Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

ISG15 as a prognostic biomarker in solitary fibrous tumour.

BACKGROUND: Solitary fibrous tumour (SFT) is a rare mesenchymal malignancy that lacks robust prognostic and predictive biomarkers. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier, associated with tumour progression, and with poor survival of SFT patients, as previous published by our group. Here, we describe the role of ISG15 in the biology of this rare tumour. METHODS: ISG15 expression was assessed by immunohistochemistry in tissue microarrays from SFT patients and tested for correlation with progression-free survival and overall survival (OS). The effects of ISG15 knockdown or induction were investigated for cancer stem cell (CSC) characteristics and for drug sensitivity in unique in vitro models of SFT. RESULTS: The prognostic value of ISG15 for OS was validated at protein level in malignant SFT patients, prospectively treated with pazopanib and enrolled in GEIS-32 trial. In SFT in vitro models, ISG15 knockdown lead to a decrease in the expression of CSC-related genes, including SOX2, NANOG, ALDH1A1, ABCB1 and ABCC1. Likewise, ISG15 downregulation decreased the clonogenic/ tumoursphere-forming ability of SFT cells, while enhancing apoptotic cell death after doxorubicin, pazopanib or trabectedin treatment in 3D cell cultures. The regulation of CSC-related genes by ISG15 was confirmed after inducing its expression with interferon-ß1; ISG15 induction upregulated 1.28- to 451-fold the expression of CSC-associated genes. CONCLUSIONS: ISG15 is a prognostic factor in malignant SFT, regulating the expression of CSC-related genes and CSCs maintenance. Our results suggest that ISG15 could be a novel therapeutic target in SFT, which could improve the efficacy of the currently available treatments.

CDKN2A deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

Nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNAs) with prognostic significance. Here, investigating 5 formalin-fixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing (WGS), we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNAs. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCL-NOS with absolute specificity. In contrast, these deletions were rare and never co-occurred in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, IPI, transplant eligibility and GATA3 expression (adjusted HR =2.53; 95% CI 1.006-6.3; p=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCL-NOS and their significance should be evaluated in prospective trials.

The mRNA levels of TGF-ß Type II receptor splice variants in monocytes are associated with disease activity in patients with rheumatoid arthritis.

OBJECTIVES: In rheumatoid arthritis (RA) patients, TGF-ß exerts a singular effect on lymphocytes, macrophages, and polymorphonuclear leukocytes. Moreover, evidences indicate that TGF-ß1 stimulation affects the expression levels of TGF-ß receptors. Therefore, we analysed in different leukocyte subpopulations, whether the mRNA abundance of TGFBR2 splice variants might be related to RA. METHODS: We isolated different leukocyte subpopulations from peripheral blood from 9 healthy control volunteers and 9 RA patients, matched by gender and age (cohort 1), and 8 additional RA patients (cohort 2). Then we quantified, by RT-qPCR, the mRNA relative abundance of TGFBR2 splice variants (namely TGFBR2A and TGFBR2B) in PMNs, and PBMCs (monocytes and non-monocytes). We first checked whether the TGFBR2-splice variant mRNA profile could be associated with any particular blood cell type both, in healthy control volunteers and in RA patients. In addition, PBMC and PMN mRNA levels were correlated, using Spearman's rank-order correlation test, with clinical and biochemical determinations of RA patients. RESULTS: We have shown that TGFBR2 exhibits an alternative splicing pattern in different subpopulations of human leucocytes from healthy controls, and the lack of it in the same cell type from RA samples. Furthermore, our study yields initial evidence that TGFBR2 mRNA expression levels in monocytes might mirror RA disease activity. CONCLUSIONS: mRNA abundance of TGFBR2 splice variants in monocytes shows changes linked to RA disease activity.

Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Original Form in Combination With Methotrexate in Patients With Rheumatoid Arthritis: A Randomized, Multicenter, Evaluator-Blinded, Noninferiority Study.

BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Patient-reported outcomes from a phase 3 study of baricitinib versus placebo or adalimumab in rheumatoid arthritis: secondary analyses from the RA-BEAM study.

BACKGROUND: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX). METHODS: In this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables. RESULTS: Compared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05). CONCLUSIONS: Baricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52). TRIAL REGISTRATION: NCT01710358.

High-throughput and quantitative genome-wide messenger RNA sequencing for molecular phenotyping.

