Comprehensive and critical view on the anti-inflammatory and immunomodulatory role of natural phenolic antioxidants.

The immune response encompasses innate and adaptive immunity, each with distinct and specific activities. The innate immune system is constituted by phagocytic cells, macrophages, monocytes and neutrophils, the cascade system, and different classes of receptors such as toll-like receptors that are exploited by the innate immune cells. The adaptive immune system is antigen-specific, encompassing memory lymphocytes and the corresponding specific receptors. Inflammation is understood as an activation of different signaling pathways such as toll-like receptors or nuclear factor kappa-light-chain-enhancer of activated B cells, with an increase in nitric oxide, inflammatory cytokines and chemokines. Increased oxidative stress has been identified as main source of chronic inflammation. Phenolic antioxidants modulate the activities of lymphocytes and macrophages by impacting cytokines and nitric oxide release, exerting anti-inflammatory effect. The nuclear-factor kappa-light-chain-enhancer of activated B cells signaling pathway and the mitogen-activated protein kinase pathway are targeted, alongside an increase in nuclear factor erythroid 2-related factor mediated antioxidant response, triggering the activity of antioxidant enzymes. The inhibitive potential on phospholipase A2, cyclooxygenase and lipoxygenase in the arachidonic acid pathway, and the subsequent reduction in prostaglandin and leukotriene generation, reveals the potential of phenolics as inflammation antagonists. The immunomodulative potential encompasses the capacity to interfere with proinflammatory cytokine synthesis and with the expression of the corresponding genes. A diet rich in antioxidants can result in prevention of inflammation-related pathologies. More investigations are necessary to establish the role of these antioxidants in therapy. The appropriate delivery system and the prooxidant effects exhibited at large doses, or in the presence of heavy metal cations should be regarded.

A pancreatic adenocarcinoma mimicking hepatoid carcinoma of uncertain histogenesis: A case report and literature review.

In rare cases, metastatic adenocarcinomas of different origin may exhibit the features of hepatoid carcinoma (HC), a rare malignant epithelial tumor, most commonly occurring in the ovaries and stomach, as well as in the pancreas and biliary ducts. A case of a 72-year-old female patient who developed a highly aggressive, poorly differentiated pancreatic ductal adenocarcinoma with peritoneal carcinomatosis, demonstrating hepatoid differentiation upon conventional hematoxylin and eosin staining is reported in the present study. The patient presented with severe abdominal pain, and the radiological investigations performed revealed ovarian and hepatic tumor masses and peritoneal lesions, which were surgically removed. The gross examination of the peritoneum and omentum revealed multiple solid, firm, grey-white nodules, diffusely infiltrating the adipose tissue. The microscopic examination revealed a malignant epithelial proliferation, composed of polygonal cells with abundant eosinophilic cytoplasm and irregular, pleomorphic nuclei. Certain cells presented with intracytoplasmic mucus inclusions, raising suspicion of a HC with an uncertain histogenesis. Immunohistochemical staining was performed, and the tumor cells were found to be positive for cytokeratin (CK)7, CK18 and mucin 5AC, whereas negative staining for CK20, caudal-type homeobox transcription factor 2, α-fetoprotein, paired box gene 8, GATA-binding protein 3 and Wilms tumor 1 were documented. Thus, the diagnosis of metastatic pancreatic adenocarcinoma was established. The main aim of the present study was to provide further knowledge concerning poorly differentiated metastatic adenocarcinoma resembling HC, emphasizing the histopathological and immunohistochemical features of these malignant lesions and raising awareness of the diagnostic difficulties that may arise, as well as the importance of the use immunohistochemistry in differentiating carcinomas of uncertain histogenesis.

Early Echocardiography and ECG Changes Following Radiotherapy in Patients with Stage II-III HER2-Positive Breast Cancer Treated with Anthracycline-Based Chemotherapy with or without Trastuzumab-Based Therapy.

