The tumor microenvironment (TME) is a complex, highly structured, and dynamic ecosystem that plays a pivotal role in the progression of both primary and metastatic tumors. Precise assessment of the dynamic spatiotemporal features of the TME is crucial for understanding cancer evolution and designing effective therapeutic strategies. Cancer is increasingly recognized as a systemic disease, influenced not only by the TME, but also by a multitude of systemic factors, including whole-body metabolism, gut microbiome, endocrine signaling, and circadian rhythm. In this review, we summarize the intrinsic, extrinsic, and systemic factors contributing to the formation of 'cold' tumors within the framework of the cancer-immunity cycle. Correspondingly, we discuss potential strategies for converting 'cold' tumors into 'hot' ones to enhance therapeutic efficacy.
- MeSH
- Circadian Rhythm MeSH
- Humans MeSH
- Tumor Microenvironment * immunology MeSH
- Neoplasms * pathology therapy MeSH
- Gastrointestinal Microbiome MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.
- Publication type
- Journal Article MeSH
- Review MeSH
Clinical trials in oncology are important tools to identify and establish new effective drugs for cancer treatment. Since the development of the concept of precision oncology, a huge number of multi-centric biomarker-driven clinical trials have been performed and promoted by either academic institutions or pharmaceutical companies. In this scenario, the role of pathologists is essential in multiple aspects, with new challenges that should be addressed. In this position paper of the European Society of Pathology, the role of pathologists as contributors to the design of the clinical trial, as local collaborators, or as members of central review laboratories is discussed. Moreover, the paper emphasizes the important role of pathologists in guiding methods and criteria of tissue biomarker testing in the biomarker-driven clinical trials. The paper also addresses issues regarding quality control, training, and the possible role of digital pathology.
- MeSH
- Clinical Trials as Topic * MeSH
- Pathology, Clinical standards methods MeSH
- Humans MeSH
- Biomarkers, Tumor * analysis MeSH
- Neoplasms * pathology drug therapy MeSH
- Pathologists * MeSH
- Societies, Medical MeSH
- Research Design standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- Europe MeSH
Asthma is a common, multifaceted respiratory disease with a major impact on quality of life. Despite increased insights into mechanisms underlying various asthma phenotypes and endotypes and the availability of targeted biologic treatment options, the disease remains uncontrolled in a substantial proportion of patients with risk of exacerbations, requiring systemic corticosteroids, and with progressive disease. Current international guidelines advocate for a personalized management approach to patients with uncontrolled severe asthma. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) asthma expert panel was convened to discuss strategies to optimize asthma care and to prevent systemic corticosteroid overuse and disease progression. In this meeting report, we summarize current concepts and recommendations and provide a rationale to implement personalized asthma management at earlier stages of the disease. The ultimate goal is to move away from the current one-size-fits-most concept, which focuses on a symptom-driven treatment strategy, and shift toward a phenotype- and endotype-targeted approach aimed at curbing the disease course by improving clinical outcomes and preserving health-related quality of life. Herein, we provide a consensus view on asthma care that advocates a holistic approach and highlight some unmet needs to be addressed in future clinical trials and population studies.
