Search Results (100)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge in oncology due to its aggressive progression, propensity for early metastasis, and resistance to conventional therapies. The development of effective and less toxic treatments is crucial for improving the prognosis of PDAC. We aimed to investigate the synergistic antitumor potential of modified FOLFIRINOX (mFOLFIRINOX) combined with natural killer (NK) cell therapy in PDAC models. Methods: We evaluated changes in NK-cell-activating ligands and apoptosis-inducing receptor expression after mFOLFIRINOX treatment both in vitro and in vivo. Subsequently, NK cells were administered to mFOLFIRINOX-pre-treated PDAC cells to assess NK cell cytotoxicity, immune responses, and tumor progression both in vitro and in vivo mouse models. Results: Treatment with mFOLFIRINOX led to the significant upregulation of NK-cell-activating ligands and apoptosis-inducing receptors across the PDAC cell lines and tumor cells collected in vivo, thereby enhancing their susceptibility to NK-cell-mediated cytotoxicity. In comparison with either treatment alone, mFOLFIRINOX and NK cell combination therapy resulted in enhanced cytolysis in all cell lines. In vivo studies demonstrated that combination therapy substantially inhibited tumor growth and prolonged survival in a mouse model. Conclusions: mFOLFIRINOX combined with NK cell therapy demonstrates enhanced antitumor activity against PDAC, potentially improving clinical outcomes. These findings highlight the need for continued research to optimize this combination strategy for clinical utility. Full article

Severe COVID-19 infection resulting in hospitalization shares features with cytokine storm syndromes (CSSs) such as hemophagocytic lymphohistiocytosis (HLH). Various published criteria were explored to define CSS among patients (n = 32) enrolled in a COVID-19 clinical trial. None of the patients met HLH-04 or HScore criteria, but the ferritin to erythrocyte sedimentation rate (ferritin–ESR) ratio and the COVID-19 cytokine storm score (CSs) identified 84% and 81% of patients, respectively. As 30–40% of patients in published secondary HLH cohorts possess rare heterozygous mutations in familial HLH (fHLH) genes, whole genome sequencing was undertaken to explore immunologic gene mutation associations among 20 patients enrolled in the trial. Rare mutations in fHLH genes were identified in 6 patients (30%), and 4 patients (20%) possessed rare mutations in DOCK8 (a novel CSS gene). Foamy viral transduction of the 3 DOCK8 missense mutations into NK-92 natural killer (NK) cells diminished NK cell cytolytic function, a feature of HLH. This severe COVID-19 cohort, like others, shares CSS features but is best identified by the ferritin–ESR ratio. Rare heterozygous CSS gene (fHLH genes and DOCK8) mutations were frequently (45%) identified in this severe COVID-19 cohort, and DOCK8 missense mutations may contribute to CSS via diminished lymphocyte cytolytic activity. Full article

The global trend of increasing mushroom consumption, combined with traditional practices in Romania and other Eastern European countries of collecting and consuming “wild mushrooms”, may contribute to the rising incidence of emergency presentations due to inedible mushroom poisoning. This study aims to identify the clinical features of mushroom poisoning by retrospectively analyzing 47 cases presented to the Emergency Department of the Bucharest Emergency Hospital between 2023 and 2024. The methodology consists of a retrospective cohort study including all patients presented to the Emergency Department of the Bucharest Emergency Hospital with symptoms following mushroom ingestion between 2023 and 2024 totaling 47 cases. Conclusions: In this cohort, most cases of wild/forest mushroom poisoning (76.59%) were diagnosed during autumn, particularly in September and October. The distribution of cases was uniform with respect to both gender and urban versus rural residence. A significant proportion of patients (74.46%) required hospitalization for surveillance and/or specific treatment. The predominant clinical presentation consisted of gastrointestinal symptoms, observed in 97.87% of cases. Full article

The present study aimed to evaluate the therapeutic benefits of a hybrid material based on gold nanoparticles and natural extracts on an experimental model of thioacetamide-induced (TAA) liver injury in rats. The nanomaterials were synthesized using a green method, with Cornus sanguinea L. extract as a reducing and capping agent (NPCS), and were then mixed with Vaccinium myrtillus L. (VL) extract in order to achieve a final mixture with enhanced properties (NPCS-VL). NPCSs were characterized using UV–vis spectrophotometry and transmission electron microscopy (TEM), which demonstrated the formation of spherical, stable gold nanoparticles with an average diameter of 20 nm. NPCS-VL’s hepatoprotective effects were evaluated through an analysis of oxidative stress, inflammation, hepatic cytolysis, histology assays, and TEM in comparison to silymarin on an animal model of thioacetamide (TAA)-induced toxic hepatitis. TAA administration determined hepatotoxicity, as it triggered redox imbalance, increased proinflammatory cytokine levels and alanine aminotransferase (ALAT) activity, and induced morphological and ultrastructural changes characteristic of liver fibrosis. In rats treated with NPCS-VL, all these pathological processes were attenuated, suggesting a potential antifibrotic effect of this hybrid bionanomaterial. Full article

