Recent Technological Developments on LGAD and iLGAD Detectors for Tracking and Timing Applications

This paper reports the last technological development on the Low Gain Avalanche Detector (LGAD) and introduces a new architecture of these detectors called inverse-LGAD (iLGAD). Both approaches are based on the standard Avalanche Photo Diodes (APD) concept, commonly used in optical and X-ray detection applications, including an internal multiplication of the charge generated by radiation. The multiplication is inherent to the basic n++-p+-p structure, where the doping profile of the p+ layer is optimized to achieve high field and high impact ionization at the junction. The LGAD structures are optimized for applications such as tracking or timing detectors for high energy physics experiments or medical applications where time resolution lower than 30 ps is required. Detailed TCAD device simulations together with the electrical and charge collection measurements are presented through this work.Comment: Keywords: silicon detectors, avalanche multiplication, timing detectors, tracking detectors. 8 pages. 8 Figure

Validation of a Microwave-Assisted Derivatization Gas Chromatography-Mass Spectrometry Method for the Quantification of 2-Hydroxybutyrate in Human Serum as an Early Marker of Diabetes Mellitus

Circulating levels of 2-hydroxybutyrate (2HB) are highly related to glycemic status in different metabolomic studies. According to recent evidence, 2HB is an early biomarker of the future development of dysglycemia and type 2 diabetes mellitus and may be causally related to the progression of normal subjects to impaired fasting glucose or insulin resistance. In the present study, we developed and validated a simple, specific and sensitive gas chromatography-mass spectrometry (GC-MS) method specifically intended to quantify serum levels of 2HB. Liquid-liquid extraction with ethyl acetate was followed by 2 min of microwave-assisted derivatization. The method presented acceptable accuracy, precision and recovery, and the limit of quantification was 5 µM. Levels of 2HB were found to be stable in serum after three freeze-thaw cycles, and at ambient temperature and at a temperature of 4 °C for up to 24 h. Extracts derivatized under microwave irradiation were stable for up to 96 h. No differences were found in 2HB concentrations measured in serum or plasma EDTA samples. In summary, the method is useful for a rapid, precise and accurate quantification of 2HB in serum samples assessed for the evaluation of dysglycemia and diabetes mellitus

Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España

Alemtuzumab; Eficacia; Práctica clínica habitualAlemtuzumab; Effectiveness; Daily clinical practiceAlemtuzumab; Eficàcia; Pràctica clínica habitualIntroduction Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. Development A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice.Introducción Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis múltiple remitente recurrente. Objetivo Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, administración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual.Sanofi-Genzyme provided financial support to this project

Sub-chronic ketamine administration increases dopamine synthesis capacity in the mouse midbrain: a preclinical in vivo PET study

PURPOSE: There is robust evidence that people with schizophrenia show elevated dopamine (DA) synthesis capacity in the striatum. This finding comes from positron emission tomography (PET) studies using radiolabelled l-3,4-dihydroxyphenylalanine (18F-DOPA). DA synthesis capacity also appears to be elevated in the midbrain of people with schizophrenia compared to healthy controls. We therefore aimed to optimise a method to quantify 18F-DOPA uptake in the midbrain of mice, and to utilise this method to quantify DA synthesis capacity in the midbrain of the sub-chronic ketamine model of schizophrenia-relevant hyperdopaminergia. PROCEDURES: Adult male C57Bl6 mice were treated daily with either ketamine (30 mg/kg, i.p.) or vehicle (saline) for 5 days. On day 7, animals were administered 18F-DOPA (i.p.) and scanned in an Inveon PET/CT scanner. Data from the saline-treated group were used to optimise an atlas-based template to position the midbrain region of interest and to determine the analysis parameters which resulted in the greatest intra-group consistency. These parameters were then used to compare midbrain DA synthesis capacity (KiMod) between ketamine- and saline-treated animals. RESULTS: Using an atlas-based template to position the 3.7 mm3 midbrain ROI with a T*-Tend window of 15-140 min to estimate KiMod resulted in the lowest intra-group variability and moderate test-retest agreement. Using these parameters, we found that KiMod was elevated in the midbrain of ketamine-treated animals in comparison to saline-treated animals (t(22) = 2.19, p = 0.048). A positive correlation between DA synthesis capacity in the striatum and the midbrain was also evident in the saline-treated animals (r2 = 0.59, p = 0.005) but was absent in ketamine-treated animals (r2 = 0.004, p = 0.83). CONCLUSIONS: Using this optimised method for quantifying 18F-DOPA uptake in the midbrain, we found that elevated striatal DA synthesis capacity in the sub-chronic ketamine model extends to the midbrain. Interestingly, the dysconnectivity between the midbrain and striatum seen in this model is also evident in the clinical population. This model may therefore be ideal for assessing novel compounds which are designed to modulate pre-synaptic DA synthesis capacity

Cdk9 and H2Bub1 signal to Clr6-CII/Rpd3S to suppress aberrant antisense transcription