BACKGROUND: We present a genome-wide messenger RNA (mRNA) sequencing technique that converts small amounts of RNA from many samples into molecular phenotypes. It encompasses all steps from sample preparation to sequence analysis and is applicable to baseline profiling or perturbation measurements. RESULTS: Multiplex sequencing of transcript 3' ends identifies differential transcript abundance independent of gene annotation. We show that increasing biological replicate number while maintaining the total amount of sequencing identifies more differentially abundant transcripts. CONCLUSIONS: This method can be implemented on polyadenylated RNA from any organism with an annotated reference genome and in any laboratory with access to Illumina sequencing.

The traditional vs "1:1:1" approach debate on massive transfusion in trauma should not be treated as a dichotomy.

Traditional transfusion guidelines suggest that fresh frozen plasma (FFP) should be given based on laboratory or clinical evidence of coagulopathy or acute loss of 1 blood volume. This approach tends to result in a significant lag time between the first units of erythrocytes and FFP in trauma requiring massive transfusion. In severe trauma, observational studies have found an association between increased survival and aggressive use of FFP and platelets such that FFP:platelet:erythrocyte ratio approaches 1:1:1 to 2 from the first units of erythrocytes given. There are considerable concerns over either approach, and no randomized controlled trials have been published comparing the 2 approaches. Nowadays, trauma clinicans are incorporating the strenghts of both approaches and are no longer treating them as a dichotomy. Specifically, "1:1:1" proponents have devised 1:1:1 activation criteria to minimize unnecessary FFP and platelet transfusion and are prepared to deactivate the protocol as soon as patient is stabilized. Similarly, 1:1:1 skeptics are more mindful of the need to be proactive about trauma coagulopathy and the inherent delays in FFP administration in trauma patients.

Laryngoscope manipulation by experienced versus novice laryngoscopists.

PURPOSE: During endotracheal intubation using a Macintosh laryngoscope blade, it has been recommended by some that the best laryngeal view is achieved with a laryngoscope handle angle of 45º from horizontal; however, this may be unnecessary. Novices are rarely taught specifically how or where to grip the laryngoscope handle. This study compared the angle and grip of the laryngoscope handle by experienced vs novice laryngoscopists to determine whether basic differences could be identified that might aid in teaching the nuances of skillful laryngoscope manipulation. METHODS: Laryngoscopists were photographed performing tracheal intubation for elective surgical patients (22 experienced laryngoscopists) and an airway trainer mannequin (22 experienced and 21 novice layngoscopists). The photographs were analyzed for laryngoscope handle angle from horizontal, eye-scope distance, and eye-scope angle. Airway trainer photographs were also assessed for hand rotational angle and distance from the laryngoscope base. RESULTS: The average laryngoscope handle angle for patient tracheal intubations was 23.7º (95% confidence interval [CI]: 21.1 to 26.2), significantly less than 45º (P < 0.001). Compared with novices, experts gripped the laryngoscope handle closer to the hinge at rest and at best laryngeal view (P = 0.001 and P = 0.003, respectively), held the laryngoscope in their fingers vs the palm of their hand (P = 0.005), and used greater eye-scope distances (P = 0.005) for airway trainer intubations. Expert technique was unchanged with patient vs airway trainer laryngoscopy. CONCLUSION: Experienced laryngoscopists used laryngoscope handle angles less than 45º from horizontal for routine intubations. Compared with novices, experts gripped the laryngoscope closer to the hinge and held the laryngoscope more in their fingers vs the palm of their hand. Sharing these important points with novices early in their instruction may improve technique and skill acquisition.

Mortality in patients with hematological malignancies, febrile neutropenia, and septic shock.

INTRODUCTION: Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM and febrile neutropenia. METHODOLOGY: We included all patients with hematological malignancies (HM) who presented fever and severe neutropenia, admitted to an oncological tertiary care center in Mexico City for one year. RESULTS: Two hundred ninety-two episodes of fever and severe neutropenia were documented; 68 patients (23.2%) developed SS. Documented clinical infection was different between SS and non-SS patients (94.1% vs. 63.4%, p < 0.001); pneumonia was the most frequent infection (36.8% vs. 23.2%, p = 0.02). Also, in SS vs. non-SS, there were more positive cultures (69.1% vs. 38.4%, p < 0.001), higher frequency of Gram-negative bacteria (89.3% vs. 63.9%, p < 0.001), particularly Escherichia coli (68% vs. 44.2%) and Klebsiella spp. (23.4% vs. 15.1%). There were no differences when multidrug-resistant (MDR) microorganisms were compared. In the multivariate analysis, associated risk factors for SS were: prolonged neutropenia, a documented site of infection, and having received highly myelosuppressive chemotherapy. Risk factors for mortality at 30 days were: older patients, prolonged neutropenia, and SS. CONCLUSIONS: Severe and prolonged neutropenia was associated with SS development and mortality at 30 days. ICU management should be offered to all critically ill patients with HM if long-term survival of the underlying malignancy is expected.