BACKGROUND Cardiotoxicity from radiotherapy and anti-cancer therapies have been reported in patients with breast cancer. This study aimed to investigate the early echocardiography and ECG changes following radiotherapy in 68 patients ages 30-78 years with stages II-III HER2-positive breast cancer treated with anthracycline-based chemotherapy with or without trastuzumab-based therapy from 2015 to 2021. MATERIAL AND METHODS We analyzed data of 68 breast cancer patients aged 30-78 years, predominantly in AJCC stages II-III (61) and HER2-positive (58), treated and monitored from 2015 to 2021. Cardiac function was assessed using echo- and electrocardiography. We employed univariate logistic models to gauge associations between pre-existing cardiac conditions, treatment modalities, and changes in cardiac function. RESULTS A decrease in the left ventricle ejection fraction (EF) by >5% was associated with heart doses >49.3 Gy and with maximum and average doses to the left anterior descending artery (LAD) exceeding 46.9 Gy and 32.7 Gy, respectively. An EF drop of ≥10% was correlated with anti-HER2 therapy, pre-existing ECG changes, and the onset of conditions in the left ventricle, major vessels, and valves. Conditions were exacerbated in patients with prior echocardiographic abnormalities, while some emerged concurrent with the EF decline. CONCLUSIONS This research emphasizes the importance of personalized heart monitoring and care for breast cancer patients undergoing multimodal therapies. Significant and potentially irreversible EF declines can result from radiation and anti-HER2 treatments.

Predicting Pregnancy Outcome in Dairy Cows: The Role of IGF-1 and Progesterone.

The purpose of this study was to determine the link between insulin-like growth factor 1 (IGF-1), progesterone (PROG), non-esterified fatty acids (NEFAs), ß-hydroxybutyrate (BHB), and glucose (GLU) and pregnancy probability after the first artificial insemination (AI) and during the first 100 days in milk (DIM), during the critical transition period. We determined levels of serum IGF-1, PROG, NEFA, BHB, and GLU in Holstein dairy cows via ELISA, using blood samples collected 7 days before parturition (DAP) until 21 days postparturition (DPP). The group was split into cows diagnosed pregnant at 100 DIM (PREG) and those that did not conceive at 100 and 150 DIM (NPREG). Serum IGF-1 and PROG median levels at 7 DAP were significantly higher in PREG vs. NPREG (p = 0.029), the only statistically significant differences across the subgroups. At 7 DAP, IGF-1 levels within the initial group showed a strong negative correlation with PROG (r = -0.693; p = 0.006), while for the PREG subgroup, the IGF-1 levels exhibited a very strong positive correlation with GLU (r = 0.860; p = 0.011) and NEFA (r = 0.872; p = 0.013). IGF-1 and PROG levels detected at 7 DAP may be useful to predict pregnancy at 100 DIM. The positive correlation of NEFA and GLU levels during the transition period demonstrates that the initial group is not in NEB; thus, the NEFA level was not a decisive factor for reproduction success.

Therapies beyond Physiological Barriers and Drug Resistance: A Pilot Study and Review of the Literature Investigating If Intrathecal Trastuzumab and New Treatment Options Can Improve Oncologic Outcomes in Leptomeningeal Metastases from HER2-Positive Breast Cancer.

Leptomeningeal metastases (LM) are a rare but rapidly fatal complication defined by the spread of tumor cells within the leptomeninges and the subarachnoid space, found in approximately 10% of patients with HER2-positive breast cancers. This pilot study evaluated the efficacy of local treatment with intrathecal Trastuzumab (IT) added to systemic treatment. The oncologic outcome of 14 patients with HER2-positive LM is reported. Seven received IT, and seven received standard of care (SOC). The mean number of IT cycles administered was 12.14 ± 4.00. The response rate to CNS after IT treatment + SOC was 71.4%, and three patients (42.8%) obtained durable responses lasting more than 12 months. The median progression-free survival (mPFS) after LM diagnosis was six months, and the median overall survival (mOS) was ten months. The mean values of the PFS in favor of IT therapy (10.6 mo vs. 6.6 mo) and OS (13.7 vs. 9.3 mo) suggest a non-negligible investigation direction in the sense of exploiting intrathecal administration as a possible treatment modality in these patients. Adverse events reported were local pain related to intrathecal administration and one case of arachnoiditis, hematoma, and CSF fistulae. Intrathecal administration of Trastuzumab, alongside systemic treatment and radiotherapy, might improve oncologic outcomes in LM HER2-positive breast cancer with manageable toxicity.