Background/Objectives: AllergoOncology is a new field of study that investigates the relationship between allergic inflammation and cancer. Mast cells and eosinophils are two critical players in allergy reactions, where they can interact and release bioactive granules. The electron microscope is an indispensable tool for analyzing membrane contacts and degranulation patterns in mast cells and eosinophils. The aim of the present ultrastructural study is to analyze the interactions between tumor-associated eosinophils and mast cells (TATEM) in nine cases of gastric cancer. Methods: Seventy-two gastric cancer samples were analyzed using light microscopy, and nine cases exhibiting TATEM were selected for additional examination by transmission electron microscopy. Results: In seven cases, there was direct interaction between non-activated eosinophils and mast cells demonstrating piecemeal degranulation and/or exocytosis. In cases 8 and 9, both cell types showed more advanced stages of degranulation. Mast cells exhibited either massive degranulation (anaphylactic type) or signs of recovery, while eosinophils displayed cytolysis, with or without extracellular trap formation (ETosis). The concurrent activation of both cell types may indicate a collaborative immune response that could affect tumor behavior. There was a trend toward an association with low-stage (I-II) gastric cancer in patients with TATEM, but this difference was not statistically significant (p = 0.06). Conclusions: This work is the first investigation to present ultrastructural evidence of the intimate relationship between degranulating mast cells and cytolytic eosinophils, with or without ETosis, in gastric cancer. These findings support the emerging field of AllergoOncology, which examines the role of allergy-like immune responses in tumor immunity. Full article

In this paper, a new TaMoNbTiZr multielement alloy has been designed, using chemical elements that exhibit extremely low bio-toxicity for the human body. The alloy was obtained by melting in vacuum arc remelting (VAR) equipment MRF ABJ 900 from high-purity chemical elements (99.5%) as mini-ingots having about 40 g weight each. The biocompatible alloys underwent changes in hardness after performing the annealing at 900 °C for 2 h, followed by cooling in water. The new alloy had an average hardness in the cast state of 545 HV0.5, and after heat treatment, it hardened to a value of 984 HV0.5, over 40% higher than that in the casting state, which ensures a longer working period. To use them as materials for medical instruments, their biocompatibility was highlighted through specific laboratory tests. For this, mesenchymal stem cells isolated from bone tissue and a human fibroblast cell line were cultured in vitro on the TaMoNbTiZr alloy’s surface. The biocompatibility of the alloy with the biological environment was evaluated by analyzing cell viability, adhesion, and proliferation, and in parallel, the cytolysis effects manifested by the increase in lactate dehydrogenase activity in the culture media were analyzed. Full article

Background and Objectives: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel biomarkers that provide insight into systemic inflammation and how the immune system responds to stress or infection. These ratios have been associated with predicting clinical outcomes in various diseases, including COVID-19. This study aims to evaluate the prognostic value of NLR and PLR in anticipating ICU admission, acute respiratory failure, and disease severity in COVID-19 patients. Materials and Methods: We conducted a retrospective, observational study that included 536 patients diagnosed with COVID-19. We analyzed the NLR and PLR values at admission and correlated them with ICU admission, the onset of acute respiratory failure, and clinical outcomes. Results: Statistical correlations were identified between elevated NLR and PLR values and the development of complications during hospitalization (p = 0.04 and p = 0.00), acute hypoxemic respiratory failure (p = 0.00), and admission to the intensive care unit (ICU) (p = 0.04). No correlations were found between the values of these ratios and mortality (p = 0.46 and p = 0.32) nor with the development of hepatic cytolysis (p = 0.79 and p = 0.87). Conclusions: NLR and PLR are reliable, easily obtainable biomarkers that can aid in the early prediction of ICU admission and disease severity in COVID-19 patients, offering valuable insights for risk stratification and clinical management. Further prospective studies are needed to validate these biomarkers as part of a broader predictive model for critical care in COVID-19. Full article