Short impact on soil microbiome of a Bacillus amyloliquefaciens QST713 based product that correlates with higher potato yield across USA.

Potato (Solanum tuberosum L.) is considered one of the most widely consumed crops worldwide, due to its high yield and nutritional profile, climate change-related environmental threats and increasing food demand. This scenario highlights the need of sustainable agricultural practices to enhance potato productivity, while preserving and maintaining soil health. Plant growth-promoting bacteria (PGPB) stimulate crop production through biofertilization mechanisms with low environmental impact. For instance, PGPB promote biological nitrogen fixation, phosphate solubilization, production of phytohormones, and biocontrol processes. Hence, these microbes provide a promising solution for more productive and sustainable agriculture. In this study, the effects of Bacillus amyloliquefaciens QST713 based-product (MINUET™, Bayer) were assessed in terms of yield, soil microbiome, potato peel and petiole nutrient profile as a promising PGPB in a wide range of potato cultivars across the United States of America. Depending on the location, potato yield and boron petiole content increased after biostimulant inoculation to maximum of 24% and 14%, respectively. Similarly, nutrient profile in potato peel was greatly improved depending on the location with a maximum of 73%, 62% and 36% for manganese, zinc and phosphorus. Notably, fungal composition was shifted in the treated group. Yield showed strong associations with specific microbial taxa, such as Pseudoarthrobacter, Ammoniphilus, Ideonella, Candidatus Berkiella, Dongia. Moreover, local networks strongly associated with yield, highlighting the important role of the native soil microbiome structure in indirectly maintaining soil health. Our results showed that treatment with B. amyloliquefaciens based product correlated with enhanced yield, with minor impacts on the soil microbiome diversity. Further studies are suggested to disentangle the underlying mechanisms of identified patterns and associations.

Could Children's Myopization Have Been Avoided during the Pandemic Confinement? The Conjunctival Ultraviolet Autofluorescence (CUVAF) Biomarker as an Answer.

BACKGROUND: The objective of this study was to evaluate the association of the presence of conjunctival ultraviolet autofluorescence (CUVAF) with the level and progression of myopia and the impact of reduced sunlight exposure during the COVID-19 pandemic confinement (PC). METHODS: A retrospective observational study was carried out using three cohorts, children (9-17 years old), young adults (18-25 years old), and adults (>40 years old) with myopia (≤0.75D) and at least three annual eye examinations (before and after PC). All participants underwent an automatic objective refraction and CUVAF area analysis. All the participants filled out a questionnaire regarding lifestyle and myopia history. RESULTS: The 298 recruited participants showed that during the PC, children's and young adults' myopia progression rate increased on average by -0.50 and -0.30 D/year, respectively, compared with the pre-pandemic level (p < 0.0001 and p < 0.01). A significantly greater progression was observed in those with low baseline myopia compared to those with moderate or high myopia (p < 0.01). CUVAF shows its protective effect associated with outdoor activity (OA) with regard to the age of onset of myopia and mean diopters (p < 0.01). In fact, although there were no differences in the increase in diopters between children with and without CUVAF during the PC, those who had CUVAF started with lower gains (-0.3 D/year) compared to those who did not (-0.5 D/year; p < 0.05). The myopia treatments (atropine drops, Ortho-K, and MiSight® contact lenses) showed a reduction effect in myopic progression rate post-PC in comparison with non-treated children (p < 0.0001, p < 0.0001 and p < 0.01, respectively). CONCLUSIONS: The strict restriction of OA during PC led to the rate of myopia progression doubling among children and young adults. This progression occurred mainly in children with previously low myopia, and CUVAF, as a biomarker of OA, reflects its potential to provide benefits in the form of recommended behavioral changes to protect against the development of myopia.

Conjunctival ultraviolet autofluorescence as a biomarker of outdoor exposure in myopia: a systematic review and meta-analysis.

