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Implants and medical devices are efficient and practical therapeutic solutions for a multitude of pathologies. Titanium and titanium alloys are used in orthopedics, dentistry, and cardiology. Despite very good mechanical properties and corrosion resistance, titanium implants can fail due to inflammatory or tissue degradation–related complications. Macrophages are major immune cells that control acceptance of failure of the implant. In this study, for the first time, we have performed a systematic analysis of the response of differentially activated human macrophages, M(Control), M(IFNγ), and M(IL-4), to the polished and porous titanium surfaces in order to identify the detrimental effect of titanium leading to the tissue destruction and chronic inflammation. Transcriptome analysis revealed that the highest number of differences between titanium and control settings are found in M(IL-4) that model healing type of macrophages. Real-time quantitative polymerase chain reaction analysis confirmed that both polished and porous titanium affected expression of cytokines, chitinases/chitinase-like proteins, and matrix metalloproteinases (MMPs). Titanium-induced release and activation of MMP7 by macrophages was enhanced by fibroblasts in both juxtacrine and paracrine cell interaction models. Production of titanium-induced MMPs and cytokines associated with chronic inflammation was independent of the presence of Staphylococcus aureus. MMP7, one of the most pronounced tissue-destroying factors, and chitinase-like protein YKL-40 were expressed in CD68+ macrophages in peri-implant tissues of patients with orthopedic implants. In summary, we demonstrated that titanium induces proinflammatory and tissue-destructing responses mainly in healing macrophages, and the detrimental effects of titanium surfaces on implant-adjacent macrophages are independent on the bacterial contamination. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the most lethal gynecologic malignancy worldwide. The major clinical challenge includes the asymptomatic state of the disease, making diagnosis possible only at advanced stages. Another OC complication is the high relapse rate and poor prognosis following the standard first-line treatment with platinum-based chemotherapy. At present, numerous clinical trials are being conducted focusing on immunotherapy in OC; nevertheless, there are still no FDA-approved indications. Personalized decision regarding the immunotherapy, including immune checkpoint blockade and immune cell-based immunotherapies, can depend on the effective antigen presentation required for the cytotoxic immune response. The major aim of our study was to uncover tumor-specific transcriptional and epigenetic changes in peripheral blood monocytes in patients with high-grade serous ovarian cancer (HGSOC). Another key point was to elucidate how chemotherapy can reprogram monocytes and how that relates to changes in other immune subpopulations in the blood. To this end, we performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from patients with HGSOC who underwent neoadjuvant chemotherapeutic treatment (NACT) and in treatment-naïve patients. Monocyte cluster was significantly affected by tumor-derived factors as well as by chemotherapeutic treatment. Bioinformatical analysis revealed three distinct monocyte subpopulations within PBMCs based on feature gene expression - CD14.Mn.S100A8.9hi, CD14.Mn.MHC2hi and CD16.Mn subsets. The intriguing result was that NACT induced antigen presentation in monocytes by the transcriptional upregulation of MHC class II molecules, but not by epigenetic changes. Increased MHC class II gene expression was a feature observed across all three monocyte subpopulations after chemotherapy. Our data also demonstrated that chemotherapy inhibited interferon-dependent signaling pathways, but activated some TGFb-related genes. Our results can enable personalized decision regarding the necessity to systemically re-educate immune cells to prime ovarian cancer to respond to anti-cancer therapy or to improve personalized prescription of existing immunotherapy in either combination with chemotherapy or a monotherapy regimen. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 15 (GDF-15) is a multifunctional cytokine that belongs to the transforming growth factor-beta (TGF-β) superfamily. GDF-15 is involved in immune tolerance and is elevated in several acute and chronic stress conditions, often correlating with disease severity and patient prognosis in cancer172 and metabolic and cardiovascular disorders. Despite these clinical associations, the molecular mechanisms orchestrating its effects remain to be elucidated. The effects of GDF-15 are pleiotropic but cell-specific and dependent on the microenvironment. While GDF-15 expression can be stimulated by inflammatory mediators, its predominant effects were reported as anti-inflammatory and pro-fibrotic. The role of GDF-15 in the macrophage system has been increasingly investigated in recent years. Macrophages produce high levels of GDF-15 during oxidative and lysosomal stress, which can lead to fibrogenesis and angiogenesis at the tissue level. At the same time, macrophages can respond to GDF-15 by switching their phenotype to a tolerogenic one. Several GDF-15-based therapies are under development, including GDF-15 analogs/mimetics and GDF-15-targeting monoclonal antibodies. In this review, we summarize the major physiological and pathological contexts in which GDF-15 interacts with macrophages. We also discuss the major challenges and future perspectives in the therapeutic translation of GDF-15. [ABSTRACT FROM AUTHOR]

Hyperglycemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycemia in the regulation of TLRs in primary human macrophages. Expression of TLRs (1–9) was examined in monocyte-derived M(NC), M(IFNγ), and M(IL4) differentiated in normoglycemic and hyperglycemic conditions. Hyperglycemia increased expression of TLR1 and TLR8 in M(NC), TLR2 and TLR6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycemia in M(IL4) was the upregulation of the TLR4 gene and protein expression. Hyperglycemia amplified TLR4-mediated response of M(IL4) to lipopolysaccharide by significantly enhancing IL1β and modestly suppressing IL10 production. In M(IL4), hyperglycemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand) amplified expression of TLR4 and production of IL1β. In summary, hyperglycemia enhanced the inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycemia can stimulate a low-grade inflammatory program in healing macrophages supporting vascular diabetic complications. [ABSTRACT FROM AUTHOR]

The increasing use of medical implants in various areas of medicine, particularly in orthopedic surgery, oncology, cardiology and dentistry, displayed the limitations in long-term integration of available biomaterials. The effective functioning and successful integration of implants requires not only technical excellence of materials but also consideration of the dynamics of biomaterial interaction with the immune system throughout the entire duration of implant use. The acute as well as long-term decisions about the efficiency of implant integration are done by local resident tissue macrophages and monocytederived macrophages that start to be recruited during tissue damage, when implant is installed, and are continuously recruited during the healing phase. Our review summarized the knowledge about the currently used macrophagesbased in vitro cells system that include murine and human cells lines and primary ex vivo differentiated macrophages. We provided the information about most frequently examined biomarkers for acute inflammation, chronic inflammation, foreign body response and fibrosis, indicating the benefits and limitations of the model systems. Particular attention is given to the scavenging function of macrophages that controls dynamic composition of peri-implant microenvironment and ensures timely clearance of microorganisms, cytokines, metabolites, extracellular matrix components, dying cells as well as implant debris. We outline the perspective for the application of 3D systems for modelling implant interaction with the immune system in human tissuespecific microenvironment avoiding animal experimentation. [ABSTRACT FROM AUTHOR]

The innate immune response represents the first-line of defense against invading pathogens. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in various aspects of innate immune function, which involves respiratory bursts and inflammasome activation. These reactive species widely distributed within the cellular environment are short-lived intermediates that play a vital role in cellular signaling and proliferation and are likely to depend on their subcellular site of formation. NADPH oxidase complex of phagocytes is known to generate superoxide anion radical (O2 •-) that functions as a precursor for antimicrobial hydrogen peroxide (H2O2) production, and H2O2 is utilized by myeloperoxidase (MPO) to generate hypochlorous acid (HOCl) that mediates pathogen killing. H2O2 modulates the expression of redox-responsive transcriptional factors, namely NF-kB, NRF2, and HIF-1, thereby mediating redox-based epigenetic modification. Survival and function of immune cells are under redox control and depend on intracellular and extracellular levels of ROS/RNS. The current review focuses on redox factors involved in the activation of immune response and the role of ROS in oxidative modification of proteins in macrophage polarization and neutrophil function. [ABSTRACT FROM AUTHOR]

