Over the recent years, our understanding of the cell death machinery of mature erythrocytes has been greatly expanded. It resulted in the discovery of several regulated cell death (RCD) pathways in red blood cells. Apoptosis (eryptosis) and necroptosis of erythrocytes share certain features with their counterparts in nucleated cells, but they are also critically different in particular details. In this review article, we summarize the cell death subroutines in the erythroid precursors (apoptosis, necroptosis, and ferroptosis) in comparison to mature erythrocytes (eryptosis and erythronecroptosis) to highlight the consequences of organelle clearance and associated loss of multiple components of the cell death machinery upon erythrocyte maturation. Recent advances in understanding the role of erythrocyte RCDs in health and disease have expanded potential clinical applications of these lethal subroutines, emphasizing their contribution to the development of anemia, microthrombosis, and endothelial dysfunction, as well as their role as diagnostic biomarkers and markers of erythrocyte storage-induced lesions. Fas signaling and the functional caspase-8/caspase-3 system are not indispensable for eryptosis, but might be retained in mature erythrocytes to mediate the crosstalk between both erythrocyte-associated RCDs. The ability of erythrocytes to switch between eryptosis and necroptosis suggests that their cell death is not a simple unregulated mechanical disintegration, but a tightly controlled process. This allows investigation of eventual pharmacological interventions aimed at individual cell death subroutines of erythrocytes.

• Klíčová slova
• Apoptosis, Cell death, Ferroptosis, Necroptosis, Red blood cell,
• MeSH
• apoptóza MeSH
• buněčná smrt MeSH
• eryptóza * MeSH
• erytrocyty * metabolismus   cytologie   MeSH
• ferroptóza MeSH
• lidé MeSH
• nekroptóza MeSH
• regulovaná buněčná smrt MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The evaluation of large experimental datasets is a fundamental aspect of research in every scientific field. Streamlining this process can improve the reliability of results while making data analysis more efficient and faster to execute. In biomedical research it is often very important to determine the type of cell death after various treatments. Thus, differentiating between viable, apoptotic, and necrotic cells provide critical insights into the treatment efficacy, a key aspect in the field of drug development. Fluorescent microscopy is perceived as a widely used technique for cell metabolism assessment and can therefore be used to investigate treatment outcomes after staining samples with cell death detection kit. However, accurate evaluation of therapeutic results requires quantitative analysis, often necessitating extensive postprocessing of imaging data. In this study, we introduce a complementary tool designed as a macro for the Fiji platform, enabling the automated postprocessing of fluorescent microscopy images to accurately distinguish and quantify viable, apoptotic, and necrotic cells.

• Klíčová slova
• apoptosis, cell death, microscopy, necrosis,
• MeSH
• apoptóza MeSH
• buněčná smrt MeSH
• fluorescenční mikroskopie * metody   MeSH
• lidé MeSH
• nekróza MeSH
• počítačové zpracování obrazu * metody   MeSH
• software MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Many cancer therapies aim to trigger apoptosis in cancer cells. Nevertheless, the presence of oncogenic alterations in these cells and distorted composition of tumour microenvironment largely limit the clinical efficacy of this type of therapy. Luckily, scientific consensus describes about 10 different cell death subroutines with different regulatory pathways and cancer cells are probably not able to avoid all of cell death types at once. Therefore, a focused and individualised therapy is needed to address the specific advantages and disadvantages of individual tumours. Although much is known about apoptosis, therapeutic opportunities of other cell death pathways are often neglected. Molecular heterogeneity of head and neck squamous cell carcinomas (HNSCC) causing unpredictability of the clinical response represents a grave challenge for oncologists and seems to be a critical component of treatment response. The large proportion of this clinical heterogeneity probably lies in alterations of cell death pathways. How exactly cells die is very important because the predominant type of cell death can have multiple impacts on the therapeutic response as cell death itself acts as a second messenger. In this review, we discuss the different types of programmed cell death (PCD), their connection with HNSCC pathogenesis and possible therapeutic windows that result from specific sensitivity to some form of PCD in some clinically relevant subgroups of HNSCC.

• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• chemorezistence MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• ferroptóza účinky léků   MeSH
• genetická heterogenita MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nekroptóza účinky léků   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyroptóza účinky léků   MeSH
• regulovaná buněčná smrt účinky léků   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH

BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.

