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Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages. [ABSTRACT FROM AUTHOR]

Background/Objectives: Myocarditis is an inflammatory disease of the myocardium and remains to this day a challenging diagnosis. A promising novel imaging method uses the expression of somatostatin receptors (SSTRs) on inflammatory cells to visualize myocardial inflammation. However, little is known about the histopathological correlate of SSTR imaging in different forms of myocarditis. Methods: In the present retrospective histopathological study, we systematically analysed the expression of SSTR subtype 2 (SSTR2) on inflammatory cells of 33 patients with biopsy- or explant-proven myocarditis (lymphocytic myocarditis (n = 5), giant-cell myocarditis (n = 11), and cardiac sarcoidosis (n = 17)), and in eight controls (multi-organ donors) without signs of myocardial inflammation and/or scars. Results: In all patients, immunohistochemical staining for SSTR2 was positive in areas with CD68-positive macrophages and multinucleated giant cells. Staining for SSTR2 was most prominent in the presence of multinucleated giant cells. The colocalization of both SSTR2 and CD68 on the same cell could be confirmed using immunofluorescence microscopy. Western blotting confirmed the upregulated expression of SSTR2 in cases of granulomatous inflammation (sarcoidosis) of the skeletal and heart muscle, in comparison with controls. Conclusions: In conclusion, our findings demonstrate the expression of SSTR2 on the protein level on CD68-positive macrophages and multinucleated giant cells in various forms of myocarditis, which provides a clear rationale for the diagnostic use of SSTR imaging in this patient group. [ABSTRACT FROM AUTHOR]

The mononuclear phagocyte system includes monocytes, macrophages, some dendritic cells, and multinuclear giant cells. These cell populations display marked heterogeneity depending on their differentiation from embryonic and bone marrow hematopoietic progenitors, tissue location, and activation. They contribute to tissue homeostasis by interacting with local and systemic immune and non-immune cells through trophic, clearance, and cytocidal functions. During evolution, they contributed to the innate host defense before effector mechanisms of specific adaptive immunity emerged. Mouse macrophages appear at mid-gestation and are distributed throughout the embryo to facilitate organogenesis and clear cells undergoing programmed cell death. Yolk sac, AGM, and fetal liver-derived tissue-resident macrophages persist throughout postnatal and adult life, supplemented by bone marrow-derived blood monocytes, as required after injury and infection. Nobel awards to Elie Metchnikoff and Paul Ehrlich in 1908 drew attention to cellular phagocytic and humoral immunity, respectively. In 2011, prizes were awarded to Jules Hoffmann and Bruce Beutler for contributions to innate immunity and to Ralph Steinman for the discovery of dendritic cells and their role in antigen presentation to T lymphocytes. We trace milestones in the history of mononuclear phagocyte research from the perspective of Nobel awards bearing directly and indirectly on their role in cellular immunity. [ABSTRACT FROM AUTHOR]

Simple Summary: Aspergillosis is an important fungal disease occurring in avian fauna, especially in birds kept in captivity. In Psittaciformes, severe disease occurs in the lungs and air sacs, with the development of white-to-yellow caseous nodules and plaques in the organs, in addition to greenish-grey fungal growth in the air sacs. Herein, we report the presence of disseminated infection with Aspergillus fumigatus in a 3-year-old male scarlet macaw parrot (Ara macao) that was presented to the Exotic Animal Clinic at the Faculty of Veterinary Medicine, Iași University of Life Sciences (Iași, Romania) for its postmortem examination. The confirmation of the fungal infection was achieved using histopathological, microbiological, and molecular methods. Since birds suffering from Aspergillus spp. do not always show respiratory issues, or their clinical signs are non-specific, this may create diagnostic difficulty for clinicians unfamiliar with the parrots' pathology. Therefore, for a definitive diagnosis, the demonstration of fungal presence by cytology or histopathology and its identification using culturing and molecular techniques is required. A 3-year-old male scarlet macaw parrot (Ara macao) was presented to the Exotic Animal Clinic at the Faculty of Veterinary Medicine, Iași University of Life Sciences (Iași, Romania) for its postmortem examination. According to the owner, the parrot had been raised only in captivity and after 5 days of inappetence, lethargy, and mild respiratory clinical signs, the parrot died. The post mortem examination revealed various-sized granulomas and caseous plaques in the lungs, air sacs, spleen, intestinal serosa, and liver. Microscopically, the granulomas were characterized by a necrotic center and the infiltration of numerous multinucleated giant cells and epithelioid-like cells and by the presence of hyphae typical of Aspergillus spp. Moreover, in the liver tissue, a diffuse inflammation, with numerous fungal hyphae, was noted. The fungal culture and the PCR assay allowed for the isolation and identification of Aspergillus fumigatus from the lung and liver samples. The macroscopical lesions and the histopathological findings, with the fungal isolation and molecular confirmation of Aspergillus fumigatus by nested PCR, provided the basis for the diagnosis of disseminated aspergillosis. To the authors' best knowledge, this is the first report of disseminated infection caused by Aspergillus fumigatus in a scarlet macaw parrot (Ara macao). [ABSTRACT FROM AUTHOR]

The objective of our study was to evaluate early and late macroscopic and histological changes associated with the use of polycaprolactone dermal filler (PCL) in the orofacial region. Forty-eight female Wistar rats were divided into the PCL group and the control group. The material was applied to the ventral tongue and submandibular region, and the animals were euthanized at three time points—24 h, and 30 and 90 days. In the PCL group, yellowish nodules were observed on the tongue at all experimental time points. At the 24 h mark, the histological analysis revealed the presence of the PCL and a predominance of lymphocytes, plasma cells, and neutrophils. At 30 and 90 days, macrophages and multinucleated giant cells predominated around the PCL spheres. Collagen density in the dermis was higher in the PCL group when compared to the control at 30 and 90 days. In the submandibular glands, an inflammatory process similar to that observed at other sites was noted, with no alterations in acinar or ductal morphology. The results of this study highlight the effectiveness of PCL as a collagen biostimulator. Nevertheless, the development of nodular lesions on the tongue signals the potential risk of complications in mobile anatomical structures. [ABSTRACT FROM AUTHOR]

In breast cancer, Targeted Axillary Dissection (TAD) allows for the selective excision of the sentinel lymph node (SLN) during primary tumor surgery. TAD consists of the resection of labelled SLNs prior to neoadjuvant chemotherapy (NACT). Numerous clinical and preclinical studies have explored the use of carbon-based colloids for SLN tattooing prior to NACT. However, carbon vectors show varying degrees of inflammatory reactions and, in about one fifth of cases, carbon particles migrate via the lymphatic pathway to other nodes, causing the SLN to mismatch the tattooed node. To overcome these limitations, in this study, we explored the use of melanin as a staining endogenous pigment. We synthesized and characterized melanin-loaded polymeric nanoparticles (Mel-NPs) and used them to tattoo lymph nodes in pig animal models given the similarity in the size of the human and pig nodes. Mel-NPs tattooed lymph nodes showed high identification rates, reaching 83.3% positive identification 16 weeks after tattooing. We did not observe any reduction in the identification as time increased, implying that the colloid is stable in the lymph node tissue. In addition, we performed histological and ultrastructural studies to characterize the biological behavior of the tag. We observed foreign-body-like granulomatous inflammatory responses associated with Mel-NPs, characterized by the formation of multinucleated giant cells. In addition, electron microscopy studies showed that uptake is mainly performed by macrophages, and that macrophages undergo cellular damage associated with particle uptake. [ABSTRACT FROM AUTHOR]