During the coronavirus disease 2019 (COVID-19) pandemic, several studies highlighted a worse prognosis for patients with alterations in liver function tests, especially those with pre-existing liver diseases. However, further studies are needed to define the long-term impact of the COVID-19 pandemic on liver diseases. Long COVID-19 encompasses a wide range of signs and symptoms, including exacerbations of pre-existing chronic conditions or new onset conditions developed after the COVID-19 acute phase. Therefore, the long-term effects of COVID-19 extensively include hepatic manifestations. The co-expression of angiotensin-converting receptor 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) has been demonstrated also in enterocytes, cholangiocytes, and hepatocytes. Studies on the post-COVID-19 sequelae have shown the presence of steatosis and necroinflammation in the liver, concomitantly with an alteration of inflammation, cytolysis and cholestasis indices. Some studies also demonstrated an increased risk for hepatobiliary pathologies, including secondary biliary cholangitis and worsening of the severity of metabolic-associated fatty liver disease (MASLD). Based on these premises, this review aims to provide an overview of the pathophysiological mechanisms contributing to COVID-19-related liver and hepatobiliary damage; explore its implications for liver inflammation and fibrosis, with a particular focus on MASLD and metabolic dysfunction-associated steatohepatitis (MASH); and analyze the short- and long-term COVID-19 sequelae. A literature search was conducted using the PubMed database for relevant studies published in English. Full article

High-entropy alloys are novel metallic materials distinguished by very special mechanical and chemical properties that are superior to classical alloys, attracting high global interest for the study and development thereof for different applications. This work presents the creation and characterisation of an FeMoTaTiZr high-entropy alloy composed of chemical constituents with relatively low biotoxicity for human use, suitable for medical tools such as surgical scissors, blades, or other cutting tools. The alloy microstructure is dendritic in an as-cast state. The chemical composition of the FeMoTaTiZr alloy micro-zone revealed that the dendrites especially contain Mo and Ta, while the inter-dendritic matrix contains a mixture of Ti, Fe, and Zr. The structural characterisation of the alloy, carried out via X-ray diffraction, shows that the main phases formed in the FeMoTaTiZr matrix are fcc (Ti₇Zr₃)_0.2 and hcp Ti₂Fe after annealing at 900 °C for 2 h, followed by water quenching. After a second heat treatment performed at 900 °C for 15 h in an argon atmosphere followed by argon flow quenching, the homogeneity of the alloy was improved, and a new compound like Fe_3.2Mo_2.1, Mo_0.93Zr_0.07, and Zr(MoO₄)₂ appeared. The microhardness increased over 6% after this heat treatment, from 694 to 800 HV_0.5, but after the second annealing and quenching, the hardness decreased to 730 HV_0.5. Additionally, a Lactate Dehydrogenase (LDH) cytotoxicity assay was performed. Mesenchymal stem cells proliferated on the new FeMoTaTiZr alloy to a confluence of 80–90% within 10 days of analysis in wells where the cells were cultured on and in the presence of the alloy. When using normal human fibroblasts (NHF), both in wells with cells cultured on metal alloys and in those without alloys, an increase in LDH activity was observed. Therefore, it can be considered that certain cytolysis phenomena (cytotoxicity) occurred because of the more intense proliferation of this cell line due to the overcrowding of the culture surface with cells. Full article

Background/Objective: Immunomodulators play a critical role in regulating immune responses, with immunostimulatory agents enhancing cancer therapy by activating immune cells such as T cells. While immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 have shown clinical success, the availability of small-molecule immunomodulators remains limited. This study aimed to identify novel small-molecule immunomodulators using the One-Bead-Two-Compound (OB2C) library approach for potential cancer immunotherapy. Methods: A OB2C library consisting of 1,764 compounds was screened to identify small-molecule immunomodulators capable of enhancing immune responses. The bead library was incubated with Jurkat cells, which express high levels of α4β1 integrin, each and every compound-bead was uniformly covered with cells. IFN-γ production was measured as a marker of immune activation. The most potent compound was further evaluated for its effects on PBMC activation and cytolytic activity against prostate cancer cells. Tumor cell viability assays were performed to evaluate its effect on immune-mediated tumor suppression. Results: Two immunomodulators, Kib-IM-1 and Kib-IM-4, were identified from a 1764-compound OB2C library. However, only Kib-IM-4 was confirmed to induce PBMC clustering and significantly enhance IFN-γ production. In addition, Kib-IM-4 promoted immune cell activation and enhanced the cytolytic activity of PBMCs against prostate cancer cells, leading to a reduction in tumor cell viability. Conclusions: These findings highlighted Kib-IM-4’s potential as a novel small-molecule immunomodulator for cancer immunotherapy. By enhancing immune cell activation and promoting tumor cell cytolysis, Kib-IM-4 represents a promising candidate for further development in cancer treatment. Full article