Introduction: Immunometabolism is essential factor of tumor progression, and tumor-associated macrophages are characterized by substantial changes in their metabolic status. In this study for the first time, we applied targeted amino acid LC-MS/MS analysis to compare amino acid metabolism of circulating monocytes isolated from patients with breast, ovarian, lung, and colorectal cancer. Methods: Monocyte metabolomics was analyzed by liquid chromatographymass spectrometry/mass spectrometry (LC-MS/ MS) analysis of amino acid extracts. The targeted analysis of 26 amino acids was conducted by LCMS/MS on an Agilent 6460 triple quadrupole mass spectrometer equipped with an electrospray ionization source and an Agilent 1260 II liquid chromatograph. Results: Comparison of monocytes of cancer patients with monocytes of healthy control individuals demonstrated that in breast cancer most pronounced changes were identified for tryptophan (AUC = 0.76); for ovarian cancer, aminobutyric acid was significantly elevated (AUC= 1.00); for lung cancer significant changes we indented for citrulline (AUC = 0.70). In order to identify key amino acids that are characteristic for monocytes in specific cancer types, we compared each individual cancer with other 3 types of cancer. We found, that aspartic acid and citrulline are specific for monocytes of patients with colorectal cancer (p<0.001, FC = 1.40 and p=0.003, FC = 1.42 respectively). Citrulline, sarcosine and glutamic acid are ovarian cancer-specific amino acids (p = 0.003, FC = 0.78, p = 0.003, FC = 0.62, p = 0.02, FC = 0.78 respectively). Glutamine, methionine and phenylalanine (p = 0.048, FC = 1.39. p = 0.03, FC = 1.27 and p = 0.02, FC = 1.41) are lung cancer-specific amino acids. Ornithine in monocytes demonstrated strong positive correlation (r = 0.63) with lymph node metastasis incidence in breast cancer patients. Methyl histidine and cysteine in monocytes had strong negative correlation with lymph node metastasis in ovarian cancer patients (r = -0.95 and r = -0.95 respectively). Arginine, citrulline and ornithine have strong negative correlation with tumor size (r = -0.78, citrulline) and lymph node metastasis (r = -0.63 for arginine and r = -0.66 for ornithine). Discussion: These alterations in monocyte amino acid metabolism can reflect the reaction of systemic innate immunity on the growing tumor. Our data indicate that this metabolic programming is cancer specific and can be inhibiting cancer progression. Cancer-specific differences in citrulline, as molecular link between metabolic pathways and epigenetic programing, provide new option for the development and validation of anti-cancer therapies using inhibitors of enzymes catalyzing citrullination. [ABSTRACT FROM AUTHOR]

The regulation of protein kinases by dephosphorylation is a key mechanism that defines the activity of immune cells. A balanced process of the phosphorylation/dephosphorylation of key protein kinases by dual-specificity phosphatases is required for the realization of the antitumor immune response. The family of dual-specificity phosphatases is represented by several isoforms found in both resting and activated macrophages. The main substrate of dual-specificity phosphatases are three components of mitogen-activated kinase signaling cascades: the extracellular signal-regulated kinase ERK1/2, p38, and Janus kinase family. The results of the study of model tumor-associated macrophages supported the assumption of the crucial role of dual-specificity phosphatases in the formation and determination of the outcome of the immune response against tumor cells through the selective suppression of mitogen-activated kinase signaling cascades. Since mitogen-activated kinases mostly activate the production of pro-inflammatory mediators and the antitumor function of macrophages, the excess activity of dual-specificity phosphatases suppresses the ability of tumor-associated macrophages to activate the antitumor immune response. Nowadays, the fundamental research in tumor immunology is focused on the search for novel molecular targets to activate the antitumor immune response. However, to date, dual-specificity phosphatases received limited discussion as key targets of the immune system to activate the antitumor immune response. This review discusses the importance of dual-specificity phosphatases as key regulators of the tumor-associated macrophage function. [ABSTRACT FROM AUTHOR]

Transcriptomic evidence from human myocardium in myocardial infarction (MI) is still not sufficient. Thus, there is a need for studies on human cardiac samples in relation to the clinical data of patients. The purpose of our pilot study was to investigate the transcriptomic profile of myocardium in the infarct zone, in comparison to the remote myocardium, in patients with fatal MI, via microarray analysis. This study included four patients with fatal MI type 1. We selected histologically verified samples from within the infarct area (n = 4) and remote myocardium (n = 4). The whole transcriptome was evaluated using microarray analysis. Differentially expressed genes (DEGs) clustered in the infarct area and in the remote myocardium allowed their differentiation. We identified a total of 1785 DEGs (8.32%) in the infarct area, including 1692 up-regulated (94.79%) and 93 down-regulated (5.21%) genes. The top 10 up-regulated genes were TRAIL, SUCLA2, NAE1, PDCL3, OSBPL5, FCGR2C, SELE, CEP63, ST3GAL3 and C4orf3. In the infarct area, we found up-regulation of seventeen apoptosis-related genes, eleven necroptosis-related, and six necrosis-related genes. Transcriptome profiling of the myocardium in patients with MI remains a relevant area of research for the formation of new scientific hypotheses and a potential way to increase the translational significance of studies into myocardial infarction. [ABSTRACT FROM AUTHOR]

