Search Results (98)

Thanatosomes (hyaline globules or death bodies) are histologically observed in various non-neoplastic and neoplastic conditions. Some of these globules are associated with apoptotic cell death. Only six documented cases of thanatosomes have been reported in breast tumors. In this rare case involving a 64-year-old Japanese woman diagnosed as having rectal cancer, preoperative computed tomography scanning revealed breast cancer in her right breast. Following a right total mastectomy, a tumor characterized as apocrine carcinoma (carcinoma with apocrine differentiation) containing thanatosomes was discovered. These globules are PAS positive and diastase resistant, exhibit deep fuchsinophilic staining with Masson’s trichrome, stain dark blue with PTAH, and are negative for mucin by Alcian blue. The tumor cells tested positive for the androgen receptor, FOXA1, and GCDFP15. Human epidermal growth factor type 2 (HER2)/neu score was 3+/positive, and the Ki-67 labeling index was 60%. Thus, the tumor represented high-grade, HER2-enriched apocrine carcinoma. Thanatosomes are immunoreactive to cleaved caspase-3 and are histological markers of high cell turnover and apoptotic cell death. Therefore, in this nonspecific microscopic neoplastic condition, they are typically linked to high-grade tumors, as this case showed. This report presents a rare case of apocrine breast cancer featuring a limited number of thanatosomes. Full article

α7 nAChRs are known to modulate several physiological and pathological functions in glial cells, and their selective activation might have anti-inflammatory effects in the central and peripheral nervous system. OL progenitors (OPCs) respond to cholinergic stimuli via muscarinic receptors that are mainly involved in the modulation of their proliferation. Conversely, the role of nicotinic receptors, particularly α7 nAChRs, has been poorly investigated. In this study, we evaluated the expression of α7 nAChRs in a model of OPCs (Oli neu) and the potential effects mediated by their selective activation. Methods: Oli neu cells were used as a murine immortalized OPCs model. The effects of α7 nAChRs stimulation on cell proliferation and survival were assessed by the MTT assay. RT-PCR and Western blot analysis were used to analyze the expression of α7 nAChRs and proliferative and differentiative markers (PCNA, MBP). LPS exposure was used to induce the environment in which the antioxidant and anti-inflammatory properties of α7 nAChRs were analyzed, evaluating NFR2 and TNF-α expression, ROS levels through DCFDA staining while Oil Red O staining was used for the analysis of lipid droplet content as a marker of cellular inflammation response. Results: The α7 nAChR is expressed both in OPCs and OLs, and its stimulation by the selective agonist ICH3 increases cell proliferation without modifying the OLs’ differentiation capability. Moreover, ICH3 showed anti-inflammatory and antioxidant effects against LPS exposure. Conclusions: The results herein obtained confirm the role of α7 nAChR in the modulation of neuroinflammatory processes as well as their protective effects on OLs. Full article

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is marked by the pathological accumulation of amyloid-β plaques and tau neurofibrillary tangles, both of which disrupt neuronal communication and function. Emerging evidence highlights the role of extracellular vesicles (EVs) as key mediators of intercellular communication, particularly in the propagation of pathological proteins in AD. Among the regulatory factors influencing EV composition and function, neuraminidase 1 (NEU1), a lysosomal sialidase responsible for desialylating glycoproteins has gained attention for its involvement in EV glycosylation. This review explores the role of NEU1 in modulating EV glycosylation, with particular emphasis on its influence on immune modulation and intracellular trafficking pathways and the subsequent impact on intercellular signaling and neurodegenerative progression. Altered NEU1 activity has been associated with abnormal glycan profiles on EVs, which may facilitate the enhanced spread of amyloid-β and tau proteins across neural networks. By regulating glycosylation, NEU1 influences EV stability, targeting and uptake by recipient cells, primarily through the desialylation of surface glycoproteins and glycolipids, which alters the EV charge, recognition and receptor-mediated interactions. Targeting NEU1 offers a promising therapeutic avenue to restore EV homeostasis and reduces pathological protein dissemination. However, challenges persist in developing selective NEU1 inhibitors and effective delivery methods to the brain. Furthermore, altered EV glycosylation patterns may serve as potential biomarkers for early AD diagnosis and monitoring. Overall, this review highlights the importance of NEU1 in AD pathogenesis and advocates for deeper investigation into its regulatory functions, with the aim of advancing therapeutic strategies and biomarker development for AD and related neurological disabilities. Full article

