Benchmarking of a multi-biomarker low-volume panel for Alzheimer's Disease and related dementia research.

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of the disease. In the research setting, participant recruitment and retention and optimization of sample use, is one of the main challenges that observational studies face. Thus, obtaining accurate established biomarker measurements for stratification and maximizing use of the precious samples is key. Accurate technologies are currently available for established biomarkers, mainly immunoassays and immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), and some of them are already being used in clinical settings. Although some immunoassays- and IP-MS based platforms provide multiplexing for several different coding proteins there is not a current platform that can measure all the stablished and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) is a mid-throughput platform with antibody-based measurements with a sequencing output that requires 15µL of sample volume to measure more than 100 analytes, including those typically assayed for AD. Here we benchmarked and compared the AD-relevant biomarkers including in the NULISA against validated assays, in both CSF and plasma. Overall, we have found that CSF measures of Aß42/40, NfL, GFAP, and p-tau217 are highly correlated and have similar predictive performance when measured by immunoassay, mass-spectrometry or NULISA. In plasma, p-tau217 shows a performance similar to that reported with other technologies when predicting amyloidosis. Other established and exploratory biomarkers (total tau, p-tau181, NRGN, YKL40, sTREM2, VILIP1 among other) show a wide range of correlation values depending on the fluid and the platform. Our results indicate that the multiplexed immunoassay platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional novel biomarkers using minimal sample volume.

Predictive Models for Assessing Patients' Response to Treatment in Metastatic Prostate Cancer: A Systematic Review.

Background and objective: The treatment landscape of metastatic prostate cancer (mPCa) has evolved significantly over the past two decades. Despite this, the optimal therapy for patients with mPCa has not been determined. This systematic review identifies available predictive models that assess mPCa patients' response to treatment. Methods: We critically reviewed MEDLINE and CENTRAL in December 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Only quantitative studies in English were included with no time restrictions. The quality of the included studies was assessed using the PROBAST tool. Data were extracted following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews criteria. Key findings and limitations: The search identified 616 citations, of which 15 studies were included in our review. Nine of the included studies were validated internally or externally. Only one study had a low risk of bias and a low risk concerning applicability. Many studies failed to detail model performance adequately, resulting in a high risk of bias. Where reported, the models indicated good or excellent performance. Conclusions and clinical implications: Most of the identified predictive models require additional evaluation and validation in properly designed studies before these can be implemented in clinical practice to assist with treatment decision-making for men with mPCa. Patient summary: In this review, we evaluate studies that predict which treatments will work best for which metastatic prostate cancer patients. We found that existing studies need further improvement before these can be used by health care professionals.

Which Patients with Prostate Cancer and Lymph Node Uptake at Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography/Computerized Tomography Scan Are at a Higher Risk of Prostate-specific Antigen Persistence After Radical Prostatectomy? Identifying Indicators of Systemic Disease by Integrating Clinical, Magnetic Resonance Imaging, and Functional Imaging Parameters.

BACKGROUND: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease. OBJECTIVE: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters. DESIGN, SETTING, AND PARTICIPANTS: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics. RESULTS AND LIMITATIONS: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%). CONCLUSIONS: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront. PATIENT SUMMARY: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography.

Research protocol to identify progression and death amongst patients with metastatic hormone-sensitive prostate cancer treated with available treatments: PIONEER IMI's "big data for better outcomes" program.

Androgen deprivation therapy-based with or without first-generation anti-androgens, was the standard of care for patients with metastatic hormone-sensitive prostate cancer (mHSPC) for decades. However, the development of docetaxel chemotherapy and new androgen receptor-targeted agents, abiraterone acetate and prednisolone, apalutamide , enzalutamide and darolutamide (in combination with docetaxel chemotherapy) has proven that combination of treatments is more effective. Recently, intensification therapy, so-called "triplets", have emerged in the armamentarium of mHSPC treatment. Metastatic disease is a clinical state that remains poorly understood. The optimal diagnostic and management of patients with mHSPC are changing thanks to the development of new imaging techniques and therapies. The primary objective of this study is to develop and validate a predictive model for the occurrence of symptomatic progression, initiation of new treatments and death amongst patients with mHSPC treated with one of the approved treatment plans, on characteristics present at admission.