The overall goal of this work was to assess the ability of Natural Killer cells to kill cultures of patient-derived glioblastoma cells. Herein we report impressive levels of NK-92 mediated killing of various patient-derived glioblastoma cultures observed at ET (effector: target) ratios of 5:1 and 1:1. This enabled direct comparison of the degree of glioblastoma cell loss across a broader range of glioblastoma cultures. Importantly, even at high ET ratios of 5:1, there are always subpopulations of glioblastoma cells that prove very challenging to kill that evade the NK-92 cells. Of value in this study has been the application of ECIS (Electric Cell–Substrate Impedance Sensing) biosensor technology to monitor the glioblastoma cells in real-time, enabling temporal assessment of the NK-92 cells. ECIS has been powerful in revealing that at higher ET ratios, the glioblastoma cells are acutely sensitive to the NK-92 cells, and the observed glioblastoma cell death is supported by the high-content imaging data. Moreover, long-term ECIS experiments reveal that the surviving glioblastoma cells were then able to grow and reseed the culture, which was evident 300–500 h after the addition of the NK-92 cells. This was observed for multiple glioblastoma lines. In addition, our imaging provides evidence that some NK-92 cells appear to be compromised early, which would be consistent with potent evasive mechanisms by the glioblastoma tumour cells. This research strongly highlights the potential for NK-92 cells to kill glioblastoma tumour cells and provides a basis to identify the mechanism utilised by the surviving glioblastoma cells that we now need to target to achieve maximal cytolysis of the resistant glioblastoma cells. It is survival of the highly resistant glioblastoma clones that results in tumour relapse. Full article

Background: Immuno-oncology has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) like pembrolizumab playing a key role. While highly effective, these therapies can also cause immune-related adverse events. This study examines the incidence and characteristics of hepatobiliary adverse events (AEs) linked to pembrolizumab, using data from the FDA Adverse Event Reporting System (FAERS). Objective: To investigate the rates of hepatobiliary AEs linked to pembrolizumab, providing insights into the risks of liver and biliary system damage in patients prescribed pembrolizumab. Methods: This study utilized the FAERS database via OpenVigil 2.1. Adverse events (AEs) related to pembrolizumab were identified and compared to those associated with other drugs. Reporting odds ratios (RORs) were calculated to assess the likelihood of hepatobiliary AEs in pembrolizumab-treated patients. Results: In total, 594 hepatic AEs and 181 biliary AEs were identified. Significant hepatic AEs included elevated ALT (ROR 3.00, 95% CI: 2.685–3.351), hepatotoxicity (ROR 6.436, 95% CI: 5.72–7.242), and hepatic cytolysis (ROR 15.721, 95% CI: 13.854–17.84). Immune-mediated hepatitis exhibited the highest ROR of 346.716 (95% CI: 303.568–395.997). For biliary AEs, cholangitis (ROR 19.597, 95% CI: 16.852–22.791) and sclerosing cholangitis (ROR 24.735, 95% CI: 19.888–30.763) were the most prominent. Conclusions: Pembrolizumab is associated with a significant risk of hepatobiliary adverse events, particularly immune-mediated hepatitis and cholangitis. The elevated RORs for these conditions highlight the importance of close monitoring and managing liver and biliary functions in patients undergoing pembrolizumab checkpoint blockade. These findings emphasize the need for personalized treatment strategies to mitigate risks and optimize outcomes in cancer immunotherapy, especially for those with preexisting hepatobiliary conditions. Full article

Background/Objectives: Magnesium plays a crucial role in immune function, influencing immunoglobulin synthesis, antibody-dependent cytolysis, and other immune processes. In renal transplant patients, magnesium deficiency is primarily induced by calcineurin inhibitor treatment, through the reduction of magnesium transporter proteins in the renal tubules, leading to magnesium loss. Methods: To assess the correlation between serum magnesium levels and the long-term outcomes of renal graft and transplant recipients, we conducted a retrospective study on 87 patients who have had a transplant for more than 5 years, a period considered immunologically stable. We evaluated laboratory parameters such as glycemia, creatinine, total protein, and C-reactive protein (CRP), as well as demographic data, primary kidney disease, donor type, comorbidities, and infection incidence. Results: This study revealed clinical stability at over 5 years post-transplantation, with no significant differences between the 5–15 and over-15-years groups with regard to major comorbidities, except for HCV infection (p = 0.018). Reduced magnesium levels were associated with impaired renal function (p = 0.017) and inflammatory syndrome (p = 0.012). Viral infections were correlated with living donor grafts (p = 0.05), hypoproteinemia, and decreased eGFR (estimated glomerular filtration rate), while bacterial infections, namely urinary tract infections (UTIs), were linked to reduced eGFR (p = 0.05, p = 0.046). Female patients with hypomagnesemia had a higher incidence of recurrent UTIs (p = 0.03). Conclusions: Hypomagnesemia correlates with increased infection risk in patients who received a renal transplant more than 5 years ago but does not significantly impact glycemic control or cardiovascular health. Full article

