Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Efficacy and safety of PARP inhibitor in non-small cell lung cancer: a systematic review with meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) has undergone a major change in the last decade in terms of survival and prognosis due to the introduction of new drugs in the last 10 years. One of the drugs with the most promising preliminary results in NSCLC are PARP inhibitors (iPARPs), whose clinical trials have very heterogeneous results. The use of iPARPs in NSCLC may lead to increased survival in several selected patients, and their use may become a standard in the coming years. However, there is currently controversy about the efficacy and safety of these drugs in NSCLC. Therefore, future studies are needed to evaluate their role in these tumours. The aim of this review is to evaluate the efficacy and safety of iPARPs in the treatment of NSCLC. METHODS: We performed a systematic review with meta-analysis using the different clinical trials (PubMed, COCHRANE, Science Direct, EMBASE and the clinical trial registry) that evaluated the efficacy and safety of iPARP in NSCLC by PRISMA criteria. The primary endpoint was to evaluate the efficacy of iPARPs in the treatment of NSCLC through overall and progression-free survival (OS and PFS). Two authors independently reviewed the articles and abstracts (A.O.H. and J.R.R.), with subsequent confirmation by a third independent reviewer (E.B.M.). The heterogeneity of the included studies in the meta-analysis was assessed by using the I2 statistic. RESULTS: A total of 14 articles were included for analysis (2,651 patients). A total of 1,503 patients were randomised in iPARP arms and 1,148 patients were included in control arms. Three clinical trials were conducted in localised or locally advanced NSCLC and 11 in advanced or metastatic stages. The global OS of the meta-analysis showed a hazard ratio (HR) of 0.85 [95% confidence interval (CI): 0.74-0.97] with a heterogeneity (I2) of 0% (P=0.84). PFS showed a HR of 0.93 (95% CI: 0.74-1.17) with an I2=51% (P=0.07). The overall adverse event rate (grade 1-5) was similar in both iPARP and placebo arms. CONCLUSIONS: iPARPs are a future promising in the treatment of NSCLC in terms of efficacy and safety. Proper patient selection [homologous recombination deficiency (HRD) positive] is key for future clinical trials. The studies conducted to date open a new approach for a novel treatment modality in NSCLC.

25-Hydroxyvitamin D Serum Levels Linked to Single Nucleotide Polymorphisms (SNPs) (rs2228570, rs2282679, rs10741657) in Skeletal Muscle Aging in Institutionalized Elderly Men Not Supplemented with Vitamin D.

Sarcopenia (Sp) is the loss of skeletal muscle mass associated with aging that results in an involution of muscle function and strength. Vitamin D deficiency is a common health problem worldwide, especially among the elderly, and hypovitaminosis D leads to musculoskeletal disorders. The aim of this study was to evaluate the impact and presence of a possible linkage between Single Nucleotide Polymorphisms (SNPs) CYP2R1 (rs10741657), GC (rs2282679), and VDR (rs2228570), serum 25-OH/D concentrations and the link with the degree of sarcopenia in 19 institutionalized elderly men not supplemented with vitamin D. Levels of 25-OH vitamin D were quantified with a commercial enzyme-linked immunosorbent assay kit and 3 SNPs were genotyped with KASPar assays. Significant differences in 25-OH/D concentration were determined between the bi-allelic combinations of rs228679 and rs228570. We detected statistically significant weak positive correlations between the AA (rs10741657 and rs228570) and TT (rs228679) and alleles and 25-OH/D and the probability of having higher 25-OH/D concentrations was 2- to 3-fold higher. However, the GG alleles of the 3 SNPs showed that the probability of having optimal 25-0H/D concentrations decreases by 32% for rs10741657, 38% for rs228679, and 74% for rs228570, showing a strong negative correlation between the degree of sarcopenia and 25-OH/D levels. Allelic variations in CYP2R1 (rs10741657), GC (rs2282679), and VDR (rs10741657) affect vitamin D levels and decisively influence the degree of sarcopenia in institutionalized elderly people.

Long COVID a New Derivative in the Chaos of SARS-CoV-2 Infection: The Emergent Pandemic?