Hematoma clearance is critical for mitigating intracerebral hemorrhage (ICH)-induced brain injury. Multinucleated giant cells (MGCs), a type of phagocyte, and the complement system may play a pivotal role in hematoma resolution, but whether the complement system regulates MGC formation after ICH remains unclear. The current study investigated the following: (1) the characteristics of MGC formation after ICH, (2) whether it was impacted by complement C3 deficiency in mice and (3) whether it also influenced hematoma degradation (hemosiderin formation). Young and aged male mice, young female mice and C3-deficient and -sufficient mice received a 30 μL injection of autologous whole blood into the right basal ganglia. Brain histology and immunohistochemistry were used to examine MGC formation on days 3 and 7. Hemosiderin deposition was examined by autofluorescence on day 28. Following ICH, MGCs were predominantly located in the peri-hematoma region exhibiting multiple nuclei and containing red blood cells or their metabolites. Aging was associated with a decrease in MGC formation after ICH, while sex showed no discernible effect. C3 deficiency reduced MGC formation and reduced hemosiderin formation. Peri-hematomal MGCs may play an important role in hematoma resolution. Understanding how aging and complement C3 impact MGCs may provide important insights into how to regulate hematoma resolution. [ABSTRACT FROM AUTHOR]

Giant cell tumor of soft tissue (GCTST) is a locally aggressive mesenchymal neoplasm of intermediate malignancy that predominantly occurs in the superficial soft tissue of the extremities. It is histologically similar to a giant cell tumor of bone (GCTB) and shows a mixture of round to oval mononuclear cells and osteoclast-like multinucleated giant cells. Currently, immunohistochemistry plays a very limited role in the diagnosis of GCTST. Primary or secondary malignant GCTST has recently been described and tumors exhibiting high-grade histological features demonstrate higher rates of distant metastasis. GCTST lacks the H3-3A gene mutations that are identified in the vast majority of GCTBs, suggesting a different pathogenesis. Surgery is the standard treatment for localized GCTST. Incomplete surgical resection is usually followed by local recurrence. Radiation therapy may be considered when the close proximity of critical structures prevents microscopically negative surgical margins. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment for GCTST. In addition, we will discuss the differential diagnosis of this peculiar neoplasm. [ABSTRACT FROM AUTHOR]

Simple Summary: Buffalo are country animals, with great adaptability, and thrive in diverse environments. The State of Pará has the largest herd of buffalo in Brazil, which can be found mainly on Marajó Island in the northern region of the state. As a result, buffalo farming has become widespread in Brazil, and it offers several products to the consumer market. However, in the State of Pará, skin diseases stand out among the diseases that affect this species. This study reports the first case of dermatitis caused by Pelodera spp. in buffalo (Bubalus bubalis) on Marajó Island, Pará. This is the first report of parasitic granulomatous dermatitis caused by Pelodera spp. in a buffalo. The affected buffalo was about seven years old, was a female of the Murrah breed and belonged to a property located on Marajó Island in the State of Pará. During the clinical examination, the animal was in a standing position and presented several multifocal nodular and placoid masses throughout the body, mostly on the forelimbs, hindlimbs, abdomen, mammary glands, perineum, vulva and tail. These masses were also observed on the nasal mucosa, head, neck, back and chest. On macroscopic examination, the skin had several multifocal-to-coalescent sessile nodular and placoid lesions. Histopathology of the skin showed a marked reduction in the number of hair follicles. In the superficial dermis, there was significant multifocal-to-coalescent inflammatory infiltration, consisting of macrophages, epithelioid macrophages, lymphocytes, plasma cells and multinucleated giant cells. In the remaining hair follicles, there were numerous cross and longitudinal sections of small rhabditoid nematodes characterized by a thin cuticle, platymyarian musculature, an intestinal tract, a rhabditiform esophagus and lateral alae (morphologically compatible with Pelodera spp.). The diagnosis of parasitic dermatitis was confirmed by histopathological skin lesions associated with the presence of intralesional rhabditiform larvae morphologically compatible with Pelodera spp. [ABSTRACT FROM AUTHOR]

Ferrets are highly susceptible to a wide range of mycobacteria, mainly M. bovis, M. avium, and M. triplex. Therefore, ferrets pose a risk of transmission of mycobacteriosis, especially zoonotically relevant tuberculosis. The aim of this study was to describe the findings of M. xenopi mycobacteriosis in a pet ferret and emphasize its zoonotic potential. A pet ferret had a history of weight loss, apathy, hyporexia, and hair loss. Abdominal ultrasound revealed splenomegaly with two solid masses and cystic lesions of the liver. Fine-needle aspiration cytology revealed numerous acid-fast bacilli in epithelioid cells, thus leading to the suspicion of mycobacterial infection. Because of its poor general condition, the ferret was euthanized. Necropsy examination revealed generalized granulomatous lymphadenitis, pneumonia, myocarditis, splenitis, and hepatitis. Histologically, in all organs, there were multifocal to coalescing areas of inflammatory infiltration composed of epithelioid macrophages, a low number of lymphocytes, and plasma cells, without necrosis nor multinucleated giant cells. Ziehl–Neelsen staining detected the presence of numerous (multibacillary) acid-fast bacteria, which were PCR-typed as M. xenopi. This is the first study showing the antimicrobial susceptibility testing of M. xenopi in veterinary medicine, describing the resistance to doxycycline. Overall, our results could facilitate further diagnosis and provide guidelines for the treatment protocols for such infections. [ABSTRACT FROM AUTHOR]

This document discusses the importance of timing in biological processes and the challenges in understanding how cells and organisms measure and regulate time. It introduces a special issue that includes articles on various aspects of temporal regulation in cells, tissues, and organisms. The articles cover topics such as the regulation of the cell cycle, the timing of mitotic divisions, the duration of the S phase of the cell cycle, the interaction between circadian clocks and other factors, and the role of microRNAs in human endometrium development. The document emphasizes the relevance of studying time-related processes in the context of an aging population and the potential for future clinical therapies. [Extracted from the article]

Although cells of the myeloid lineages, including tissue macrophages and conventional dendritic cells, were rapidly recognized, in addition to CD4+ T lymphocytes, as target cells of HIV-1, their specific roles in the pathophysiology of infection were initially largely neglected. However, numerous studies performed over the past decade, both in vitro in cell culture systems and in vivo in monkey and humanized mouse animal models, led to growing evidence that macrophages play important direct and indirect roles as HIV-1 target cells and in pathogenesis. It has been recently proposed that macrophages are likely involved in all stages of HIV-1 pathogenesis, including virus transmission and dissemination, but above all, in viral persistence through the establishment, together with latently infected CD4+ T cells, of virus reservoirs in many host tissues, the major obstacle to virus eradication in people living with HIV. Infected macrophages are indeed found, very often as multinucleated giant cells expressing viral antigens, in almost all lymphoid and non-lymphoid tissues of HIV-1-infected patients, where they can probably persist for long period of time. In addition, macrophages also likely participate, directly as HIV-1 targets or indirectly as key regulators of innate immunity and inflammation, in the chronic inflammation and associated clinical disorders observed in people living with HIV, even in patients receiving effective antiretroviral therapy. The main objective of this review is therefore to summarize the recent findings, and also to revisit older data, regarding the critical functions of tissue macrophages in the pathophysiology of HIV-1 infection, both as major HIV-1-infected target cells likely found in almost all tissues, as well as regulators of innate immunity and inflammation during the different stages of HIV-1 pathogenesis. [ABSTRACT FROM AUTHOR]