50-W vs 40-W During High-Power Short-Duration Ablation for Paroxysmal Atrial Fibrillation: A Multicenter Prospective Study.

BACKGROUND: High-power short-duration (HPSD) radiofrequency ablation of atrial fibrillation (AF) increases first-pass pulmonary vein isolation (PVI) and freedom from atrial arrhythmias while decreasing procedural time. However, the optimal power setting in terms of safety and efficacy has not been determined. OBJECTIVES: This study compared the procedural characteristics and clinical outcomes of 50-W vs 40-W during HPSD ablation of paroxysmal AF. METHODS: Patients from the REAL-AF prospective multicenter registry (Real-World Experience of Catheter Ablation for Treatment of Symptomatic Paroxysmal and Persistent Atrial Fibrillation) undergoing HPSD ablation of paroxysmal AF, either using 50-W or 40-W, were included. The primary efficacy outcome was freedom from all-atrial arrhythmias. The primary safety outcome was the occurrence of any procedural complication at 12 months. Secondary outcomes included procedural characteristics, AF-related symptoms, and the occurrence of transient ischemic attack or stroke at 12 months. RESULTS: A total of 383 patients were included. Freedom from all-atrial arrhythmias at 12 months was 80.7% in the 50-W group and 77.3% in the 40-W group (Log-rank P = 0.387). The primary safety outcome occurred in 3.7% of patients in the 50-W group vs 2.8% in the 40-W group (P = 0.646). The 50-W group had a higher rate of first-pass PVI (82.3% vs 76.2%; P = 0.040) as well as shorter procedural (67 minutes [IQR: 54-87.5 minutes] vs 93 minutes [IQR: 80.5-111 minutes]; P < 0.001) and radiofrequency ablation times (15 minutes [IQR: 11.4-20 minutes] vs 27 minutes [IQR: 21.5-34.6 minutes]; P < 0.001) than the 40-W group. CONCLUSIONS: There was no significant difference in freedom from all-atrial arrhythmias or procedural safety outcomes between 50-W and 40-W during HPSD ablation of paroxysmal AF. The use of 50-W was associated with a higher rate of first-pass PVI as well as shorter procedural times.

Identification of the Optimal Candidates for Nodal Staging with Extended Pelvic Lymph Node Dissection Among Prostate Cancer Patients Who Underwent Preoperative Prostate-specific Membrane Antigen Positron Emission Tomography. External Validation of the Memorial Sloan Kettering Cancer Center and Briganti Nomograms and Development of a Novel Tool.

BACKGROUND: Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases. OBJECTIVE: To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting. DESIGN, SETTING, AND PARTICIPANTS: Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools. RESULTS AND LIMITATIONS: Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation. CONCLUSIONS: Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population. PATIENT SUMMARY: Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases.

Edible and medicinal mushrooms (Pleurotus ostreatus, Ustilago maydis, Ganoderma lucidum) reduce endoplasmic reticulum stress and inflammation in adipose tissue of obese Wistar rats fed with a high fat plus saccharose diet.

