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Background: Inflammation following transcatheter aortic valve implantation (TAVI) is associated with an increased risk of adverse outcomes. The aim of this study was to compare the inflammatory response between low radial force valves (Acurate neo2, Boston Scientific) and high radial force valves (Evolut R/Pro, Medtronic; SAPIEN Edwards Lifesciences; and Myval, Meril valves)., Methods: We conducted a retrospective study of patients with severe aortic stenosis treated with TAVI between 2021 and 2022. The primary endpoint was the difference in the inflammatory response between low radial force valves and high radial force valves, measured as the difference between post-procedural and pre-procedural high-sensitivity C-reactive protein levels (hsCRP delta)., Results: A total of 114 patients were included, of which 65 patients (57%) received a low radial force valve. The hsCRP delta was lower in the low radial force valve group compared to the high radial force valve group (8.7 [2.1-15.6] mg/L vs. 18.8 mg/dL [6.4-19] mg/L; P=0.003), due to a lower post-implantation hsCRP (8.9 [5.45-19.6] mg/L vs. 15.8 [9.8-27.3] mg/L; P=0.013). The incidence of new left bundle branch block (LBBB) after TAVI was lower in the low radial force valve group compared to the high radial force valve group (11 [17%] vs. 18 [37%]; P=0.020)., Conclusions: Low radial force TAVI prostheses were associated with a lower inflammatory response, and a lower incidence of new LBBB compared to the radial force valve group, suggesting that inflammation may contribute to the increased risk of conduction disturbances.

Background: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed., Methods: We analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra., Results: CRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04-0.28], p < 0.0001 and OR 0.35 [95% CI 0.14-0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14)., Conclusion: Patients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels., Competing Interests: Declaration of Competing Interest Dr. Abbate and Dr. Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC in the past. Dr. Abbate has also served as a consultant to Cardiol Therapeutics, Kiniksa Pharmaceuticals, Implicit Biosciences, Novo Nordisk, Olatec, and R-Pharm. The remaining authors have no disclosures to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra., Methods: We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials., Results: We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05)., Conclusions: Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.

Background: Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians., Objective: To describe the prevalence of moderate-severe aortic stenosis (AS) in patients with wild type transthyretin amyloidosis (ATTRwt). Also, describe the clinical features, echocardiographic characteristics and clinical evolution., Method: Retrospective cohort of patients with diagnosis of ATTRwt, belonging to Hospital Italiano de Buenos Aires Institutional Amyloidosis Registry, from 30/11/2007 to 31/05/2021. Patients follow up was carried out through the institution clinical history. The prevalence of moderate-severe AE was estimated and presented as a percentage with its 95% confidence interval (95% CI). The characteristics were compared by groups according to whether or not they had moderate-severe AS., Results: 104 patients with ATTRwt were included. Median follow up was 476 days [interquartile range: 192-749]. Moderate-severe AS prevalence at the ATTRwt time of diagnosis was 10.5% (n = 11; 95% CI: 5-18%). The median age of patients with AS moderate-severe at the time of diagnosis of ATTRwt was 86 years [78-91] and the male sex predominated (82%). Most of the patients had a history of heart failure (n = 8) and atrial fibrillation (n = 8) prior to the diagnosis of ATTRwt. Most of the patients were subclassified as low flow low gradient severe AS group (n = 7). Four patients underwent some intervention on the aortic valve. During follow-up, 5 patients (46%) were hospitalized for decompensated heart failure and 4 (36%) died., Conclusions: In our cohort, the coexistence of both pathologies had a similar prevalence as reported in the international literature. It was an elderly population with a high percentage of atrial fibrillation and history of heart failure. Most of the patients presented with severe AS with low flow low gradient., (Copyright: © 2024 Permanyer.)

Competing Interests: Declaration of Competing Interest Drs. Abbate and Van Tassell have served as consultants to Swedish Orphan Biovitrum LLC. Dr. Abbate has also served as a consultant to Cardiol Therapeutics, Kiniksa Pharmaceuticals, Implicit Biosciences, Novo Nordisk, Olatec, and R-Pharm. The remaining authors have no competing interest to declare.