Coronavirus disease 2019 (COVID-19) is a multisystem illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can manifest with a multitude of symptoms in the setting of end-organ damage, though it is predominantly respiratory. However, various symptoms may remain after acute SARS-CoV-2 infection, and this condition is referred to as "Long COVID" (LC). Patients with LC may develop multi-organ symptom complex that remains 4-12 weeks after the acute phase of illness, with symptoms intermittently persisting over time. The main symptoms are fatigue, post-exertional malaise, cognitive dysfunction, and limitation of functional capacity. Pediatric patients developed the main symptoms of LC like those described in adults, although there may be variable presentations of LC in children. The underlying mechanisms of LC are not clearly known, although they may involve pathophysiological changes generated by virus persistence, immunological alterations secondary to virus-host interaction, tissue damage of inflammatory origin and hyperactivation of coagulation. Risk factors for developing LC would be female sex, more than five early symptoms, early dyspnea, previous psychiatric disorders, and alterations in immunological, inflammatory and coagulation parameters. There is currently no specific treatment for LC, but it could include pharmacological treatments to treat symptoms, supplements to restore nutritional, metabolic, and gut flora balance, and functional treatments for the most disabling symptoms. In summary, this study aims to show the scientific community the current knowledge of LC.

Glycophosphopeptical AM3 Food Supplement: A Potential Adjuvant in the Treatment and Vaccination of SARS-CoV-2.

The world is currently experiencing the coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome-2 (SARS-CoV-2). Its global spread has resulted in millions of confirmed infections and deaths. While the global pandemic continues to grow, the availability of drugs to treat COVID-19 infections remains limited to supportive treatments. Moreover, the current speed of vaccination campaigns in many countries has been slow. Natural substrates with biological immunomodulatory activity, such as glucans, may represent an adjuvant therapeutic agent to treat SARS-CoV-2. AM3, a natural glycophosphopeptical, has previously been shown to effectively slow, with no side effects, the progression of infectious respiratory diseases by regulating effects on innate and adaptive immunity in experimental models. No clinical studies, however, exist on the use of AM3 in SARS-CoV-2 infected patients. This review aims to summarize the beneficial effects of AM3 on respiratory diseases, the inflammatory response, modulation of immune response, and attenuation of muscle. It will also discuss its potential effects as an immune system adjuvant for the treatment of COVID-19 infections and adjuvant for SARS-CoV-2 vaccination.

Clinical Perspective and Translational Oncology of Liquid Biopsy.

The term liquid biopsy (LB) refers to the study of circulating tumor cells, circulating tumors nucleic acids free of cells or contained in exosomes, and information about platelets associated with tumors. LB can be performed in different biofluids and allows the limitations of tissue biopsy to be overcome offering possibilities of tumor identification reflecting in real time tumor heterogeneity. In addition, LB allows screening and early detection of cancer, real-time monitoring of therapy, stratification and therapeutic intervention, a therapeutic target and resistance mechanism, and a risk of metastatic relapse. Currently, LB has been shown to be effective for its application in different types of tumors including lung, colorectal, prostate, melanoma, breast and pancreatic cancer, by the determination and identification of biomarkers that with a high probability have the potential to change the way in which medical oncology could predict the course of the disease. These biomarkers make it possible to capture the heterogeneity of the cancer, monitor its clonal evolution, indicate new treatments or retreatments and evaluate the responses to different evolutionary and/or therapeutic pressures in the cancer disease.

Liquid Biopsy as Novel Tool in Precision Medicine: Origins, Properties, Identification and Clinical Perspective of Cancer's Biomarkers.

In recent years, there has been an increase in knowledge of cancer, accompanied by a technological development that gives rise to medical oncology. An instrument that allows the implementation of individualized therapeutic strategies is the liquid biopsy. Currently, it is the most innovative methodology in medical oncology. Its high potential as a tool for screening and early detection, the possibility of assessing the patient's condition after diagnosis and relapse, as well as the effectiveness of real-time treatments in different types of cancer. Liquid biopsy is capable of overcoming the limitations of tissue biopsies. The elements that compose the liquid biopsy are circulating tumor cells, circulating tumor nucleic acids, free of cells or contained in exosomes, microvesicle and platelets. Liquid biopsy studies are performed on various biofluids extracted in a non-invasive way, and they can be performed both from the blood and in urine, saliva or cerebrospinal fluid. The development of genotyping techniques, using the elements that make up liquid biopsy, make it possible to detect mutations, intertumoral and intratumoral heterogeneity, and provide molecular information on cancer for application in medical oncology in an individualized way in different types of tumors. Therefore, liquid biopsy has the potential to change the way medical oncology could predict the course of the disease.