This work aimed to evaluate some of the probiotic features and safety of the bacteriocin-producing Latilactobacillus sakei subsp. sakei 2a. The effect of selected commercial drugs from different generic groups and antibiotics on the growth of Ltb. sakei subsp. sakei 2a was also determined. The presence of virulence factors was determined based on PCR with total DNA from Ltb. sakei subsp. sakei 2a. Good growth of Ltb. sakei subsp. sakei 2a was recorded in MRS broth supplemented with 0.2% or 0.4% oxbile or in MRS broth adjusted to a pH from 5.0–9.0. Auto-aggregation of Ltb. sakei subsp. sakei 2a was 62.59%. Different levels of co-aggregation were recorded between Ltb. sakei subsp. sakei 2a and Enterococcus faecalis ATCC19443, Ltb. sakei ATCC15521 and Listeria monocytogenes ScottA. Growth of Ltb. sakei subsp. sakei 2a was not inhibited by commercial drugs from different generic groups. The inhibitory effect on the growth of Ltb. sakei subsp. sakei 2a was recorded only in the presence of Arotin [selective serotonin reuptake inhibitor antidepressant] Minimal Inhibition Concentration (MIC) 1.0 mg/mL, Atlansil [Antiarrhythmic] MIC 0.625 mg/mL, Diclofenac potassium [non-steroidal anti-inflammatory drug (NSAID)] MIC 2.5 mg/mL and Spidufen [NSAID] MIC 15.0 mg/mL. Only two antibiotics tested in this study, Amoxil and Urotrobel, inhibited the growth of Ltb. sakei subsp. sakei 2a with a MIC of <0.5 mg/mL and 5.0 mg/mL, respectively. However, Ltb. sakei subsp. sakei 2a generated positive PCR results on the DNA level for vanA (vancomycin resistance), hyl (hyaluronidase), esp (enterococcal surface protein), ace (adhesion of collagen) and cilA (cytolisin) and a high virulence profile when examined for the presence of virulence factors. It is important to underline that cytolysis has been described as a virulence and antibacterial factor. Full article

Background/Objectives: Cytolytic vaginosis or, classically, Doderlein’s cytolysis is characterized by significant growth of species of the Lactobacillus genus, which leads to high amounts of lactic acid in the vaginal environment. Lactobacillus crispatus has been proposed as a key pathogen in this clinical condition. The symptomatology of cytolytic vaginosis is commonly confused with that of vulvovaginal candidosis, leading to inadequate and ineffective azole therapies. Nevertheless, historically, the use of sodium bicarbonate intimate baths was an effective way to reduce the symptoms of cytolytic vaginosis. Methods: In this study, four HPMC gel prototypes were developed, containing sodium bicarbonate concentrations ranging from 4% to 7% (w/w). These gels were evaluated for their physicochemical properties, antimicrobial activity, interference with lactobacilli adhering to cells, and cellular and tissue biocompatibility. Results: The gels presented pH values of around 9.0, and osmolality between 706 mOsm/kg (F4) and 1065 mOsm/kg (F7). The viscosity upon heating to physiologic temperature and dilution with simulated vaginal fluid was highly affected by the concentration of sodium bicarbonate. Gels with higher sodium bicarbonate concentrations (F6 and F7) were not shown to be stable in these conditions. All formulations exhibited effective antimicrobial activity against seven L. crispatus strains, with MIC values ranging from 6.25% to 25% (v/v) in terms of dilution. Additionally, the 4% (w/w) gel significantly interfered with the adhesion of L. crispatus to epithelial cells in competition and exclusion assays, reducing adhesion by more than 90% in relation to the control. Cytotoxicity tests on the Hec-1A, HeLa, and VK2/E6E7 cell lines indicated that the F4 and F5 gels demonstrated lower cytotoxicity levels compared to those with higher concentrations. Furthermore, ex vivo assays using porcine vaginal tissue confirmed that the 4% gel was non-toxic at a 25% (v/v) dilution. Conclusions: Based on these results, the 4% (w/w) sodium bicarbonate gel (F4) emerges as a promising therapeutic option for cytolytic vaginosis, offering effective bacterial interference, favourable physicochemical properties, and biocompatibility suitable for vaginal application. Full article