Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development.

BACKGROUND: Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. RESULTS: Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. CONCLUSIONS: Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85 mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.

Underreporting of Cases in the COVID-19 Outbreak of Borriana (Spain) during Mass Gathering Events in March 2020: A Cross-Sectional Study.

Determining the number of cases of an epidemic is the first function of epidemiological surveillance. An important underreporting of cases was observed in many locations during the first wave of the COVID-19 pandemic. To estimate this underreporting in the COVID-19 outbreak of Borriana (Valencia Community, Spain) in March 2020, a cross-sectional study was performed in June 2020 querying the public health register. Logistic regression models were used. Of a total of 468 symptomatic COVID-19 cases diagnosed in the outbreak through anti-SARS-CoV-2 serology, 36 cases were reported (7.7%), resulting in an underreporting proportion of 92.3% (95% confidence interval [CI], 89.5-94.6%), with 13 unreported cases for every reported case. Only positive SARS-CoV-2 polymerase chain reaction cases were predominantly reported due to a limited testing capacity and following a national protocol. Significant factors associated with underreporting included no medical assistance for COVID-19 disease, with an adjusted odds ratio [aOR] of 10.83 (95% CI 2.49-47.11); no chronic illness, aOR = 2.81 (95% CI 1.28-6.17); middle and lower social classes, aOR = 3.12 (95% CI 1.42-6.85); younger age, aOR = 0.97 (95% CI 0.94-0.99); and a shorter duration of illness, aOR = 0.98 (95% CI 0.97-0.99). To improve the surveillance of future epidemics, new approaches are recommended.

Preclinical evaluation of [225Ac]Ac-crown-TATE - An alpha-emitting radiopharmaceutical for neuroendocrine tumors.

BACKGROUND: Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([225Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [225Ac]Ac3+, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [225Ac]Ac3+; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [155Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT. METHODS: Crown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD7.4 was measured as the indication of hydrophilicity. Free [225Ac]Ac3+ release from [225Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [225Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [225Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE. RESULTS: [225Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD7.4 = -1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [225Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls. CONCLUSIONS: This preclinical study demonstrated the therapeutic efficacy of [225Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.

Inflammatory Bowel Disease and Cardiovascular Disease: An Integrative Review With a Focus on the Gut Microbiome.

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory condition of the gastrointestinal tract. Recent research indicates a significant link between IBD and cardiovascular disease (CVD), the leading cause of global morbidity and mortality. This review examines the association between IBD and CVD, emphasizing the role of the gut microbiome in this relationship. IBD patients have a higher risk of cardiovascular events, such as coronary artery disease, heart failure, and cerebrovascular incidents, primarily due to chronic systemic inflammation, genetic factors, and gut microbiota imbalance (dysbiosis). Dysbiosis in IBD increases intestinal permeability, allowing bacterial products to enter the bloodstream, which promotes inflammation and endothelial dysfunction, contributing to CVD. Understanding the gut microbiome's role in IBD and CVD suggests new therapeutic interventions. Modulating the microbiome through diet, probiotics, and fecal microbiota transplantation (FMT) are promising research avenues. These interventions aim to restore a healthy gut microbiota balance, potentially reducing inflammation and improving cardiovascular outcomes. Additionally, the review emphasizes the importance of regular cardiovascular risk assessments and personalized preventive measures in managing IBD patients. Such measures include routine monitoring of cardiovascular health, tailored lifestyle modifications, and early intervention strategies to mitigate cardiovascular risk. By integrating current knowledge, this review aims to improve understanding and management of the interconnected pathophysiology of IBD and CVD. This approach will ultimately enhance patient outcomes and provide a foundation for future research and clinical practice guidelines in this area.

NFAT5 counters long-term IFN-I responses in hematopoietic stem cells to preserve reconstitution potential.

Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors (MPPs) after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant. Evidence from competitive transplant assays shows that these defects are HSC-intrinsic. NFAT5-deficient HSCs exhibit enhanced expression of type I interferon (IFN-I) response genes after transplant, and suppressing IFN-I-receptor prevents their exacerbated differentiation and cell death after reconstitution and improves long-term regeneration potential. Blockade of IFN-I receptor also prevented the overdifferentiation of NFAT5-deficient HSCs after bone marrow ablation. These findings show that long-term IFN-I responses to different hematopoietic stressors drive HSCs towards more differentiated progenitors, and that NFAT5 has an HSC-intrinsic role limiting IFN-I responses to preserve reconstitution potential. Our identification of cell-intrinsic mechanisms that strengthen the resistance of HSCs to stress could help to devise approaches to protect long-term stemness during the treatment of hematopoietic malignancies.

Design and development of a new pictorial tool to facilitate communication around advance care planning.

BACKGROUND: Advance care planning (ACP) aims to ensure that people with chronic or advanced disease receive medical care that is consistent with their values and preferences. However, professionals may find it challenging to engage these patients in conversations about the end of life. We sought to develop a pictorial tool to facilitate communication around ACP. METHODS: This was a three-phase study. In phase 1, we used the nominal group and Delphi techniques to achieve expert consensus regarding the conceptual content of the tool. In phase 2, a professional cartoonist was commissioned to create a series of cartoons representing each of the content areas resulting from the Delphi process. The pictorial tool was then administered (phase 3) with a sample of individuals with advanced/chronic disease to explore whether the cartoons were easy to understand and conveyed the intended message. RESULTS: Following a three-round Delphi process, consensus was reached regarding a set of 12 key content areas that should be considered in the context of an ACP interview. The cartoons created to represent each of the 12 areas were then reviewed and ordered so as to reflect the typical stages of an end-of-life care interview. After administering the pictorial tool with 24 frail older adults with advanced/chronic disease, changes were made to 9 of the 12 cartoons. CONCLUSIONS: The new pictorial tool comprises a set of 12 cartoons that can guide professionals as they seek to engage frail older adults with advanced/chronic disease in conversations about the end of life and ACP.

Nephrotoxicity Associated with Cytoreductive Surgery Combined with Cisplatin-Based Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignant Disease: A Systematic Review and Meta-Analysis.

Background: Cisplatin is employed in hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) for peritoneal surface malignancies (PSMs). The main concern regarding intraperitoneal cisplatin administration is nephrotoxicity. Numerous reports in this context are available. Our objective was to conduct a systematic review and meta-analysis to assess cisplatin-based HIPEC-related nephrotoxicity (CHRN). Methods: A systematic literature review on CHRN after CRS for the treatment of PSMs was performed. The literature search was carried out using Medline, Cochrane, and Embase. The last day of the search was 23 October 2023. PRISMA guidelines were used. A meta-analysis was then conducted. The main endpoint was the incidence of acute and chronic renal impairment after CHRN. Secondary endpoints included the potential impact of several clinical variables on the primary endpoint and a critical appraisal of the different renal impairment scales employed. Results: Our study included 26 articles with a total sample of 1473 patients. The incidence of acute kidney injury (AKI) was 18.6% (95% CI: 13.6-25%, range of true effects 3-59%). For chronic kidney disease, it was 7% (95% CI: 3-15.3%, range of true effects 1-53%). The variables that statistically influenced these results were the scale used to measure renal insufficiency, the use of nephroprotective agents, and the presence of pre-existing renal disease. Conclusions: The reported incidence of renal impairment following cisplatin-based HIPEC is highly variable. The incidence of renal failure obtained in this meta-analysis should be used as a reference for subsequent reports on this topic. Further prospective studies are warranted to establish optimal and standardized management.

Biodistribution of the cationic host defense peptide LL-37 using SPECT/CT.

