Obesity, characterized by excessive adipose tissue accumulation, has reached epidemic proportions globally, and strongly correlates with various diseases, including cardiovascular disease, diabetes, and cancer. This burden is increasingly affecting adolescents. The Mediterranean diet, known for its health benefits, is being increasingly studied for its potential in preventing metabolic diseases like obesity. This study aims to characterize and quantify the phenolic compounds in typical Mediterranean diet products, such as sourdough bread, chickpeas, pomegranate juice, nuts, and olive oil, which can be part of personalized dietary interventions targeting youth obesity thanks to their nutritional profile and phytochemical content. Using UHPLC-MSn, a total of 93 phenolic compounds across 12 subclasses were identified, with notable differences in both the number and concentration of compounds among food products. The diversity of phenolic compounds suggests potential synergistic effects, which may contribute to the bioactive profile of the Mediterranean diet and its association with health-promoting outcomes. This work provides a comprehensive reference for the phenolic composition of Mediterranean diet foods, supporting their selection in nutritional interventions.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is characterized by exposed necrotic bone that often progresses with increasing pain and impaired quality of life. Zoledronate, the most potent and widely used bisphosphonate, has been strongly associated with BRONJ development following invasive dental procedures. Given the rising incidence of BRONJ, understanding and implementing effective preventive strategies have become imperative. Biomaterials based on synthetic hydroxyapatite and beta-tricalcium phosphate have been investigated as potential preventive agents. Their therapeutic rationale is supported by two key principles: the well-documented chemical interaction of calcium phosphates with bisphosphonates when used as drug carriers, and the established clinical use of synthetic calcium phosphate biomaterials in dentistry for bone regeneration. This review examines the underlying mechanisms of this preventive therapeutic strategy and evaluates studies investigating synthetic calcium phosphate biomaterials for BRONJ prevention through zoledronate adsorption at jaw wound sites, thereby reducing soft tissue toxicity and promoting healing. The evidence supports the protective effect of these biomaterials as a scientifically grounded preventive approach for BRONJ.

Butyrate, a short-chain fatty acid produced by the fermentation of soluble dietary fiber by gut bacteria, also functions as a histone deacetylase inhibitor known to induce apoptosis and promote differentiation in colon tumor cells. During tumorigenesis, cancer cells undergo metabolic reprogramming to meet energetic and biosynthetic demands, increasing glycolytic metabolism and reducing oxidative metabolism-a phenomenon known as the Warburg effect. This study aimed to evaluate the impact of butyrate on the aggressiveness-related metabolic phenotype of three colon cancer cell lines (LS1034, C2BBe1, and WiDr). Butyrate's effects were assessed through fluorine-18 fluorodeoxyglucose ([18F]FDG) uptake, flow cytometry analysis of cytoplasmic and membrane expression of glucose transporters (GLUT1, GLUT3, GLUT5, and GLUT12), lactate production, and analysis of Krebs cycle turnover and glycolysis-Krebs cycle coupling using nuclear magnetic resonance isotopomer profiling. [18F]FDG uptake decreased in C2BBe1 and WiDr cells, whereas an opposite response was observed in LS1034 cells, which also exhibited reduced GLUT5 expression. These uptake patterns were consistent with lactate production measurements, and an enhancement of oxidative metabolism was detected in C2BBe1 and WiDr cells. Although butyrate was consumed by all three cell lines, its metabolic handling appeared to differ in LS1034 cells, possibly reflecting cytotoxic stress and/or distinct metabolic regulation mechanisms. Overall, these findings indicate that butyrate exerts cell-line-dependent metabolic effects in colorectal cancer cells. In C2BBe1 and WiDr cells, butyrate exposure was broadly consistent with the attenuation of glycolytic/Warburg-associated features, whereas LS1034 cells displayed a divergent response and were interpreted separately. These data support further investigation of butyrate as a modulator of colorectal cancer cell metabolism, while highlighting the heterogeneity of metabolic responses across tumor models.

Background/Objectives: Osteonecrosis of the jaw, a non-healing wound, is a side effect in patients treated with nitrogen-containing bisphosphonates (e.g., zoledronate) after some oral procedures. Considering zoledronate toxicity in surgical wounds and the capacity of calcium phosphate synthetic compounds to adsorb it, the aim of this work was to demonstrate and elucidate the mechanism underlying this adsorption. Methods: Four different calcium phosphate synthetic bone substitutes were used in this study: AdBone® BCP (0.5–1 mm), Guidor® easy-graft (0.5–1 mm), Maxresorb® (0.5–1 mm) and Maxresorb® (0.8–1.5 mm). The materials were incubated in aqueous zoledronate solutions. Samples of the solutions obtained after 1, 2, 3, 6, 24, 48, 72 and 120 h of conditioning were then analyzed by spectrophotometry to measure their absorbance and subsequently characterized by micro-elemental analysis. Results: All four materials demonstrated time-dependent zoledronate adsorption. AdBone® BCP achieved the most rapid and sustained sequestration, reaching 80% reduction at 24 h and stabilizing at 85% from 72 h onwards without re-release. Maxresorb® formulations showed comparable kinetics through 72 h (70–75%) but exhibited partial re-release at 120 h. Guidor® easy-graft showed negligible adsorption through the first 24 h, consistent with the physical barrier effect of its PLGA coating. Spectrophotometric findings were independently confirmed by elemental analysis. Conclusions: This work confirms zoledronate adsorption by calcium phosphate synthetic biomaterials. Among the tested materials, AdBone® BCP demonstrated the most favorable adsorption profile, with kinetics well matched to the critical window of alveolar wound healing. These findings support the use of biphasic calcium phosphate bone substitutes as a local strategy to reduce free zoledronate bioavailability at the surgical site, potentially lowering the risk of MRONJ in patients undergoing dentoalveolar procedures under bisphosphonate therapy.

BACKGROUND:More than 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases (CRCLM), which is the main cause of death for more than 60% of these patients. The aim of this study was to correlate the clinical and pathological characteristics of the primary CRC and CRCLM, with emphasis in predicting the histological growth pattern of the CRCLM. METHODS:Cohort of 73 patients with CRC. Analysis of clinical data and blinded pathological review was performed related with primary tumor and CRCLM features. The analysis was performed in SPSS (version 27) with a significance level of 5%. RESULTS:A statistically significant association was found between tumor size and metastasis growth pattern (P = .002), with larger tumors giving rise to metastases with a nondesmoplastic growth pattern. Lymphovascular invasion (LVI) was associated with metachronous CRCLM (P = .043). In the absence of LVI, the time required for CRCLM to appear was significantly longer (P = .011). The number of metastases was significantly higher (P = .049) in tumors without LVI when compared to tumors with LVI. There was a statistically significant association between CRC high-grade inflammation and the desmoplastic metastases growth pattern of the CRCLM (P = .017). CONCLUSION:The possibility of predicting the CRCLM histological growth pattern resorting to primary CRC characteristics would be useful for proper patient selection for surgery and adapting biological therapies.

As the prevalence of cancer continues to rise in a rapidly aging population, the integration of advancements in computational capabilities with oncological practices presents promising opportunities for enhancing cancer treatment management. In silico modeling has emerged as a key approach for studying the radiobiological aspects of cancer, providing novel pathways for understanding cellular mechanisms and potential future improvements in clinical radiotherapy. This review examines significant advancements and ongoing challenges in simulating the complex interactions of ionizing radiation with cancer cells. We explore the utility and limitations of current in silico models, including agent-based models and hybrid approaches that integrate cellular behavior with radiobiological effects using Monte Carlo tools. The paper highlights key developments that have enabled more accurate simulations of DNA damage, various repair processes, and the influence of the microenvironment on cellular radiosensitivity. Looking ahead, we address the need for further refinement of these models and their integration with experimental data to enhance predictive accuracy and potential clinical applications. The capacity of these models to potentiate personalized cancer therapy is emphasized, highlighting the ongoing shift towards more comprehensive and sophisticated computational approaches.