PCR Array Profiling of miRNA Expression Involved in the Differentiation of Amniotic Fluid Stem Cells toward Endothelial and Smooth Muscle Progenitor Cells.

Differentiation of amniotic fluid stem cells (AFSCs) into multiple lineages is controlled by epigenetic modifications, which include DNA methylation, modifications of histones, and the activity of small noncoding RNAs. The present study investigates the role of miRNAs in the differentiation of AFSCs and addresses how their unique signatures contribute to lineage-specific differentiation. The miRNA profile was assessed in AFSCs after 4 weeks of endothelial and muscular differentiation. Our results showed decreased expression of five miRNAs (miR-18a-5p, miR-125b-5p, miR-137, miR-21-5p, and let-7a) and increased expression of twelve miRNAs (miR-134-5p, miR-103a-3p, let-7i-5p, miR-214-3p, let-7c-5p, miR-129-5p, miR-210-3p, let-7d-5p, miR-375, miR-181-5p, miR-125a-5p, and hsa-let-7e-5p) in endothelial progenitor cells (EPCs) compared with undifferentiated AFSCs. AFSC differentiation into smooth muscle revealed notable changes in nine out of the 84 tested miRNAs. Among these, three miRNAs (miR-18a-5p, miR-137, and sa-miR-21-5p) were downregulated, while six miRNAs (miR-155-5p, miR-20a-5p, let-7i-5p, hsa-miR-134-5p, hsa-miR-214-3p, and hsa-miR-375) exhibited upregulation. Insights from miRNA networks promise future advancements in understanding and manipulating endothelial and muscle cell dynamics. This knowledge has the potential to drive innovation in areas like homeostasis, growth, differentiation, and vascular function, leading to breakthroughs in biomedical applications and therapies.

Enhanced Magnetic Hyperthermia Performance of Zinc Ferrite Nanoparticles under a Parallel and a Transverse Bias DC Magnetic Field.

The collective organization of magnetic nanoparticles (MNPs) influences significantly their hyperthermic properties, relevant for their in vitro and in vivo applications. We report a systematic investigation of the effects of the concentration and the static bias direct current (DC) magnetic field superposed over the alternating magnetic field (AMF), both in a parallel and perpendicular configuration, on the specific absorption rate (SAR) by using zinc ferrite MNPs. The nonmonotonic dependence of the SAR on the concentration, with a maximum at very small concentrations (c ≤ 0.1 mgFe/mL), followed by a minimum at 0.25 mgFe/mL, and the second maximum of 3.3 kW/gFe at around 1 mgFe/mL, was explained by the passage of the MNPs from a single particle behavior to a collective one and the role of the dipolar interactions. By superposing a static 10 kA/m bias DC field on the AMF we obtained an increase in the SAR for both parallel and perpendicular orientations, up to 4285 W/gFe and 4070 W/gFe, respectively. To the best of our knowledge, this is the first experimental proof of a significant enhancement of the SAR produced by a perpendicular DC field. The effect of the DC field to increase the SAR is accompanied by an increase in the hyperthermia coercive field (HcHyp) for both configurations. No enhancement of the DC fields was noticed for the MNPs immobilized in a solid matrix but the DC field increases the HcHyp only in the parallel configuration. This translates into a higher SAR value for the perpendicular configuration as compared to the parallel configuration. These results have practical applications for magnetic hyperthermia.

