Has Coca-Cola treatment become the first-line therapy for gastric bezoars, both in general and specifically for western countries?

Phytobezoars is a rare disease and less common in Western countries. The stomach is the primary site for these formations, and endoscopic treatment involving fragmentation and extraction has traditionally been the most effective approach. However, medical treatments using enzymatic and chemical agents, such as cellulase and Coca-Cola, aimed at dissolving the bezoars, have also been utilized, showing varying degrees of resolution success. Notably, the oral dissolution treatment with Coca-Cola has emerged as a promising, simpler, and more cost-effective method. The study by Liu et al represents an important step in clinical research on this topic, despite some limitations that need addressing for a more comprehensive understanding of its findings. Key considerations for future research include sample size calculation, endoscopic procedure details, outpatient vs. inpatient treatment, and detailed cost calculations. The study's exclusions, such as patients with upper gastric surgery, phytobezoars older than 14 d, and cases of gastroparesis, limit its applicability to broader populations, especially in Western countries. Given the promising outcomes of the Coca-Cola treatment, it's advocated as a first-line therapy for phytobezoars. Nonetheless, further research is essential to overcome these limitations. However special situations such as perforation or small bowel obstruction will require surgical treatment.

Precision in detecting colon lesions: A key to effective screening policy but will it improve overall outcomes?

Colonoscopy is the gold standard for the screening and diagnosis of colorectal cancer, resulting in a decrease in the incidence and mortality of colon cancer. However, it has a 21% rate of missed polyps. Several strategies have been devised to increase polyp detection rates and improve their characterization and delimitation. These include chromoendoscopy (CE), the use of other devices such as Endo cuffs, and major advances in endoscopic equipment [high definition, magnification, narrow band imaging, i-scan, flexible spectral imaging color enhancement, texture and color enhancement imaging (TXI), etc.]. In the retrospective study by Hiramatsu et al, they compared white-light imaging with CE, TXI, and CE + TXI to determine which of these strategies allows for better definition and delimitation of polyps. They concluded that employing CE associated with TXI stands out as the most effective method to utilize. It remains to be demonstrated whether these results are extrapolatable to other types of virtual CE. Additionally, further investigation is needed in order to ascertain whether this strategy could lead to a reduction in the recurrence of excised lesions and potentially lower the occurrence of interval cancer.

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Lipidome Profiling in Childhood Obesity Compared to Adults: A Pilot Study.

The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome of adults with obesity before and after bariatric surgery. Ten pediatric (PE) and thirty adult (AD) patients with obesity were prospectively recruited at a referral single center. The PE cohort received lifestyle recommendations. The AD cohort underwent bariatric surgery. Clinical parameters and lipidome were analyzed in serum before and after six months of metabolic intervention. The abundance of phosphatidylinositols in the PE cohort and phosphatidylcholines in the AD significantly increased, while O-phosphatidylserines in the PE cohort and diacyl/triacylglycerols in the AD decreased. Fifteen lipid species were coincident in both groups after lifestyle intervention and bariatric surgery. Five species of phosphatidylinositols, sphingomyelins, and cholesteryl esters were upregulated. Eight species of diacylglycerols, glycerophosphoglycerols, glycerophosphoethanolamines, and phosphatidylcholines were downregulated. Most matching species were regulated in the same direction except for two phosphatidylinositols: PI(O-36:2) and PI(O-34:0). A specific set of lipid species regulated after bariatric surgery in adult individuals was also modulated in children undergoing lifestyle intervention, suggesting they may constitute a core circulating lipid profile signature indicative of early development of obesity and improvement after clinical interventions regardless of individual age.

Novel pharmacological approaches in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.

Síndrome de Wildervanck: reporte de un caso clínico / Wildervanck syndrome: clinical case report

El síndrome de Wildervanck (cérvico-óculo-acústico) es una patología muy rara, caracterizada por la tríada clásica de fusión de vértebras cervicales o anomalía de Klippel-Feil, síndrome de Duane (paresia del VI par craneal) e hipoacusia. Se han descrito, además, otras afecciones a nivel vascular, cardíaco y musculoesquelético. En este caso clínico, describimos a una paciente que cumple la tríada cardinal, además de presentar datos clínicos adicionales que no han sido reportados con anterioridad, lo cual contribuye a la ampliación del fenotipo de la enfermedad. Asimismo, realizamos una revisión de la literatura respecto a este síndrome

Wildervanck syndrome (also known as cervico-oculo-acoustic dysplasia) is a very rare disease, characterized by the typical triad of cervical vertebral fusion or Klippel-Feil anomaly, Duane syndrome (paresis of the sixth cranial nerve), and hearing loss. Other vascular, cardiac, and musculoskeletal conditions have also been described. In this case report, we describe a patient who met the cardinal triad and also presented additional clinical data that have not been previously reported, which contribute to broadening the disease phenotype. We have also reviewed the bibliography related to this syndrome.