Human cathelicidin LL-37, a cationic host defense peptide (CHDP), has several important physiological roles, including antimicrobial activity, immune modulation, and wound healing, and is a being investigated as a therapeutic candidate for several indications. While the effects of endogenously produced LL-37 are well studied, the biodistribution of exogenously administered LL-37 are less known. Here we assess the biodistribution of a gallium-67 labeled variant of LL-37 using nuclear imaging techniques over a 48 h period in healthy mice. When administered as an intravenous bolus just over 20 µg, the LL-37-based radiotracer was rapidly cleared from the blood, largely by the liver, while an appreciable fraction of the dose temporarily distributed to the lungs. When administered subcutaneously at the same dose level, the radiotracer was absorbed systemically following a two-phase kinetic model and was predominately cleared renally. Uptake into sites rich in immune cells, such as the lymph nodes and the spleen, was observed for both routes of administration. Scans of free gallium-67 were also performed as controls. Important preclinical insights into the biodistribution of exogenously administered LL-37 were gained from this study, which can aid in the understanding of this and related cationic host-defense peptides.

Selective decontamination of the digestive tract in a burns unit reduces the incidence of hospital-acquired infections: A retrospective before-and-after cohort study.

OBJECTIVE: To evaluate the effect of selective decontamination of the digestive tract (SDD) on hospital-acquired infections (HAIs) in patients with acute burn injury requiring admission to a Burns Unit (BU). DESIGN: Retrospective before-and-after cohort study, between January 2017 and June 2023. SDD was implemented in March 2019, dividing patients into two groups. SETTING: Four-bed BU, in a referral University Hospital in Spain. PATIENTS: All the patients admitted during the study period were eligible for analysis. Patients who died or were discharged within 48hours of admission, and patients with an estimated survival less than 10% not considered for full escalation of therapy were excluded. INTERVENTION: SDD comprised the administration of a 4-day course of an intravenous antibiotic, and an oral suspension and oral topical paste of non-absorbable antibiotics during the stay in the BU. MAIN VARIABLE OF INTEREST: Incidence of HAIs during the stay in the BU. SECONDARY OUTCOMES: incidence of specific types of infections by site (bacteremia, pneumonia, skin and soft tissue infection) and microorganism (Gram-positive, Gram-negative, fungi), and safety endpoints. RESULTS: We analyzed 72 patients: 27 did not receive SDD, and 45 received SDD. The number of patients who developed HAIs were 21 (77.8%) and 21 (46.7%) in the non-SDD and the SDD groups, respectively (p=0.009). The number of hospital-acquired infectious episodes were 2.52 (1.21-3.82) and 1.13 (0.54-1.73), respectively (p=0.029). CONCLUSIONS: SDD was associated with a reduced incidence of bacterial HAIs and a decrease in the number of infectious episodes per patient.

Cellular interactions and microenvironment dynamics in skeletal muscle regeneration and disease.

Skeletal muscle regeneration relies on the intricate interplay of various cell populations within the muscle niche-an environment crucial for regulating the behavior of muscle stem cells (MuSCs) and ensuring postnatal tissue maintenance and regeneration. This review delves into the dynamic interactions among key players of this process, including MuSCs, macrophages (MPs), fibro-adipogenic progenitors (FAPs), endothelial cells (ECs), and pericytes (PCs), each assuming pivotal roles in orchestrating homeostasis and regeneration. Dysfunctions in these interactions can lead not only to pathological conditions but also exacerbate muscular dystrophies. The exploration of cellular and molecular crosstalk among these populations in both physiological and dystrophic conditions provides insights into the multifaceted communication networks governing muscle regeneration. Furthermore, this review discusses emerging strategies to modulate the muscle-regenerating niche, presenting a comprehensive overview of current understanding and innovative approaches.

Glucose metabolism outcomes after pituitary surgery in patients with acromegaly.

AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.

In vivoquantitative SPECT imaging of actinium-226: feasibility and proof-of-concept.