• Klíčová slova
• Combination therapy, Meta-analysis, Metastatic renal cell carcinoma, Programmed cell death-1 inhibitors, Programmed cell death-ligand 1 inhibitors,
• MeSH
• antigeny CD274 antagonisté a inhibitory   imunologie   MeSH
• antigeny CD279 antagonisté a inhibitory   imunologie   MeSH
• inhibitory kontrolních bodů aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• karcinom z renálních buněk farmakoterapie   imunologie   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• nádory ledvin farmakoterapie   imunologie   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů MeSH
• PDCD1 protein, human MeSH Prohlížeč

Rapidly growing body of evidence on cell death mechanisms and its disorders during last five years has replaced old paradigms and opened new horizons in medicine. Identification of different morphological and signaling aspects, as well as variances in requirement for energy enabled us to construct a theory of three main types of cell death: necrosis, apoptosis, and lysosomal cell death. Mitochondria, certain oncoproteins such as Bcl-2 family, and special catabolic enzymes participating in cellular demise might serve as targets for pharmacological manipulation. Upregulation or downregulation of programmed cell death has been implicated in ischemic, neurodegenerative, and autoimmune disorders, as well as in oncology and chronic inflammation. This minireview brings a short overview of genesis and development of theories on programmed cell death and apoptosis, summarizes basic relevant facts on apoptotic mechanisms and draws a new hypothesis on possible implication in medicine and surgery.

• MeSH
• apoptóza * účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• lidé MeSH
• mitochondrie fyziologie   MeSH
• nekróza MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cell viability and cytotoxicity assays are highly important for drug screening and cytotoxicity tests of antineoplastic or other therapeutic drugs. Even though biochemical-based tests are very helpful to obtain preliminary preview, their results should be confirmed by methods based on direct cell death assessment. In this study, time-dependent changes in quantitative phase-based parameters during cell death were determined and methodology useable for rapid and label-free assessment of direct cell death was introduced. The goal of our study was distinction between apoptosis and primary lytic cell death based on morphologic features. We have distinguished the lytic and non-lytic type of cell death according to their end-point features (Dance of Death typical for apoptosis versus swelling and membrane rupture typical for all kinds of necrosis common for necroptosis, pyroptosis, ferroptosis and accidental cell death). Our method utilizes Quantitative Phase Imaging (QPI) which enables the time-lapse observation of subtle changes in cell mass distribution. According to our results, morphological and dynamical features extracted from QPI micrographs are suitable for cell death detection (76% accuracy in comparison with manual annotation). Furthermore, based on QPI data alone and machine learning, we were able to classify typical dynamical changes of cell morphology during both caspase 3,7-dependent and -independent cell death subroutines. The main parameters used for label-free detection of these cell death modalities were cell density (pg/pixel) and average intensity change of cell pixels further designated as Cell Dynamic Score (CDS). To the best of our knowledge, this is the first study introducing CDS and cell density as a parameter typical for individual cell death subroutines with prediction accuracy 75.4% for caspase 3,7-dependent and -independent cell death.

• MeSH
• algoritmy MeSH
• apoptóza * účinky léků   MeSH
• buněčná smrt * účinky léků   MeSH
• buňky ultrastruktura   MeSH
• časosběrné zobrazování metody   MeSH
• časové faktory MeSH
• kultivované buňky MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• optické zobrazování metody   MeSH
• počet buněk MeSH
• statistické modely MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.

• Klíčová slova
• CAR T cells, antigen-presenting cells, chemotherapy, danger signals, dendritic cell, immune-checkpoint blockers, immunogenic cell death, immunotherapy,
• MeSH
• buněčná smrt MeSH
• cytokiny metabolismus   MeSH
• imunogenní buněčná smrt MeSH
• lidé MeSH
• nádory * MeSH
• protinádorové látky * farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• protinádorové látky * MeSH

Currently it is not clear what type of the final cellular response (i.e. cell death modality or senescence) is induced upon chronic intracellular zinc depletion in colon cancer cells. To address this question, isogenic colon cancer lines SW480 and SW620 exposed to low zinc environment were studied over the period of 6 weeks. Low zinc environment reduced total as well as free intracellular zinc content in both cell lines. Decreased intracellular zinc content resulted in changes in cellular proliferation, cell cycle distribution and activation of stress signaling. In addition, colonocytes with low zinc content displayed increased levels of oxidative stress, changes in mitochondrial activity but in the absence of significant DNA damage. Towards the end of treatment (4th-6th week), exposed cells started to change morphologically, and typical markers of senescence as well as cell death appeared. Of two examined colon cancer cell lines, SW480 cells proved to activate predominantly senescent phenotype, with frequent form of demise being necrosis and mixed cell death modality but not apoptosis. Conversely, SW620 cells activated mostly cell death, with relatively equal distribution of apoptosis and mixed types, while senescent phenotypes and necrosis were present only in a small fraction of cell populations. Addition of zinc at the beginning of 4th week of treatment significantly suppressed cell death phenotypes in both cell lines but had no significant effect on senescence. In conclusion, presented results demonstrate variability of responses to chronic zinc depletion in colon cancer as modeled in vitro.