- MeSH
- Anti-Asthmatic Agents * therapeutic use MeSH
- Asthma * prevention & control therapy drug therapy MeSH
- Precision Medicine MeSH
- Remission Induction MeSH
- Consensus MeSH
- Quality of Life MeSH
- Humans MeSH
- Disease Management MeSH
- Disease Progression MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Consensus Development Conference MeSH
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
- Leukemia, Lymphocytic, Chronic, B-Cell * genetics pathology MeSH
- Cyclin D1 genetics metabolism MeSH
- Cyclin-Dependent Kinase Inhibitor p21 * genetics metabolism MeSH
- Cell Cycle Checkpoints * genetics MeSH
- Humans MeSH
- MicroRNAs * genetics metabolism MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation genetics MeSH
- Heat-Shock Proteins MeSH
- Gene Expression Regulation, Leukemic MeSH
- Carrier Proteins genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Precise localization of peripheral nerve injuries and evaluation of their prognosis based on clinical and electrodiagnostic examinations are particularly challenging in the acute phase. High-resolution ultrasound (HRUS) may offer a viable and cost-effective imaging option for assessing the morphology of nerve injuries. Consequently, a systematic review and meta-analysis of studies on the use of ultrasound for diagnosing traumatic nerve injuries were conducted. A total of 15 studies were included, reporting the most recent findings on using HRUS in the diagnosis of traumatic nerve injury. These studies assessed the diagnostic test accuracy of ultrasound for the detection of traumatic nerve injury in 272 participants, with the cross-sectional area at the site of traumatic nerve injury also reported in 1,249 participants. The pooled sensitivity and specificity of the included studies were 92% confidence interval (CI) (0.89-0.95) and 86% CI (0.82-0.89), respectively. The positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 13.76 CI (1.41-134.34), 0.08 CI (0.03-0.18), and 286.23 CI (21.22-3,860.40), respectively. In the summary of the receiver operating characteristic curve, the area under the curve was 0.986, and the Q* index was 0.949. Based on the current literature, HRUS has shown promising results in addition to its availability and feasibility. HRUS can serve as a valuable complement to clinical and electrodiagnostic examinations for diagnosing traumatic peripheral nerve injuries. Further research is recommended to better understand the ultrasound characteristics of these injuries.
- MeSH
- Humans MeSH
- Peripheral Nerve Injuries * diagnostic imaging diagnosis MeSH
- Ultrasonography * methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Review MeSH
- Systematic Review MeSH
Cyanobacteria are prokaryotic organisms characterised by their complex structures and a wide range of pigments. With their ability to fix CO2, cyanobacteria are interesting for white biotechnology as cell factories to produce various high-value metabolites such as polyhydroxyalkanoates, pigments, or proteins. White biotechnology is the industrial production and processing of chemicals, materials, and energy using microorganisms. It is known that exposing cyanobacteria to low levels of stressors can induce the production of secondary metabolites. Understanding of this phenomenon, known as hormesis, can involve the strategic application of controlled stressors to enhance the production of specific metabolites. Consequently, precise measurement of cyanobacterial viability becomes crucial for process control. However, there is no established reliable and quick viability assay protocol for cyanobacteria since the task is challenging due to strong interferences of autofluorescence signals of intercellular pigments and fluorescent viability probes when flow cytometry is used. We performed the screening of selected fluorescent viability probes used frequently in bacteria viability assays. The results of our investigation demonstrated the efficacy and reliability of three widely utilised types of viability probes for the assessment of the viability of Synechocystis strains. The developed technique can be possibly utilised for the evaluation of the importance of polyhydroxyalkanoates for cyanobacterial cultures with respect to selected stressor-repeated freezing and thawing. The results indicated that the presence of polyhydroxyalkanoate granules in cyanobacterial cells could hypothetically contribute to the survival of repeated freezing and thawing.
PURPOSE OF REVIEW: A critical evaluation of contemporary literature regarding the role of big data, artificial intelligence, and digital technologies in precision cardio-oncology care and survivorship, emphasizing innovative and groundbreaking endeavors. RECENT FINDINGS: Artificial intelligence (AI) algorithm models can automate the risk assessment process and augment current subjective clinical decision tools. AI, particularly machine learning (ML), can identify medically significant patterns in large data sets. Machine learning in cardio-oncology care has great potential in screening, diagnosis, monitoring, and managing cancer therapy-related cardiovascular complications. To this end, large-scale imaging data and clinical information are being leveraged in training efficient AI algorithms that may lead to effective clinical tools for caring for this vulnerable population. Telemedicine may benefit cardio-oncology patients by enhancing healthcare delivery through lowering costs, improving quality, and personalizing care. Similarly, the utilization of wearable biosensors and mobile health technology for remote monitoring holds the potential to improve cardio-oncology outcomes through early intervention and deeper clinical insight. Investigations are ongoing regarding the application of digital health tools such as telemedicine and remote monitoring devices in enhancing the functional status and recovery of cancer patients, particularly those with limited access to centralized services, by increasing physical activity levels and providing access to rehabilitation services. SUMMARY: In recent years, advances in cancer survival have increased the prevalence of patients experiencing cancer therapy-related cardiovascular complications. Traditional cardio-oncology risk categorization largely relies on basic clinical features and physician assessment, necessitating advancements in machine learning to create objective prediction models using diverse data sources. Healthcare disparities may be perpetuated through AI algorithms in digital health technologies. In turn, this may have a detrimental effect on minority populations by limiting resource allocation. Several AI-powered innovative health tools could be leveraged to bridge the digital divide and improve access to equitable care.
