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BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.
- MeSH
- chronická lymfatická leukemie * genetika patologie MeSH
- cyklin D1 genetika metabolismus MeSH
- inhibitor p21 cyklin-dependentní kinasy * genetika metabolismus MeSH
- kontrolní body buněčného cyklu * genetika MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- proliferace buněk genetika MeSH
- proteiny teplotního šoku MeSH
- regulace genové exprese u leukemie MeSH
- transportní proteiny genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.
- MeSH
- adjuvantní chemoterapie metody MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- invazivní růst nádoru MeSH
- karcinom z přechodných buněk farmakoterapie patologie MeSH
- lidé MeSH
- nádory močového měchýře farmakoterapie patologie MeSH
- síťová metaanalýza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
Molecular surveillance was widely used during the COVID-19 pandemic to detect rapidly emerging variants and monitor the transmission of SARS-CoV-2 within communities. In 2021, the Czech COVID-19 Genomics Consortium (COG-CZ) was set up to coordinate a new SARS-CoV-2 molecular surveillance network. In the Czech Republic, molecular surveillance employed whole genome sequencing (WGS) and variant discrimination polymerase chain reaction (VD-PCR) on samples collected through passive, active and sentinel surveillance. All WGS data was uploaded to GISAID and the PANGO lineages used by GISAID were compared to the main variants determined by VD-PCR. To assess the effectiveness and reliability of the gathered data in adapting pandemic responses, the capabilities and turnaround times of the molecular surveillance methods are evaluated. VD-PCR results were available within 48 h of sample collection for 81.5% of cases during the Delta/Omicron transition. WGS enabled the detection of low-frequency novel variants in infection clusters. WGS surveillance showed there was community spread of AY.20.1, a variant that gained novel mutations within the Czech Republic. Molecular surveillance informed the implementation of public health measures; temporal comparisons of restrictions and outcomes are described. Further areas for improvement have been identified for monitoring and managing future pandemics.
- MeSH
- COVID-19 * epidemiologie virologie MeSH
- genom virový MeSH
- lidé MeSH
- pandemie MeSH
- SARS-CoV-2 * genetika izolace a purifikace MeSH
- sekvenování celého genomu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.
- MeSH
- epitelo-mezenchymální tranzice fyziologie MeSH
- lidé MeSH
- nádory prostaty * patologie metabolismus terapie farmakoterapie MeSH
- NF-kappa B metabolismus MeSH
- proteiny hedgehog metabolismus MeSH
- signální transdukce * fyziologie MeSH
- transformující růstový faktor beta metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Epilepsy is a neurological disease characterized by epileptic seizures, which commonly manifest with pronounced frequency and amplitude changes in the EEG signal. In the case of focal seizures, initially localized pathological activity spreads from a so-called "onset zone" to a wider network of brain areas. Chimeras, defined as states of simultaneously occurring coherent and incoherent dynamics in symmetrically coupled networks are increasingly invoked for characterization of seizures. In particular, chimera-like states have been observed during the transition from a normal (asynchronous) to a seizure (synchronous) network state. However, chimeras in epilepsy have only been investigated with respect to the varying phases of oscillators. We propose a novel method to capture the characteristic pronounced changes in the recorded EEG amplitude during seizures by estimating chimera-like states directly from the signals in a frequency- and time-resolved manner. We test the method on a publicly available intracranial EEG dataset of 16 patients with focal epilepsy. We show that the proposed measure, titled Amplitude Entropy, is sensitive to the altered brain dynamics during seizure, demonstrating its significant increases during seizure as compared to before and after seizure. This finding is robust across patients, their seizures, and different frequency bands. In the future, Amplitude Entropy could serve not only as a feature for seizure detection, but also help in characterizing amplitude chimeras in other networked systems with characteristic amplitude dynamics.
OBJECTIVES: Artificial Intelligence (AI), particularly deep learning, has significantly impacted healthcare, including dentistry, by improving diagnostics, treatment planning, and prognosis prediction. This systematic mapping review explores the current applications of deep learning in dentistry, offering a comprehensive overview of trends, models, and their clinical significance. MATERIALS AND METHODS: Following a structured methodology, relevant studies published from January 2012 to September 2023 were identified through database searches in PubMed, Scopus, and Embase. Key data, including clinical purpose, deep learning tasks, model architectures, and data modalities, were extracted for qualitative synthesis. RESULTS: From 21,242 screened studies, 1,007 were included. Of these, 63.5% targeted diagnostic tasks, primarily with convolutional neural networks (CNNs). Classification (43.7%) and segmentation (22.9%) were the main methods, and imaging data-such as cone-beam computed tomography and orthopantomograms-were used in 84.4% of cases. Most studies (95.2%) applied fully supervised learning, emphasizing the need for annotated data. Pathology (21.5%), radiology (17.5%), and orthodontics (10.2%) were prominent fields, with 24.9% of studies relating to more than one specialty. CONCLUSION: This review explores the advancements in deep learning in dentistry, particulary for diagnostics, and identifies areas for further improvement. While CNNs have been used successfully, it is essential to explore emerging model architectures, learning approaches, and ways to obtain diverse and reliable data. Furthermore, fostering trust among all stakeholders by advancing explainable AI and addressing ethical considerations is crucial for transitioning AI from research to clinical practice. CLINICAL RELEVANCE: This review offers a comprehensive overview of a decade of deep learning in dentistry, showcasing its significant growth in recent years. By mapping its key applications and identifying research trends, it provides a valuable guide for future studies and highlights emerging opportunities for advancing AI-driven dental care.