Cannabidiol (CBD) is the primary non-psychoactive chemical from Cannabis Sativa, a plant used for centuries for both recreational and medicinal purposes. CBD lacks the psychotropic effects of Δ9-tetrahydrocannabinol (Δ9-THC) and has shown great therapeutic potential. CBD exerts a wide spectrum of effects at a molecular, cellular, and organ level, affecting inflammation, oxidative damage, cell survival, pain, vasodilation, and excitability, among others, modifying many physiological and pathophysiological processes. There is evidence that CBD may be effective in treating several human disorders, like anxiety, chronic pain, psychiatric pathologies, cardiovascular diseases, and even cancer. Multiple cellular and pre-clinical studies using animal models of disease and several human trials have shown that CBD has an overall safe profile. In this review article, we summarize the pharmacokinetics data, the putative mechanisms of action of CBD, and the physiological effects reported in pre-clinical studies to give a comprehensive list of the findings and major effects attributed to this compound.

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients., (© 2023. The Author(s).)

Introduction: Lower limb peripheral artery disease (PAD) presents high morbidity and mortality. Women represent a small subgroup in different studies, with scarce evidence regarding the prognosis of this gender on PAD. The aim of the present work was to determine the prognostic impact of female gender on lower limb PAD revascularization., Methods: This was a retrospective, single-center study, including patients undergoing symptomatic lower limb PAD revascularization., Results: Among a total of 309 patients included in the study, 109 belonged to the female gender (35%). Women were older and presented lower prevalence of cardiovascular risk factors compared with the male gender. All-cause mortality (22% vs. 12%, p = 0.02) and rehospitalizations for chronic limb-threatening ischemia (18% vs. 10%, p = 0.04) rates were significantly higher in women. In a multivariate regression model, female gender was independently associated with all-cause mortality (OR 2.19 [95% CI: 1.06-4.51], p = 0.03). The timeto-event showed that women exhibited 93% more risk of suffering death than men, after adjusting for clinically relevant variables (HR 1.93 [95% CI: 1.04-3.56], p = 0.04)., Discussion: Women with symptomatic PAD revascularization presented worse prognosis than men in terms of all-cause mortality and re-hospitalizations for chronic limb-threatening ischemia rates. Therefore, it is essential to achieve an adequate control of cardiovascular risk factors, as well as to optimize medical treatment in female patients.

Background: Peripheral artery disease (PAD) is a frequent cause of morbidity and mortality. It may present with diverse clinical presentations. The aim of this study was to evaluate the prognosis of these clinical presentations., Methods: We performed a retrospective cohort study, in which symptomatic PAD patients were included from 2014 to 2020 at a university hospital in Argentina. We classified symptomatic PAD in intermittent claudication (IC), chronic limb-threatening ischemia (CLTI) and acute ischemia (AI). Our primary endpoint was to compare the composite of all-cause mortality and major amputation events between the three groups., Results: We included 309 patients, with a median follow up of 1.87 years (IQR 0.72-3.67). The primary endpoint was more prevalent in CLTI and AI patients (33% and 33.3%) compared to IC patients (8.1%), P<0.001. CLTI and AI were independently associated with the primary endpoint after adjusting for clinical variables of interest (OR 4.04 95%CI [1.86-9.07], P<0.001 and OR 5.40 95%CI [2.18-13.7], P<0.001, respectively). Mortality incidence rate (per 100 patients/year) was similar between AI and CLTI patients (14.2 95% CI [8.0-24.1] and 13.1 95%CI [8.8-19.7], respectively, P=0.67) but higher compared to IC (2.9 95%CI [1.6-5.1], P<0.01). Major amputation events were more prevalent in CLTI (16.5%) compared to AI (8.9%) and IC patients (1.2%), P<0.01., Conclusions: Those with CLTI and AI have a particular increased risk of all-cause death and major amputation events. Although mortality incidence was similar between AI and CLTI patients, the latter have an increased risk of major amputation events compared to AI and IC patients.

