Magnetic nanosensors optimized for rapid and reversible self-assembly

Magnetic nanoparticle-based sensors for MRI have been accelerated to a timescale of seconds using densely-functionalized particles of small size. Parameters that increase response rates also result in large nuclear magnetic relaxation rate and light scattering changes, allowing signals to be detected almost immediately after changes in calcium concentration.United States. National Institutes of Health (DP2-OD2114)United States. National Institutes of Health (R01-DA28299)United States. National Institutes of Health (R01-NS76462

HAPLN1 potentiates peritoneal metastasis in pancreatic cancer

The presence of peritoneal metastasis in pancreatic cancers is associated with poor prognosis. Here the authors show that hyaluronan and proteoglycan link protein-1 (HAPLN1) promotes tumour cell plasticity and pro-tumoral immune microenvironment to facilitate peritoneal dissemination in pancreatic cancers. Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC

Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells

Methylation of the cytosine is the most frequent epigenetic modification of DNA in mammalian cells. In humans, most of the methylated cytosines are found in CpG-rich sequences within tandem and interspersed repeats that make up to 45% of the human genome, being Alu repeats the most common family. Demethylation of Alu elements occurs in aging and cancer processes and has been associated with gene reactivation and genomic instability. By targeting the unmethylated SmaI site within the Alu sequence as a surrogate marker, we have quantified and identified unmethylated Alu elements on the genomic scale. Normal colon epithelial cells contain in average 25 486 ± 10 157 unmethylated Alu's per haploid genome, while in tumor cells this figure is 41 995 ± 17 187 (P = 0.004). There is an inverse relationship in Alu families with respect to their age and methylation status: the youngest elements exhibit the highest prevalence of the SmaI site (AluY: 42%; AluS: 18%, AluJ: 5%) but the lower rates of unmethylation (AluY: 1.65%; AluS: 3.1%, AluJ: 12%). Data are consistent with a stronger silencing pressure on the youngest repetitive elements, which are closer to genes. Further insights into the functional implications of atypical unmethylation states in Alu elements will surely contribute to decipher genomic organization and gene regulation in complex organisms

The long-term outcomes of CIS patients in the Barcelona inception cohort : Looking back to recognize aggressive MS

Altres ajuts: This study has been funded by European Regional Development Fund and co-funded by Instituto Carlos III. It has also received support by a grant from Genzyme foundation (GENZYME-2015-01) granted to M.T. and from the 'Red Española de Esclerosis Múltiple (REEM)', which is sponsored by FIS, the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness in Spain, and the 'Ajuts per donar Suport als Grups de Recerca de Catalunya', which is sponsored by the 'Agència de Gestió d'Ajuts Universitaris i de Recerca' (AGAUR) of the Generalitat de Catalunya in Spain.To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28-95) versus 7 (1-19) and 3 (1-24) versus 0 (0-1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS

Circuit reliability prediction: Challenges and solutions for the device time-dependent variability characterization roadblock

Copyright IEEEThe characterization of the MOSFET Time-Dependent Variability (TDV) can be a showstopper for reliability-Aware circuit design in advanced CMOS nodes. In this work, a complete MOSFET characterization flow is presented, in the context of a physics-based TDV compact model, that addresses the main TDV characterization challenges for accurate circuit reliability prediction at design time. The pillars of this approach are described and illustrated through examples.This work was supported by the VIGILANT Project (PID2019-103869RB / AEI / 10.13039/501100011033) and the TEC2016-75151-C3-R Project (AEI/FEDER, UE).Peer reviewe

Humoral and Cellular Immune Responses After a 3-dose Course of mRNA-1273 COVID-19 Vaccine in Kidney Transplant Recipients: A Prospective Cohort Study.

In kidney transplant recipients, there is discordance between the development of cellular and humoral response after vaccination against SARS-CoV-2. We sought to determine the interplay between the 2 arms of adaptive immunity in a 3-dose course of mRNA-1273 100 μg vaccine. Methods: Humoral (IgG/IgM) and cellular (N- and S-ELISpot) responses were studied in 117 kidney and 12 kidney-pancreas transplant recipients at the following time points: before the first dose, 14 d after the second dose' and before and after the third dose, with a median of 203 and 232 d after the start of the vaccination cycle, respectively. Results: After the second dose, 26.7% of naive cases experienced seroconversion. Before the third dose and in the absence of COVID-19, this percentage increased to 61.9%. After the third dose, seroconversion occurred in 80.0% of patients. Naive patients who had at any time point a detectable positivity for S-ELISpot were 75.2% of the population, whereas patients who maintained S-ELISpot positivity throughout the study were 34.3%. S-ELISpot positivity at 42 d was associated with final seroconversion (odds ratio' 3.14; 95% confidence interval' 1.10-8.96; P = 0.032). Final IgG titer was significantly higher in patients with constant S-ELISpot positivity (P < 0.001). Conclusions: A substantial proportion of kidney transplant recipients developed late seroconversion after 2 doses. Cellular immunity was associated with the development of a stronger humoral respons

Programa E-Health ICOnnecta't: un ecosistema para fomentar el bienestar en cáncer a través de la propuesta europea ONCOMMUN

Introducción: A pesar de que los tratamientos psico-oncológicos han demostrado su efectividad en disminuir el malestar emocional y mejorar la calidad de vida de las personas con cáncer, aún existen numerosas barreras que limitan su acceso. La transformación a online de esta atención se plantea como una solución para aumentar la cobertura del servicio y mejorar su coste-utilidad. Objetivo: Crear un ecosistema digital de salud para reducir el impacto del cáncer, aumentando el bienestar y la calidad de vida del ciudadano con cáncer. Método: Programa dirigido a pacientes diagnosticadas de cáncer de mama en fase de supervivencia aguda. Es un programa de atención escalonada dividido en 4 niveles de intervención jerarquizados por complejidad: Nivel 1, cribado y monitorización psicosocial; Nivel 2, Campus: psicoeducación y educación sanitaria; Nivel 3, soporte psicosocial comunitario; y Nivel 4, tratamiento psicoterapéutico grupal. Resultados: En 2019, 259 mujeres fueron incluidas en el programa (39,91% de los nuevos casos de cáncer de mama en los centros participantes). Solo el 3,47% (n = 9) requirió atención clínica especializada (Nivel 4). Conclusión: El programa Iconnecta't adopta un modelo integrado de atención psicosocial en cáncer que se adecúa a las necesidades específicas de los supervivientes. Da solución a algunas de las barreras de la atención sanitaria tradicional, democratizando el acceso a los servicios mediante el uso de tecnologías de uso común en la mayoría de ciudadanos. En un futuro próximo se prevé la implementación progresiva a otras neoplasias, junto con un ensayo clínico controlado y aleatorizado que evaluará su eficacia

Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial.

Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging-Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing