Explore the vast range of titles available.

Background Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4–myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. Methods The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4–MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4–MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. Results CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4–MD-2 complex and decreased the resulting TLR4–MD-2 dimerization in Ba/F3 cells. Conclusions These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4–MD-2 complex, a potential key target for controlling neuroinflammation.

To appraise the ability of a radiomics signature to predict clinical outcome after stereotactic body radiation therapy (SBRT) for pancreas carcinoma. A cohort of 100 patients was included in this retrospective, single institution analysis. Radiomics texture features were extracted from computed tomography (CT) images obtained for the clinical target volume. The cohort of patients was randomly divided into two separate groups for the training (60 patients) and validation (40 patients). Cox regression models were built to predict overall survival and local control. The significant predictors at univariate analysis were included in a multivariate model. The quality of the models was appraised by means of area under the curve and concordance index. A clinical-radiomic signature associated with Overall Survival (OS) was found significant in both training and validation sets (p = 0.01 and 0.05 and concordance index 0.73 and 0.75 respectively). Similarly, a signature was found for Local Control (LC) with p = 0.007 and 0.004 and concordance index 0.69 and 0.75. In the low risk group, the median OS and LC in the validation group were 14.4 and 28.6 months while in the high-risk group were 9.0 and 17.5 months respectively. A CT based radiomic signature was identified which correlate with OS and LC after SBRT and allowed to identify low and high-risk groups of patients.

Background To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma. Methods A set of 138 consecutive patients (112 males and 26 females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis. Results The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p  < 0.05, AUC of ROC 0.6659, C.I.: 0.5585–0.7732; model-2: GLNU p  < 0.05, AUC 0.6396, C.I.:0.5266–0.7526. The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p  < 0.0001, compacity p  < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232–0.8797)). Conclusion A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.

Background Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. Methods The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG 35-55 ) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB 1 , CB 2 , and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). Results Vehicle-MOG 35-55 -immunized (MOG 35-55 ) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1–5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 were significantly increased in MOG 35-55 mice at 14 PID. In MOG 35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1β, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG 35-55 mice ( p  < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB 2 receptors showed a significant upregulation in vehicle-MOG 35-55 mice at 14 PID. Instead, CB 1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB 2 mRNAs were significantly downregulated as compared to vehicle MOG 35-55 mice. Conclusions The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG 35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB 2 receptors.

Background Mitochondria are central regulators of cellular bioenergetics, calcium homeostasis and apoptosis. Beyond these classical roles, emerging evidence highlights their pivotal involvement in inflammation and related disease progression. Under physiological conditions, mitochondria sustain metabolism and signaling; however, when dysfunctional, they can release mitochondrial damage-associated molecular patterns, such as mitochondrial DNA, reactive oxygen species, cardiolipin and ATP, into the intra- or extracellular environment. Main body The release of these mitochondrial components activates innate immune receptors and inflammasomes, thereby initiating or sustaining inflammatory cascades implicated in aging and a broad range of diseases, including cancer and neurodegenerative, cardiovascular, gastrointestinal and respiratory disorders. Mitochondrial calcium signaling plays a crucial role in energy production and metabolic adaptation; yet when dysregulated, it promotes ROS generation, membrane permeabilization and cell death, all of which further amplify inflammation. Structural and functional mitochondrial messengers, including mtDNA fragments and mitochondria-derived vesicles, also contribute to intercellular communication, enhancing immune activation or driving chronic inflammation depending on their context. Therapeutically, mitochondria are emerging as promising targets to counteract inflammation. Investigational strategies include mitochondrial transplantation, engineered mitovesicles, pharmacological modulators of Ca 2 + flux, antioxidants, and agents that restore mitochondrial biogenesis and metabolism. By reestablishing mitochondrial integrity, these interventions aim to reduce inflammatory signaling, restore cellular homeostasis, and slow disease progression. Conclusions This review underscores mitochondria as both initiators and regulators of inflammatory processes across multiple diseases, highlighting their dual role as drivers of pathology and as promising therapeutic targets. A deeper understanding of mitochondrial signaling, mitochondrial messengers, and inter-organelle communication will be essential for developing effective mitochondria-based therapies to mitigate inflammation and improve patient outcomes.