Background: Peripheral artery disease (PAD) frequently affects multiple segments of the limbs. Contradictory data have reported worse prognosis in aortoiliac lesions, nevertheless, diabetes and chronic limb ischemia frequently affects the infrapatellar territory. Our aim was to assess the impact of infrapatellar disease in cardiovascular outcomes., Methods: We performed a retrospective, observational cohort study at a university hospital in Argentina. Electronic health records were retrospectively reviewed including symptomatic PAD patients requiring revascularization. A multivariable regression model was performed to account for confounders. The primary endpoint was a composite of hospitalizations due to chronic limb threatening ischemia (CLTI) and major amputation events between infrapatellar and suprapatellar patients. Minor amputation events, all-cause death, myocardial infarction (MI), stroke, and major cardiovascular events (MACE) were secondary endpoints., Results: From January 2014 through July 2020, a total of 309 patients were included in the analysis. 151 patients had suprapatellar disease, and 158 had infrapatellar disease. The primary composite endpoint occurred in 35 patients (22.2%) in the infrapatellar patients and 18 patients (11.9%) in the suprapatellar patients (HR = 2.16; 95% confidence interval [CI]= [1.22-3.82]; p = 0.008). Both components of the primary outcomes occurred more frequently in infrapatellar patients.Minor amputation events were more prevalent in infrapatellar patients (HR = 5.09; 95% CI = [1.47-17.6]; p = 0.010). Death,MI, stroke, and MACE events were not different among groups (all p > 0.05)., Conclusion: Infrapatellar disease was anindependent factor for increased hospitalization of CLTI, major and minor amputations events, compared to suprapatellardisease in symptomatic revascularized PAD patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the progressive loss of motor neurons, which leads to a reduction in strength and exercise capacity. Although the concept of "Exercise is Medicine" is accepted for many diseases, the role of exercise in individuals with ALS is still debated. The aim of this study was to propose a tailored exercise training program that was both safe and effective for individuals with ALS, and to evaluate the effects of this combined, moderate-intensity, aerobic and strength training program on aerobic capacities, strength, and physical function. Sixteen individuals with ALS were randomly assigned to either a training (three times a week for 12 weeks; TRAIN, n = 8) or usual care (continued their usual standard of care and served as control; UC, n = 8) group. Peak power, peak oxygen uptake, as well as the gas exchange threshold (GET) during a cardiopulmonary exercise test (CPET) on a cycle ergometer, and the maximal strength (1RM) of the knee extensor muscles, were evaluated before and after 12 weeks. Participants also performed the "Timed Up and Go" (TUG) and the "6-min walking" (6MWT) tests. The ALS Functional Rating Scale revisited (ALSFRS-R), the ALS Severity Scale (ALS-SS), and the McGill quality of life (QoL) questionnaire were also measured. The GET increased from 0.94 ± 0.08 to 1.06 ± 0.10 L min -1 in TRAIN ( p = 0.009) and decreased from 0.79 ± 0.17 to 0.72 ± 0.17 L min -1 in UC ( p = 0.001). There was a significant difference between groups for changes in TUG (9.1 ± 5.5% improvement in TRAIN and 56.8 ± 18.5% worsening in UC, p = 0.002), ALSFRS-R (4.7 ± 2.6% decrease in TRAIN and 23.0 ± 5.6% decrease in UC, p = 0.007), and for the ALS-SS (2.2 ± 2.1% decrease in TRAIN and 12.4 ± 4.4% decrease in UC, p = 0.04). Even if the 1RM of the knee-extensor muscles showed a tendency to increase in TRAIN (70.1 ± 30.0%, p = 0.07), there was not a statistically significant difference ( p = 0.57) with respect to the changes in the UC group (44.9 ± 20.7% increase, p = 0.11). This study showed that a combined moderate-intensity aerobic and strength training program, tailored to the physical capacities of each individual, can improve aerobic fitness and maintain physical function in individuals with ALS., (Copyright © 2019 Ferri, Lanfranconi, Corna, Bonazzi, Marchese, Magnoni and Tremolizzo.)

