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Pharmaceutics Jun 2024HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on...
HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody-drug conjugate (ADC) Enhertu was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients' access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment.
PubMed: 38931874
DOI: 10.3390/pharmaceutics16060752 -
Molecules (Basel, Switzerland) Jun 2024This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory...
This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.
Topics: Humans; NF-E2-Related Factor 2; Ferroptosis; Xanthophylls; Heme Oxygenase-1; Cell Line, Tumor; Phospholipid Hydroperoxide Glutathione Peroxidase; Molecular Docking Simulation; Reactive Oxygen Species; Signal Transduction; Tongue Neoplasms; Receptors, Transferrin; Membrane Potential, Mitochondrial; Kelch-Like ECH-Associated Protein 1; Gene Expression Regulation, Neoplastic; Amino Acid Transport System y+; Superoxide Dismutase; Down-Regulation; Antigens, CD
PubMed: 38930897
DOI: 10.3390/molecules29122832 -
Molecules (Basel, Switzerland) Jun 2024Nutraceutical immune support offers potential for designing blends with complementary mechanisms of action for robust support of innate immune alertness. We documented...
Effects of a β-Glucan-Rich Blend of Medicinal Mushrooms and Botanicals on Innate Immune Cell Activation and Function Are Enhanced by a Very Low Dose of Bovine Colostrum Peptides.
Nutraceutical immune support offers potential for designing blends with complementary mechanisms of action for robust support of innate immune alertness. We documented enhanced immune activation when bovine colostrum peptides (BC-Pep) were added to an immune blend (IB) containing β-glucans from yeast, shiitake, maitake, and botanical non-β-glucan polysaccharides. Human peripheral blood mononuclear cells (PBMCs) were cultured with IB, BC-Pep, and IB + BC-Pep for 20 h, whereafter expression of the activation marker CD69 was evaluated on NK cells, NKT cells, and T cells. Cytokine levels were tested in culture supernatants. PBMCs were co-cultured with K562 target cells to evaluate T cell-mediated cytotoxicity. IB + BC-Pep triggered highly significant increases in IL-1β, IL-6, and TNF-α, above that of cultures treated with matching doses of either IB or BC-Pep. NK cell and T cell activation was increased by IB + BC-Pep, reaching levels of CD69 expression several fold higher than either BC-Pep or IB alone. IB + BC-Pep significantly increased T cell-mediated cytotoxic killing of K562 target cells. This synergistic effect suggests unique amplification of signal transduction of NK cells and T cells due to modulation of IB-induced signaling pathways by BC-Pep and is of interest for further pre-clinical and clinical testing of immune defense activity against virally infected and transformed cells.
Topics: Animals; Cattle; Humans; Colostrum; Immunity, Innate; beta-Glucans; Peptides; Killer Cells, Natural; Cytokines; Lymphocyte Activation; Leukocytes, Mononuclear; Agaricales; Antigens, Differentiation, T-Lymphocyte; T-Lymphocytes; K562 Cells; Antigens, CD; Lectins, C-Type
PubMed: 38930852
DOI: 10.3390/molecules29122787 -
Microorganisms Jun 2024(1) Background: we determined the prevalence of the hepatitis B virus (HBV) amongst people without human immunodeficiency virus (HIV) in rural and peri-urban areas in...
(1) Background: we determined the prevalence of the hepatitis B virus (HBV) amongst people without human immunodeficiency virus (HIV) in rural and peri-urban areas in Botswana. (2) Methods: We screened for the hepatitis B surface antigen (HBsAg) from archived plasma samples of people without HIV (n = 2135) randomly selected from the Botswana Combination Prevention Program (BCPP) (2013-2018). We sequenced 415 bp of the surface region using BigDye sequencing chemistry. (3) Results: The median age of participants was 31 (IQR: 24-46) and 64% (1360/2135) were female. HBV prevalence was 4.0% (86/2135) [95% CI: 3.3-4.9]) and ranged between 0-9.2%. Older participants (>35 years) had increased odds of HBV positivity (OR: 1.94; 95% CI: [1.32-2.86]; = 0.001). Thirteen samples were sequenced and seven (53.8%) were genotype A, three (23.1%) were genotype D and genotype E each. Clinically significant mutations were identified in the surface region, but no classic drug resistance mutations were identified. (4) Conclusions: We report an HBV prevalence of 4.0% (95% CI 3.3-4.9) among people without HIV in rural and peri-urban communities in Botswana with varying rates in different communities. A comprehensive national HBV program is required in Botswana to guide HBV prevention, testing and management.
PubMed: 38930589
DOI: 10.3390/microorganisms12061207 -
Microorganisms May 2024Brucellosis is an important bacterial disease of livestock and the most common zoonotic disease. The current vaccines are effective but unsafe, as they result in animal...