Integrin αV (IαV) and the urokinase-type plasminogen activator receptor (uPAR) are key mediators of tumor malignancy in Glioblastoma. This study aims to characterize IαV/uPAR interaction in GBM and investigate the role played by glycans in this scenario. Protein expression and interaction were confirmed via confocal microscopy and co-immunoprecipitation. The role of N-glycosylation was evaluated using Swainsonine (SW) and PNGase F. IαV glycoproteomic analysis was performed by mass spectrometry. Sialic acids and glycan structures in IαV/uPAR interaction were tested using neuraminidase A (NeuA) and lectin interference assays, respectively. Protein expression and their interaction were detected in GBM cells, but not in low-grade glioma cells, even in cells transfected to overexpress uPAR. SW, PNGase, and NeuA treatments significantly reduced IαV/uPAR interaction. Also, lectin interference assays indicated that β1-6 branched glycans play a crucial role in this interaction. Analysis of the IαV glycosylation profile revealed the presence of complex and hybrid N-glycans in GBM, while only oligomannose N-glycans were identified in low-grade glioma. N-glycosylation inhibition and sialic acid removal reduced AKT phosphorylation. Our findings demonstrate, for the first time, the interaction between IαV and uPAR in GBM cells, highlighting the essential role of N-glycosylation, particularly β1-6 branched glycans and sialic acids. Full article

Background and Objectives: Standard treatment in metastatic breast cancer with positive estrogen receptors and negative HER2neu is represented by CDK4 inhibitors combined with aromatase inhibitors or fulvestrant. Palliative radiotherapy is indicated for symptoms or local–regional control. Multiple preclinical data suggest a potential synergistic effect when CDK4/6 inhibitors and radiotherapy are administered concurrently. We are trying to address some questions and/or to establish correlations within a subgroup of patients with unusual toxicities, the safety of combined treatments, the correlation with radiotherapy techniques and fractionation schemas. Also, we are aware that some organs at risk of a rapid turnover are more vulnerable to the occurrence of acute toxicities. Materials and Methods: This retrospective study includes 20 patients with metastatic breast cancer, treated with CDK4 inhibitors and radiotherapy on 29 disease sites; we followed the compliance and toxicities of combined treatments. Results: Regarding the recorded hematological toxicities, grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy was recorded; grade 2, leucopenia during radiotherapy presented in three cases without radiotherapy interrupting and leucopenia with neutropenia grade 3 presented in one case after pleural secondary lesion’s irradiation. Non-hematological grade 3 toxicities occurred in two cases: one case with grade 3 enteritis, at 2 weeks from bone metastases irradiation—iliac bone (in field toxicity) and one case with radiodermitis during radiotherapy on the breast and lymph node level, in the second week of external radiotherapy (RTE). Conclusions: In all analyzed cases, we obtained control of irradiated lesions. Secondary toxicities occurred only in irradiated areas. A close monitoring of patients during combined treatment must be considered and we are confident that in the future it will be possible to identify the subgroup of patients with a high risk of unusual toxicities occurring; additionally, we hope that using more conforming radiotherapy techniques minimizes the organ being at risk from radiation doses. Full article