Obesity is an increasing global public health problem. A strategy to treat obesity is the use of functional foods. Edible and medicinal mushrooms contain diverse bioactive compounds showing important antihyperlipidemic, antioxidant, and prebiotic properties. We analysed the effects of adding (10%) of Pleurotus ostreatus (Po, basidiomata), Ganoderma lucidum (Gl, basidiomata), or Ustilago maydis (Um, galls), milled, to a high fat plus saccharose diet (HFD + S) for 6 months in a model of obesity with Wistar rats. We assessed weight gain, body composition, lipid parameters, endoplasmic reticulum stress (proteins and inflammatory markers: BiP, XBP-1, JNK, p-JNK, TNF-α), and adiponectin in subcutaneous adipose tissue (SAT). The consumption of edible and medicinal mushrooms decreased weight gain (-17.2-30.1%) and fat mass (-23.7-43.1%), maintained fat-free mass, reduced levels of serum biochemical parameters (TC: -40.1-44.1%, TG: -37.7-51.6%, LDL-C: -64.5-71.1%), and prevented adipocyte hypertrophy (-30.9-36.9%) and collagen deposition (-70.9-73.7%) in SAT. Compared with the HFD + S group, mushroom consumption by Wistar rats significantly reduced the expression of proteins associated with endoplasmic reticulum stress and inflammation (BiP: -72.2-88.2%; XBP-1: -71.5-81.8%; JNK: -71.2-90.0%; p-JNK: -37.3-81.0%; TNF-α: -80.7-91.5%), whereas significantly increased adiponectin protein expression (246.4-654.2%) in SAT. These effects outperformed those obtained through the commercial lipid-lowering drug atorvastatin, contributing synergistically to prevent further obesity-related dysfunctions, such as insulin resistance derived from inflammation and ER stress in adipose tissue. Bioactive compounds from edible, functional and medicinal mushrooms represent new emerging therapies for obesity treatments using natural products.

Effects of Mexican Ganoderma lucidum extracts on liver, kidney, and the gut microbiota of Wistar rats: A repeated dose oral toxicity study.

Well-characterized and standardized extracts of a Mexican genotype of Ganoderma lucidum (Gl), a medicinal mushroom, cultivated on oak sawdust (Gl-1) or oak sawdust plus acetylsalicylic acid (Gl-2, ASA), have been shown to exert antioxidant, hypocholesterolemic, anti-inflammatory, prebiotic, and anticancer properties. However, toxicity analyses still need to be carried out. Different doses of these Gl-1 or Gl-2 extracts were administered to Wistar rats for 14 days in a repeated dose oral toxicity study. We assessed the external clinical signs, biochemical parameters, liver and kidney tissues, injury and inflammation biomarkers, gene expression, inflammatory responses, proinflammatory mediators, and gut microbiota. Gl extracts had no significant adverse, toxic or harmful effects on male and female rats compared to the control groups. No injury or dysfunction were recorded in the kidney or liver, as there were no significant abnormal variations in organ weight, tissue histopathology, serum biochemical parameters (C-reactive protein, creatinine, urea, glucose, ALT and AST transaminases, TC, LDL-c, TG, HDL-c), urinary parameters (creatinine, urea nitrogen, albumin, the albumin-to-creatinine ratio, glucose), injury and inflammatory biomarkers (KIM-1/TIM-1, TLR4, and NF-кB protein expression; IL-1ß, TNF-α and IL-6 gene expression), or the expression of genes linked to cholesterol metabolism (HMG-CoA, Srebp2, Ldlr). Gl-1 and Gl-2 extracts showed prebiotic effects on the gut microbiota of male and female Wistar rats. Bacterial diversity and relative bacterial abundance (BRA) increased, positively modulating the Firmicutes/Bacteroidetes ratio. The ASA (10 mM) added to the substrate used for mushroom cultivation changed properties and effects of the Gl-2 extract on Wistar rats. The no-observed-adverse-effect-level (NOAEL) was 1000 mg/kg body weight/day of Gl-1 or Gl-2 extracts. Clinical trials are recommended for further exploring the potential therapeutic applications of studied extracts.

KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells.

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.

Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma.

Fifty percent of diffuse large B cell lymphoma (DLBCL) cases lack cell-surface expression of the class I major histocompatibility complex (MHC-I), thus escaping recognition by cytotoxic T cells. Here we show that, across B cell lymphomas, loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. To identify the involved mechanisms, we performed whole exome and targeted HLA deep-sequencing in 74 DLBCL samples, and found somatic inactivation of B2M and the HLA-I loci in 80% (34 of 42) of MHC-INEG tumors. Furthermore, 70% (22 of 32) of MHC-IPOS DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-IPOS/mono), indicating allele-specific inactivation. MHC-INEG and MHC-IPOS/mono cases harbored significantly higher mutational burden and inferred neoantigen load, suggesting potential coselection of HLA-I loss and sustained neoantigen production. Notably, the analysis of >500,000 individuals across different cancer types revealed common germline HLA-I homozygosity, preferentially in DLBCL. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multistep process of HLA-I loss in DLBCL development including both germline and somatic events, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

Correction to: Overlapping genetic architecture between Parkinson disease and melanoma.

The original version of this article unfortunately contained a mistake. Supplementary Tables 3 and 4 are not available with the rest of the supplementary material available online.

Calidad de la dieta según el Índice de Alimentación Saludable: Análisis en la población adulta de la ciudad de Rosario, Argentina / Diet quality according to the Healthy Eating Index: Analysis in the adult population of Rosario City, Argentina

Introducción: el Índice de Alimentación Saludable (IAS) fue desarrollado en base a las recomendaciones de las guías alimentarias para la población americana y es de utilidad para identificar los grupos de alimentos que presentan menor consumo en relación a las recomendaciones y los grupos poblacionales con alimentación de baja calidad. Objetivo: estimar la calidad de la dieta en la población adulta de la ciudad de Rosario, e identificar su relación con variables sociodemográficas, indicadores antropométricos y del estilo de vida. Materiales y Método: investigación observacional, descriptiva y transversal de una muestra por cuotas estratificada de 1200 adultos entre 18 a 70 años. Se empleó la metodología actualizada en el 2010 para el cálculo de IAS, a partir de la información obtenida del recordatorio de 24 horas. Se utilizó un cuestionario para relevar las variables sociodemográficas y el consumo de tabaco, se realizaron mediciones antropométricas, la actividad física se midió con el cuestionario IPAQ y el consumo de alcohol por frecuencia de consumo. Las asociaciones se evaluaron mediante test Chi cuadrado y la diferencia de medias por Anova, considerando p<0,05. Resultados: los adultos evaluados tenían en promedio 39±15 años, el 69% fueron mujeres, el 32% con estudios terciarios completos o más, 56% tenía un IMC≥25 kg/m², 34% presentaba riesgo según circunferencia de cintura, 54% realizaba <150 min/sem de actividad física, 67% consumía alcohol y 26% era fumador actual. El IAS alcanzó un promedio de 48,5±15,1 puntos, los valores más alejados del ideal se encontraron en los pescados, mariscos y proteínas vegetales (0,7/5); granos enteros (1,5/10); granos y cereales refinados (2/10); frutas (1,7/5); vegetales verdes y legumbres (1,7/5); ácidos grasos (3,7/10) y lácteos (4,3/10). El 58,6% tuvo una dieta de pobre calidad (IAS <50). Se observó una alimentación menos saludable en los hombres (p<0,05), adultos jóvenes (p<0,01), aquellos con menor nivel educativo (p<0,01), los individuos que realizan <150 minutos semanales de actividad física moderada o intensa (p<0,01) y los que fuman en la actualidad (p<0,01). Conclusión: La alimentación de la población estudiada demuestra características poco saludables. La identificación de grupos de mayor riesgo permitirá orientar mejor las acciones educativas y sanitarias tendientes a modificar estilos de vida y hábitos alimentarios.