Outdoor exposure is considered the primary modifiable risk factor in preventing the development of myopia. This effect is thought to be attributed to the light-induced synthesis and release of dopamine in the retina. However, until recent years, there was no objective quantifiable method available to measure the association between time spent outdoors and myopia. It is only recently that the conjunctival ultraviolet autofluorescence (CUVAF) area, serving as a biomarker for sun exposure, has begun to be utilized in numerous studies. To provide a comprehensive summary of the relevant evidence pertaining to the association between the CUVAF area and myopia across different geographic regions and age groups, a systematic review and meta-analysis were conducted. The search encompassed multiple databases, including MEDLINE, SCIENCE DIRECT, GOOGLE SCHOLAR, WEB OF SCIENCE, and SCOPUS, and utilized specific search terms such as "conjunctival ultraviolet autofluorescence", "CUVAF", "UVAF", "objective marker of ocular sun exposure", "myopia", "degenerative myopia", and "high myopia". The bibliographic research included papers published between the years 2006 and 2022. A total of 4051 records were initially identified, and after duplicates were removed, 49 articles underwent full-text review. Nine articles were included in the systematic review. These studies covered myopia and outdoor exposure across different regions (Australia, Europe and India) with a total population of 3615 individuals. They found that myopes generally had smaller CUVAF areas compared to non-myopes. The meta-analysis confirmed this, revealing statistically smaller CUVAF areas in myopic patients, with a mean difference of - 3.30 mm2 (95% CI - 5.53; - 1.06). Additionally, some studies showed a positive correlation between more outdoor exposure and larger CUVAF areas. In terms of outdoor exposure time, myopic patients reported less time outdoors than non-myopic individuals, with a mean difference of - 3.38 h/week (95% CI - 4.66; - 2.09). Overall, these findings highlight the connection between outdoor exposure, CUVAF area and myopia, with regional variations playing a significant role. The results of this meta-analysis validate CUVAF as a quantitative method to objectively measure outdoor exposure in relation with myopia development.

The Impact of Long COVID on Cognitive Performance and Sleep Quality: An Analysis of the Rancagua Chilean Study (RACHIS).

Background Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to prolonged symptoms post-recovery, commonly known as long-term coronavirus disease 2019 (COVID-19) or "long COVID." Neuropsychiatric consequences of long COVID include cognitive dysfunction and sleep disturbances, which significantly impair daily living. This study aimed to explore the impact of long COVID on cognitive performance and sleep quality in patients receiving outpatient care. Material and methods This study involved a random sample of 138 of 363 patients, corresponding to 38% of the cohort, who tested positive for SARS-CoV-2 via polymerase chain reaction (PCR) between May 2020 and April 2021. These unvaccinated, non-hospitalized individuals, predominantly exhibiting mild disease symptoms, were prospectively assessed 11 months post-positive PCR test. After informed consent, demographic data, memory, and concentration impairment levels were collected through interviews. Participants reporting cognitive symptoms underwent the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MOCA), and the Pittsburgh Sleep Quality Index. Statistical analyses were conducted, including Student's t-test, Chi-square, Fisher's test, Kruskal-Wallis test, and Pearson correlation coefficient, with a significance threshold set at p<0.05. Results Of the 138 participants, 76 (55.1%) were female and 62 (44.9%) were male. The mean age was 45.9 years (± 13.0), with an average educational attainment of 10.4 years (± 3.7). Roughly 50% of the patients reported significant memory and concentration issues (p<0.001). Thirty-three participants underwent detailed cognitive assessments, revealing a 2:1 female-to-male ratio and a significantly higher prevalence of depression in female participants. Cognitive deficits were diagnosed in five (15.2%) participants via the MMSE and in 26 (78.8%) via the MOCA test, with notable deficits in visuospatial/executive functions, language repeat, and deferred recall (p<0.001). A lower educational level was correlated with higher cognitive deficits (p=0.03). Conclusion The study findings reveal that cognitive impairments, as a consequence of COVID-19, can persist up to 11 months post-infection. The MOCA test proved more effective in diagnosing these deficits and requires adjustments based on educational background. Sleep parameters remained largely unaffected in this cohort, likely attributed to the mild nature of the initial symptoms and the outpatient management of the disease.

Ensembl 2011.

The Ensembl project (http://www.ensembl.org) seeks to enable genomic science by providing high quality, integrated annotation on chordate and selected eukaryotic genomes within a consistent and accessible infrastructure. All supported species include comprehensive, evidence-based gene annotations and a selected set of genomes includes additional data focused on variation, comparative, evolutionary, functional and regulatory annotation. The most advanced resources are provided for key species including human, mouse, rat and zebrafish reflecting the popularity and importance of these species in biomedical research. As of Ensembl release 59 (August 2010), 56 species are supported of which 5 have been added in the past year. Since our previous report, we have substantially improved the presentation and integration of both data of disease relevance and the regulatory state of different cell types.