Oral squamous cell carcinoma (OSCC) is a common type of head and neck malignancy that represents a significant global health issue. Sialylations are common events in tumor transformation, proliferation, metastasis, and immune evasion. Modifications in sialylation can be detected by lectins, whose changes in OSCC have been related to grade, invasion, and metastasis. The presence of 9-O-acetylated sialic acid (Neu5,9Ac₂) in OSCC cells and its potential expression, modification, and role are unknown. This study aimed to analyze the expression of Neu5,9Ac₂ using the Macrobrachium rosenbergii lectin (MrL) that recognizes this sialic acid (Neu5Ac) residue and also compare its effect on the SCC-152 cell line (CRL-3240, ATCC) and immortalized keratinocytes (HaCaT) as a control. We observed by immunocytochemistry that SCC-152 cells expressed more Neu5,9Ac₂ compared to HaCaT cells; the specificity of MrL was confirmed after the sialidase treatment of cells in which the loss of lectin’s recognition of Neu5,9Ac₂ was observed. The electrophoretic profile was similar between both cell line types; however, the Western blot showed differences in the glycoprotein patterns recognized by lectin for each cell type. MrL increased the proliferation of SCC-152 cells, as well as the integrity and morphology of the colonies. Therefore, our results suggest that Neu5,9Ac₂ glycosylated receptors could be involved in the survival and proliferation of OSCC cells, which offers a promising avenue for developing diagnostic and prognostic tools (tumor markers) against oral squamous cell carcinoma in the future. Full article

Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial–mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize. Full article

CD169 is a sialic acid-binding immunoglobulin-like lectin (Siglec-1, sialoadhesin) that is expressed by subsets of tissue-resident macrophages and circulating monocytes. This receptor interacts with α2,3-linked Neu5Ac on glycoproteins as well as glycolipids present on the surface of immune cells and pathogens. CD169-expressing macrophages exert tissue-specific homeostatic functions, but they also have opposing effects on the immune response. CD169⁺ macrophages act as a pathogen filter, protect against infectious diseases, and enhance adaptive immunity, but at the same time pathogens also exploit them to enable further dissemination. In cancer, CD169⁺ macrophages in tumor-draining lymph nodes are correlated with better clinical outcomes. In inflammatory diseases, CD169 expression is upregulated on monocytes and on monocyte-derived macrophages and this correlates with the disease state. Given their role in promoting adaptive immunity, CD169⁺ macrophages are currently investigated as targets for vaccination strategies against cancer. In this review, we describe the studies investigating the importance of CD169 and CD169⁺ macrophages in several disease settings and the vaccination strategies currently under investigation. Full article

Background/Objectives: In 2022, approximately 2.3 million women were diagnosed with breast cancer worldwide, resulting in 670,000 deaths, which accounted for 6.9% of all cancer-related deaths. In the United States, 1 in 8 women will be diagnosed with breast cancer during their lifetime. It was estimated that 2024 would identify about 310,720 women and 2800 men diagnosed with invasive breast cancer. The future global burden of breast cancer is projected to rise to over 3 million new cases and 1 million deaths by 2040. Approximately 20% of breast cancer diagnoses are triple-negative breast cancer (TNBC), a type of cancer that lacks receptors for estrogen (ER-negative), progesterone (PR-negative), and human epidermal growth factor receptor 2 (HER2/neu-negative). Consequently, TNBC does not respond to hormonal or targeted therapies, making it challenging to treat due to its rapid growth, metastasis, and high recurrence rate within the first three years of therapy. Alternative chemotherapies are needed to address this problem. A pharmacological dose of vitamin C (high-dose VC) has been identified as a potential treatment for some cancer cells. The present study aimed to evaluate whether VC has a therapeutic effect on TNBC, using MDA-MB-231 cells as the model. Additionally, VC’s effects were trialed on other cancer cells such as MCF7 and on non-cancerous kidney HEK 293 and lung CCL205 cells. Methods: The MTT assay, Hoechst 33342 staining, nuclear-ID red/green staining, Rhodamine 123 staining, and Western blot analysis were employed to test the hypothesis that a pharmacological dose of VC can kill TNBC cells. Results: The upregulation of Apaf-1 and caspases -7, -8, and -9, the inhibition of matrix metalloproteinases (MMP-2 and MMP-9), a reduction in cell cycle protein expression, and the enhancement of tumor suppressor proteins such as p53 and p21 indicate that a pharmacological dose of VC has promising anti-cancer properties in the treatment of breast cancers. Conclusions: Pharmacological dose of VC exerts significant anti-cancer effects in MDA-MB-231 cells by promoting apoptosis, inhibiting metastasis, disrupting cell cycle progression, and enhancing tumor suppressor activity. Full article