Recent evidence indicates that immune cells contribute to the formation of tumor metastases by regulating the pre-metastatic niche. Whether tumor-derived factors involved in primary tumor formation play a role in metastasis formation is poorly characterized. Oxysterols act as endogenous regulators of lipid metabolism through the interaction with the nuclear Liver X Receptors-(LXR)α and LXRβ. In the context of tumor development, they establish a pro-tumor environment by dampening antitumor immune responses, and by recruiting pro-angiogenic and immunosuppressive neutrophils. However, the ability of LXR/oxysterol axis to promote tumor invasion and metastasis by exploiting immune cells, is still up to debate. In this study we provide evidence that oxysterols participate in the primary growth of orthotopically implanted 4T1 breast tumors by establishing a tumor-promoting microenvironment. Furthermore, we show that oxysterols are involved in the metastatic spread of 4T1 breast tumors, since their enzymatic inactivation mediated by the sulfotransferase 2B1b, reduces the number of metastatic cells in the lungs of tumor-bearing mice. Finally, we provide evidence that oxysterols support the metastatic cascade by modifying the lung metastatic niche, particularly allowing the recruitment of tumor-promoting neutrophils. These results identify a possible new metastatic pathway to target in order to prevent metastasis formation in breast cancer patients.

Lanfranconi, Francesca, Luca Pollastri, Giovanni Corna, Manuela Bartesaghi, Massimiliano Novarina, Alessandra Ferri, and Giuseppe Andrea Miserocchi. The elusive path of brain tissue oxygenation and cerebral perfusion in harness hang syncope in mountain climbers. High Alt Med Biol. 18:363-371, 2017., Aim: Harness hang syncope (HHS) is a risk that specifically affects wide ranges of situations requiring safety harnesses in mountains. An irreversible orthostatic stasis could lead to death if a prompt rescue is not performed. We aimed at evaluating the risk of developing HHS and at identifying the characteristics related to the pathogenesis of HHS., Results: Forty adults (aged 39.1 [8.2] years) were enrolled in a suspension test lasting about 28.7 (11.4) minutes. We measured cardiovascular parameters, and near infrared spectroscopy (NIRS) was used to assess cerebral hypoxia by changes in the concentration of oxyhemoglobin (Δ[HbO 2 ]) and de-oxyhemoglobin (Δ[HHb]). In the four participants who developed HHS: (1) systolic and diastolic blood pressure showed ample oscillations with a final abrupt drop (∼30 mmHg); (2) Δ[HbO 2 ] increased after 8-12 minutes of suspension and reached a plateau before HHS; and (3) Δ[HHb] decreased with a final abrupt increase before syncope., Conclusions: Participants who developed HHS failed to activate cardiovascular reflexes that usually safeguard O 2 availability to match the metabolic needs of the brain tissue. Since cerebral hypoxia was detected as an early phenomenon by Δ[HbO 2 ] and Δ[HHb] changes, NIRS measurement appears to be the most important parameter to monitor the onset of HHS.

Objective: The signals causing the resolution of muscle inflammation are only partially characterized. The long pentraxin PTX3, which modulates leukocyte recruitment and activation, could contribute., Methods: We analysed the expression of ptx3 after muscle injury and verified whether hematopoietic precursors are a source of the protein. The kinetics of regeneration and leukocytes infiltration, the accumulation of cell remnants and anti-histidyl-t-RNA synthetase autoantibodies were compared in wild-type and ptx3 -deficient mice., Results: Ptx3 expression was up-regulated three-five days after injury and restricted to the extracellular matrix. Cellular debris and leukocytes persisted in the muscle of ptx3 -deficient mice for a long time after wild-type animals had healed. ptx3 -deficient macrophages expressed receptors involved in apoptotic cell clearance and engulfed dead cells in vitro . Accumulation of cell debris in a pro-inflammatory microenvironment was not sufficient to elicit autoantibodies., Conclusion: PTX3 generated in response to muscle injury prompts the clearance of debris and the termination of the inflammatory response.