Identification of Compound Heterozygous EVC2 Gene Variants in Two Mexican Families with Ellis-van Creveld Syndrome.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. METHODS: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. RESULTS: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. CONCLUSION: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.

Wildervanck syndrome: clinical case report. / Síndrome de Wildervanck: reporte de un caso clínico.

Wildervanck syndrome (also known as cervico-oculo-acoustic dysplasia) is a very rare disease, characterized by the typical triad of cervical vertebral fusion or Klippel-Feil anomaly, Duane syndrome (paresis of the sixth cranial nerve), and hearing loss. Other vascular, cardiac, and musculoskeletal conditions have also been described. In this case report, we describe a patient who met the cardinal triad and also presented additional clinical data that have not been previously reported, which contribute to broadening the disease phenotype. We have also reviewed the bibliography related to this syndrome.

El síndrome de Wildervanck (cérvico-óculo-acústico) es una patología muy rara, caracterizada por la tríada clásica de fusión de vértebras cervicales o anomalía de Klippel-Feil, síndrome de Duane (paresia del VI par craneal) e hipoacusia. Se han descrito, además, otras afecciones a nivel vascular, cardíaco y musculoesquelético. En este caso clínico, describimos a una paciente que cumple la tríada cardinal, además de presentar datos clínicos adicionales que no han sido reportados con anterioridad, lo cual contribuye a la ampliación del fenotipo de la enfermedad. Asimismo, realizamos una revisión de la literatura respecto a este síndrome.

Utilidad de la midodrina para controlar el síncope vasovagal: ¿la recomienda la evidencia? / Usefulness of Midodrine for the Control of Recurrent Vasovagal Syncope: Does the Evidence Recommend it? / Utilidade da midodrina no controle da síncope vasovagal: as evidencias a recomendam?

Introducción:El síncope vasovagal es la principal causa de pérdida transitoria de la conciencia, y es un motivo de consulta cada vez más frecuente en pediatría y medicina del adulto. La midodrina es un agonista de los recepto-res alfa, de acción periférica, empleada principalmente en el manejo de la hipotensión ortostática; sin embargo, también se ha evaluado en el síncope vasovagal, con resultados prometedores.Objetivo:Analizar la evidencia más reciente sobre la utilidad de la midodrina para el control y la prevención del síncope vasovagal.Materiales y métodos: Se realizó una búsqueda bibliográfica utilizando términos de búsqueda como Vasovagal Syncope y Midodrine, así como sinónimos, que se combinaron con operadores booleanos, en cinco bases de datos, hasta octubre del 2022. Se incluyeron estudios originales, revisiones sistemáticas y metanálisis, publicados tanto en inglés como en español.Resultados:Ensayos controlados aleatorizados y revisiones sistemáticas y metanálisis difieren ligeramente entre resultados, pero estos demuestran un efecto global protector. La evidencia más reciente y completa indica que utilizar este agente reduce significativamente la positividad al realizar la prueba de la mesa inclinada y que previene la aparición de episodios sincopales.Conclusiones:Aunque la evidencia actual sobre la eficacia de la midodrina respecto a la prevención y control del síncope vasovagal es limitada, se observa un efecto protector significativo, porque disminuye el riesgo de sufrir un episodio sincopal, aproximadamente hasta en un 50 %.Palabras clave: midodrina; síncope vasovagal; síncope; adrenérgicos; medicina basada en la evidencia

Introduction: Vasovagal syncope is the main cause of transient loss of consciousness, being an in-creasingly frequent reason for consultation in pediatrics and adult medicine. Midodrine, a periphe-rally acting alpha-receptor agonist, is mainly used in the management of orthostatic hypotension. However, it has also been evaluated in vasovagal syncope, with promising results. Objective: To analyze the most recent evidence on the usefulness of midodrine for the control and prevention of vasovagal syncope. Materials and Methods: A literature search was performed using search terms such as "Vasovagal Syncope" and "Midodrine," as well as synonyms, which were combined with Boolean operators, in 5 databases until October 2022. Original studies, systematic reviews and meta-analyses, published in both English and Spanish, were included. Results: Randomized controlled trials and systematic reviews and meta-analyses differ slightly between results, but these demonstrate an overall protective effect. The most recent and complete evidence shows that using this agent significantly reduces the probability of positivity when performing the tilt table test and prevents the occurrence of syncopal episodes. Conclusions: Although current evidence on the efficacy of midodrine with respect to the prevention and control of vasovagal syncope is limited, a significant protective effect is observed, reducing the risk of suffering syncopal episode by approximately up to 50%