The most common histological subtypes of endometrial cancer consist of endometrioid and uterine serous carcinoma, with the latter being more aggressive and accompanied by poor prognosis. Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor associated with cell proliferation, differentiation, and survival. HER2 positivity can be diagnosed in many solid tumors. It has been found that approximately one-third of the patients diagnosed with serous carcinoma may overexpress HER2/neu protein and/or show the amplification of the c-erBb2 gene. The prognostic and predictive value of HER2 biomarker is nowadays highlighted and the updates of HER2-directed treatment offer new opportunities for improved efficacy and survival. A number of HER2-targeted therapies have become available in recent years and have had promising results, prompting full drug approvals and additional investigation in many cancer types, among which is endometrial cancer. Data from clinical trials combining classical chemotherapy with anti-HER2 agents, mainly trastuzumab, alone or in combination with pertuzumab, do exist and have been incorporated into international guidelines. Moreover, further research with antibody–drug conjugates and tyrosine kinase inhibitors is being conducted. Acquired resistance remains an important problem, and its underlying mechanisms in endometrial cancer are mostly unknown. Studies exploring earlier use of Her2-directed therapy are also on the way. The purpose of this literature review is to describe the available therapies in the current clinical practice and the most prominent research data regarding the future. In any case, a number of unmet medical needs do exist for HER2-positive serous endometrial cancer, and additional research and studies are warranted to provide further understanding and improved outcomes for this tumor type. Full article

Stroke is one of the leading causes of chronic disability in humans. It has been proposed that the endogenous neural stem/progenitor cells generate new neurons in the damaged area. Still, the contribution of these cells is negligible because a low number of newborn mature neurons are formed. Tlx conventional knock-out mice, Tlx-CreERT2 mice, and Tlx-overexpressing (Tlx-OE) mice were specifically chosen for their unique genetic characteristics, which were crucial for the experiments. Permanent and transient middle cerebral artery occlusion was used to induce stroke in the mice. Immunostainings for doublecortin and GFP/BrdU/NeuN were performed to study neurogenesis and fate mapping. The rotarod test was performed to assess motor deficits. Here, we show that stroke-induced neurogenesis is dramatically increased with the additional expression of two copies of the nuclear receptor-coding gene tailless (Tlx, also known as Nr2e1), which has been shown to be a master regulator of subventricular zone (SVZ) neural stem cells (NSCs). We show that Tlx expression is upregulated after stroke, and stroke-induced neurogenesis is blocked when Tlx is inactivated. Tlx overexpression in NSCs leads to massive induction of neurogenesis via stroke. More newborn mature neurons are formed in Tlx-overexpressing mice, leading to improved coordination and motor function recovery. Most importantly, we also demonstrate that this process is sustained in aged mice, where stroke-induced neurogenesis is nearly undetectable in wild-type animals. This study provides the first stem cell-specific genetic evidence that endogenous NSCs can be exploited by manipulating their master regulator, Tlx, and thus suggests a novel therapeutic strategy for neuronal repair. Full article

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on 20 July 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and October 2024, Wezlana^® (Amgen ABP 654), Uzpruvo^® (Alvotech AVT04) and Pyzchiva^® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma^® (Celltrion Healthcare CT-P43) was approved by the EMA in August 2024. Otulfi^® (Fresenius Kabi/Formycon) was approved by the FDA in October 2024. Several other potential biosimilar candidates are under development, including BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g., Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review summarizes the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs. Full article