Objective.225Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however,225Ac (t1/2= 9.9 d) lacks direct gamma emissions forin vivoimaging.226Ac (t1/2= 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation of225Ac radiopharmaceuticals.226Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study forin vivoquantitative226Ac SPECT imaging and validation of activity estimation.Approach.226Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [226Ac]Ac3+was radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours. Mice with AR42J tumour xenografts were injected with either 2 MBq of [226Ac]Ac-crown-TATE or 4 MBq of free [226Ac]Ac3+activity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-based226Ac activity measurements were assessed from volumes of interest within tumours and organs of interest. Imaging data was compared withex vivobiodistribution measured via gamma counter.Main results. We present, to the best of our knowledge, the first everin vivoquantitative SPECT images of226Ac activity distributions. Time-activity curves derived from SPECT images quantify thein vivobiodistribution of [226Ac]Ac-crown-TATE and free [226Ac]Ac3+activity. Image-based activity measurements in the tumours and organs of interest corresponded well withex vivobiodistribution measurements.Significance. Here in, we established the feasibility ofin vivo226Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitativein vivopharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency.

Bioelectrical Impedance Vector Analysis, Nutritional Ultrasound®, and Handgrip Strength as Innovative Methods for Monitoring Critical Anorexia Nervosa Physical Recovery: A Pilot Study.

Eating disorders (EDs) manifest as persistent disruptions in eating habits or related behaviors, significantly impacting physical health and psychosocial well-being. Nutritional assessment in ED patients is crucial for monitoring treatment efficacy. While dual-energy X-ray absorptiometry (DEXA) remains standard, interest in alternative methods such as bioelectrical impedance vector analysis (BIVA) and Nutritional Ultrasound® (NU) has risen due to their affordability and portability. Additionally, hand dynamometry offers a user-friendly approach to assessing grip strength (HGS), indicative of nutritional status. A prospective study was carried out to evaluate the utility of BIVA, NU®, and HGS in 43 female AN patients. Measurements were taken at baseline and hospital discharge. A total of 41 patients completed the study. After the intervention, numerous BIVA-related parameters such as fat (3.5 ± 2 kg vs. 5.3 ± 2.7 kg, p < 0.001) and free fat mass (33.9 ± 3.8 kg vs. 37.5 ± 4.1 kg, p < 0.001) were partially restored. Similarly, Nutritional Ultrasound® showed promising results in assessing body composition changes such as total abdominal fat tissue (0.5 ± 0.3 cm vs. 0.9 ± 0.3 cm, p < 0.05). In the same way, rectus femoris cross-sectional area values correlated with clinical outcomes such as free fat mass (0.883, p < 0.05) and appendicular muscle mass (0.965, p < 0.001). HGS reached the normality percentile after the intervention (21.6 ± 9.1 kg vs. 25.9 ± 12.3 kg, p < 0.05), demonstrating a significant association between grip strength and body composition parameters such as free fat mass (0.658, p < 0.001) and appendicular muscle mass (0.482, p < 0.001). Incorporating BIVA-, NU®-, and HGS-enhanced nutritional assessment into the treatment of AN patients offers cost-effective, portable, and non-invasive alternatives to DEXA. These techniques offer valuable insights into changes in body composition and nutritional status, which, in turn, facilitate treatment monitoring and contribute to improved patient outcomes.

Systematic review and meta-analysis of the incidence of incisional hernia in urological surgery.

PURPOSE: To evaluate the incidence of incisional hernia in patients undergoing direct access to the abdominal cavity in urological surgery. METHODS: We conducted a systematic review in Pubmed, Embase, and Cochrane Central from 1980 to the present according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Eighty-four studies were selected for inclusion in this analysis, and meta-analysis and meta-regression were performed. RESULTS: The total incidence in the 84 studies was 4.8% (95% CI 3.7% - 6.2%) I2 93.84%. Depending on the type of incision, it was higher in the open medial approach: 7.1% (95% CI 4.3%-11.8%) I2 92.45% and lower in laparoscopic surgery: 1.9% (95% CI 1%-3.4%) I2 71, 85% According to access, it was lower in retroperitoneal: 0.9% (95% CI 0.2%-4.8%) I2 76.96% and off-midline: 4.7% (95% CI 3.5%-6.4%) I2 91.59%. Regarding the location of the hernia, parastomal hernias were more frequent: 15.1% (95% CI 9.6% - 23%) I2 77.39%. Meta-regression shows a significant effect in reducing the proportion of hernias in open lateral, laparoscopic and hand-assisted compared to medial open access. CONCLUSION: The present review finds the access through the midline and stomas as the ones with the highest incidence of incisional hernia. The use of the lateral approach or minimally invasive techniques is preferable. More prospective studies are warranted to obtain the real incidence of incisional hernias and evaluate the role of better techniques to close the abdomen.