Ergonomic assessment for the task of repairing computers in a manufacturing company: A case study.

BACKGROUND: Manufacturing industry workers who repair computers may be exposed to ergonomic risk factors. OBJECTIVES: This project analyzes the tasks involved in the computer repair process to (1) find the risk level for musculoskeletal disorders (MSDs) and (2) propose ergonomic interventions to address any ergonomic issues. METHODS: Work procedures and main body postures were video recorded and analyzed using task analysis, the Rapid Entire Body Assessment (REBA) postural method, and biomechanical analysis. RESULTS: High risk for MSDs was found on every subtask using REBA. Although biomechanical analysis found an acceptable mass center displacement during tasks, a hazardous level of compression on the lower back during computer's transportation was detected. CONCLUSIONS: This assessment found ergonomic risks mainly in the trunk, arm/forearm, and legs; the neck and hand/wrist were also compromised. Opportunities for ergonomic analyses and interventions in the design and execution of computer repair tasks are discussed.

Pioderma gangrenoso peri-ileostomía / Peri-ileostomy pyoderma gangrenosum. Case report

El pioderma gangrenoso es una de las complicaciones más graves que se pueden presentar tras la realización de un estoma. A pesar de los pocos casos descritos en la literatura, se considera que está infradiagnosticado. Se presenta un caso de pioderma gangrenoso peri-ileostomía en una paciente sometida a pancoloproctectomía e ileostomía definitiva por colitis ulcerosa. El tratamiento se basó en curas locales, adecuación de los dispositivos colectores, aplicación tópica de tacrolimus y administración sistémica de corticoides, adalimumab y antibióticos. La curación se produjo en ocho semanas de manera satisfactoria (AU)

Pyoderma gangrenosum is one of the most severe complications that can occur following stoma placement. Despite few cases reported in the literature, it is considered an underdiagnosed entity. We present a case of peri-ileostomy pyoderma gangrenosum (PPG) in a patient who underwent a pancoloproctectomy and permanent ileostomy due to ulcerative colitis (UC). Treatment was based on local cures, proper fitting of ostomy devices, topical tacrolimus and systemic corticosteroids, adalimumab and antibiotics. Satisfactory resolution was achieved in eight weeks (AU)

Hibernoma inguinal. Ejemplo de tumor adiposo poco frecuente / Inguinal hibernoma, a rare tumour of the adipose tissue. A case report

Presentamos en nuestro trabajo un hibernoma localizado en la región inguinal, diagnosticado en un varón de 64 años. Elementos clave para el diagnóstico fueron la identificación del tejido graso pardo y la ausencia de lipoblastos, lo que nos permitió descartar la posibilidad de un liposarcoma. Los estudios inmunohistoquímicos y citogenéticos apoyaron nuestra sospecha diagnostica(AU)

A case of hibernoma located in the inguinal region in a 64 year old male is presented. The identification of brown adipose tissue and the absence of lipoblasts were the most important diagnostic features, essential in the differential diagnosis with liposarcoma. Immunohistochemistry and cytogenetics confirmed the diagnosis of a hibernoma(AU)

Deficient spindle assembly checkpoint in multiple myeloma.

Multiple myeloma (MM) is a hematological disease characterized by an abnormal accumulation of plasma cells in the bone marrow. These cells have frequent cytogenetic abnormalities including translocations of the immunoglobulin heavy chain gene and chromosomal gains and losses. In fact, a singular characteristic differentiating MM from other hematological malignancies is the presence of a high degree of aneuploidies. As chromosomal abnormalities can be generated by alterations in the spindle assembly checkpoint (SAC), the functionality of such checkpoint was tested in MM. When SAC components were analyzed in MM cell lines, the RNA levels of most of them were conserved. Nevertheless, the protein content of some key constituents was very low in several cell lines, as was the case of MAD2 or CDC20 in RPMI-8226 or RPMI-LR5 cells. The recovery of their cellular content did not substantially affect cell growth, but improved their ability to segregate chromosomes. Finally, SAC functionality was tested by challenging cells with agents disrupting microtubule dynamics. Most of the cell lines analyzed exhibited functional defects in this checkpoint. Based on the data obtained, alterations both in SAC components and their functionality have been detected in MM, pointing to this pathway as a potential target in MM treatment.