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF- dependent manner, and stabilin-2- deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates., Introduction The coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the plasma as a noncovalent complex, with VWF serving as a carrier to protect FVIII from [...]

The interaction between trophoblasts, stroma cells, and immune cells at the maternal–fetal interface constitutes the functional units of the placenta, which is crucial for successful pregnancy outcomes. However, the investigation of this intricate interplay is restricted due to the absence of efficient experimental models. To address this challenge, a robust, reliable methodology for generating placenta villi organoids (PVOs) from early, late, or diseased pregnancies using air–liquid surface culture is developed. PVOs contain cytotrophoblasts that can self‐renew and differentiate directly, along with stromal elements that retain native immune cells. Analysis of scRNA sequencing and WES data reveals that PVOs faithfully recapitulate the cellular components and genetic alterations of the corresponding source tissue. Additionally, PVOs derived from patients with preeclampsia exhibit specific pathological features such as inflammation, antiangiogenic imbalance, and decreased syncytin expression. The PVO‐based propagation of primary placenta villi should enable a deeper investigation of placenta development and exploration of the underlying pathogenesis and therapeutics of placenta‐originated diseases. [ABSTRACT FROM AUTHOR]

Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer. [ABSTRACT FROM AUTHOR]

The aim of our study was to compare the features of macrophage (mf) composition of the kidneys in patients with fatal myocardial infarction (MI) and in patients without cardiovascular diseases (CVD). We used kidney fragments taken during autopsy. Macrophage infiltration was assessed by immunohistochemistry: antibodies CD68 were used as a common mf marker, CD80—M1 type mf marker, CD163, CD206, and stabilin-1—M2 type. Macrophage composition of the kidneys in patients with fatal MI was characterized by the predominance of CD163+ cells among studied cells, and the control group was characterized by the predominance of CD163+, CD206+, and CD68+. In patients with MI, biphasic response from kidney cells was characterized for CD80+ and CD206+: their number decreased by the long-term period of MI; other cells did not show any dynamics. The exact number of CD80+ cells in kidneys of individuals without CVD was slightly higher than in patients with MI, and the number of CD206+—strikingly predominant. Subsequent analysis of CD80+ and CD206+ cells in a larger sample, as well as comparison of data with results obtained from survivors of MI, may bring us closer to understanding whether the influence on these cells can serve as a new target in personalized therapy in postinfarction complications. [ABSTRACT FROM AUTHOR]

The immune component of the tumor microenvironment is essential for the regulation of cancer progression. In breast cancer (BC), a patient's tumor mass is frequently infiltrated by neutrophils (tumor-associated neutrophils, TANs). Our study addressed the role of TANs and their mechanism of action in BC. Using quantitative IHC, ROC, and Cox analysis, we demonstrated that a high density of TANs infiltrating the tumor parenchyma was predictive of poor prognosis and of decreased progression-free survival of patients with BC, who underwent surgical tumor removal without previous neoadjuvant chemotherapy, in 3 different cohorts: training, validation, and independent cohorts. Conditioned medium from human BC cell lines prolonged the lifespan of healthy donor neutrophils ex vivo. Neutrophils activated by the supernatants of BC lines demonstrated an increased ability to stimulate proliferation, migration, and invasive activity of BC cells. Cytokines involved in this process were identified using antibody arrays. The relationship between these cytokines and the density of TANs was validated by ELISA and IHC in fresh BC surgical samples. It was determined that tumor-derived G-CSF significantly extended the lifespan and increased the metastasis-promoting activities of neutrophils via the PI3K-AKT and NF-κB pathways. Simultaneously, TAN-derived RLN2 promoted the migratory abilities of MCF7 cells via PI3K-AKT-MMP-9. Analysis of tumor tissues from 20 patients with BC identified a positive correlation between the density of TANs and the activation of the G-CSF-RLN2-MMP-9 axis. Finally, our data demonstrated that TANs in human BC have detrimental effects, supporting malignant cell invasion and migration. [ABSTRACT FROM AUTHOR]