Melioidosis, a severe tropical illness caused by Burkholderia pseudomallei, poses significant treatment challenges due to limited therapeutic options and the absence of effective vaccines. The pathogen's intrinsic resistance to numerous antibiotics and propensity to induce sepsis during acute infections further complicate management strategies. Thus, exploring alternative methods for prevention and treatment is crucial. Monoclonal antibodies (mAbs) have emerged as a promising strategy for the prevention and treatment of infectious diseases. This study focused on generating three mAbs (13F1, 14G11, and 15D9) targeting hemolysin-coregulated protein 1 (Hcp1), a protein involved in the type VI secretion system cluster 1 (T6SS1) of B. pseudomallei. Notably, pretreatment with 13F1 mAb significantly reduced the intracellular survival of B. pseudomallei and inhibited the formation of macrophage-derived multinucleated giant cells (MNGCs). This protective effect was also observed in vivo. We identified a sequence of amino acids (Asp95-Leu114) within Hcp1 as the likely binding site for 13F1 mAb. In summary, our findings reveal that 13F1 mAb counteracts infection by targeting Hcp1, offering potential new targets and insights for melioidosis prevention. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) melioidosis caused by Burkholderia pseudomallei is being increasingly reported. Because of the high mortality associated with CNS melioidosis, understanding the underlying mechanism of B. pseudomallei pathogenesis in the CNS needs to be intensively investigated to develop better therapeutic strategies against this deadly disease. The type VI secretion system (T6SS) is a multiprotein machine that uses a spring-like mechanism to inject effectors into target cells to benefit the infection process. In this study, the role of the T6SS accessory protein TagAB-5 in B. pseudomallei pathogenicity was examined using the human microglial cell line HCM3, a unique resident immune cell of the CNS acting as a primary mediator of inflammation. We constructed B. pseudomallei tagAB-5 mutant and complementary strains by the markerless allele replacement method. The effects of tagAB-5 deletion on the pathogenicity of B. pseudomallei were studied by bacterial infection assays of HCM3 cells. Compared with the wild type, the tagAB-5 mutant exhibited defective pathogenic abilities in intracellular replication, multinucleated giant cell formation, and induction of cell damage. Additionally, infection by the tagAB-5 mutant elicited a decreased production of interleukin 8 (IL-8) in HCM3, suggesting that efficient pathogenicity of B. pseudomallei is required for IL-8 production in microglia. However, no significant differences in virulence in the Galleria mellonella model were observed between the tagAB-5 mutant and the wild type. Taken together, this study indicated that microglia might be an important intracellular niche for B. pseudomallei, particularly in CNS infection, and TagAB-5 confers B. pseudomallei pathogenicity in these cells. [ABSTRACT FROM AUTHOR]

Hitherto, calcified aortic valves (AVs) and failing bioprosthetic heart valves (BHVs) have been investigated by similar approaches, mostly limited to various immunostaining techniques. Having employed multiple immunostaining combinations, we demonstrated that AVs retain a well-defined cellular hierarchy even at severe stenosis, whilst BHVs were notable for the stochastic degradation of the extracellular matrix (ECM) and aggressive infiltration by ECM-digesting macrophages. Leukocytes (CD45+) comprised ≤10% cells in the AVs but were the predominant cell lineage in BHVs (≥80% cells). Albeit cells with uncertain immunophenotype were rarely encountered in the AVs (≤5% cells), they were commonly found in BHVs (≥80% cells). Whilst cell conversions in the AVs were limited to the endothelial-to-mesenchymal transition (represented by CD31+α-SMA+ cells) and the formation of endothelial-like (CD31+CD68+) cells at the AV surface, BHVs harboured numerous macrophages with a transitional phenotype, mostly CD45+CD31+, CD45+α-SMA+, and CD68+α-SMA+. In contrast to immunostaining, which was unable to predict cell function in the BHVs, our whole-specimen, nondestructive electron microscopy approach (EM-BSEM) was able to distinguish between quiescent and matrix-degrading macrophages, foam cells, and multinucleated giant cells to conduct the ultrastructural analysis of organelles and the ECM, and to preserve tissue integrity. Hence, we suggest EM-BSEM as a technique of choice for studying the cellular landscape of BHVs. [ABSTRACT FROM AUTHOR]

A 75-year-old female with a history of stomach cancer and depression was referred to our hospital for left cervical lymphadenopathy. The biopsy of her left cervical lymph node revealed noncaseating granulomas with multinucleated giant cells. The positron emission tomography/computed tomography (PET/CT) indicated general lymphadenopathy (left supraclavicular left axillary, hepatic lymph nodes), except for the hilar lymph node. Both histology by transbronchial lung biopsy (TBLB) and analysis of broncho alveolar lavage fluid (BALF) were indicative of sarcoidosis. C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were increased in the sera. An alternative cause of granulomatous disease was ruled out, and on follow-up, she was diagnosed with sarcoidosis. Two years later, she was hospitalized for fever, anorexia, lymph node tenderness, and erythema nodosum with significant increases in CRP and sIL-2R. After admission, the repetitive axillary lymph biopsy showed the same histological findings as before, but the G-band staining showed clonal abnormalities. Bone marrow biopsy revealed abnormal lymphocytes with petal-like nuclei. Finally, she was diagnosed with malignant lymphoma infiltrating the bone marrow. After CHOP-based chemotherapy, her laboratory data, lymphadenopathy, and clinical findings improved, and she was discharged from the hospital on the 90th day. Careful medical treatment, including genetic analysis of the lymph node, is necessary in patients with sarcoidosis if lymphadenopathy is predominant. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a common and highly malignant primary tumor of the central nervous system in adults. Ever more recent papers are focusing on understanding the role of the tumor microenvironment (TME) in affecting tumorigenesis and the subsequent prognosis. We assessed the impact of macrophages in the TME on the prognosis in patients with recurrent GBM. A PubMed, MEDLINE and Scopus review was conducted to identify all studies dealing with macrophages in the GBM microenvironment from January 2016 to December 2022. Glioma-associated macrophages (GAMs) act critically in enhancing tumor progression and can alter drug resistance, promoting resistance to radiotherapy and establishing an immunosuppressive environment. M1 macrophages are characterized by increased secretion of proinflammatory cytokines, such as IL-1ß, tumor necrosis factor (TNF), IL-27, matrix metalloproteinase (MMPs), CCL2, and VEGF (vascular endothelial growth factor), IGF1, that can lead to the destruction of the tissue. In contrast, M2 is supposed to participate in immunosuppression and tumor progression, which is formed after being exposed to the macrophage M-CSF, IL-10, IL-35 and the transforming growth factor-ß (TGF-β). Because there is currently no standard of care in recurrent GBM, novel identified targeted therapies based on the complex signaling and interactions between the glioma stem cells (GSCs) and the TME, especially resident microglia and bone-marrow-derived macrophages, may be helpful in improving the overall survival of these patients in the near future. [ABSTRACT FROM AUTHOR]

Granuloma annulare (GA) is a benign, self-limiting granulomatous inflammatory disease that exhibits different histologic patterns. Infrequently, granuloma annulare can be associated with malignancy, the so-called malignancy-associated granuloma annulare (MGA). In this study, we aimed to compare the clinical and histopathological differences between GA and MGA. We retrospectively reviewed patient charts and identified 35 patients diagnosed with GA and concurrent hematological or solid organ malignancies as a case group. Additionally, we identified 33 patients without any known solid organ or hematological malignancy as a control group. MGA is commonly seen in the seventh decade of life, while GA affects the younger population. MGA is most commonly presented in the extremities of the body. The most common malignancy associated with MGA was chronic lymphocytic leukemia. Prostate cancer was the most common type of solid organ malignancy that was associated with MGA. The most common histopathological pattern seen in MGA was interstitial, comprising half of the cases. Multinucleated giant cells were present in half of the MGA cases and in most of the control group. In the literature, there are no established features that distinguish MGA from GA. Although MGA and GA have overlapping features, in our series, we found that the interstitial pattern was more common in MGA, while the necrobiotic pattern was more common in GA. [ABSTRACT FROM AUTHOR]

Although COVID-19 may cause various and multiorgan diseases, few research studies have examined the postmortem pathological findings of SARS-CoV-2-infected individuals who died. Active autopsy results may be crucial for understanding how COVID-19 infection operates and preventing severe effects. In contrast to younger persons, however, the patient's age, lifestyle, and concomitant comorbidities might alter the morpho-pathological aspects of the damaged lungs. Through a systematic analysis of the available literature until December 2022, we aimed to provide a thorough picture of the histopathological characteristics of the lungs in patients older than 70 years who died of COVID-19. A thorough search was conducted on three electronic databases (PubMed, Scopus, and Web of Science), including 18 studies and a total of 478 autopsies performed. It was observed that the average age of patients was 75.6 years, of which 65.4% were men. COPD was identified in an average of 16.7% of all patients. Autopsy findings indicated significantly heavier lungs, with an average weight of the right lung of 1103 g, while the left lung mass had an average weight of 848 g. Diffuse alveolar damage was a main finding in 67.2% of all autopsies, while pulmonary edema had a prevalence of between 50% and 70%. Thrombosis was also a significant finding, while some studies described focal and extensive pulmonary infarctions in 72.7% of elderly patients. Pneumonia and bronchopneumonia were observed, with a prevalence ranging from 47.6% to 89.5%. Other important findings described in less detail comprise hyaline membranes, the proliferation of pneumocytes and fibroblasts, extensive suppurative bronchopneumonic infiltrates, intra-alveolar edema, thickened alveolar septa, desquamation of pneumocytes, alveolar infiltrates, multinucleated giant cells, and intranuclear inclusion bodies. These findings should be corroborated with children's and adults' autopsies. Postmortem examination as a technique for studying the microscopic and macroscopic features of the lungs might lead to a better knowledge of COVID-19 pathogenesis, diagnosis, and treatment, hence enhancing elderly patient care. [ABSTRACT FROM AUTHOR]