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection.

Objective Obesity is linked to perturbations in energy balance mechanisms, including ghrelin and leptin actions at the hypothalamic circuitry of neuropeptide Y (NPY) and melanocortin. However, information about the regulation of this system in the periphery is still scarce. Our objective was to study the regulation of the NPY/melanocortin system in the adipose tissue (AT) and evaluate its therapeutic potential for obesity and type 2 diabetes. Methods The expression of the NPY/melanocortin receptors’ levels was assessed in the visceral AT of individuals with obesity and altered metabolism. Protein levels of these receptors were evaluated in cultured adipocytes incubated with ghrelin (30 and 100 ng/mL) and leptin (1 and 10 nM) and in the AT of an animal model with a mutation in the leptin receptor (ZSF1 rat), to understand their regulation by leptin and ghrelin. The vertical sleeve gastrectomy animal model was used to evaluate the putative therapeutic potential of the NPY/melanocortin system. Results In this study, we unravelled that leptin (1 nM and 10 nM) selectively reduced the levels of NPY5R and MC3R but no other NPYR/MCRs in cultured adipocytes. In turn, acylated ghrelin (100ng/mL) significantly increased NPY1R, but the inhibition of its receptor also abrogates MC3R levels. However, in the Lepr-deficient ZSF1 rat, both NPY5R and MC3R levels were reduced, along with other NPYRs and MCRs, suggesting that leptin resistance negatively affects NPY and melanocortin signalling. In human adipose tissue, we found a downregulation of genes encoding the NPY and melanocortin receptors in the visceral AT of individuals with obesity and insulin resistance, being correlated with genes regulating metabolic activity. Additionally, diabetic obese rats submitted to vertical sleeve gastrectomy showed increased levels of NPY, melanocortin, ghrelin, and leptin receptors in the AT, including MC3R, suggesting it may constitute a therapeutic target in obesity. Conclusions Our results suggest that the AT NPY/melanocortin system, particularly the MC3R, may be involved in the neuroendocrine regulation of adipocyte metabolism. Altogether, our work shows MC3R is under the control of the ghrelin/leptin duo, is reduced in patients with obesity and prediabetes, and may constitute a therapeutic target in obesity.

Background: More than 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases (CRCLM), which is the main cause of death for more than 60% of these patients. The aim of this study was to correlate the clinical and pathological characteristics of the primary CRC and CRCLM, with emphasis in predicting the histological growth pattern of the CRCLM. Methods: Cohort of seventy-three patients with CRC. Analysis of clinical data and blinded pathological review was performed related with primary tumor and CRCLM features. The analysis was performed in SPSS (version 27) with a significance level of 5%. Results: A statistically significant association was found between tumor size and metastasis growth pattern (p=0.002), with larger tumors giving rise to metastases with a non-desmoplastic growth pattern. Lymphovascular invasion (LVI) was associated with metachronous CRCLM (p=0.043). In the absence of LVI, the time required for CRCLM to appear was significantly longer (p=0.011). The number of metastases was significantly higher (p=0.049) in tumors without LVI when compared to tumors with LVI. There was a statistically significant association between CRC high-grade inflammation and the desmoplastic metastases growth pattern of the CRCLM (p= 0.017). Conclusion: The possibility of predicting the CRCLM histological growth pattern resorting to primary CRC characteristics would be useful for proper patient selection for surgery and adapting biological therapies.