Introduction: Patient safety aims to achieve healthcare free of damage. The World Health Organization indicates that this objective is achieved through communication, analysis, and prevention of adverse events in patients. Organizational culture has been identified as one of the main factors for interventions aimed to reduce medical errors; and an essential component of safety culture is the attitude of health professionals towards medical error. Attitudes can be improved through appropriate education in biomedical careers but its inclusion in Argentina is scarce. The Attitudes Questionnaire for Patient Safety, measures knowledge, beliefs, and attitudes about patient safety and could be a useful tool in our country., Objectives: To validate the modified attitudes for patient safety questionnaire to measure knowledges, beliefs, and attitudes of medical students at CEMIC University Institute. To describe the level of knowledges, beliefs, and attitudes in patient safety of medical students at CEMIC University Institute in 2012, 2015 and 2016., Methods: Design: descriptive study. Scope: Exploratory. Setting: the CEMIC University Institute in Buenos Aires, Argentina. Population: medical students of 4th and 5th year. Sampling: a sample size of 100 participants was estimated to derive meaningful estimates as per a Cronbach's alpha> 0.60., Results: The reliability of the instrument (internal consistency) by Cronbach's alpha showed an overall correlation of 0.695. Suitable Cronbach's alpha values were obtained in all categories, except in two: importance of patient safety in the curriculum and the inevitability of error. The responses on knowledge, attitudes and perceptions about patient safety in the three cohorts showed that 57% of students believe they understand concepts about patient safety, 53% consider their training prepares them to understand the cause of medical errors, only 59% believe that human error is inevitable and 98% believe that real professionals do not make mistakes. Lastly, 64% believe that this knowledge is only acquired from clinical experience., Conclusion: This study shows that the APSQ-III modified survey is valid and could be used in Argentina and the region to measure the impact of incorporating patient safety topics in the medical curriculum.

Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.

Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumor-derived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1 + islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC-neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients., Competing Interests: The authors declare no conflict of interest.

Macrophages recruited at the site of sterile muscle damage play an essential role in the regeneration of the tissue. In this article, we report that the selective disruption of macrophage ferroportin (Fpn) results in iron accumulation within muscle-infiltrating macrophages and jeopardizes muscle healing, prompting fat accumulation. Macrophages isolated from the tissue at early time points after injury express ferritin H, CD163, and hemeoxygenase-1, indicating that they can uptake heme and store iron. At later time points they upregulate Fpn expression, thus acquiring the ability to release the metal. Transferrin-mediated iron uptake by regenerating myofibers occurs independently of systemic iron homeostasis. The inhibition of macrophage iron export via the silencing of Fpn results in regenerating muscles with smaller myofibers and fat accumulation. These results highlight the existence of a local pathway of iron recycling that plays a nonredundant role in the myogenic differentiation of muscle precursors, limiting the adipose degeneration of the tissue., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background: Current interventions in amyotrophic lateral sclerosis (ALS) are focused on supporting quality of life (QoL) and easing pain with a multidisciplinary approach., Objective: Primary aim of this pilot work assessed feasibility, safety, tolerability and satisfaction of osteopathic manual treatment (OMT) in 14 ALS outpatients., Methods: Patients were randomized according to an initial single-blind design (12 weeks, T0-T1), in order to receive OMT (weekly for 4 weeks, and fortnightly for the following 8 weeks) versus usual-care (n=7 each group), followed by an OMT open period (T1-T2, once a week for 8 weeks, n=10). Secondary aims included blind osteopathic assessment of somatic dysfunctions (SD) for goal attainment scale (GAS) calculation, Brief Pain Inventory-short form and McGill QoL-16 items., Results: OMT was demonstrated feasible and safe and patients displayed high satisfaction (T1-VAS=8.34 ± 0.46; T2-VAS=8.52 ± 0.60). Considering secondary aims no significant differences emerged. Finally, at study entry (T0), a cervico-dorsal SD was found in 78% of ALS patients versus 28% of healthy matched controls (p<0.01)., Conclusion: OMT was found feasible, safe and satisfactory in ALS. The lack of secondary aim differences can be due to the limited sample size. OMT could be an interesting option to explore in ALS.