Epidemiology of Immune-Mediated Glomerulopathies before and after SARS-CoV-2 Vaccination: A Tertiary Referral Hospital Experience.

BACKGROUND: Vaccination is a known trigger for the appearance of immune-mediated glomerulopathies (IMG). The appearance of IMG after SARS-CoV-2 vaccination with suspected causality has been described. Our aim is to analyze the incidence of IMG flares before and after SARS-CoV-2 vaccination in our center. METHODS: All persons with native kidney biopsy (KB) from January 2019 to March 2022 in our center were included in the study. We compared the incidence of IMG before and after the start of vaccination. We also collected information about whether the patients had received a SARS-CoV-2 vaccine or have suffered from COVID in the six weeks before the IMG. We also evaluated the analytical characteristics of the outbreaks. RESULTS: A total of 386 KB were studied. Of them, 86/218 (39.4%) were IMG performed pre- and 85/168 (50.6%) post-SV (029). The incidence of idiopathic nephrotic syndrome (INS), studied separately, was also significantly increased post-vaccination (n = 18 (10.7%)) compared to pre-vaccination (n = 11 (5%)) (p = 0.036). There were no differences in the incidence of vasculitis or IgA nephropathy. Up to 17 (20%) flares occurred 6 weeks before SARS-CoV-2 vaccination and only 2 (2.4%) within the first 6 weeks after SARS-CoV-2 infection. Within those 17 flares, the most common diagnosis was IgAN (n = 5 (29.4%)); a total of 14 (82.4%) received an mRNA vaccine and 9 (52.9%) took place after the 1st vaccine dose. There were 13 cases of minimal change disease (MCD) with debut/recurrence pre-SV and 20 MCD with debut/recurrence post-SV (p = 0.002). CONCLUSIONS: The incidence of IMG, INS and MCD flares in our center increased significantly after SARS-CoV-2 vaccination. Importantly, 20% of IMG flares took place within the first 6 weeks after receiving a vaccine dose, with the first dose being the riskiest one and IgAN the most frequent diagnosis.

A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

Matrix Metalloproteinase 13 Is Associated with Age-Related Choroidal Neovascularization.

Age-related macular degeneration (AMD) is a leading cause of severe vision loss in older individuals in developed countries. Despite advances in our understanding of AMD, its pathophysiology remains poorly understood. Matrix metalloproteinases (MMPs) have been proposed to play a role in AMD development. In this study, we aimed to characterize MMP-13 in AMD. We used retinal pigment epithelial cells, a murine model of laser-induced choroidal neovascularization, and plasma samples from patients with neovascular AMD to conduct our study. Our results show that MMP13 expression significantly increased under oxidative stress conditions in cultured retinal pigment epithelial cells. In the murine model, MMP13 was overexpressed in both retinal pigment epithelial cells and endothelial cells during choroidal neovascularization. Additionally, the total MMP13 levels in the plasma of patients with neovascular AMD were significantly lower than those in the control group. This suggests a reduced diffusion from the tissues or release from circulating cells in the bloodstream, given that the number and function of monocytes have been reported to be deficient in patients with AMD. Although more studies are needed to elucidate the role of MMP13 in AMD, it could be a promising therapeutic target for treating AMD.

Somatic evolution of marine transmissible leukemias in the common cockle, Cerastoderma edule.

Transmissible cancers are malignant cell lineages that spread clonally between individuals. Several such cancers, termed bivalve transmissible neoplasia (BTN), induce leukemia-like disease in marine bivalves. This is the case of BTN lineages affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and northwest Africa. To investigate the evolution of cockle BTN, we collected 6,854 cockles, diagnosed 390 BTN tumors, generated a reference genome and assessed genomic variation across 61 tumors. Our analyses confirmed the existence of two BTN lineages with hemocytic origins. Mitochondrial variation revealed mitochondrial capture and host co-infection events. Mutational analyses identified lineage-specific signatures, one of which likely reflects DNA alkylation. Cytogenetic and copy number analyses uncovered pervasive genomic instability, with whole-genome duplication, oncogene amplification and alkylation-repair suppression as likely drivers. Satellite DNA distributions suggested ancient clonal origins. Our study illuminates long-term cancer evolution under the sea and reveals tolerance of extreme instability in neoplastic genomes.