Introdução: a síncope vasovagal é a principal causa de perda transitória de consciência e é um motivo cada vez mais comum de consulta em pediatria e medicina de adultos. A midodrina é um agonista do receptor alfa de ação periférica usado principalmente no tratamento da hipotensão ortostática; no entanto, ela também foi avaliada na síncope vasovagal, com resultados promissores. Objetivo: Revisar as evidências mais recentes sobre a utilidade da midodrina para o controle e a pre-venção da síncope vasovagal. Materiais e métodos: Foi realizada uma pesquisa na literatura usando termos de pesquisa como Va-sovagal, Syncope e Medodrine, bem como sinônimos, que foram combinados com operadores boo-leanos, em cinco bancos de dados, até outubro de 2022. Foram incluídos estudos originais, revisões sistemáticas e metanálises, publicados em inglês e espanhol. Resultados: Os ensaios clínicos randomizados, as revisões sistemáticas e as metanálises diferem ligei-ramente entre os resultados, mas demonstram um efeito protetor geral. As evidências mais recentes e abrangentes indicam que o uso desse agente reduz significativamente a positividade no teste de inclinação da mesa e evita a ocorrência de episódios de síncope. Conclusões: Embora as evidências atuais sobre a eficácia da midodrina em relação à prevenção e ao controle da síncope vasovagal sejam limitadas, observa-se um efeito protetor significativo, pois ela diminui o risco de sofrer um episódio sincopal em aproximadamente 50%

Challenging Endocrine Sensitivity of Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with the Combination of Eribulin and Endocrine Therapy: The REVERT Study.

BACKGROUND: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. METHODS: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/- AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. RESULTS: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8-55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7-71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. CONCLUSION: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo-endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.

Exploring the immunomodulatory role of virtual memory CD8+ T cells: Role of IFN gamma in tumor growth control.

Virtual memory CD8+ T cells (TVM) have been described as cells with a memory-like phenotype but without previous antigen (Ag) exposure. TVM cells have the ability to respond better to innate stimuli rather than by TCR engagement, producing large amounts of interferon gamma (IFNγ) after stimulation with interleukin (IL)-12 plus IL-18. As a result of the phenotypic similarity, TVM cells have been erroneously included in the central memory T cell subset for many years. However, they can now be discriminated via the CD49d receptor, which is up-regulated only on conventional memory T cells (TMEM) and effector T cells (TEFF) after specific cognate Ag recognition by a TCR. In this work we show that systemic expression of IL-12 plus IL-18 induced an alteration in the normal TVM vs TMEM/TEFF distribution in secondary lymphoid organs and a preferential enrichment of TVM cells in the melanoma (B16) and the pancreatic ductal adenocarcinoma (KPC) tumor models. Using our KPC bearing OT-I mouse model, we observed a significant increase in CD8+ T cell infiltrating the tumor islets after IL-12+IL-18 stimulation with a lower average speed when compared to those from control mice. This finding indicates a stronger interaction of T cells with tumor cells after cytokine stimulation. These results correlate with a significant reduction in tumor size in both tumor models in IL-12+IL-18-treated OT-I mice compared to control OT-I mice. Interestingly, the absence of IFNγ completely abolished the high antitumor capacity induced by IL-12+IL-18 expression, indicating an important role for these cytokines in early tumor growth control. Thus, our studies provide significant new information that indicates an important role of TVM cells in the immune response against cancer.

TIM3 Expression in Anaplastic-Thyroid-Cancer-Infiltrating Macrophages: An Emerging Immunotherapeutic Target.

