lncRNA prognosis signature was constructed based on the lncRNAs in ceRNA. Finally, the influence of independent lncRNAs on ccRCC was explored.

Results: A total of 35 ferroptosis-related mRNAs, 356 lncRNAs and 132 miRNAs were sorted out after differential expression analysis in the TCGA-KIRC. Subsequently, overlapping lncRNA-miRNA and miRNA-mRNA interactions among the RNAHybrid, StarBase and TargetScan databases were constructed and identified; then a ceRNA network with 77 axes related to ferroptosis was established utilizing mutual miRNAs in 2 interaction networks as nodes. Next, a 6-ferroptosis-lncRNA signature including PVT1, CYTOR, MIAT, SNHG17, LINC00265, and LINC00894 was identified in the training set. Kaplan-Meier analysis, PCA, t-SNE analysis, risk score curve, and receiver operating characteristic (ROC) curve were performed to confirm the validity of the signature in the training set and verified in the validation set. Finally, single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) analysis showed that the signature was related to immune cell infiltration.

Conclusions: Our research underlines the role of the 6-ferroptosis-lncRNA signature as a predictor of prognosis and a therapeutic alternative for ccRCC.

The so-called "amyloid cascade hypothesis" provides an elegant explanation of Alzheimer's disease (AD), has motivated the amyloid-lowering therapeutic strategy, and led to the elaboration of a rich experimental and conceptual toolkit for the field to progress. But it might be incorrect. The scientific evidence base supporting the efficacy and safety of current anti-amyloid antibody treatments in AD is weak. Nevertheless, we argue that there is a bias towards the amyloid-lowering therapeutic strategy amongst key opinion leaders in the research and advocacy communities. To demonstrate this, we first focus on the AD lexicon: while any accrual of amyloid on a brain PET scan can now permit diagnosis/definition of AD, lowering positron emission tomography (PET) amyloid is considered disease modification, and treatment-induced side-effects are hidden behind neutral-sounding acronyms: ARIA (amyloid-β (Aβ)-related imaging abnormalities: brain bleeding and swelling) and ARPA (amyloid-β (Aβ) removal-related pseudo-atrophy: brain shrinkage). Second, we underline that drugmakers did not test anti-amyloid antibodies against the best proven interventions and did not adequately inform trial participants of risks, thus violating research ethics of the Declaration of Helsinki on 2 counts. In conclusion, we are critical of over-reliance on the idea that PET amyloid-lowering treatments for AD are a therapeutic revolution as claimed, and consider that optimism does not excuse a lack of scientific, regulatory, and ethical integrity. We argue for rigorous, properly controlled (e.g. donepezil) anti-amyloid trials demonstrating cognitive and functional benefit before accepting amyloid-lowering drugs as the new standard of care for AD patients.

Background: The clinical response rate for molecularly targeted medications is limited despite significant advancements in molecularly targeted therapy for hepatocellular carcinoma (HCC). Therefore, it is necessary to find new and robust therapeutic targets for the treatment of HCC. Recent research has shown that mesoderm/mesenchyme homeobox gene 1 (Meox1) is closely associated with cancer progression.

Objectives: The aim of this study was to evaluate the clinical relevance as well as biological function of Meox1 in HCC.

Material and methods: Meox1 protein expression level was identified through immunohistochemistry (IHC) examination of pathological tissues from 25 HCC patients. The aim of the analysis was to investigate the relationship between clinicopathological traits and Meox1 expression. Biological function assays of Meox1 in HCC, including proliferation, colony formation, migration, and invasion, were performed with Huh7 and Hep3B cells.

Results: In this study, Meox1 expression in HCC tissues was significantly higher (p < 0.05) compared to paracancerous tissues. Especially in HCC tissues of patients with cirrhosis, the level of Meox1 expression was significantly elevated when compared to HCC tissues of patients without cirrhosis (p < 0.05). High Meox1 expression was significantly associated with tumor-node-metastasis (TNM) stage (p < 0.05) and the Barcelona Clinic Liver Cancer (BCLC) stage (p < 0.05). Moreover, Meox1 silencing suppressed the proliferation, colony formation, migration, and invasion of Huh7 and Hep3B cells.

Conclusions: Our data reveal that Meox1 may play a crucial role in the development of HCC, and given the function of Meox1 in proliferation and metastasis, targeting Meox1 may offer a promising approach for combined and adjuvant therapeutics of HCC.

Background: The imbalance between supply and demand for organ donations remains a hot topic for international debate. Brain-dead organ donors (DBDs) constitute the majority of organ donations in Poland.

Objectives: To identify the factors that guided intensivists in qualifying a brain-dead patient as a potential organ donor, and whether the factors that significantly influenced the decision to qualify constituted an actual contraindication.

Material and methods: We performed a retrospective study based on data from the Silesian ICU Registry from 2010-2020 and publicly available information from Poltransplant. We compared the demographic and clinical characteristics of patients diagnosed with brain death who were identified as eligible and ineligible organ donors.

Results: Out of 25,465 patients enrolled in the Silesian ICU Registry, brain death was diagnosed in 385 (1.51%) study participants, and 61 of the records were excluded due to data incompleteness. In the remaining group (n = 324), there were 201 men and 123 women. Of them, only 180 study participants were reported as eligible donors (55.5%). Six patients had absolute contraindications to organ donation.

Conclusions: A relatively small number of patients diagnosed with brain death were qualified by intensivists as eligible organ donors, with a limited number of medical factors influencing this decision. This means that other non-medical factors may affect the qualification of DBDs for organ procurement.

Background: Previous research has shown that moral judgments are affected by social cognitive abilities, such as theory of mind (ToM). This study examines how information about an actor's beliefs and the consequences of their actions affect the moral evaluation of the character's behavior in social events. Our research builds upon previous studies, which have shown that these factors contribute differently to moral judgments made by both adults and young children.

Objectives: This study aimed to explore how participants with schizophrenia and healthy controls read stories about social situations in the context of moral judgments.

Material and methods: The study used the research procedure that included 4 variants of 16 scenarios describing social situations, and thus comprising 64 stories. After each story, participants evaluated their confidence level on a 4-point scale. To assess delusional beliefs, the Polish adaptation of the Peters Delusion Inventory (PDI) questionnaire and the Paranoia Checklist (PCh) were used. Respondents completed these questionnaires after completing the scenario test procedure.

Results: In social situations, patients with paranoid schizophrenia were found to evaluate actions of protagonists who attempted to harm another person more leniently than when it was an accident. Conversely, healthy individuals judged those actors who expressed intentions to hurt another person significantly more harshly than in an accident situation. Metacognition measures show that paranoid schizophrenia patients make moral judgments with high confidence, despite being based on an incorrect reading of the other person's intentions.

Conclusions: The study indicates that ToM has a significant impact on the moral judgment of others. Decreased moral cognition can result from both positive and negative symptoms. Deficits related to metacognition can also sustain such cognitive distortions.