Antioxidant, Anti-inflammatory, and Immunomodulatory Roles of Nonvitamin Antioxidants in Anti-SARS-CoV-2 Therapy.

Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.

Multivariate Risk Analysis of RAS, BRAF and EGFR Mutations Allelic Frequency and Coexistence as Colorectal Cancer Predictive Biomarkers.

BACKGROUND: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its predicted evolution. METHODS: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF, and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations of AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation, and invasiveness). RESULTS: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4), and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF and NRAS G12/G13 mutations co-existed in tumors with invasiveness limited to the submucosa. CONCLUSIONS: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.

Maternal HPV Infection and the Estimated Risks for Adverse Pregnancy Outcomes-A Systematic Review.

BACKGROUND: Human Papilloma Virus (HPV) represents the most prevalent genital infection in young women of reproductive age. OBJECTIVE: This systematic review aims to estimate the effect of HPV infection during pregnancy and assess the correlation between HPV and adverse pregnancy outcomes. MATERIALS AND METHODS: The search strategy has been developed based on the PICOS framework: Population (pregnant women infected with HPV), Intervention (HPV infection confirmed by molecular tests), Comparator (pregnant women without HPV infection), Outcomes (adverse pregnancy outcomes) and Study design (observational studies). We searched PubMed, Web of Science, and Scopus databases on 8 January 2022 by using the following keywords: "HPV", "prematurity", "preterm birth", "miscarriage", "premature rupture of membranes", "adverse pregnancy outcome", "low birth weight", "fetal growth restriction", "pregnancy-induced hypertensive disorders", "preeclampsia". Selection criteria were HPV infection confirmed within maximum 2 years before pregnancy with a molecular test and adverse pregnancy outcomes. (Results: Although numerous studies are conducted on this topic, data are still controversial regarding identifying maternal HPV infection as a risk factor for adverse pregnancy outcomes. More prospective large cohort studies are needed to prove a causative relationship.

Antioxidant, anti-inflammatory and immunomodulatory roles of vitamins in COVID-19 therapy.

oxidative stress is caused by an abundant generation of reactive oxygen species, associated to a diminished capacity of the endogenous systems of the organism to counteract them. Activation of pro-oxidative pathways and boosting of inflammatory cytokines are always encountered in viral infections, including SARS-CoV-2. So, the importance of counteracting cytokine storm in COVID-19 pathology is highly important, to hamper the immunogenic damage of the endothelium and alveolar membranes. Antioxidants prevent oxidative processes, by impeding radical species generation. It has been proved that vitamin intake lowers oxidative stress markers, alleviates cytokine storm and has a potential role in reducing disease severity, by lowering pro-inflammatory cytokines, hampering hyperinflammation and organ failure. For the approached compounds, direct antiviral roles are also discussed in this review, as these activities encompass secretion of antiviral peptides, modulation of angiotensin-converting enzyme 2 receptor expression and interaction with spike protein, inactivation of furin protease, or inhibition of pathogen replication by nucleic acid impairment induction. Vitamin administration results in beneficial effects. Nevertheless, timing, dosage and mutual influences of these micronutrients should be carefullly regarded.

Long-Term Outcome of Patients with Stage II and III Muscle-Invasive Urothelial Bladder Cancer after Multimodality Approach. Which Is the Best Option?