Anaplastic thyroid cancer (ATC) is a clinically aggressive form of undifferentiated thyroid cancer with limited treatment options. Immunotherapy for patients with ATC remains challenging. Tumor-associated macrophages (TAMs) constitute over 50% of ATC-infiltrating cells, and their presence is associated with a poor prognosis. Consequently, the development of new therapies targeting immune checkpoints in TAMs is considered a promising therapeutic approach for ATC. We have previously shown that soluble factors secreted by ATC cells induced pro-tumor M2-like polarization of human monocytes by upregulating the levels of the inhibitory receptor TIM3. Here, we extended our observations on ATC-cell-induced xenograft tumors. We observed a large number of immune cells infiltrating the ATC xenograft tumors. Significantly, 24-28% of CD45+ immune cells were macrophages (CD11b+ F4/80+). We further showed that 40% of macrophages were polarized toward a M2-like phenotype, as assessed by CD206 expression and by a significant increase in the Arg1/iNOS (M2/M1) ratio. Additionally, we found that ATC xenograft tumors had levels of TIM3 expression when determined by RT-PCR and immunofluorescence assays. Interestingly, we detected the expression of TIM3 in macrophages in ATC tumors by flow cytometry assays. Furthermore, TIM3 expression correlated with macrophage marker expression in human ATC. Our studies show that TIM3 is a newly identified immune checkpoint in macrophages. Since TIM3 is known as a negative immune regulator, it should be considered as a promising immunotherapeutic target for ATC.

Virtual Memory CD8+ T Cells: Origin and Beyond.

The presence of CD8+ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8+ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

OBJECTIVES: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. METHODS: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. RESULTS: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. CONCLUSIONS: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules.

Systemic sterile induced-co-expression of IL-12 and IL-18 drive IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain.

The development of neuroinflammation, as well as the progression of several neurodegenerative diseases, has been associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. However, the mechanism by which this occurs remains unclear. Here, we addressed the effect of systemic sterile induced-co-expression of IL-12 and IL-18, in the establishment of a novel cytokine-mediated model of neuroinflammation. Following peripheral hydrodynamic shear of IL-12 plus IL-18 cDNAs in C57BL/6 mice, we induced systemic and persistent level of IL-12, which in turn promoted the elevation of circulating pro-inflammatory cytokines TNF-α and IFN-γ, accompanied with splenomegaly. Moreover, even though we identified an increased gene expression of both TNF-α and IFN-γ in the brain, we observed that only IFN-γ, but not TNF-α signaling through its type I receptor, was required to induce both the trafficking of leukocytes from the periphery toward the brain and upregulate MHC-II in microglia and inflammatory monocytes. Therefore, only TNF-α was shown to be dispensable, revealing an IFN-γ-dependent activation of microglia and recruitment of leukocytes, particularly of highly activated inflammatory monocytes. Taken together, our results argue for a systemic cytokine-mediated establishment and development of neuroinflammation, having identified IFN-γ as a potential target for immunomodulation.

Safety levels of systemic IL-12 induced by cDNA expression as a cancer therapeutic.

Aim: The aim of this work is to utilize a gene expression procedure to safely express systemic IL-12 and evaluate its effects in mouse tumor models. Materials & methods: Secondary lymphoid organs and tumors from EL4 and B16 tumor-bearing mice were analyzed by supervised and unsupervised methods. Results: IL-12 cDNA induced systemic IL-12 protein levels lower than the tolerated dose in patients. Control of tumor growth was observed in subcutaneous B16 and EL4 tumors. Systemic IL-12 expression induced a higher frequency of both total tumor-infiltrated CD45+ cells and proliferative IFN-γ+CD8+ T cells along with a lower frequency of CD4+FOXP3+ and CD11b+Gr-1+ cells. Conclusion: This approach characterizes the systemic effects of IL-12, helping to improve treatment of metastases or solid tumors.

Lay abstract IL-12 has emerged as a potent cytokine in mediating antitumor activity in preclinical models of cancer. However, this antitumor response has not yet been translated into the clinic because of toxic side effects. The aim of our work is to analyze the effects of IL-12 in mouse tumor models. We demonstrate that one injection of IL-12 cDNA can induce systemic IL-12 levels in serum even lower than the tolerated dose in patients. At this dose, an efficient control of tumor growth can be observed. We found a higher frequency of both total tumor-infiltrated leukocytes and IFN-γ-producing CD8⁺ T cells along with a lower frequency of regulatory CD4⁺FOXP3⁺ and CD11b⁺Gr1⁺ cells. Our work demonstrates that IL-12 cDNA can safely be used to treat cancer.