Background To analyze RapidPlan knowledge-based models for DVH estimation of organs at risk from breast cancer VMAT plans presenting arc sectors en-face to the breast with zero dose rate, feature imposed during the optimization phase (avoidance sectors AS). Methods CT datasets of twenty left breast patients in deep-inspiration breath-hold were selected. Two VMAT plans, PartArc and AvoidArc, were manually generated with double arcs from ~ 300 to ~ 160°, with the second having an AS en-face to the breast to avoid contralateral breast and lung direct irradiation. Two RapidPlan models were generated from the two plan sets. The two models were evaluated in a closed loop to assess the model performance on plans where the AS were selected or not in the optimization. Results The PartArc plans model estimated DVHs comparable with the original plans. The AvoidArc plans model estimated a DVH pattern with two steps for the contralateral structures when the plan does not contain the AS selected in the optimization phase. This feature produced mean doses of the contralateral breast, averaged over all patients, of 0.4 ± 0.1 Gy, 0.6 ± 0.2 Gy, and 1.1 ± 0.2 Gy for the AvoidArc plan, AvoidArc model estimation, RapidPlan generated plan, respectively. The same figures for the contralateral lung were 0.3 ± 0.1 Gy, 1.6 ± 0.6 Gy, and 1.2 ± 0.5 Gy. The reason was found in the possible incorrect information extracted from the model training plans due to the lack of knowledge about the AS. Conversely, in the case of plans with AS set in the optimization generated with the same AvoidArc model, the estimated and resulting DVHs were comparable. Whenever the AvoidArc model was used to generate DVH estimation for a plan with AS, while the optimization was made on the plan without the AS, the optimizer evidentiated the limitation of a minimum dose rate of 0.2 MU/°, resulting in an increased dose to the contralateral structures respect to the estimation. Conclusions The RapidPlan models for breast planning with VMAT can properly estimate organ at risk DVH. Attention has to be paid to the plan selection and usage for model training in the presence of avoidance sectors.

Purpose: To ascertain whether a new delivery system (the Halcyon system) equipped with dual-layer stacked multileaf collimator operating in a mode, which allows independent, fully interdigitating motion of both layers and 6 flattening filter free energy, could generate plans of high clinical quality compared to a well-established delivery system with single layer multileaf collimator. Methods: Twenty patients in each of the 3 groups (advanced head and neck, breast, and high-risk prostate) were selected for an in silico planning study. For each patient, reference plans were developed for volumetric modulated arc therapy technique with 6 MV photon beams from a TrueBeam linear accelerator and compared against the corresponding plans for the Halcyon system. Plan comparison was performed in terms of dose volume histogram quantitative analysis. Results: Concerning the planning target volumes, with identical dose calculation and optimization algorithms and with identical planning techniques, no clinically relevant difference in coverage (D98%), hot spot (D2%), or homogeneity was observed. Similarly, for all the organs at risk, the dosimetric findings showed that (1) all planning constraints were met by the 2 delivery systems and (2) although statistical significant differences were reported for most of the parameters but none of these were judged of potential clinical relevance. Conclusion: The data presented confirmed that the new delivery system can generate treatment plans for volumetric modulated arc therapy with the same dosimetric quality of what is achievable with other systems routinely used in the clinics without significantly changing the current practice. Additional studies which customize the optimization parameters for each delivery device would complement the spectrum of investigations.