Combination of granulocyte-monocyte apheresis and ustekinumab: Multicentre and retrospective study.

OBJECTIVE: Granulocyte-monocyte apheresis (GMA) has shown to be safe and effective in ulcerative colitis (UC), also in combination with biologics, mainly with anti-TNF. The aim of this study was to evaluate the efficacy and safety of combining GMA after primary non-response (PNR) or loss of response (LOR) to ustekinumab (UST) in patients with UC. PATIENTS AND METHODS: A retrospective study was performed in 12 IBD Units, including all patients with refractory UC or unclassified IBD (IBD-U) who received combined GMA plus UST. The number and frequency of GMA sessions, filtered blood volume and time of each session were registered. Efficacy was assessed 1 and 6 months after finishing GMA by partial Mayo score, C-reactive protein (CRP) and fecal calprotectin (FC). Descriptive statistics and non-parametric tests were used in the statistical analysis. RESULTS: Seventeen patients were included (15 UC, 2 IBD-U; median age 47 years [IQR, 35-61]; 59% male; 53% E3). Most patients (89%) had prior exposure to anti-TNF agents and 53% to vedolizumab; 65% were also receiving steroids at baseline. Median partial Mayo score at baseline was 6 (IQR, 5-7) and it significantly decreased after 1 and 6 months (p=0.042 and 0.007, respectively). Baseline FC significantly decreased after 6 months (p=0.028) while no differences were found in CRP. During follow-up, 18% patients started a new biologic therapy and 12% required surgery; 64% of patients under steroids were able to discontinue them. Adverse events were reported in one patient. CONCLUSION: GMA can recapture the response to UST in selected cases of UC after PNR or LOR to this drug.

Lysyl Oxidase in Ectopic Cardiovascular Calcification: Role of Oxidative Stress.

Lysyl oxidase (LOX)-mediated extracellular matrix crosslinking modulates calcification in atherosclerosis and aortic valve disease; however, this enzyme also induces oxidative stress. We addressed the contribution of LOX-dependent oxidative stress to cardiovascular calcification. LOX is upregulated in human-calcified atherosclerotic lesions and atheromas from atherosclerosis-challenged LOX transgenic mice (TgLOXVSMC) and colocalized with a marker of oxidative stress (8-oxo-deoxyguanosine) in vascular smooth muscle cells (VSMCs). Similarly, in calcific aortic valves, high LOX expression was detected in valvular interstitial cells (VICs) positive for 8-oxo-deoxyguanosine, while LOX and LOXL2 expression correlated with osteogenic markers (SPP1 and RUNX2) and NOX2. In human VICs, mito-TEMPO and TEMPOL attenuated the increase in superoxide anion levels and the mineralization induced by osteogenic media (OM). Likewise, in OM-exposed VICs, ß-aminopropionitrile (a LOX inhibitor) ameliorated both oxidative stress and calcification. Gain- and loss-of-function approaches in VICs demonstrated that while LOX silencing negatively modulates oxidative stress and calcification induced by OM, lentiviral LOX overexpression exacerbated oxidative stress and VIC calcification, effects that were prevented by mito-TEMPO, TEMPOL, and ß-aminopropionitrile. Our data indicate that LOX-induced oxidative stress participates in the procalcifying effects of LOX activity in ectopic cardiovascular calcification, and highlight the multifaceted role played by LOX isoenzymes in cardiovascular diseases.