Sialic acid is a diverse group of monosaccharides often found on the termini of N- and O-linked glycans as well as being components of glycoconjugates. Hypersialylation has been associated with the progression of chronic inflammation-mediated diseases such as cardiovascular disease and cancer. Given its role in infection and disease-related processes, sialic acid is a promising target for therapeutic approaches that utilize carbohydrate-binding molecules. In this study, we screened for sialic acid-recognizing variable lymphocyte receptors (VLRBs) or ccombodies from inshore hagfish (Eptatretus burgeri) using a synthetic Neu5Ac-glycoconjugate as an antigen in immunoassay. Resulting ccombodies, 2D8, 5G11, 4A1, and 5F8 were further characterized in terms of their binding activity and specificity. A competitive ELISA using free haptens showed strong inhibition using either N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). The half-maximal inhibitory concentrations (IC₅₀) for Neu5Ac ranged from 7.02 to 17.06 mM, with candidates 4A1 and 5G11 requiring the least and highest amounts, respectively. IC₅₀ values for Neu5Gc ranged from 8.12 to 13.91 mM, for 4A1 and 5G11, respectively. Candidate ccombodies also detected naturally occurring sialic acid from known sialoglycoproteins using a dot blot assay. Neu5Gc-5G11 and Neu5Ac-2D8 yielded the strongest and weakest docking interactions with affinity values of −5.9 kcal/mol and −4.9 kcal/mol, respectively. Hydrogen bonding and hydrophobic interactions were predicted to be the predominant noncovalent forces observed between the ccombodies and sialic acid. This study demonstrates that glycan-binding VLRBs from hagfish hold promise in augmenting the glycobiologists’ toolkit in investigating the roles of glycans in human and animal health and disease. Full article

Background/Objectives: Triple-negative breast cancer is difficult to treat due to the absence of hormone receptors and Her2neu. Sacituzumab govitecan is a new therapeutic approach that uses an antibody directed against the Trop-2 antigen present in solid epithelial tumors, linked to the active metabolite SN-38, similar to irinotecan, to specifically target cancer cells while minimizing damage to healthy cells. The objective of the present review was to evaluate the efficacy and safety of sacituzumab govitecan as a single treatment in patients with triple-negative breast cancer and to compare its results with the standard conventional chemotherapy regimen currently used in this disease. Methods: A systematic review of randomized clinical trials of sacituzumab govitecan was performed. The search was performed in Medline (PubMed), Web of Science, and Cochrane from September 2022 to January 2024. Results: Thirty-eight articles are included and evaluated according to inclusion and exclusion criteria corresponding to the two most relevant clinical trials, including specific analyses of cohorts and subgroup study arms within these trials. Data from more recent clinical trials are also reviewed. Conclusions: The efficacy results showed a significantly greater clinical benefit with sacituzumab govitecan compared to standard chemotherapy in patients with triple-negative breast cancer. This drug will become a treatment of substantial impact in future treatment guidelines for this type of cancer. Full article

Leptin is a hormone produced by the small intestines and adipose tissue that promotes feelings of satiety. Leptin receptors (LepRs) are highly expressed in the hypothalamus, enabling central neural control of hunger. Interestingly, LepRs are also expressed in several other regions of the body and brain, notably in the cerebral cortex and hippocampus. These brain regions mediate higher-order sensory, motor, cognitive, and memory functions, which can be profoundly altered during periods of hunger and satiety. However, LepR expression in these regions has not been fully characterized on a cell-type-specific basis, which is necessary to begin assessing their potential functional impact. Consequently, we examined LepR expression on neurons and glia in the forebrain using a LepR-Cre transgenic mouse model. LepR-positive cells were identified using a ‘floxed’ viral cell-filling approach and co-labeling immunohistochemically for cell-type-specific markers, i.e., NeuN, VGlut2, GAD67, parvalbumin, somatostatin, 5-HT3R, WFA, S100β, and GFAP. In the cortex, LepR-positive cells were localized to lower layers (primarily layer 6) and exhibited non-pyramidal cellular morphologies. The majority of cortical LepR-positive cells were neurons, while the remainder were identified primarily as astrocytes or other glial cells. The majority of cortical LepR-positive neurons co-expressed parvalbumin, while none expressed somatostatin or 5-HT3R. In contrast, all hippocampal LepR-positive cells were neuronal, with none co-expressing GFAP. These data suggest that leptin can potentially influence neural processing in forebrain regions associated with sensation and limbic-related functions. Full article