- Publication type
- Journal Article MeSH
The precise measurement of cell temperature and an in-depth understanding of thermogenic processes are critical in unraveling the complexities of cellular metabolism and its implications for health and disease. This review focuses on the mechanisms of local temperature generation within cells and the array of methods developed for accurate temperature assessment. The contact and noncontact techniques are introduced, including infrared thermography, fluorescence thermometry, and other innovative approaches to localized temperature measurement. The role of thermogenesis in cellular metabolism, highlighting the integral function of temperature regulation in cellular processes, environmental adaptation, and the implications of thermogenic dysregulation in diseases such as metabolic disorders and cancer are further discussed. The challenges and limitations in this field are critically analyzed while technological advancements and future directions are proposed to overcome these barriers. This review aims to provide a consolidated resource for current methodologies, stimulate discussion on the limitations and challenges, and inspire future innovations in the study of cellular thermodynamics.
- MeSH
- Humans MeSH
- Temperature MeSH
- Thermogenesis * physiology MeSH
- Thermography * methods MeSH
- Thermometry methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Cervical cancer (CC) is the fourth most common malignant tumor in women worldwide. Detecting different biomarkers together on single cells by novel method mass cytometry could contribute to more precise screening. Liquid-based cytology (LBC) cervical samples were collected (N = 53) from women categorized as normal and precancerous lesions. Human papillomavirus was genotyped by polymerase chain reaction, while simultaneous examination of the expression of 29 proteins was done by mass cytometry (CyTOF). Differences in cluster abundances were assessed with Spearman's rank correlation as well as high dimensional data analysis (t-SNE, FlowSOM). Cytokeratin (ITGA6, Ck5, Ck10/13, Ck14, Ck7) expression patterns allowed determining the presence of different cells in the cervical epithelium. FlowSOM analysis enabled to phenotype cervical cells in five different metaclusters and find new markers that could be important in CC screening. The markers Ck18, Ck18, and CD63 (Metacluster 3) showed significantly increasing associated with severity of the precancerous lesions (Spearman rank correlation rho 0.304, p = 0.0271), while CD71, KLF4, LRIG1, E-cadherin, Nanog and p53 (Metacluster 1) decreased with severity of the precancerous lesions (Spearman rank correlation rho -0.401, p = 0.0029). Other metaclusters did not show significant correlation, but metacluster 2 (Ck17, MCM, MMP7, CD29, E-cadherin, Nanog, p53) showed higher abundance in low- and high-grade intraepithelial lesion cases. CyTOF appears feasible and should be considered when examining novel biomarkers on cervical LBC samples. This study enabled us to characterize different cells in the cervical epithelium and find markers and populations that could distinguish precancerous lesions.
- MeSH
- Cervix Uteri pathology metabolism MeSH
- Adult MeSH
- Uterine Cervical Dysplasia diagnosis pathology MeSH
- Papillomavirus Infections pathology diagnosis virology MeSH
- Kruppel-Like Factor 4 * MeSH
- Middle Aged MeSH
- Humans MeSH
- Biomarkers, Tumor * genetics metabolism MeSH
- Uterine Cervical Neoplasms * diagnosis pathology genetics MeSH
- Precancerous Conditions * pathology diagnosis MeSH
- Flow Cytometry * methods MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