The immuno-compatibility of implant materials is a key issue for both initial and long-term implant integration. Ceramic implants have several advantages that make them highly promising for long-term medical solutions. These beneficial characteristics include such things as the material availability, possibility to manufacture various shapes and surface structures, osteo-inductivity and osteo-conductivity, low level of corrosion and general biocompatibility. The immuno-compatibility of an implant essentially depends on the interaction with local resident immune cells and, first of all, macrophages. However, in the case of ceramics, these interactions are insufficiently understood and require intensive experimental examinations. Our review summarizes the state of the art in variants of ceramic implants: mechanical properties, different chemical modifications of the basic material, surface structures and modifications, implant shapes and porosity. We collected the available information about the interaction of ceramics with the immune system and highlighted the studies that reported ceramic-specific local or systemic effects on the immune system. We disclosed the gaps in knowledge and outlined the perspectives for the identification to ceramic-specific interactions with the immune system using advanced quantitative technologies. We discussed the approaches for ceramic implant modification and pointed out the need for data integration using mathematic modelling of the multiple ceramic implant characteristics and their contribution for long-term implant bio- and immuno-compatibility. [ABSTRACT FROM AUTHOR]

Introduction: Circulating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation. Methods: Patients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS. Results: In patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN metastasis. NGS analysis identified tumor-specific transcriptional programming of monocytes in all CRC patients compared to healthy individuals. The key transcriptional difference between monocytes of patients with colon and rectal cancer was increased expression of PFKFB3, activator of glycolysis that is currently considered as therapy target for major solid cancers. PFKFB3-expressing monocyte-derived macrophages massively infiltrated tumor in colon. Nanostring technology identified correlation of PFKFB3 with amount and tumor-promoting properties of TAMs in colon but not in rectal cancer. PFKFB3 was indicative for tumor relapse specifically in colon cancer. Discussion: Our findings provide essential argument towards CRC definition to cover two clinically distinct cancers – colon cancer and rectal cancer, that differentially interact with innate immunity. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that constitute up to 50% of the cell mass of human tumors. TAMs interact with the components of the tumor microenvironment (TME) by using scavenger receptors (SRs), a large superfamily of multifunctional receptors that recognize, internalize and transport to the endosomal/lysosomal pathway apoptotic cells, cytokines, matrix molecules, lipid modified lipoproteins and other unwanted-self ligands. In our review, we summarized state-of-the art for the role of macrophage scavenger receptors in tumor development and their significance as cancer biomarkers. In this review we focused on functional activity of TAM-expressing SRs in animal models and in patients, and summarized the data for different human cancer types about the prognostic significance of TAM-expressed SRs. We discussed the role of SRs in the regulation of cancer cell biology, cell-cell and cell-matrix interaction in TME, immune status in TME, angiogenesis, and intratumoral metabolism. Targeting of tumor-promoting SRs can be a promising therapeutic approach in anticancer therapy. In our review we provide evidence for both tumor supporting and tumor inhibiting functions of scavenger receptors expressed on TAMs. We focused on the key differences in the prognostic and functional roles of SRs that are specific for cancer types. We highlighted perspectives for inhibition of tumor-promoting SRs in anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Our review summarizes the evidence that COVID-19 can be complicated by SARS-CoV-2 infection of immune cells. This evidence is widespread and accumulating at an increasing rate. Research teams from around the world, studying primary and established cell cultures, animal models, and analyzing autopsy material from COVID-19 deceased patients, are seeing the same thing, namely that some immune cells are infected or capable of being infected with the virus. Human cells most vulnerable to infection include both professional phagocytes, such as monocytes, macrophages, and dendritic cells, as well as nonprofessional phagocytes, such as B-cells. Convincing evidence has accumulated to suggest that the virus can infect monocytes and macrophages, while data on infection of dendritic cells and B-cells are still scarce. Viral infection of immune cells can occur directly through cell receptors, but it can also be mediated or enhanced by antibodies through the Fc gamma receptors of phagocytic cells. Antibody-dependent enhancement (ADE) most likely occurs during the primary encounter with the pathogen through the first COVID-19 infection rather than during the second encounter, which is characteristic of ADE caused by other viruses. Highly fucosylated antibodies of vaccinees seems to be incapable of causing ADE, whereas afucosylated antibodies of persons with acute primary infection or convalescents are capable. SARS-CoV-2 entry into immune cells can lead to an abortive infection followed by host cell pyroptosis, and a massive inflammatory cascade. This scenario has the most experimental evidence. Other scenarios are also possible, for which the evidence base is not yet as extensive, namely productive infection of immune cells or trans-infection of other non-immune permissive cells. The chance of a latent infection cannot be ruled out either. [ABSTRACT FROM AUTHOR]