Long term function of implantable biomaterials are determined by their integration with the host's body. Immune reactions against these implants could impair the function and integration of the implants. Some biomaterial-based implants lead to macrophage fusion and the formation of multinucleated giant cells, also known as foreign body giant cells (FBGCs). FBGCs may compromise the biomaterial performance and may lead to implant rejection and adverse events in some cases. Despite their critical role in response to implants, there is a limited understanding of cellular and molecular mechanisms involved in forming FBGCs. Here, we focused on better understanding the steps and mechanisms triggering macrophage fusion and FBGCs formation, specifically in response to biomaterials. These steps included macrophage adhesion to the biomaterial surface, fusion competency, mechanosensing and mechanotransduction-mediated migration, and the final fusion. We also described some of the key biomarkers and biomolecules involved in these steps. Understanding these steps on a molecular level would lead to enhance biomaterials design and improve their function in the context of cell transplantation, tissue engineering, and drug delivery. [ABSTRACT FROM AUTHOR]

Giant cell tumor of soft tissue (GCTST) is a defined disease entity that has a morphology similar to giant cell tumor of bone (GCTB). The malignant transformation of GCTST has not been reported, and a kidney primary is extremely rare. We report the case of a 77-year-old Japanese male, who was diagnosed with primary GCTST of the kidney and showed peritoneal dissemination, considered to be a malignant transformation of GCTST, in 4 years and 5 months. Histologically, the primary lesion showed characteristics of round cells with not prominent atypia, multi-nucleated giant cells, and osteoid formation, and carcinoma components were not found. The peritoneal lesion was characterized by osteoid formation and round to spindle-shaped cells, but differed in nuclear atypia, and multi-nucleated giant cells were not detected. Immunohistochemical and cancer genome sequence analysis suggested these tumors were sequential. This is a first report of a case that we could diagnose as primary GCTST of the kidney and could be determined as malignant transformation of GCTST in the clinical course. Analysis of this case will be examined in the future when genetic mutations and the disease concepts of GCTST are established. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian ageing is considered the major contributor to the age-related loss of fertility. Previous studies in mice evidenced the presence of a unique population of multinucleated giant cells in the stroma of the ovaries from older animals. Their presence correlated negatively with the ovarian follicle pool. The aims of the present work were to identify and characterize the presence of ovarian multinucleated giant cells in the goat and sheep ovary. The study of the ovarian morphology points to an age-related decrease in the primordial follicle pool, as observed in humans and mice. Additionally, with the aid of Sudan black B staining and autofluorescence detection, multinucleated giant cells were identified in the ovaries of mature females of both species. Implications of this research outcome are discussed, considering the presence of multinucleated giant cells in an age at which a decrease in reproductive potential is expected. Future studies should explore the potential mechanism and possible impairment on the ovarian function and, consequently, fertility. Ovarian ageing stands as the major contributor towards fertility loss. As such, there is an urge for studies addressing the mechanisms that promote ovarian ageing and new strategies aiming to delay it. Recently, the presence of a unique population of multinucleated giant cells has been identified in the ovaries of reproductively aged mice. These cells have been considered hallmarks of ovarian ageing. However, up to date multinucleated giant cells have only been described in the ovaries of the mice. Therefore, the aim of the present work was to evaluate and characterize the presence of such hallmarks of ovarian ageing in the sheep and the goat. In this study, ovaries from juvenile (6 months) and mature animals (18–24 months) were used. The hematoxylin and eosin technique was performed to describe the ovarian morphology and evaluate the ovarian follicle reserve pool. Sudan black B staining and the detection of autofluorescence emission were used to identify and characterize the presence of multinucleated giant cells. Statistical analyses were performed with GraphPad Prism 9.0.0. A decrease in the follicle reserve pool and the presence of multinucleated giant cells, with lipofuscin accumulation and the emission of autofluorescence, were observed in the ovaries of the mature animals of both species. Our results support the interest in the use of the ovine and the caprine model, that share physiological and pathophysiological characteristics with humans, in future studies addressing ovarian ageing. [ABSTRACT FROM AUTHOR]

The contractile cells of skeletal muscles, called myofibers, are elongated multinucleated syncytia formed and maintained by the fusion of proliferative myoblasts. Human myofibers can be hundreds of microns in diameter and millimeters in length. Myofibers are non-mitotic, obviating the need for microtubules in cell division. However, microtubules have been adapted to the unique needs of these cells and are critical for myofiber development and function. Microtubules in mature myofibers are highly dynamic, and studies in several experimental systems have demonstrated the requirements for microtubules in the unique features of muscle biology including myoblast fusion, peripheral localization of nuclei, assembly of the sarcomere, transport and signaling. Microtubule-binding proteins have also been adapted to the needs of the skeletal muscle including the expression of skeletal muscle-specific protein isoforms generated by alternative splicing. Here, we will outline the different roles microtubules play in skeletal muscle cells, describe how microtubule abnormalities can lead to muscle disease and discuss the broader implications for microtubule function. [ABSTRACT FROM AUTHOR]

The overall effect of senescence on cancer progression and cancer cell resistance to X-ray radiation (IR) is still not fully understood and remains controversial. How to induce tumor cell senescence and which senescent cell characteristics will ensure the safest therapeutic strategy for cancer treatment are under extensive investigation. While the evidence for passage number-related effects on malignant primary cells or cell lines is compelling, much less is known about how the changes affect safety and Senescence-Associated Secretory Phenotype (SASP), both of which are needed for the senescence cell-based vaccine to be effective against cancer. The present study aimed to investigate the effects of repeated passaging on the biological (self-renewal capacity and radioresistance) and functional (senescence) characteristics of the different populations of short- and long-term passaging glioblastoma multiforme (GBM) cells responding to senescence-inducing DNA-damaging IR stress. For this purpose, we compared radiobiological effects of X-ray exposure on two isogenic human U87 cell lines: U87L, minimally cultured cells (<15 passages after obtaining from the ATCC) and U87H, long-term cultured cells (>3 years of continuous culturing after obtaining from the ATCC). U87L cells displayed IR dose-related changes in the signs of IR stress-induced premature senescence. These included an increase in the proportion of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and concomitant decrease in the proportion of Ki67-positive cells and metabolically active cells. However, reproductive survival of irradiated short-term cultured U87L cells was higher compared to long-term cultured U87H cells, as the clonogenic activity results demonstrated. In contrast, the irradiated long-term cultured U87H cells possessed dose-related increases in the proportion of multinucleated giant cancer cells (MGCCs), while demonstrating higher radiosensitivity (lower self-renewal) and a significantly reduced fraction of DNA-replicating cells compared to short-term cultured U87L cells. Conditioned culture medium from U87H cells induced a significant rise of SA-β-Gal staining in U87L cells in a paracrine manner suggesting inherent SASP. Our data suggested that low-dose irradiated long-term cultured GBM cells might be a safer candidate for a recently proposed senescence cell-based vaccine against cancer. [ABSTRACT FROM AUTHOR]