• Klíčová slova
• Cell death modalities, Colon cancer, Senescence, Stress kinases, Zinc,
• MeSH
• apoptóza fyziologie   MeSH
• buněčná smrt fyziologie   MeSH
• buněčný cyklus fyziologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory tračníku metabolismus   patologie   MeSH
• nekróza metabolismus   patologie   MeSH
• oxidační stres fyziologie   MeSH
• poškození DNA fyziologie   MeSH
• proliferace buněk fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• stárnutí buněk fyziologie   MeSH
• zinek metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• zinek MeSH

The character of programmed cell death (PCD) in plants differs in connection with the context, triggering factors and differentiation state of the target cells. To study the interconnections between cell cycle progression and cell death induction, we treated synchronized tobacco BY-2 cells with cadmium ions that represent a general abiotic stressor influencing both dividing and differentiated cells in planta. Cadmium induced massive cell death after application in all stages of the cell cycle; however, both the progression and the forms of the cell death differed pronouncedly. Apoptosis-like PCD induced by cadmium application in the S and G2 was characterized by pronounced internucleosomal DNA fragmentation. In contrast, application of cadmium in M and G1 phases was not accompanied by DNA cleavage, indicating suppression of autolysis and non-programmed character of the death. We interpret these results in the context of the situation in planta, where the induction of apoptosis-like PCD in the S and G2 phase might be connected with a need to preserve genetic integrity of dividing meristematic cells, whereas suppression of PCD response in differentiated cells (situated in G1/G0 phase) might help to avoid death of the whole plant, and thus enable initiation of the recovery and adaptation processes.

• MeSH
• apoptóza * MeSH
• buněčný cyklus * MeSH
• fragmentace DNA MeSH
• kultivované buňky MeSH
• mitotický index MeSH
• sírany farmakologie   MeSH
• sloučeniny kadmia farmakologie   MeSH
• tabák cytologie   účinky léků   genetika   MeSH
• viabilita buněk MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cadmium sulfate MeSH Prohlížeč
• sírany MeSH
• sloučeniny kadmia MeSH

Polymorphonuclear neutrophils (PMNs) play a key role in host defense. However, their massive accumulation at the site of inflammation can delay regenerative healing processes and can initiate pathological inflammatory processes. Thus, the efficient clearance of PMNs mediated by the induction of regulated cell death is a key process preventing the development of these pathological conditions. Myeloperoxidase (MPO), a highly abundant enzyme in PMN granules, primarily connected with PMN defense machinery, is suggested to play a role in PMN-regulated cell death. However, the contribution of MPO to the mechanisms of PMN cell death remains incompletely characterized. Herein, the process of the cell death of mouse PMNs induced by three different stimuli - phorbol 12-myristate 13-acetate (PMA), opsonized streptococcus (OST), and N-formyl-met-leu-phe (fMLP) - was investigated. MPO-deficient PMNs revealed a significantly decreased rate of cell death characterized by phosphatidylserine surface exposure and cell membrane permeabilization. An inhibitor of MPO activity, 4-aminobenzoic acid hydrazide, did not exhibit a significant effect on PMA-induced cell death compared to MPO deficiency. Interestingly, only the limited activation of markers related to apoptotic cell death was observed (e.g. caspase 8 activation, Bax expression) and they mostly did not correspond to phosphatidylserine surface exposure. Furthermore, a marker characterizing autophagy, cleavage of LC3 protein, as well as histone H3 citrullination and its surface expression was observed. Collectively, the data show the ability of MPO to modulate the life span of PMNs primarily through the potentiation of cell membrane permeabilization and phosphatidylserine surface exposure.

• Klíčová slova
• annexin V, apoptosis, cell death, inflammation, myeloperoxidase, neutrophils,
• MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neutrofily metabolismus   patologie   MeSH
• peroxidasa nedostatek   metabolismus   MeSH
• regulovaná buněčná smrt MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• peroxidasa MeSH