Cancer continues to be a serious threat to human health worldwide. Lung, prostate and triple-negative breast cancers are amongst the most incident and deadliest cancers. Steroidal compounds are one of the most diversified therapeutic classes of compounds and they were proven to be efficient against several types of cancer. The epoxide function has been frequently associated with anticancer activity, particularly the 1,2-epoxide function. For this reason, three 1,2-epoxysteroid derivatives previously synthesised (EP1, EP2 and EP3) and one synthesised for the first time (oxysteride) were evaluated against H1299 (lung), PC3 (prostate) and HCC1806 (triple-negative breast) cancer cell lines. A human non-tumour cell line, MRC-5 (normal lung cell line) was also used. EP2 was the most active compound in all cell lines with IC50 values of 2.50, 3.67 and 1.95 µM, followed by EP3 with IC50 values of 12.65, 15.10 and 14.16 µM in H1299, PC3 and HCC1806 cells, respectively. Additional studies demonstrated that EP2 and EP3 induced cell death by apoptosis at lower doses and apoptosis/necrosis at higher doses, proving that their effects were dose-dependent. Both compounds also exerted their cytotoxicity by ROS production and by inducing double-strand breaks. Furthermore, EP2 and EP3 proved to be much less toxic against a normal lung cell line, MRC5, indicating that both compounds might be selective, and they also demonstrated suitable in silico ADME and toxicity parameters. Finally, none of the compounds induced haemoglobin release. Altogether, these results point out the extreme relevance of both compounds, especially EP2, in the potential treatment of these types of cancer.

In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (CTX), immunotherapy (IT) and tyrosine kinase inhibitors (TKI) have shown remarkable results. However, not all patients with NSCLC respond to these drug treatments or receive durable benefits. In this framework, metabolomics has been applied to improve the diagnosis, treatment, and prognosis of lung cancer and particularly lung adenocarcinoma (AdC). In our study, metabolomics was used to analyze plasma samples from 18 patients with AdC treated with CTX or IT via 1H-NMR spectroscopy. Relevant clinical information was gathered, and several biochemical parameters were also evaluated throughout the treatments. During the follow-up of patients undergoing CTX or IT, imaging control is recommended in order to assess the effectiveness of the therapy. This evaluation is usually performed every three treatments. Based on this procedure, all the samples were collected before the beginning of the treatment and after three and six treatments. The identified and quantified metabolites in the analyzed plasma samples were the following: isoleucine, valine, alanine, acetate, lactate, glucose, tyrosine, and formate. Multivariate/univariate statistical analyses were performed. Our data are in accordance with previous published results, suggesting that the plasma glucose levels of patients under CTX become higher throughout the course of treatment, which we hypothesize could be related to the tumor response to the therapy. It was also found that alanine levels become lower during treatment with CTX regimens, a fact that could be associated with frailty. NMR spectra of long responders’ profiles also showed similar results. Based on the results of the study, metabolomics can represent a potential option for future studies, in order to facilitate patient selection and the monitoring of therapy efficacy in treated patients with AdC. Further studies are needed to improve the prospective identification of predictive markers, particularly glucose and alanine levels, as well as confer guidance to NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.

Abstract This chapter describes situations where individuals may be potentially exposed to ionizing radiation in accidental, occupational, or public exposures excluding those from clinical radiotherapy. Each exposure type can have very specific characteristics ranging in radiation quality, dose, dose rate, length of exposures, and proportion of the body acute exposure. As such, some long-term health effects of low-dose exposures are described including effects on the embryo and fetus, heritable diseases, cataracts, and cardiovascular effects. Special focus on exposure to radon is included along with the health effects specific to this exposure situation. Accidental and malicious exposures can also include high-dose scenarios that can lead to the development of acute radiation syndrome (ARS). Details of ARS are described along with how it can be diagnosed. In some exposure scenarios, large numbers of individuals are exposed such that triage is required to quickly identify those needing medical intervention to mitigate ARS. Strategies for triage for treatment are described with respect to trauma, contamination, and exposure along with a discussion of suggested countermeasures for internal exposure and medical follow-up after exposure. In order to assist with determining the dose of radiation an individual has been exposed to, several biodosimetry techniques are described. The final section focuses on the radiation protection system including definitions of quantities commonly used and the limits of exposure.