Introduction: The Healthy Eating Index (HEI) was developed based on the recommendations of the dietary guidelines for the American population and is useful to identify food groups that have lower consumption in relation to recommendations and population groups with low diet quality. Objective: To estimate the quality of the diet in the adult population of the city of Rosario, and to identify its relationship with sociodemographic, anthropometric indicators and lifestyle variables. Materials and Methods: Observational, descriptive and cross-sectional research of a stratified sample of 1200 adults aged 18 to 70 years. The updated methodology of HEI 2010 was used, based on the information obtained from the 24-hour recall. A questionnaire was used to collect sociodemographic variables and tobacco consumption, alcohol consumption was assessed by frequency of consumption, anthropometric measurements were measured and physical activity was assessed with the IPAQ questionnaire. The associations were evaluated by Chi square test and the difference of means by Anova (p<0,05). Results: The average age of adults evaluated was 39±15 years, 69% were women, 32% had completed tertiary studies or more, 56% with BMI≥25 kg/m², 34% had risk according to waist circumference, 54% realized <150 min/week of physical activity, 67% consumed alcohol and 26% were current smokers. The HEI reached an average of 48.5±15.1 points, the values farthest from the ideal were found in fish, shellfish and vegetable proteins (0.7/5); whole grains (1.5/10); refined grains and cereals (2/10); fruit (1.7/5); green vegetables and legumes (1.7/5); fatty acids (3.7/10) and dairy (4.3/10). The 58.6% had a poor quality diet (HEI <50). In men (p<0,05), young adults (p<0,01), those with a lower educational level (p<0,01), individuals who perform <150 minutes per week of moderate or intense physical activity (p<0,01) and those who smoke have observed a less healthy diet (p<0,01). Conclusion: The diet of the studied population shows unhealthy characteristics. The identification of groups of greater risk will allow to orient better the educative and sanitary actions tending to modify styles of life and alimentary habits.

Overlapping genetic architecture between Parkinson disease and melanoma.

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma.

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.

The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10-15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Pyogenic Liver Abscess with Delayed Presentation After Appendectomy.

Liver abscess is a serious condition that is uncommon in otherwise normal children. Predisposing factors include immunosuppression, surgery and travel to certain areas. We present a patient with liver abscess 4 months after appendectomy. In addition, we reviewed 7 cases of liver abscess that occurred in a 22-year period.

Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis.

The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.

Osteomielitis Esclerosante de Garré. Reporte de un caso en un Servicio Pediátrico / Sclerosing Osteomyelitis of Garre: Report of a Case in a Pediatrics Department

Introducción: La osteomielitis esclerosante crónica de Garré (OECG) es una entidad rara que afecta a niños y adultos jóvenes. El proceso de OEG se caracteriza por una respuesta osteoblástica marcada, que en general puede aparecer en huesos largos o mandíbula, si bien la descripción original fue en mandíbula. Caso clínico: Masculino de 14 años con historia de tumefacción en cara de una semana de evolución con signos inflamatorios y drenaje espontáneo de líquido purulento. Inicialmente fue tratado con antibióticos, debido a la presencia de un área de celulitis. Además se realizó drenaje del área abscedada y exodoncia. No hubo aislamiento microbiológico posterior. Dada la mala respuesta a la medicación antibiótica, se realizó una gammagrafía ósea que arrojó por resultado la hipercaptación de la rama maxilar, confirmándose luego el diagnóstico de OEG en la biopsia de hueso. Discusión: Pocos casos clínicos de Osteomielitis Crónica de Garré han sido reportados. La mayoría de los reportes coinciden que la OECG afecta a niños y adultos jóvenes. Las localizaciones más frecuentes son las regiones metafisiarias de los huesos largos y la mandíbula. La causa se desconoce, pero los hallazgos microscópicos suponen el posible origen infeccioso .

Introduction: Chronic sclerosingosteomy elitis of Garre (GSO) isa rare entity that affects childrenand young adults. The GSO processis characterized by a marked osteoblastic response, generally appearing in the long bones or mandible,with the original description being of a case in the mandible...

Diagnóstico antropométrico de peso y talla y estrategias alimentarias de una población vulnerable / Anthropometric diagnosis of weight and height and feeding strategies of a vulnerable population

En el presente trabajo de investigación, se determinó el diagnóstico antropométrico de 320 niños de la Villa 31 y 31 bis de Retiro mediante mediciones de peso y talla. Paralelamente se analizaron, a través de 53 encuestas, las estrategias alimentarias que sus madres utilizan actualmente para lograr una buena nutrición familiar. Se observó que, en la actualidad, a 10 años de la profunda crisis del 2001, el sobrepeso aparece como el principal problema nutricional en la población infantil, encontrándose una prevalencia del 10,3% en menores de 2 años, 21,5% en niños de 2 a 10 años y 23,8% en mayores de 10 años.