To report our experience with the cases of TFEB rearranged RCC, with particular attention to the clinicopathological, immunohistochemical and molecular features of these tumors and to their predictive markers of response to therapy. We have retrieved the archives of 9749 renal cell carcinomas in the Institute of Urology, Peking University and found 96 rearranged RCCs between 2013 and 2022. Among these renal tumors, ten cases meet the morphologic, immunohistochemical and FISH characterization for TFEB rearranged RCC. The 10 patients' mean and median age is 34.9 and 34 years, respectively (range 23–55 years old), and the male to female ratio is 1:1.5. Macroscopically, these tumors generally have a round shape and clear boundary. They present with variegated, grayish yellow and grayish brown cut surface. The average maximum diameter of the tumor is 8.5 cm and the median 7.7 (ranged from 3.4 to 16) cm. Microscopically, the tumor is surrounded by a thick local discontinuous pseudocapsule. All tumors exhibit two types of cells: voluminous, clear and eosinophilic cytoplasm cells arranged in solid sheet, tubular growth pattern with local cystic changes, and papillary, pseudopapillary and compact nested structures are also seen in a few cases. Non-neoplastic renal tubules are entrapped in the tumor. A biphasic "rosette-like" pattern, psammomatous calcifications, cytoplasmic vacuolization, multinucleated giant cells and rhabdomyoid phenotype can be observed in some tumors. A few tumors may be accompanied by significant pigmentation or hemorrhage and necrosis. The nucleoli are equivalent to the WHO/ISUP grades 2–4. All tumors are moderately to strongly positive for Melan-A, TFEB, Vimentin and SDHB, and negative for CK7, CAIX, CD117, EMA, SMA, Desmin and Actin. CK20 and CK8/18 are weakly positive. In addition, AE1/AE3, P504s, HMB45 and CD10 are weakly moderately positive. TFE3 is moderately expressed in half of the cases. PAX8 can be negative, weakly positive or moderately-strongly positive. The therapy predictive marker for PD-L1 (SP263) is moderately to strongly positive membranous staining in all cases. All ten tumors demonstrate a medium frequency of split TFEB fluorescent signals ranging from 30 to 50% (mean 38%). In two tumors, the coincidence of the TFEB gene copy number gains are observed (3–5 fluorescent signals per neoplastic nuclei). Follow-up is available for all patients, ranging from 4 to 108 months (mean 44.8 and median 43.4 months). All patients are alive, without tumor recurrences or metastases. We described a group of TFEB rearranged RCC identified retrospectively in a large comprehensive Grade III hospital in China. The incidence rate was about 10.4% of rearranged RCCs and 0.1% of all the RCCs that were received in our lab during the ten-year period. The gross morphology, histological features, and immunohistochemistry of TFEB rearranged RCC overlapped with other types of RCC such as TFE3 rearranged RCC, eosinophilic cystic solid RCC, or epithelioid angiomyolipoma, making the differential diagnosis challenging. The diagnosis was based on TFEB fluorescence in situ hybridization. At present, most of the cases reported in the literature have an indolent clinical behavior, and only a small number of reported cases are aggressive. For this small subset of aggressive cases, it is not clear how to plan treatment strategies, or which predictive markers could be used to assess upfront responses to therapies. Between the possible options, immunotherapy currently seems a promising strategy, worthy of further exploration. In conclusion, we described a group of TFEB rearranged RCC identified in a large, comprehensive Grade III hospital in China, in the last 10 years. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to summarize and analyze the clinical data of intestinal tuberculosis (ITB) in order to provide guidance for accurate diagnosis and treatment of ITB. Methods: This study consecutively included patients with ITB who were admitted to our hospital from 2008 to 2021 and retrospectively analyzed their clinical features. Results: Forty-six patients were included. The most common clinical symptom was weight loss (67.4%). Seventy percent of 20 patients were positive for tuberculin skin test; 57.1% of 14 patients were positive for mycobacterium tuberculosis specific cellular immune response test, while 84.6% of 26 patients were positive for tuberculosis infection T cell spot test. By chest computed tomography (CT) examination, 25% and 5.6% of 36 patients were diagnosed with active pulmonary tuberculosis and with inactive pulmonary tuberculosis, respectively. By abdominal CT examination, the most common sign was abdominal lymph node enlargement (43.2%). Forty-two patients underwent colonoscopy, and the most common endoscopic manifestation was ileocecal ulcer (59.5%), followed by colonic ulcer (35.7%) and ileocecal valve deformity (26.2%). ITB most frequently involved the terminal ileum/ileocecal region (76.1%). Granulomatous inflammation with multinucleated giant cells and caseous necrosis was found via endoscopic biopsies, the ultrasound-guided percutaneous biopsy of enlarged mesentery lymph nodes, and surgical interventions. The acid-fast bacilli were discovered in 53.1% of 32 samples. Twenty-one cases highly suspected of ITB were confirmed after responding to empiric anti-tuberculosis therapy. Conclusions: It was necessary to comprehensively analyze clinical features to make an accurate diagnosis of ITB and aid in distinguishing ITB from diseases such as Crohn's disease and malignant tumors. [ABSTRACT FROM AUTHOR]

Radioresistance compromises the efficacy of radiotherapy for glioblastoma multiforme (GBM), the most devastating and common brain tumor. The present study investigated the relationship between radiation tolerance and formation of polyploid/multinucleated giant (PGCC/MGCC) and quiescent/senescent slow-cycling cancer cells in human U-87, LN-229, and U-251 cell lines differing in TP53/PTEN status and radioresistance. We found significant enrichment in MGCC populations of U-87 and LN-229 cell lines, and generation of numerous small mononuclear (called Raju cells, or RJ cells) U-87-derived cells that eventually form cell colonies, in a process termed neosis, in response to X-ray irradiation (IR) at single acute therapeutic doses of 2–6 Gy. For the first time, single-cell high-content imaging and analysis of Ki-67- and EdU-coupled fluorescence demonstrated that the IR exposure dose-dependently augments two distinct GBM cell populations. Bifurcation of Ki-67 staining suggests fast-cycling and slow-cycling populations with a normal-sized nuclear area, and with an enlarged nuclear area, including one resembling the size of PGCC/MGCCs, that likely underlie the highest radioresistance and propensity for repopulation of U-87 cells. Proliferative activity and anchorage-independent survival of GBM cell lines seem to be related to neosis, low level of apoptosis, fraction of prematurely stress-induced senescent MGCCs, and the expression of p63 and p73, members of p53 family transcription factors, but not to the mutant p53. Collectively, our data support the importance of the TP53wt/PTENmut genotype for the maintenance of cycling radioresistant U-87 cells to produce a significant amount of senescent MGCCs as an IR stress-induced adaptation response to therapeutic irradiation doses. [ABSTRACT FROM AUTHOR]

Simple Summary: Syngnathids are teleost fish that include seahorses (Hippocampus ssp.), pipefishes (Syngnathus spp.), common seadragons (Phyllopteryx taeniolatus) and leafy seadragons (Phycodurus eques). Some species are currently threatened. Reproduction and maintenance in aquariaare complicated and highly contagious diseases, such as mycobacteriosis, can trigger numerous casualties. The most frequently common species observed in fish are Mycobacterium marinum, M. fortuitum and M. chelonae, which belong to the group of non-tuberculous mycobacteria. Stress factors, poor water quality, bad management and high population densities are associated with a higher prevalence of this disease. This study describes the clinical signs and granulomatous lesions associated with mycobacteriosis in syngnathids. M. fortuitum and Mycobacterium spp. were isolated in 4 and 14 syngnathids, respectively. Seven samples were positive against M. chelonae and M. marinum common primers. Considering the scarcity of pathological studies in syngnathids, these findings can help to improve the clinical management and survival of these animals in captivity. Mycobacteriosis is an important disease that affects captive and wild aquatic fish. Syngnathids are susceptible to infection by non-tuberculous mycobacteria. The aim of this study was to describe clinical signs, and macroscopic and histological lesions in 25 syngnathids and the molecular characterization of the causative mycobacteria. Clinical presentation ranged from sudden death to non-specific signs, including anorexia, poor body condition, weight loss and marked dyspnea with increased respiratory effort and rate. Gross lesions were mostly ulcers on the tail and small white nodules in the liver, coelomic cavity and inside the eye. The most affected organs were gills, liver, intestine and coelomic mesentery. Microscopic lesions consisted of areas of multifocal to diffuse granulomatous inflammation and bacterial emboli with numerous intralesional acid-fast bacilli. Epithelioid cells, multinucleated giant cells, lymphocytes and fibrous connective tissue, which are commonly observed in granulomatous inflammation, were not observed here. In the real-time PCR, M. fortuitum, M. chelonae and M. marinum common primers, Mycobacterium spp. were detected in 4, 7 and 14 individuals, respectively. In addition, this is the first description of mycobacteriosis found in Syngnathus acus. [ABSTRACT FROM AUTHOR]

Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure. [ABSTRACT FROM AUTHOR]

Bone defects have prompted the development of biomaterial-based bone substitutes for restoring the affected tissue completely. Although many biomaterials have been designed and evaluated, the combination of properties required in a biomaterial for bone tissue engineering still poses a challenge. In this study, a chitosan–silica-based biocomposite was synthetized, and its physicochemical characteristics and biocompatibility were characterized, with the aim of exploring the advantages and drawbacks of its use in bone tissue engineering. Dynamic light scattering measurements showed that the mean hydrodynamic size of solid silica particles (Sol-Si) was 482 ± 3 nm. Scanning electron microscopy of the biocomposite showed that Sol-Si were homogenously distributed within the chitosan (CS) matrix. The biocomposite swelled rapidly and was observed to have no cytotoxic effect on the [3T3] cell line within 24 h. Biocompatibility was also analyzed in vivo 14 days post-implant using a murine experimental model (Wistar rats). The biocomposite was implanted in the medullary compartment of both tibiae (n = 12). Histologically, no acute inflammatory infiltrate or multinucleated giant cells associated to the biocomposite were observed, indicating good biocompatibility. At the tissue–biocomposite interface, there was new formation of woven bone tissue in close contact with the biocomposite surface (osseointegration). The new bone formation may be attributed to the action of silica. Free silica particles originating from the biocomposite were observed at the tissue–biocomposite interface. According to our results, the biocomposite may act as a template for cellular interactions and extracellular matrix formation, providing a structural support for new bone tissue formation. The CS/Sol-Si biocomposite may act as a Si reservoir, promoting new bone formation. A scaffold with these properties is essential for cell differentiation and filling a bone defect. [ABSTRACT FROM AUTHOR]

Random electrospun three-dimensional fiber membranes mimic the extracellular matrix and the interfibrillar spaces promotes the flow of nutrients for cells. Electrospun PLGA membranes were analyzed in vitro and in vivo after being sterilized with gamma radiation and bioactivated with fibronectin or collagen. Madin-Darby Canine Kidney (MDCK) epithelial cells and primary fibroblast-like cells from hamster's cheek paunch proliferated over time on these membranes, evidencing their good biocompatibility. Cell-free irradiated PLGA membranes implanted on the back of hamsters resulted in a chronic granulomatous inflammatory response, observed after 7, 15, 30 and 90 days. Morphological analysis of implanted PLGA using light microscopy revealed epithelioid cells, Langhans type of multinucleate giant cells (LCs) and multinucleated giant cells (MNGCs) with internalized biomaterial. Lymphocytes increased along time due to undegraded polymer fragments, inducing the accumulation of cells of the phagocytic lineage, and decreased after 90 days post implantation. Myeloperoxidase+ cells increased after 15 days and decreased after 90 days. LCs, MNGCs and capillaries decreased after 90 days. Analysis of implanted PLGA after 7, 15, 30 and 90 days using transmission electron microscope (TEM) showed cells exhibiting internalized PLGA fragments and filopodia surrounding PLGA fragments. Over time, TEM analysis showed less PLGA fragments surrounded by cells without fibrous tissue formation. Accordingly, MNGC constituted a granulomatous reaction around the polymer, which resolves with time, probably preventing a fibrous capsule formation. Finally, this study confirms the biocompatibility of electrospun PLGA membranes and their potential to accelerate the healing process of oral ulcerations in hamsters' model in association with autologous cells. [ABSTRACT FROM AUTHOR]

In the last decade, there has been a tremendous revival of interest in monocyte and macrophages. He showed in the rat model that aging increases the number of M1 (CD68+) and M2 (CD163+) macrophages in the liver and that both macrophage subtypes stored iron. Iron was suggested to shift macrophage phenotype to the M2 subtype, but its effect on macrophage proliferation was unknown. Chronic low-grade inflammation involving macrophage activity promotes the development of another inflammatory disease, i.e., osteoarthritis (OA). [Extracted from the article]

Simple Summary: Neurological melioidosis, caused by Burkholderiapseudomallei, can lead to the development of severe symptoms associated with the nervous system. However, the pathogenic mechanism through which this bacterium infects neuronal cells has not been studied. This study showed that B. pseudomallei can infect human neuronal SH-SY5Y cells in vitro. Cycle-inhibiting factor (Cif), a type III secreted effector, is one of the virulence factors produced by B. pseudomallei upon infection. The B. pseudomallei cif-deleted mutant reduced the ability to invade neuronal cells compared with the parental strain. Our finding indicates that Cif is associated with B. pseudomallei invasion of human neuronal cells. Burkholderia pseudomallei is a pathogenic bacterium that causes human melioidosis, which is associated with a high mortality rate. However, the underlying mechanisms of B. pseudomallei pathogenesis are largely unknown. In this study, we examined the infection of human neuronal SH-Sy5y cells by several clinically relevant B. pseudomallei strains. We found that all tested B. pseudomallei strains can invade SH-Sy5y cells, undergo intracellular replication, cause actin-tail formation, and form multinucleated giant cells. Additionally, a deletion mutant of B. pseudomallei cycle-inhibiting factor (cif) was constructed that exhibited reduced invasion in SH-Sy5y cells. Complementation of cif restored invasion of the B. pseudomallei cif-deleted mutant. Our findings enhance understanding of B. pseudomallei pathogenicity in terms of the virulence factor Cif and demonstrate the function of Cif in neurological melioidosis. This may eventually lead to the discovery of novel targets for treatment and a strategy to control the disease. [ABSTRACT FROM AUTHOR]

Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell subsets, B cells, plasma cells, dendritic cells and mycobacterial antigen were labelled by immunohistochemistry, and lipids and acid-fast bacteria (AFB) were labelled by specific staining. Granulomas with central caseous necrosis developed at the injection site of most goats though lesion size and extent of necrosis differed between vaccine strains. CD4+ T and B cells were more scarce and CD8+ cells were more numerous in granulomas induced by recombinant derivatives compared to their parental BCG strain. Further, the numbers of MNGCs and cells with lipid bodies were markedly lower in groups administered with recombinant BCG strains. Microscopic detection of AFB and mycobacterial antigen was rather frequent in the area of central necrosis, however, the isolation of bacteria in culture was rarely successful. In summary, BCG and its recombinant derivatives induced reproducibly subcutaneous caseous granulomas in goats that can be easily monitored and surgically removed for further studies. The granulomas reflected the genetic modifications of the recombinant BCG-derivatives and are therefore suitable models to compare reactions to different mycobacteria or TB vaccines. [ABSTRACT FROM AUTHOR]

In people living with HIV, Mycobacterium tuberculosis (Mtb) is the major cause of death. Due to the increased morbidity/mortality in co-infection, further research is urgently required. A limiting factor to research in HIV and HIV/Mtb co-infection is the lack of accessible in vivo models. Next-generation humanized mice expressing HLA transgenes report improved human immune reconstitution and functionality, which may better recapitulate human disease. This study compares well-established huNRG mice and next-generation HLA I/II-transgenic (huDRAG-A2) mice for immune reconstitution, disease course, and pathology in HIV and TB. HuDRAG-A2 mice have improved engraftment of key immune cell types involved in HIV and TB disease. Upon intravaginal HIV-1 infection, both models developed significant HIV target cell depletion in the blood and tissues. Upon intranasal Mtb infection, both models sustained high bacterial load within the lungs and tissue dissemination. Some huDRAG-A2 granulomas appeared more classically organized, characterized by focal central necrosis, multinucleated giant cells, and foamy macrophages surrounded by a halo of CD4+ T cells. HIV/Mtb co-infection in huNRG mice trended towards worsened TB pathology and showed potential for modeling co-infection. Both huNRG and huDRAG-A2 mice are viable options for investigating HIV and TB, but the huDRAG-A2 model may offer advantages. [ABSTRACT FROM AUTHOR]