Evaluation of an educational intervention (edworkcases) involving clinical cases and Nursing students: a cross-sectional observational study / Avaliação de uma intervenção educacional (edworkcases) envolvendo casos clínicos e estudantes de Enfermagem: um estudo observacional transversal / Evaluación de una intervención educativa (edworkcases) que involucra casos clínicos y estudiantes de Enfermería: estudio transversal y observacional

Abstract Objective: to evaluate the impact of the (edworkcases) educational intervention on students' evaluation outcomes in their clinical practices, their attitudes towards Nursing diagnoses, and their satisfaction. Method: this study used a cross-sectional observational design. The participants were 69 third-year Nursing students from a public university in Madrid, Spain. The data analysed in the study were the grades obtained by students for their clinical practices, as well as pre-post intervention scores on the Positions on Nursing Diagnosis Scale and a satisfaction survey. A means comparison by participation in the project (yes/no) was carried out using Student's t-test. A means comparison by professor was conducted using Kruskal-Wallis tests. Results: participation rate: 72.4%; 92% of the participants were women; median age = 21 years old. Statistically significant differences were found between participants and non-participants in terms of mean score in the Overall Evaluation and in the Case Study Evaluation, with higher scores found among the group of participants. The mean score for attitudes towards Nursing diagnoses was 99.9 (SD=2.8) before the intervention and 111.1 (SD=2.9) after the intervention [95% CI: 3.3-19.2]. Conclusion: the use of (edworkcases) as part of the practical training was considered satisfactory, enabling theory and practice to be combined and improving students' attitudes towards Nursing diagnoses.

Resumo Objetivo: avaliar o impacto da intervenção educacional (edworkcases) nos resultados da avaliação dos alunos em suas práticas clínicas, suas atitudes em relação aos diagnósticos de Enfermagem e sua satisfação. Método: estudo observacional transversal, realizado com 69 estudantes do terceiro ano de Enfermagem de uma universidade pública de Madri, Espanha. Os dados analisados foram obtidos das notas dos alunos em suas práticas clínicas, bem como, os escores pré- e pós-intervenção na Escala de Posições frente ao Diagnóstico de Enfermagem e uma pesquisa de satisfação. A comparação de médias por participação no projeto (sim/não) foi realizada por meio do teste t de Student. A comparação de médias por professor foi realizada por meio de testes de Kruskal-Wallis. Resultados: taxa de participação: 72,4%; 92% dos participantes eram mulheres; mediana de idade de 21 anos. Foram encontradas diferenças estatisticamente significativas entre participantes e não participantes em termos de pontuação média na Avaliação Geral e na Avaliação do Estudo de Caso, com maiores pontuações encontradas entre o grupo de participantes. A pontuação média das atitudes em relação aos diagnósticos de Enfermagem foi de 99,9 (DP=2,8) antes da intervenção e 111,1 (DP=2,9) após a intervenção [IC 95%: 3,3-19,2]. Conclusão: a utilização de edworkcases como parte do treinamento prático foi considerada satisfatória, permitindo a articulação teoria e prática e melhorando as atitudes dos alunos em relação aos diagnósticos de Enfermagem.

Resumen Objetivo: evaluar el efecto de la intervención educativa (edworkcases) sobre los resultados de la evaluación de los estudiantes en sus prácticas clínicas, sus actitudes hacia los diagnósticos de Enfermería y su nivel de satisfacción. Método: en este estudio se empleó un diseño transversal y observacional. Los participantes fueron 68 estudiantes de tercer año de la carrera de Enfermería de una universidad pública de Madrid, España. Los datos que se analizaron en el estudio fueron las calificaciones obtenidas por los estudiantes en sus prácticas clínicas, al igual que las puntuaciones antes y después de la intervención en la Escala de Posicionamiento ante el Diagnóstico de Enfermería y en una encuesta de satisfacción. Se utilizó la prueba t de Student para realizar una comparación de valores medios por participación en el proyecto (sí/no). La comparación de valores medios por profesor se llevó a cabo por medio de pruebas Kruskal-Wallis. Resultados: índice de participación: 72,4%; el 92% de los participantes eran mujeres, con una mediana de edad de 21 años. Se encontraron diferencias estadísticamente significativas entre participantes y no participantes en cuanto a la puntuación media en la Evaluación General y en la Evaluación de Estudios de Caso, con puntuaciones más elevadas en el grupo de participantes. Las puntuaciones medias correspondientes a las actitudes con respecto a los diagnósticos de Enfermería fueron 99,9 (SD=2,8) y 111.1 (SD=2.9) antes y después de la intervención, respectivamente [IC 95%: 3,3-19,2]. Conclusión: se consideró satisfactorio utilizar edworkcases como parte te la capacitación práctica, lo que permitió combinar teoría y práctica y mejorar las actitudes de los estudiantes con respecto a los diagnósticos de Enfermería.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis.

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1'-dioctadecyl-3,3,3',3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.