Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has ...recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.
Aims: No long-term studies of renal function evolution in morbidly obese (MO) patients after weight loss are available. The aim of our work was to ascertain the long-term influence of drastic weight ...reduction on renal function in MO patients with obesity-related glomerular lesions. Methods: 92 MO patients with normal renal function and biopsy evidence of mild obesity-related glomerulopathy underwent bariatric surgery (BS) and subsequent drastic weight loss. A long-term prospective follow-up (mean duration: 76 ± 42 months) was carried out. Basal renal biopsies and basal and long-term metabolic and renal function studies were performed in all cases. Linear mixed models were applied. Results: Blood pressure dropped early after BS and remained stable thereafter. Creatinine clearance and BMI fell in the first 2 years, rose slightly after 5 years and then remained stable. Serum creatinine and albuminuria decreased throughout the follow-up period. Renal function and albuminuria evolution showed non-significant differences in relation to the number of glomerular lesions. Conclusions: Drastic weight loss in BS-treated MO patients with pre-surgical normal renal function and mild obesity-related glomerular lesions is associated with short- and long-term maintenance of normal renal function and improvement in both arterial hypertension and albuminuria.
Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (
) and activin A receptor type II-like 1 (
) ...genes are detected in more than 90% of the patients undergoing molecular testing. The identification of variants of unknown significance is often seen as a challenge in clinical practice that makes family screening and genetic counseling difficult. Here, we show that the implementation of cDNA analysis to assess the effect of splice site variants on mRNA splicing is a powerful tool.
Gene panel sequencing of genes associated with HHT and other arteriovenous malformation-related syndromes was performed. To evaluate the effect of the splice site variants, cDNA analysis of
and
genes was carried out.
three novel splice site variants were identified in
(c.68-2A > T and c.1311+4_1311+8del) and
(c.526-6C > G) genes correspondingly in three individuals with HHT that met ≥ 3 Curaçao criteria. All three variants led to an aberrant splicing inducing exon skipping (
:c.68-2A > T and
:c.526-6C > G) or intron retention (
:c.1311+4_1311+8del) allowing the confirmation of the predicted effect on splicing and the reclassification from unknown significance to pathogenic/likely pathogenic of two of them.
RNA analysis should be performed to assess and/or confirm the impact of variants on splicing. The molecular diagnosis of HHT patients is crucial to allow family screening and accurate genetic counseling. A multidisciplinary approach including clinicians and geneticists is crucial when dealing with patients with rare diseases.
Abstract Background Spinal anesthesia has been considered inappropriate for ambulatory surgery patients because of concern about voiding dysfunction. The purpose of this study was to analyze the ...relationship between voiding interval and type of surgery under spinal anesthesia with lidocaine and to identify other nonanesthetic risk factors for delayed voiding. Patients and methods A prospective study of 406 patients undergoing to ambulatory surgery under spinal anesthesia with lidocaine was performed. Voiding interval was defined as the time in minutes from the injection of local anesthetic to the patient's first spontaneous voiding. Univariate and multivariate linear regression models were constructed to identify risk factors associated with length of voiding interval. Results A total of 187 patients underwent herniorrhaphy; 187 patients underwent lower limb surgery; and 32 patients went benign anorectal surgery. The mean ± sd voiding interval was 230 ± 50.5 minutes. Factors associated with length of voiding interval in the univariate analysis were sex, body mass index (BMI), type and duration of surgery, lidocaine dose, and volume of fluid administered. Factors that remained significant in the multivariate model were sex, BMI, lidocaine dose and type of surgery: spontaneous voiding came later after inguinal herniorrhaphy surgery than after lower-limb surgery (regression coefficient 20 minutes; 95% confidence interval 11.5–29.8). Multivariate models performed for each type of surgery separately identified sex and lidocaine dose as factors related to length of voiding interval in all types of surgery. Conclusions A longer voiding interval was associated with inguinal herniorrhaphy, spinal lidocaine dose, and male sex.
Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy. These conditions are distinguished ...by bilateral and relatively symmetrical abnormalities in the macula that significantly impair central visual function. Recent strides in fundus imaging, especially optical coherence tomography (OCT), have enhanced our comprehension and diagnostic capabilities for MD. OCT enables the identification of neurosensory retinal disorganization patterns and the extent of damage to retinal pigment epithelium (RPE) and photoreceptor cells in the dystrophies before visible macular pathology appears on fundus examinations. It not only helps us in diagnostic retinal and choroidal pathologies but also guides us in monitoring the progression of, staging of, and response to treatment. In this review, we summarize the key findings on OCT in some of the most common MD.
The Eastern woodchuck (
) has been extensively used in research of chronic hepatitis B and liver cancer because its infection with the woodchuck hepatitis virus closely resembles a human hepatitis B ...virus infection. Development of novel immunotherapeutic approaches requires genetic information on immune pathway genes in this animal model. The woodchuck genome was assembled with a combination of high-coverage whole-genome shotgun sequencing of Illumina paired-end, mate-pair libraries and fosmid pool sequencing. The result is a 2.63 Gigabase (Gb) assembly with a contig N50 of 74.5 kilobases (kb), scaffold N50 of 892 kb, and genome completeness of 99.2%. RNA sequencing (RNA-seq) from seven different tissues aided in the annotation of 30,873 protein-coding genes, which in turn encode 41,826 unique protein products. More than 90% of the genes have been functionally annotated, with 82% of them containing open reading frames. This genome sequence and its annotation will enable further research in chronic hepatitis B and hepatocellular carcinoma and contribute to the understanding of immunological responses in the woodchuck.