Brucellosis is an important bacterial disease of livestock and the most common zoonotic disease. The current vaccines are effective but unsafe, as they result in animal abortions and are pathogenic to humans. Virus-like particles are being investigated as molecular scaffolds for foreign antigen presentation to the immune system. Here, we sought to develop a new-generation vaccine by presenting selected T cell epitopes on the surface of Orbivirus core-like particles (CLPs) and transiently expressing these chimeric particles in plants. We successfully demonstrated the assembly of five chimeric CLPs in plants, with each CLP presenting a different T cell epitope. The safety and protective efficacy of three of the highest-yielding CLPs was investigated in a mouse model of brucellosis. All three plant-expressed chimeric CLPs were safe when inoculated into BALB/c mice at specific antigen doses. However, only one chimeric CLP induced protection against the virulent strain challenge equivalent to the protection induced by the commercial Rev1 vaccine. Here, we have successfully shown the assembly, safety and protective efficacy of plant-expressed chimeric CLPs presenting T cell epitopes. This is the first step in the development of a safe and efficacious subunit vaccine against brucellosis.
PubMed: 38930429
DOI: 10.3390/microorganisms12061047 -
Medicina (Kaunas, Lithuania) Jun 2024Inflammatory proteins and their prognostic value in patients with carotid artery stenosis (CAS) have not been adequately studied. Herein, we identified CAS-specific...
Inflammatory proteins and their prognostic value in patients with carotid artery stenosis (CAS) have not been adequately studied. Herein, we identified CAS-specific biomarkers from a large pool of inflammatory proteins and assessed the ability of these biomarkers to predict adverse events in individuals with CAS. Samples of blood were prospectively obtained from 336 individuals (290 with CAS and 46 without CAS). Plasma concentrations of 29 inflammatory proteins were determined at recruitment, and the patients were followed for 24 months. The outcome of interest was a major adverse cardiovascular event (MACE; composite of stroke, myocardial infarction, or death). The differences in plasma protein concentrations between patients with vs. without a 2-year MACE were determined using the independent -test or Mann-Whitney test to identify CAS-specific prognostic biomarkers. Kaplan-Meier and Cox proportional hazards analyses with adjustment for baseline demographic and clinical characteristics were performed to assess the prognostic value of differentially expressed inflammatory proteins in predicting a 2-year MACE in patients with CAS. The mean age of the cohort was 68.8 (SD 10.2) years and 39% were female. The plasma concentrations of two inflammatory proteins were significantly higher in individuals with a 2-year MACE relative to those without a 2-year MACE: IL-6 (5.07 (SD 4.66) vs. 3.36 (SD 4.04) pg/mL, = 0.03) and CD163 (233.825 (SD 230.306) vs. 159.673 (SD 175.669) pg/mL, = 0.033). Over a follow-up period of 2 years, individuals with elevated levels of IL-6 were more likely to develop MACE (HR 1.269 (95% CI 1.122-1.639), = 0.042). Similarly, over a 2-year period, patients with high levels of CD163 were more likely to develop MACE (HR 1.413 (95% CI 1.022-1.954), = 0.036). The plasma levels of inflammatory proteins IL-6 and CD163 are independently associated with adverse outcomes in individuals with CAS. These CAS-specific prognostic biomarkers may assist in the risk stratification of patients at an elevated risk of a MACE and subsequently guide further vascular evaluation, specialist referrals, and aggressive medical/surgical management, thereby improving outcomes for patients with CAS.
Topics: Humans; Female; Carotid Stenosis; Male; Biomarkers; Aged; Middle Aged; Prospective Studies; Inflammation; Receptors, Cell Surface; Prognosis; Interleukin-6; Proportional Hazards Models; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Kaplan-Meier Estimate; Myocardial Infarction; Cardiovascular Diseases; Stroke
PubMed: 38929614
DOI: 10.3390/medicina60060997 -
Medicina (Kaunas, Lithuania) Jun 2024Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo...
Combining Endocrine Therapy with Trastuzumab Emtansine Improves Progression-Free Survival and Overall Survival in HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer.
Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; = 0.00004) and median OS (35.0 vs. 23.1 months; = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; = 0.049). The safety profiles were consistent with previous T-DM1 studies. The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy.
Topics: Humans; Breast Neoplasms; Female; Middle Aged; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Aged; Progression-Free Survival; Adult; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Immunological; Neoplasm Metastasis; Aged, 80 and over; Trastuzumab; Receptors, Estrogen
PubMed: 38929568
DOI: 10.3390/medicina60060951 -
Medicina (Kaunas, Lithuania) May 2024Hepatocellular carcinoma (HCC) is a prevalent form of malignancy that is characterized by high mortality rates and prognosis that remain suboptimal, largely due to...