Background and Objectives: There is no consensus regarding the optimal therapy sequence in stage II and III bladder cancer. The study aimed to evaluate the long-term oncologic outcomes in patients with bladder cancer after a multimodality approach. Materials and methods: Medical files of 231 consecutive patients identified with stage II (46.8%), IIIA (30.3%), and IIIB (22.9%) transitional cell carcinoma of the bladder (BC) treated with a multimodality approach were retrospectively reviewed. The treatment consisted of transurethral resections or cystectomy, radiotherapy alone or concurrent chemoradiotherapy as definitive treatment, or neoadjuvant chemotherapy using platinum salt regimens. Results: Median age at diagnosis was 65 ± 10.98 years. Radical or partial cystectomy was performed in 88 patients (37.1%), and trans-urethral resection of bladder tumor (TURBT) alone was performed in 143 (61.9%) patients. Overall, 40 patients (17.3%) received neoadjuvant chemotherapy and 82 (35.5%) received definitive chemoradiotherapy. After a median follow-up of 30.6 months (range 3-146 months), the median disease-free survival (DFS) for an entire lot of patients was 32 months, and the percentage of patients without recurrence at 12, 24, and 36 months was 86%, 58%, and 45%, respectively. Patients receiving neoadjuvant chemotherapy had a better oncologic outcome compared to patients without neoadjuvant chemotherapy (median DFS not reached vs. 31 months, p = 0.038, HR = 0.55, 95% CI 0.310-0.951). There was a trend for better 3-year DFS with radical cystectomy vs. TURBT (60 months vs. 31 months, p = 0.064). Definitive chemoradiotherapy 3-year DFS was 58% compared to 44% in patients who received radiotherapy or chemotherapy alone. Conclusions: In patients with stages II and III, both neoadjuvant chemotherapy and concurrent radio-chemotherapy are valid options for treatment and must be part of a multidisciplinary approach.

Composition-Based Risk Estimation of Mycotoxins in Dry Dog Foods.

The risk of mycotoxins co-occurrence in extrusion-produced dry foods increases due to their composition based on various grains and vegetables. This study aimed to validate a risk estimation for the association between ingredients and the ELISA-detected levels of DON, FUM, ZEA, AFs, T2, and OTA in 34 dry dog food products. The main ingredients were corn, beet, and oil of different origins (of equal frequency, 79.41%), rice (67.6%), and wheat (50%). DON and FUM had the strongest positive correlation (0.635, p = 0.001). The presence of corn in the sample composition increased the median DON and ZEA levels, respectively, by 99.45 µg/kg and 65.64 µg/kg, p = 0.011. In addition to DON and ZEA levels, integral corn presence increased the FUM median levels by 886.61 µg/kg, p = 0.005. For corn gluten flour-containing samples, DON, FUM, and ZEA median differences still existed, and OTA levels also differed by 1.99 µg/kg, p < 0.001. Corn gluten flour presence was strongly associated with DON levels > 403.06 µg/kg (OR = 38.4, RR = 9.90, p = 0.002), FUM levels > 1097.56 µg/kg (OR = 5.56, RR = 1.45, p = 0.048), ZEA levels > 136.88 µg/kg (OR = 23.00, RR = 3.09, p = 0.002), and OTA levels > 3.93 µg/kg (OR = 24.00, RR = 3.09, p = 0.002). Our results suggest that some ingredients or combinations should be avoided due to their risk of increasing mycotoxin levels.

Key biomarkers within the colorectal cancer related inflammatory microenvironment.

Therapeutic approaches focused on the inflammatory microenvironment are currently gaining more support, as biomolecules involved in the inflammatory colorectal cancer (CRC) tumor microenvironment are being explored. We analyzed tumor and paired normal tissue samples from CRC patients (n = 22) whom underwent tumor resection surgery. We assessed 39 inflammation-involved biomolecules (multiplex magnetic bead-based immunoassay), CEA and CA19-9 (ELISA assay) and the tissue expression levels of occludin and also pErk, STAT1 and STAT3 transcriptional factors (western blot). Tumor staging has been established by histopathological evaluation of HE stained tumor tissue sections. We report 32 biomarkers displaying statistically significant differences in tumor vs. control. Additionally, positive statistical biomarker correlations were found between MMP2-IL8 and BAFF-IL8 (Pearson correlation coefficients > 0.751), while APRIL-MMP2, APRIL-BAFF and APRIL-IL8 were negatively correlated (correlation coefficients < - 0.650). While APRIL, BAFF, IL8 and MMP2 did not modulate with tumor stage, they were inversely related to the immune infiltrate level and CD163 tissue expression. We conclude that the significantly decreased APRIL and increased BAFF, IL8 and MMP2 expression were tumor-specific and deserve consideration in the development of new treatments. Also, the positive correlation between Chitinase 3-like 1 and IL8 (0.57) or MMP2 (0.50) suggest a role in tumor growth and metastasis pathways.