Background
Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine ...the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma.
Methods
Subjects were recruited into a COPD (emphysema versus airway disease EvA) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values).
Results
There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts.
Conclusion
Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
In a chronic obstructive pulmonary disease (COPD) cohort (EvA, n = 283), 12 genes, whereas in asthma cohort (UBIOPRED, n = 85), 1197 genes in bronchial epithelial brushes were correlated with a blood eosinophil count. The gene CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
Background
Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial ...changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non‐established biomarkers or effective treatments are available, partly due to the lack of validated disease models.
Methods
We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA‐seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls.
Results
Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P‐value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three‐fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time‐course autophagosome formation (LC3BII 39% reduced, P‐value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P‐value < 0.05) and function (30.2%‐decrease in respiration, 45.6%‐decline in enzymatic activity (P‐value < 0.001), 14.3%‐higher oxidative stress, 135.2%‐increased antioxidant defence (P‐value < 0.05), 11.6%‐reduced mitochondrial membrane potential (P‐value < 0.05) and 42.8%‐reduced mitochondrial elongation (P‐value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8‐fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis.
Conclusions
These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.
•Analysing the context in which health professionals accept influenza vaccination.•The analysis will help develop strategies to promote vaccination.•Reasons for acceptance or refusal of the influenza ...vaccine in the COVID-19 context.
With the outbreak of the SARS-CoV-2 pandemic, the uncertainty about the real impact of coinfection with other viruses, and the increased risk of mortality in the case of coinfection with the influenza virus, health authorities recommended an increase in influenza vaccination coverage among at-risk groups to minimize the possible impact on individuals and the healthcare system. Recommendations for influenza vaccination during the 2020–2021 campaign in Catalonia were focused on increasing vaccination coverage, especially for social and healthcare workers, elderly people and at-risk individuals of any age. The objectives for the 2020–2021 season in Catalonia were to reach 75 % for the elderly and for social and healthcare workers, and 60 % for pregnant women and at-risk groups. In the case of healthcare professionals and those over 65 years of age, the target was not met. Vaccination coverage reached 65.58 % and 66.44 %, respectively (in the 2019–2020 campaign it was 39.08 %).
Analysing and following up on the background and context in which health professionals accept influenza vaccination will help develop strategies for long-term influenza vaccination campaigns. The present study looks at healthcare professionals in a specific territory where the reasons for acceptance or refusal of the influenza vaccine during the 2021–2022 vaccination campaign, as well as the reasons for acceptance or refusal of the COVID-19 vaccine, were analysed by means of an online survey.
Calculations suggested that a random sample of 290 individuals would be sufficient to estimate, with 95% confidence and a precision of +/- 5 percentage units, a population percentage that was expected to be around 30%. The required replacement rate was 10%.
The R statistical software (version 3.6.3) was used for the statistical analysis. Confidence intervals were 95 % and contrasts with a p-value of < 0.05 were considered significant.
Of the 1921 professionals to whom the survey was sent, 586 (30.5%) responded to all the questions. 95.2% of respondents were vaccinated against COVID-19 and 66.2% against influenza.
It was observed that the relationship between sociodemographic characteristics and the decision to get vaccinated was different for influenza and COVID-19. The reasons for accepting the COVID-19 vaccine with the highest percentage were firstly protecting family (82.2%), self-protection (74.9%) and also protecting patients (57.8%). Otherwise, other reasons not described in the survey (50%) and mistrust (42.3%) were the reasons for rejecting the COVID-19 vaccine.
Regarding influenza, the most relevant reasons for which professionals got vaccinated were self-protection (70.7%), protecting family (69.7%) and protecting patients (58.4%). Reasons for refusing the influenza vaccine were reasons not mentioned in the survey (29.1%) and the low probability of suffering complications (27.4%).
Analysing the context, territory, sector, and the reasons for both accepting and refusing a vaccine will help develop effective strategies. Although vaccination coverage against COVID-19 was very high throughout Spain, a marked increase in influenza vaccination in the context of COVID-19 was observed among healthcare professionals in the Central Catalonia region compared to the previous pre-pandemic campaign.
Although routinely monitored by ground based air quality networks, the particulate matter distribution could be eventually better described with remote sensing techniques. However, valid ...relationships between ground level and columnar ground based quantities should be known beforehand. In this study we have performed a comparison between particulate matter measurements at ground level at different cut sizes (10, 2.5 and 1.0 μm), and the aerosol optical depth obtained by means of a ground based sunphotometer during a multiinstrumental field campaign held in El Arenosillo (Huelva, Spain) from 28 June to 4 July 2006. All the PM fractions were very well correlated with AOD with correlation coefficients that ranged from 0.71 to 0.81 for PM10, PM2.5 and PM1. Furthermore, the influence of the mixing layer height in the correlations was explored. The improvement in the correlation when the vertical distribution is taken into account was significant for days with a homogeneous mixing layer. Moreover, the chemical analysis of the individual size fractions allowed us to study the origin of the particulate matter. Secondary components were the most abundant and also well correlated in the three size fractions; but for PM10 fraction, chemical species related to marine origin were best correlated. Finally, we obtained a relationship between MODIS L3 AOD from collection 5.1 and the three PM cut sizes. In spite of being a relatively clean environment, all the techniques were able to capture similar day to day variations during this field campaign.
Key Points
The relationship between ground and columnar aerosol burdens has been studied
The influence of the mixing layer and aerosol chemistry has been analyzed
A remote transport pollution episode was identified and discussed
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