Simple Summary: Aging is a progressive decline of an organism over time. In contrast, senescence occurs throughout an organism's lifespan. It is a cell-cycle arrest preventing the proliferation of damaged cells. Cellular and molecular senescence timing is crucial for the pace of aging and disease development and progression. The accumulation of senescent cells during a lifespan leads to organismal senescence. Senescent multinucleated giant cells are present in many age-related diseases and cancer. Although senescence was assumed to be irreversible, studies now show that senescent multinucleated giant cells overcome senescence in various cancers, becoming the source of highly aggressive mononucleated stem-like cells, which divide and initiate tumor development and progression. This review introduces the subject of senescence, aging, and the formation of senescent multinucleated giant cells. We define senescence and aging and describe how molecular and cellular senescence leads to organismal senescence. We review the latest information on senescent cells' cellular and molecular phenotypes. We describe molecular and cellular features of aging and senescence and the role of multinucleated giant cells in aging-related conditions and cancer. We explain how multinucleated giant cells form and their role in aging arteries and gonads. We also describe how multinucleated giant cells and the reversibility of senescence initiate cancer and lead to cancer progression and metastasis. We also describe molecules and pathways regulating aging and senescence in model systems and their applicability to clinical therapies in age-related diseases. [ABSTRACT FROM AUTHOR]

Polyoxometalate nanoparticles (POMs) are a class of compounds made up of multiple transition metals linked together using oxygen atoms. POMs commonly include group 6 transition metals, with two of the most common forms using molybdenum and tungsten. POMs are suggested to exhibit antimicrobial effects. In this study, we developed two POM preparations to study anti-cancer activity. We found that Mo-POM (NH4)Mo7O24) and W-POM (H3PW12O40) have anti-cancer effects on glioblastoma cells. Both POMs induced morphological changes marked by membrane swelling and the presence of multinucleated cells that may indicate apoptosis induction along with impaired cell division. We also observed significant increases in lipid oxidation events, suggesting that POMs are redox-active and can catalyze detrimental oxidation events in glioblastoma cells. Here, we present preliminary indications that molybdenum polyoxometalate nanoparticles may act like ferrous iron to catalyze the oxidation of phospholipids. These preliminary results suggest that Mo-POMs (NH4)Mo7O24) and W-POMs (H3PW12O40) may warrant further investigation into their utility as adjunct cancer therapies. [ABSTRACT FROM AUTHOR]

Osteoclasts are multinucleated bone-resorbing cells that are formed by the fusion of macrophages. Recently, we identified Rab44, a large Rab GTPase, as an upregulated gene during osteoclast differentiation that negatively regulates osteoclast differentiation. However, the molecular mechanisms by which Rab44 negatively regulates osteoclast differentiation remain unknown. Here, we found that the GDP form of Rab44 interacted with the actin-binding protein, Coronin1C, in murine macrophages. Immunoprecipitation experiments revealed that the interaction of Rab44 and Coronin1C occurred in wild-type and a dominant-negative (DN) mutant of Rab44, but not in a constitutively active (CA) mutant of Rab44. Consistent with these findings, the expression of the CA mutant inhibited osteoclast differentiation, whereas that of the DN mutant enhanced this differentiation. Using a phase-contrast microscope, Coronin1C-knockdown osteoclasts apparently impaired multinuclear formation. Moreover, Coronin1C knockdown impaired the migration and chemotaxis of RAW-D macrophages. An in vivo experimental system demonstrated that Coronin1C knockdown suppresses osteoclastogenesis. Therefore, the decreased cell formation and fusion of Coronin1C-depleted osteoclasts might be due to the decreased migration of Coronin1C-knockdown macrophages. These results indicate that Coronin1C is a GDP-specific Rab44 effector that controls osteoclast formation by regulating cell motility in macrophages. [ABSTRACT FROM AUTHOR]

Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte–macrophage lineage are highly fusogenic. They create syncytial multinucleated giant cells (MGCs) such as osteoclasts (OCs), MGCs associated with the areas of infection/inflammation, and foreign body-induced giant cells (FBGCs). The fusion of monocytes/macrophages with tumor cells may promote cancer metastasis. We describe types and examples of monocyte–macrophage lineage cell fusion and the role of actin-based structures in cell fusion. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung inflammation is commonly assessed in asthmatic horses by bronchoalveolar lavage fluid (BALF) cytology. Among the cell types commonly found in equine BALF samples, macrophages are the most abundant. The clinical significance of the abnormal cytological appearance of macrophages in samples from diseased horses is largely disregarded. The present work focuses on cytological alterations observed in macrophages during a chronic inflammatory disease such as equine asthma. Our data, although limited in number, support macrophage fusion (resulting in multinucleated giant cells) as a mechanism of interest in the classification of equine asthma phenotypes, as it was significantly associated with the inflammatory signature and chronicity of the disease. Equine asthma is currently diagnosed by the presence of increased neutrophil (>5%), mast cell (>2%), and/or eosinophil (>1%) differential cell count. Macrophages are normal resident cells within the alveoli. Their presence in BALF is considered normal, but the clinical implication of the presence of activated or fused macrophages (giant multinucleated cells, GMC) is currently overlooked. We aimed to assess the prevalence, cytological determinants, and clinical significance of increased GMC counts in BALF of 34 asthmatic horses compared to 10 controls. Counts were performed on 15 randomly selected high magnification fields per cytospin slide (40×), and expressed as GMC:single macrophage (GMC:M) ratio. Regression models were used for statistical analysis. GMC was frequently observed in both asthmatic and control horses, with an increased prevalence of equine asthma (p = 0.01). GMC:M ratio was significantly higher in severe vs. mild to moderate equine asthmatic and control horses. In asthmatic horses, an increased GMC:M ratio was significantly associated with BALF mastocytosis (p = 0.01), once adjusting for age and the presence and severity of clinical signs of the horses. Tachypnea was the only clinical sign that tended to be positively associated with GMC:M ratio after adjustment (p = 0.08). In conclusion, our data suggest that a relationship might exist between molecular mechanisms regulating GMC formation and mast cell recruitment in the equine lung. The same mechanisms could lead to tachypnea even in the absence of respiratory effort at rest. We suggest including GMC count in the basic cytological assessment of BALF samples to gain more insights into their role in equine asthma. [ABSTRACT FROM AUTHOR]

Osteo-conductive bone substitute materials are required in dentistry. In this study, highly pressed nano-hydroxyapatite/collagen (P-nHAP/COL) composites were formed by a hydraulic press. Critical-size bone defects (Φ = 6 mm) were made in the cranial bones of 10-week-old Wistar rats, in which P-nHAP/COL and pressed collagen (P-COL) specimens were implanted. Defect-only samples (DEF) were also prepared. After the rats had been nourished for 3 days, 4 weeks, or 8 weeks, ossification of the cranial defects of the rats was evaluated by micro-computed tomography (micro-CT) (n = 6 each). Animals were sacrificed at 8 weeks, followed by histological examination. On micro-CT, the opacity of the defect significantly increased with time after P-nHAP/COL implantation (between 3 days and 8 weeks, p < 0.05) due to active bone regeneration. In contrast, with P-COL and DEF, the opacity increased only slightly with time after implantation, indicating sluggish bone regeneration. Histological inspections of the defect zone implanted with P-nHAP/COL indicated the adherence of multinucleated giant cells (osteoclasts) to the implant with phagocytosis and fragmentation of P-nHAP/COL, whereas active bone formation occurred nearby. Fluorescent double staining indicated dynamic bone-formation activities. P-nHAP/COL is strongly osteo-conductive and could serve as a useful novel bone substitute material for future dental implant treatments. [ABSTRACT FROM AUTHOR]