Monocytes in peripheral blood circulation are the precursor of essential cells that control tumor progression, that include tumor-associated macrophages (TAMs), dendritic cells (DCs) and myeloid-derive suppressor cells (MDSC). Monocytes-derived cells orchestrate immune reactions in tumor microenvironment that control disease outcome and efficiency of cancer therapy. Four major types of anti-cancer therapy, surgery, radiotherapy, chemotherapy, and most recent immunotherapy, affect tumor-associated macrophage (TAM) polarization and functions. TAMs can also decrease the efficiency of therapy in a tumor-specific way. Monocytes is a major source of TAMs, and are recruited to tumor mass from the blood circulation. However, the mechanisms of monocyte programming in circulation by different therapeutic onsets are only emerging. In our review, we present the stateof- the art about the effects of anti-cancer therapy on monocyte progenitors and their dedifferentiation, on the content of monocyte subpopulations and their transcriptional programs in the circulation, on their recruitment into tumor mass and their potential to give origin for TAMs in tumor-specific microenvironment. We have also summarized very limited available knowledge about genetics that can affect monocyte interaction with cancer therapy, and highlighted the perspectives for the therapeutic targeting of circulating monocytes in cancer patients. We summarized the knowledge about the mediators that affect monocytes fate in all four types of therapies, and we highlighted the perspectives for targeting monocytes to develop combined and minimally invasive anti-cancer therapeutic approaches. [ABSTRACT FROM AUTHOR]

Tissue homeostasis and remodeling are processes that involve high turnover of biological macromolecules. Many of the waste molecules that are by-products or degradation intermediates of biological macromolecule turnover enter the circulation and are subsequently cleared by liver sinusoidal endothelial cells (LSEC). Besides the mannose receptor, stabilin-1 and stabilin-2 are the major scavenger receptors expressed by LSEC. To more clearly elucidate the functions of stabilin-1 and -2, we have generated mice lacking stabilin-1, stabilin-2, or both stabilin-1 and -2 ([Stab1.sup.-/-][Stab2.sup.-/-] mice). Mice lacking either stabilin-1 or stabilin-2 were phenotypically normal; however, [Stab1.sup.-/-][Stab2.sup.-/-] mice exhibited premature mortality and developed severe glomerular fibrosis, while the liver showed only mild perisinusoidal fibrosis without dysfunction. Upon kidney transplantation intoWT mice, progression of glomerular fibrosis was halted, indicating the presence of profibrotic factors in the circulation of [Stab1.sup.-/-][Stab2.sup.-/-] mice. While plasma levels of known profibrotic cytokines were unaltered, clearance of the TGF-β family member growth differentiation factor 15 (GDF-15) was markedly impaired in [Stab1.sup.-/-][Stab2.sup.-/-] mice but not in either [Stab1.sup.-/-] or [Stab2.sup.-/-] mice, indicating that it is a common ligand of both stabilin-1 and stabilin-2. These data lead us to conclude that stabilin-1 and -2 together guarantee proper hepatic clearance of potentially noxious agents in the blood and maintain tissue homeostasis not only in the liver but also distant organs., Introduction Tissue homeostasis and remodeling are accompanied by high turnover of all categories of biological macromolecules including proteins, proteoglycans, and polysaccharides as well as nucleic acids and lipids (1). During [...]