Abstract Various exogeneous and endogenous factors constantly cause damages in the biomolecules within a cell. For example, per day, 10,000–100,000 molecular lesions occur in DNA per cell. The molecule modifications that are formed disturb the structure and function of the affected molecules. The purpose of this chapter is to introduce the damages to biomolecules caused by radiation, the associated repair pathways, and the effect on the cellular function. Special interest lies on the damages induced to DNA, the carrier of the human genome, and the consequence to genomic integrity, cell death, and cell survival. Additionally, related effects regarding inflammation and immunity, epigenetic factors, and omics are discussed. The chapter concludes with an explanation of the molecular factors of cellular hyper-radiosensitivity and induced radiation resistance.

The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients.

Background: In the past years, treatment of advanced non-small cell lung cancer (NSCLC) has suffered a variety of alterations. Chemotherapy (QT), immune checkpoint inhibitors (ICIs), tyrosina kinase inhibitors have shown remarkable results. However, not all patients with NSCLC respond to these treatments or receive durable benefits. Thus, patient selection, as well as the identification of predictive biomarkers, represent a vital approach in the study of lung cancer. In this framework, metabolomics has been used in early diagnosis, to personalize treatment and to improve prognosis. Aims: To use metabolomic alterations in order to guide treatment choice. Methods: Metabolomics was used to analyze the serum samples from 18 patients with Lung Adenocarcinoma (AdC) treated with QT and ICIs. All the samples were collected before, after 3 and 6 treatments, and were analyzed by NMR spectroscopy. Multivariate/univariate statistical analyses were used to discover significant differences between the two treatment groups. Results: Significantly, we showed that the serum glucose levels of patients under QT became higher throughout the treatment course, which could be related to tumour response to therapy. It was also significantly found that alanine levels were higher in the QT group, and became lower during the treatment course, fact that was not observed in the IT group. This lead to the hypothesis that it could be associated to frailty. Conclusions: Metabolomics represents a potential strategy for the real-time patient selection and monitoring of therapy efficacy in treated patients with AdC. Newer studies are needed in order to improve the prospective identification of predictive markers.

Cold atmospheric plasma (CAP) has been studied for cancer treatment. One of its forms, CAP activated liquids (CAPAL), may be an alternative to intravesical agents to treat bladder cancer (BC). The surgical bipolar resectoscope, when in use, is a source of thermal plasma (TP), which exerts effects on the surrounding sodium chloride solution for irrigation (NaCl 0.9%), transforming it into a TP activated liquid (TPAL), which is produced in very close contact with the bladder wall. To accelerate a possible introduction of plasma-activated liquid in the treatment of BC, we decided to compare the properties and biological effects of CAPAL and TPAL. An electronic device was designed by our group to create CAP. TP was produced by a resectoscope. NaCl 0.9% was exposed to CAP or TP during short periods of time (30, 60, 120, 180 seconds) creating CAPAL or TPAL. The reactive oxygen and nitrogen species (RONS) activity was evaluated using the OxiSelect™ RONS Assay Kit in each activated liquid. BC cell lines, TCCSUP (grade IV) and HT-1376 (grade III), were incubated with CAPAL or TPAL. Metabolic activity was evaluated by MTT assay and protein content by SRB assay, 24h post-incubation. In comparison to non irradiated NaCl 0.9%, both CAPAL and TPAL, in all exposure times resulted in a significant rise in the activity of RONS. Regarding the biological activity of the activated liquids in the BC cell lines, both CAPAL and TPAL induced a decrease in cell metabolic activity and protein content in an exposure-time dependent manner. CAPAL induced a higher antitumor effect on the high-grade cell line (TCCSUP), while TPAL had a similar effect on both cell lines. Comparing the two activated liquids, CAPAL required longer exposure times to achieve the same effects observed with TPAL at lower exposure times. This study shows that PAL can be a therapeutic agent for BC. Both TPAL and CAPAL showed similar biologics in BC cells. Currently, in clinical practice, TPAL is already in close contact with the bladder wall during surgery, however only briefly and diluted by irrigation. This work intends to get one step closer to demonstrate that CAPAL can be a safe and effective BC treatment.