IntroductionBiliary tract cancers (BTC) are rare malignancies arising from biliary system. Systemic therapy is the cornerstone for stage IV disease, with poor overall survival (OS). Evidence is lacking about safety and efficacy of local ablative treatments, such as surgery and stereotactic body radiotherapy (SBRT) in the context of metastatic BTC (mBTC).Materials and methodsWe retrospectively analyzed clinical outcomes for a cohort of mBTC patients treated with SBRT for oligometastatic disease. Inclusion criteria were 1–5 distant metastases; SBRT with a dose/fraction of a least 5 Gy to a biological effective dose (BED) of at least 40 Gy considering an α/β of 10 Gy. Analyzed outcomes included local control (LC), distant progression-free survival (DPFS), PFS, and OS.Results51 patients meeting the inclusion criteria. Primary tumor sites were intrahepatic cholangiocarcinoma (35%), extrahepatic cholangiocarcinoma (31%), ampullary adenocarcinoma (20%), gallbladder adenocarcinoma (14%). 21 patients were treated on liver lesions, 17 on nodal metastasis, 5 patients on lung lesions, 4 patients on recurrence along the extrahepatic bile duct. After a median follow-up of 14 months median OS was 13.7 months, 1- and 2-year OS were 58% and 41%, respectively. Node and lung as metastatic sites were associated with a longer OS (p < 0.001). Median LC was 26.8 months, and intrahepatic cholangiocarcinoma was associated with longer LC (p = 0.036). Median DPFS was 11 months, with 1- and 2-year DPFS of 48% and 27.8%, respectively. Ten patients reported grade 1–2 toxicity and 2 cases of acute G3 biliary obstruction.ConclusionsStereotactic body radiotherapy (SBRT) is feasible in the context of mBTC. OS and PFS results are promising, considering that our patients were heavily pre-treated with systemic therapy. Patients with nodal or lung relapse have better prognosis. Distant relapses remain the main pattern of failure, but treatment of all metastatic sites seems to improve DMFS.

Background During these last years, new agents have dramatically improved the survival of the metastatic patients. Oligometastases represent a continuous field of interest in which the integration of metastases-directed therapy and drugs could further improve the oncologic outcomes. Herein a narrative review is performed regarding the main rationale in combining immunotherapy and target therapies with SBRT looking at the available clinical data in case of oligometastatic NSCLC, Melanoma and Kidney cancer. Material and method Narrative Review regarding retrospective and prospective studies published between January 2009 to November 2019 with at least 20 patients analyzed. Results Concerning the combination between SBRT and Immunotherapy, the correct sequence of remains uncertain, and seems to be drug-dependent. The optimal patients’ selection is crucial to expect substantial benefits to SBRT/Immunotherapy combination and, among several factors. A potential field of interest is represented by the so-called oligoprogressed disease, in which SBRT could improve the long-term efficacy of the existing target therapy. Conclusions A low tumor burden seems to be the most relevant, thus making the oligometastatic disease represent the ideal setting for the use of combination therapies with immunological drugs.

PurposeFor patients with oligometastatic/oligorecurrent/oligoprogressive lymph node metastases from PCa, metastases-directed therapy is an emerging strategy. The aim of this retrospective study was to evaluate the oncological outcome and pattern of recurrence in patients treated with stereotactic body radiation therapy (SBRT) to lymph node metastases.MethodsIn this multi-institutional analysis, patients with a maximum of five lymph node metastases from PCa treated with SBRT were included. Primary endpoints of the analysis were local control (LC), out-of-field nodal progression-free survival (NPFS), overall progression-free survival (PFS), and overall survival (OS).Results109 patients and 155 lymph node metastases were evaluated. Patients’ median age was 70.8 years (range 51–84) and median PSA before SBRT was 1.88 ng/ml (range 0.3–45.5 ng/ml). The dose delivered to the target ranged from 25 to 48 Gy in 4–7 fractions; median BED1.5 Gy was 198 Gy (range 108.3–432 Gy). With a median follow-up of 16 months, LC rates at 1 and 3 years were 93% and 86%, respectively. In-field progression of disease was observed in 11 (7%) lesions. One- and 3‑year NPFS was 59% and 29%, and median NPFS was 15 months. Rates of OS at 1 and 3 years were 100% and 95%. The median time to administration of a systemic treatment after SBRT was 7.8 months (1.7–54.8).ConclusionSBRT is an effective and well-tolerated treatment option in the management of lymph node metastases from PCa. Prospective trials are necessary to better select patients who benefit most from this ablative focal treatment and better define the recurrence patterns.