Human Eye Optics within a Non-Euclidian Geometrical Approach and Some Implications in Vision Prosthetics Design.

An analogy with our previously published theory on the ionospheric auroral gyroscope provides a new perspective in human eye optics. Based on cone cells' real distribution, we model the human eye macula as a pseudospherical surface. This allows the rigorous description of the photoreceptor cell densities in the parafoveal zones modeled further by an optimized paving method. The hexagonal photoreceptors' distribution has been optimally projected on the elliptical pseudosphere, thus designing a prosthetic array counting almost 7000 pixel points. Thanks to the high morphological similarities to a normal human retina, the visual prosthesis performance in camera-free systems might be significantly improved.

Dietary AGEs involvement in colonic inflammation and cancer: insights from an in vitro enterocyte model.

The number of colon cancer cases is increasing worldwide, and type II diabetes patients have an increased risk of developing colon cancer. Diet-borne advanced glycation end-products (AGEs) may promote neoplastic transformation; however, the mechanisms involved remain elusive. The present study helped to define the relationship between dietary AGEs and cancer progression. C2BBe1 adenocarcinoma enterocytes were exposed to 200 µg/mL glycated casein (AGEs-Csn) for up to 24 h. AGEs-Csn exposure resulted in increased cell proliferation, maladaptative changes in SOD and CAT activity and moderate levels of hydrogen peroxide (H2O2) intracellular accumulation. AGEs-Csn activated pro-survival and proliferation signalling, such as the phosphorylation of mTOR (Ser2448) and Akt (Ser473). GSK-3ß phosphorylation also increased, potentially inducing extracellular matrix remodelling and thus enabling metastasis. Moreover, AGEs-Csn induced MMP-1, -3, -7, -9 and -10 expression and activated MMP-2 and MMP-9, which are regulators of the extracellular matrix and cytokine functions. AGEs-Csn induced inflammatory responses that included extracellular IL-1ß at 6 h; time-dependent increases in IL-8; RAGE and NF-κB p65 upregulation; and IκB inhibition. Co-treatment with anti-RAGE or anti-TNF-α blocking antibodies and AGEs-Csn partially counteracted these changes; however, IL-8, MMP-1 and -10 expression and MMP-9 activation were difficult to prevent. AGEs-Csn perpetuated signalling that led to cell proliferation and matrix remodelling, strengthening the link between AGEs and colorectal cancer aggressiveness.

George Marinesco in the Constellation of Modern Neuroscience.

George Marinesco is the founder of Romanian School of Neurology and one of the most remarkable neuroscientists of the last century. He was the pupil of Jean-Martin Charcot in Salpêtrière Hospital in Paris, France, but visited many other neurological centers where he met the entire constellation of neurologists of his time, including Camillo Golgi and Santiago Ramón y Cajal. The last made the preface of Nervous Cell, written in French by Marinesco. The original title was "La Cellule Nerveuse" and is considered even now a basic reference book for specialists in the field. He was a refined clinical observer with an integrative approach, as could be seen from the multitude of his discoveries. The descriptions of the succulent hand in syringomyelia, senile plaque in old subjects, palmar jaw reflex known as Marinesco-Radovici sign, or the application of cinematography in medicine are some of his important contributions. He was the first who described changes of locus niger in a patient affected by tuberculosis, as a possible cause in Parkinson disease. Before modern genetics, Marinesco and Sjögren described a rare and complex syndrome bearing their names. He was a hardworking man, focused on his scientific research, did not accepted flattering of others and was a great fighter against the injustice of the time.