Targeting the tumor microenvironment focusing on immune cells has recently become a standard of care for some tumors. Indeed, antibodies blocking immune checkpoints (e.g., anti-CTLA-4 and anti-PD1 mAbs) have been approved by regulatory agencies for the treatment of some solid tumors based upon successes in many clinical trials. Although tumor metabolism has always attracted the attention of tumor biologists, only recently have oncologists renewed their interest in this field of tumor biology research. This has highlighted the possibility to pharmacologically target rate-limiting enzymes along key metabolic pathways of tumor cells, such as lipogenesis and aerobic glycolysis. Altered tumor metabolism has also been shown to influence the functionality of the tumor microenvironment as a whole, particularly the immune cell component of thereof. Cholesterol, oxysterols and Liver X receptors (LXRs) have been investigated in different tumor models. Recent in vitro and in vivo results point to their involvement in tumor and immune cell biology, thus making the LXR/oxysterol axis a possible target for novel antitumor strategies. Indeed, the possibility to target both tumor cell metabolism (i.e., cholesterol metabolism) and tumor-infiltrating immune cell dysfunctions induced by oxysterols might result in a synergistic antitumor effect generating long-lasting memory responses. This review will focus on the role of cholesterol metabolism with particular emphasis on the role of the LXR/oxysterol axis in the tumor microenvironment, discussing mechanisms of action, pros and cons, and strategies to develop antitumor therapies based on the modulation of this axis.

Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.

The aim of this study was to verify whether macrophages influence the fate of transplanted mesoangioblasts--vessel-associated myogenic precursors--in a model of sterile toxin-induced skeletal muscle injury. We have observed that in the absence of macrophages, transplanted mesoangioblasts do not yield novel fibers. Macrophages retrieved from skeletal muscles at various times after injury display features that resemble those of immunoregulatory macrophages. Indeed, they secrete IL-10 and express CD206 and CD163 membrane receptors and high amounts of arginase I. We have reconstituted the muscle-associated macrophage population by injecting polarized macrophages before mesoangioblast injection: alternatively activated, immunoregulatory macrophages only support mesoangioblast survival and function. This action depends on the secretion of IL-10 in the tissue. Our results reveal an unanticipated role for tissue macrophages in mesoangioblast function. Consequently, the treatment of muscle disorders with mesoangioblasts should take into consideration coexisting inflammatory pathways, whose activation may prove crucial for its success.

High-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecules, favors tissue regeneration via recruitment and activation of leukocytes and stem cells. Here we demonstrate, in a model of acute sterile muscle injury, that regeneration is accompanied by active reactive oxygen species (ROS) production counterbalanced and overcome by the generation of antioxidant moieties. Mitochondria are initially responsible for ROS formation. However, they undergo rapid disruption with almost complete disappearance. Twenty-four hours after injury, we observed a strong induction of MURF1 and atrogin-1 ubiquitin ligases, key signals in activation of the proteasome system and induction of muscle atrophy. At later time points, ROS generation is maintained by nonmitochondrial sources. The antioxidant response occurs in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes, such as superoxide dismutase 1 (SOD1) and thioredoxin. HMGB1, a protein thiol, weakly expressed in healthy muscles, increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. We propose that the early antioxidant response in regenerating muscle limits HMGB1 oxidation, thus allowing successful muscle regeneration.