Hepatocellular carcinoma (HCC) is a prevalent form of malignancy that is characterized by high mortality rates and prognosis that remain suboptimal, largely due to treatment resistance mechanisms. Recent studies have implicated cancer stem cells (CSCs), particularly those expressing epithelial cell adhesion molecule (EpCAM), in HCC progression and resistance. In the present study, we sought to assess EpCAM expression in HCC patients and its correlation with various clinicopathological parameters. Tissue samples from 42 HCC patients were subjected to immunohistochemical staining to evaluate EpCAM expression. Clinicopathological data were obtained including the size, grade and stage of tumors, vascular invasion status, alpha-fetoprotein levels, and cirrhosis status. The Chi square and Fisher's exact tests were employed to assess the association between categorical groups. Independent Student-t test or Mann-Whitney U test was used to investigate the association between continuous patient characteristics and survival. Immunohistochemical analysis revealed EpCAM expression in 52.5% of HCC cases. EpCAM-positive tumors exhibited characteristics indicative of aggressive disease, including larger tumor sizes ( = 0.006), greater tumor multiplicity ( = 0.004), higher grades ( = 0.002), more advanced stages ( = 0.003), vascular invasion ( = 0.023), elevated alpha-fetoprotein levels ( = 0.013), and cirrhosis ( = 0.052). Survival analysis demonstrated that EpCAM expression was significantly associated with lower overall rates of survival and higher rates of recurrence in HCC patients. Our findings suggest that EpCAM expression may serve as a prognostic biomarker for HCC with a potential role in patient management. Targeting EpCAM-positive CSCs may represent a promising approach to overcome treatment resistance and improve clinical outcomes in HCC. However, further investigation into the molecular mechanisms underlying EpCAM's role in HCC progression is warranted to facilitate the development of personalized therapeutic interventions.
Topics: Humans; Carcinoma, Hepatocellular; Epithelial Cell Adhesion Molecule; Liver Neoplasms; Male; Female; Middle Aged; Neoplastic Stem Cells; Biomarkers, Tumor; Aged; Adult; Immunohistochemistry; Prognosis; alpha-Fetoproteins
PubMed: 38929532
DOI: 10.3390/medicina60060915 -
International Journal of Molecular... Jun 2024Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence...
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of , , and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant and glioblastomas, wild-type glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67.
Topics: Humans; Glioblastoma; Tumor Suppressor Protein p53; Ki-67 Antigen; Female; Middle Aged; Male; Aged; Adult; Isocitrate Dehydrogenase; Brain Neoplasms; X-linked Nuclear Protein; Neovascularization, Pathologic; Microvascular Density; Retrospective Studies; Endoglin; Antigens, CD34; Biomarkers, Tumor; Immunohistochemistry
PubMed: 38928515
DOI: 10.3390/ijms25126810 -
International Journal of Molecular... Jun 2024Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach...
Higher EpCAM-Positive Extracellular Vesicle Concentration in Ascites Is Associated with Shorter Progression-Free Survival of Patients with Advanced High-Grade Serous Carcinoma.
Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach are extensively being sought. Tumor-derived extracellular vesicles (EVs) that can be isolated from ascites and blood of HGSC patients are such promising biomarkers. Epithelial cell adhesion molecule (EpCAM) expression is upregulated in most epithelium-derived tumors; however, studies on prognostic value of EpCAM overexpression in ovarian carcinoma have shown contradictory results. The aim of our study was to evaluate the potential of total and EpCAM-positive EVs as prognostic and predictive biomarkers for advanced HGSC. Flow cytometry was used to determine the concentration of total and EpCAM-positive EVs in paired pretreatment ascites and plasma samples of 37 patients with advanced HGSC who underwent different first-line therapy. We found that higher EpCAM-positive EVs concentration in ascites is associated with shorter progression-free survival (PFS) regardless of treatment strategy. We also found a strong correlation of EpCAM-positive EVs concentration between ascites and plasma. Our findings indicate that EpCAM-positive EVs in ascites of patients with advanced HGSC have the potential to serve as prognostic biomarkers for predicting early recurrence and thereby likelihood of more aggressive tumor biology and development of chemoresistance.
Topics: Humans; Epithelial Cell Adhesion Molecule; Extracellular Vesicles; Female; Ascites; Middle Aged; Aged; Biomarkers, Tumor; Progression-Free Survival; Cystadenocarcinoma, Serous; Ovarian Neoplasms; Prognosis; Adult; Neoplasm Grading
PubMed: 38928484
DOI: 10.3390/ijms25126780