- MeSH
- deep learning * MeSH
- lidé MeSH
- zubní lékařství * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- systematický přehled MeSH
Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.
- MeSH
- humanizované monoklonální protilátky terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- inhibitory kontrolních bodů * terapeutické užití MeSH
- karcinom z přechodných buněk farmakoterapie mortalita patologie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- monoklonální protilátky MeSH
- nádory močového měchýře farmakoterapie patologie mortalita MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití škodlivé účinky MeSH
- randomizované kontrolované studie jako téma MeSH
- síťová metaanalýza * MeSH
- urologické nádory farmakoterapie mortalita patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
CONTEXT: The optimal therapeutic agent with respect to metastatic sites is unclear in advanced urothelial carcinoma (UC). OBJECTIVE: To investigate the metastatic organotropism differential treatment response in patients with advanced or metastatic UC. EVIDENCE ACQUISITION: A systematic search and network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The primary endpoints of interest were the objective response rate, overall survival (OS), and progression-free survival with respect to different metastatic sites. EVIDENCE SYNTHESIS: Twenty-six trials comprising 9082 patients met our eligibility criteria, and a formal NMA was conducted. Durvalumab plus tremelimumab as first-line systemic therapy was significantly associated with better OS than chemotherapy in visceral metastasis (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.67-0.98). Pembrolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with visceral metastasis (HR 0.75, 95% CI 0.60-0.95). Atezolizumab as second-line systemic therapy was significantly associated with better OS than chemotherapy in patients with liver metastasis (in the population of >5% of tumor-infiltrating immune cells) and lymph node metastasis (HR 0.51, 95% CI 0.28-0.96, and HR 0.59, 95% CI 0.37-0.96, respectively). CONCLUSIONS: Administration of immune-oncology treatments with respect to metastatic sites in patients with advanced or metastatic UC might have a positive impact on survival outcomes in both the first- and the second-line setting. Nevertheless, further investigations focusing on metastatic organotropism differential response with reliable oncological outcomes are needed to identify the optimal management strategy for these patients. PATIENT SUMMARY: Although the supporting evidence for oncological benefits of therapeutic systemic agents with respect to metastatic sites is not yet strong enough to provide a recommendation in advanced or metastatic urothelial carcinoma, clinicians may take into account tumor organotropism only in discussion with the patient fully informed on the optimal treatment decision to be taken.
- MeSH
- karcinom z přechodných buněk * farmakoterapie sekundární mortalita patologie MeSH
- lidé MeSH
- metastázy nádorů MeSH
- randomizované kontrolované studie jako téma * MeSH
- síťová metaanalýza * MeSH
- urologické nádory farmakoterapie patologie mortalita MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.
Hepatocellular carcinoma (HCC) is primary liver cancer, frequently diagnosed at advanced stages with limited therapeutic options. MicroRNAs (miRNAs) regulate target gene expression and through inhibitory competitive binding of miRNA influence cellular processes including carcinogenesis. Extensive evidence proved that certain miRNA's are specifically expressed in neoplastic tissues of HCC patients and are confirmed as important factors that can participate in the regulation of key signalling pathways in cancer cells. As such, miRNAs have a great potential in the clinical diagnosis and treatment of HCC and can improve the limitations of standard diagnosis and treatment. Long non-coding RNAs (lncRNAs) have a critical role in the development and progression of HCC. HCC-related lncRNAs have been demonstrated to exhibit abnormal expression and contribute to transformation process (such as proliferation, apoptosis, accelerated vascular formation, and gain of invasive potential) through their interaction with DNA, RNA, or proteins. LncRNAs can bind mRNAs to release their target mRNA and enable its translation. These lncRNA-miRNA networks regulate cancer cell expression and so its proliferation, apoptosis, invasion, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and autophagy. In this narrative review, we focus on miRNA and lncRNA in HCC tumor tissue and their interaction as current tools, and biomarkers and therapeutic targets unravelled in recent years.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