High-resolution genome-wide analysis of chromosomal alterations in elastofibroma.

Elastofibroma is a rare, benign fibrous proliferation that most commonly occur in periscapular soft tissues and is characterized by accumulated elastic fibers. Although the lesion is generally regarded as a reactive process, an unusual fibroblastic pseudotumor or as a fibroelastic tumor-like lesion, its etiology remains unknown. Cytogenetic studies in these lesions detected chromosomal instability and some recurrent clonal chromosomal changes, which raised the possibility that the lesion represents a neoplastic process. Here, we report the genomic alterations detected by array-based comparative genomic hybridization (aCGH) and by multiplex ligation-dependent probe amplification (MLPA) in two cases of elastofibroma. Both cases showed losses on 1p, 13q, 19p, and 22q by aCGH. In addition, deletion of CASR (3q21), GSTP1 (11q13), BRCA2 (13q12) and gains on APC (5q21) and PAH (12q23) were observed by MLPA in both samples. Genomic screening studies of this fibrous proliferation may lead to identify chromosomal regions containing genes involved in the development of elastofibromas.

Temporal evolution of organic carbon and nitrogen forms in volcanic soils under broom scrub affected by a wildfire.

The evolution of total N, total oxidizable C, water-soluble NH(4)(+)-N, exchangeable NH(4)(+)-N and soluble NO(3)(-)-N was studied in Canarian volcanic soils under mountainous legume scrub affected by a wildfire by June 2003. Three systematic soil samplings in the burned area and in neighbouring non-burned sampling points were carried out 3, 7 and 12 months after the fire event. The results showed an important mobilization of N (as total N and soluble and exchangeable NH(4)(+)-N) in the soil within the burned area at short term, with a simultaneous depletion of nitrates. Later on, the water-soluble NH(4)(+)-N levels remained nearly constant along the study period in the burned area, whereas the exchangeable NH(4)(+) decreased progressively. Nitrates were found to increase inside and outside the burned area, but the increase rate was much higher for the burned samples. Total N fluctuated along the year, although its levels were generally higher in the burned area. However, such a response pattern of N to fire in this environment was insufficient to prompt the recovery of the plant cover.

Análisis del proceso evaluador de los proyectos de investigación en el Fondo de Investigación Sanitaria / Analysis of evaluation process in research projects submitted to the Fondo de Investigación Sanitaria, Spain

Fundamento: La promoción y el fomento de la investigación es actualmente una de las estrategias fundamentales sobre la que se asienta el desarrollo de nuestra sociedad moderna. Los países están invirtiendo grandes recursos destinados a este fin, y por ello se hace necesario un proceso serio y riguroso de evaluación de la investigación, así como el análisis de los resultados obtenidos en los numerosos proyectos de investigación subvencionados tanto en convocatorias públicas como privadas, para asegurar el buen fin de las inversiones realizadas. Material y método: Se ha analizado una muestra de 431 proyectos pertenecientes a la convocatoria FIS de 1998. Las evaluaciones FIS y ANEP (Agencia Nacional de Evaluación y Prospectiva) fueron analizadas y puntuadas (calidad de evaluación) en sus principales contenidos por tres evaluadores independientes; asimismo, los resultados fueron sometidos a comparaciones intraagencia e interagencia. Resultados: En la evaluación FIS intervinieron 20 comisiones, y el análisis intraFIS detectó que la calidad de la evaluación era dependiente de la comisión correspondiente responsable de la evaluación (F = 3,71; p < 0,001) y de la duración propuesta para el proyecto evaluado (F = 3,42; p < 0,05), pero no del evaluador. Por otro lado, la calidad de la evaluación ANEP era dependiente de los tres factores anteriormente mencionados. Globalmente, la calidad de la evaluación ANEP fue mejor que la evaluación FIS en los proyectos de 3 años, pero no fue significativamente distinta para los proyectos de uno a dos años. En todos los casos, las evaluaciones con resultados final negativo (denegación de la financiación) tuvieron una calidad media más alta que las positivas. Conclusiones: Los resultados obtenidos aconsejan una modificación de la estructura evaluativa y de la composición de las comisiones científico-técnicas del FIS que tenga como finalidad una mejora del proceso de evaluación de los proyectos de investigación presentados en convocatoria pública al FIS. (AU)