The ossifying variant and the granular cell variant are rare subtypes of cutaneous fibrous histiocytoma (CFH), characterized by islands of mature metaplastic bone tissue rimmed by multinucleated osteoclast-like giant cells and by large-sized cells with granular cytoplasm and mildly hyperchromatic nuclei with inconspicuous nucleoli, respectively. We herein present two cases of these unusual CFH variants in a 37-year-old woman and in a 38-year-old man, respectively. The main differential diagnoses, including both benign and malignant lesions, are also discussed. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapy is the therapy of choice for epithelial ovarian cancer (EOC). Acquired resistance to platinum (PT) is a frequent event that leads to disease progression and predicts poor prognosis. To understand possible mechanisms underlying acquired PT-resistance, we have recently generated and characterized three PT-resistant isogenic EOC cell lines. Here, we more deeply characterize several PT-resistant clones derived from MDAH-2774 cells. We show that, in these cells, the increased PT resistance was accompanied by the presence of a subpopulation of multinucleated giant cells. This phenotype was likely due to an altered progression through the M phase of the cell cycle and accompanied by the deregulated expression of genes involved in M phase progression known to be target of mutant TP53. Interestingly, we found that PT-resistant MDAH cells acquired in the TP53 gene a novel secondary mutation (i.e., S185G) that accompanied the R273H typical of MDAH cells. The double p53S185G/R273H mutant increases the resistance to PT in a TP53 null EOC cellular model. Overall, we show how the selective pressure of PT is able to induce additional mutation in an already mutant TP53 gene in EOC and how this event could contribute to the acquisition of novel cellular phenotypes. [ABSTRACT FROM AUTHOR]

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)--upon infection--to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls the autophagic flux. This enables the virus to maximize its replication and attenuate the innate immune responses that it activates. In this review, we discuss the relationship between HCV and autophagy, and the crosstalk between HCV-induced autophagy and host innate immune responses. [ABSTRACT FROM AUTHOR]

Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Loss of wild-type p53 function is widely accepted to be permissive for the development of multinucleated giant cells. However, whether therapy-induced multinucleation is associated with cancer cell death or survival remains controversial. Herein, we demonstrate that exposure of p53-deficient or p21WAF1 (p21)-deficient solid tumor-derived cell lines to ionizing radiation (between 2 and 8 Gy) results in the development of multinucleated giant cells that remain adherent to the culture dish for long times post-irradiation. Somewhat surprisingly, single-cell observations revealed that virtually all multinucleated giant cells that remain adherent for the duration of the experiments (up to three weeks post-irradiation) retain viability and metabolize 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), and the majority (>60%) exhibit DNA synthesis. We further report that treatment of multinucleated giant cells with pharmacological activators of apoptosis (e.g., sodium salicylate) triggers their demise. Our observations reinforce the notion that radiation-induced multinucleation may reflect a survival mechanism for p53/p21-deficient cancer cells. With respect to evaluating radiosensitivity, our observations underscore the importance of single-cell experimental approaches (e.g., single-cell MTT) as the creation of viable multinucleated giant cells complicates the interpretation of the experimental data obtained by commonly-used multi-well plate colorimetric assays. [ABSTRACT FROM AUTHOR]

Implant therapy using osseointegratable titanium (Ti) dental implants has revolutionized clinical dental practice and has shown a high rate of success. However, because a metallic implant is in contact with body tissues and fluids in vivo, ions/particles can be released into the biological milieu as a result of corrosion or biotribocorrosion. Ultrananocrystalline diamond (UNCD) coatings possess a synergistic combination of mechanical, tribological, and chemical properties, which makes UNCD highly biocompatible. In addition, because the UNCD coating is made of carbon (C), a component of human DNA, cells, and molecules, it is potentially a highly biocompatible coating for medical implant devices. The aim of the present research was to evaluate tissue response to UNCD-coated titanium micro-implants using a murine model designed to evaluate biocompatibility. Non-coated (n = 10) and UNCD-coated (n = 10) orthodontic Ti micro-implants were placed in the hematopoietic bone marrow of the tibia of male Wistar rats. The animals were euthanized 30 days post implantation. The tibiae were resected, and ground histologic sections were obtained and stained with toluidine blue. Histologically, both groups showed lamellar bone tissue in contact with the implants (osseointegration). No inflammatory or multinucleated giant cells were observed. Histomorphometric evaluation showed no statistically significant differences in the percentage of BIC between groups (C: 53.40 ± 13% vs. UNCD: 58.82 ± 9%, p > 0.05). UNCD showed good biocompatibility properties. Although the percentage of BIC (osseointegration) was similar in UNCD-coated and control Ti micro-implants, the documented tribological properties of UNCD make it a superior implant coating material. Given the current surge in the use of nano-coatings, nanofilms, and nanostructured surfaces to enhance the biocompatibility of biomedical implants, the results of the present study contribute valuable data for the manufacture of UNCD coatings as a new generation of superior dental implants. [ABSTRACT FROM AUTHOR]

Injectable bone substitutes (IBS) are increasingly being used in the fields of orthopedics and maxillofacial/oral surgery. The rheological properties of IBS allow for proper and less invasive filling of bony defects. Vaterite is the most unstable crystalline polymorph of calcium carbonate and is known to be able to transform into hydroxyapatite upon contact with an organic fluid (e.g., interstitial body fluid). Two different concentrations of hydrogels based on poly(ethylene glycol)-acetal-dimethacrylat (PEG-a-DMA), i.e., 8% (w/v) (VH-A) or 10% (w/v) (VH-B), were combined with vaterite nanoparticles and implanted in subcutaneous pockets of BALB/c mice for 15 and 30 days. Explants were prepared for histochemical staining and immunohistochemical detection methods to determine macrophage polarization, and energy-dispersive X-ray analysis (EDX) to analyze elemental composition was used for the analysis. The histopathological analysis revealed a comparable moderate tissue reaction to the hydrogels mainly involving macrophages. Moreover, the hydrogels underwent a slow cellular infiltration, revealing a different degradation behavior compared to other IBS. The immunohistochemical detection showed that M1 macrophages were mainly found at the material surfaces being involved in the cell-mediated degradation and tissue integration, while M2 macrophages were predominantly found within the reactive connective tissue. Furthermore, the histomorphometrical analysis revealed balanced numbers of pro- and anti-inflammatory macrophages, demonstrating that both hydrogels are favorable materials for bone tissue regeneration. Finally, the EDX analysis showed a stepwise transformation of the vaterite particle into hydroxyapatite. Overall, the results of the present study demonstrate that hydrogels including nano-vaterite particles are biocompatible and suitable for bone tissue regeneration applications. [ABSTRACT FROM AUTHOR]

Distribution of different types of atherosclerotic lesions in the arterial wall is not diffuse, but is characterized by mosaicism. The causes of such distribution remain to be established. At the early stages of atherogenesis, low-density lipoprotein (LDL) particles and immune cells penetrate into the intimal layer of the arterial wall through the endothelium. In adult humans, the luminal surface of the arterial wall is a heterogeneous monolayer of cells with varying morphology including typical endothelial cells (ECs) and multinucleated variant endothelial cells (MVECs). We hypothesized that distribution of MVECs in the endothelial monolayer can be related to the distribution pattern of early atherosclerotic lesions. We obtained en face preparations of intact adult (22–59 years old) aortic wall sections that allowed us to study the endothelial monolayer and the subendothelial layer. We compared the distribution of MVECs in the endothelial monolayer with the localization of early atherosclerotic lesions in the subendothelial layer, which were characterized by lipid accumulation and immune cell recruitment. In primary culture, MVECs demonstrated increased phagocytic activity compared to mononuclear ECs. Moreover, we have shown that unaffected aortic intima contained associates formed as a result of aggregation and/or fusion of LDL particles that are non-randomly distributed. This indicated that MVECs may be involved in the accumulation of LDL in the subendothelial layer through increased transcytosis. Interaction of LDL with subendothelial cells of human aorta in primary culture increased their adhesive properties toward circulating immune cells. Study of unaffected aortic intima revealed non-random distribution of leukocytes in the subendothelial layer and increased localization of CD45+ leukocytes in the subendothelial layer adjacent to MVECs. Together, our observations indicate that MVECs may be responsible for the distribution of atherosclerotic lesions in the arterial wall by participating in LDL internalization and immune cell recruitment. [ABSTRACT FROM AUTHOR]