Mono-ubiquitylation of histone H2B (H2Bub1) and phosphorylation of elongation factor Spt5 by cyclin-dependent kinase 9 (Cdk9) occur during transcription by RNA polymerase II (RNAPII), and are mutually dependent in fission yeast. It remained unclear whether Cdk9 and H2Bub1 cooperate to regulate the expression of individual genes. Here, we show that Cdk9 inhibition or H2Bub1 loss induces intragenic antisense transcription of ∼10% of fission yeast genes, with each perturbation affecting largely distinct subsets; ablation of both pathways de-represses antisense transcription of over half the genome. H2Bub1 and phospho-Spt5 have similar genome-wide distributions; both modifications are enriched, and directly proportional to each other, in coding regions, and decrease abruptly around the cleavage and polyadenylation signal (CPS). Cdk9-dependence of antisense suppression at specific genes correlates with high H2Bub1 occupancy, and with promoter-proximal RNAPII pausing. Genetic interactions link Cdk9, H2Bub1 and the histone deacetylase Clr6-CII, while combined Cdk9 inhibition and H2Bub1 loss impair Clr6-CII recruitment to chromatin and lead to decreased occupancy and increased acetylation of histones within gene coding regions. These results uncover novel interactions between co-transcriptional histone modification pathways, which link regulation of RNAPII transcription elongation to suppression of aberrant initiation

The consecutive disparity of precipitation in conterminous Spain

Precipitation irregularity constitutes a constraint for natural systems and socio-economic activities, particularly in water-scarce environments. Standard variability statistics such as the standard deviation, variance, and coefficient of variation do not consider the chronological order of these values. In Climatology, however, the temporal order of meteorological events is a relevant factor that can affect natural and socio-economic systems. In order to evaluate the disparity between consecutive values in precipitation series, we applied the Consecutive Disparity Index (D) to the monthly grid with the highest spatial resolution (10×10 km) existing in Peninsular Spain for the period December 1915–November 2015. Monthly, seasonal, and annual D values show an increase from north to southwest, especially in July and August. The D values for the month-to-month correlative series and for monthly mean precipitation reveal a relatively similar pattern. In the latter case, however, the low values are recorded towards southern Spain, following some mountain ranges in the Centre-East of the territory. Monthly, seasonal, and annual precipitation values are also negatively correlated with the corresponding D values. © 2021, The Author(s)

Multiple cycles of dose-intensive chemotherapy with repeated stem cell support as induction treatment in metastatic breast cancer: a feasibility study

The purpose of this trial was to study feasibility and tolerance of a dose-intensive multicyclic alternating induction chemotherapy with repeated stem cell support in a series of 43 metastatic breast cancer patients. Anthracycline-naive patients (n = 21) received cyclophosphamide 2.5 g/m2 plus doxorubicin 80 mg/m2 alternating every 14 days with paclitaxel 200-350 mg/m2 plus cisplatin 120 mg/m2. Patients who had previously received anthracyclines (n = 22) received cisplatin 120 mg/m2 plus etoposide 600 mg/m2 alternating with paclitaxel 200-350 mg/m2 plus ifosfamide 8 g/m2. Peripheral blood stem cells were infused after every course except the first, with a median CD34+ dose of 2.1 ´ 106/kg per cycle. Positive selection of CD34+ cells was performed in good mobilizers. The median number of cycles administered was six (4-8), and the time interval between them was 17 days. Median summation dose intensities (SDI) actually administered for the CA-TP and PE-TI protocol were 4.95 and 4.69, respectively (87% of scheduled SDI). There were 15 complete (35%) and 21 partial responses (49%), for an overall response rate of 84% (95% CI, 73%-95%). Infection or neutropenic fever occurred in 50% of the cycles. There was one treatment-related death. After a median follow-up of 26 months, the median event-free-survival was 12 months (95% CI: 10-14) and overall survival was 31 months. These high dose-intensity induction treatments seem to be feasible with sequential stem cell support

Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

Copyright: 2013 Hermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma

Epidemiology and molecular characterization of Carnivore protoparvovirus-1 infection in the wild felid Leopardus guigna in Chile

Landscape anthropization has been identified as one of the main drivers of pathogen emergence worldwide, facilitating pathogen spillover between domestic species and wildlife. The present study investigated Carnivore protoparvovirus-1 infection using molecular methods in 98 free-ranging wild guignas (Leopardus guigna) and 262 co-occurring owned, free-roaming rural domestic cats. We also assessed landscape anthropization variables as potential drivers of infection. Protoparvovirus DNA was detected in guignas across their entire distribution range, with observed prevalence of 13.3% (real-time PCR) and 9% (conventional PCR) in guignas, and 6.1% (conventional PCR) in cats. Prevalence in guigna did not vary depending on age, sex, study area or landscape variables. Prevalence was higher in juvenile cats (16.7%) than in adults (4.4%). Molecular characterization of the virus by amplification and sequencing of almost the entire vp2 gene (1, 746 bp) from one guigna and five domestic cats was achieved, showing genetic similarities to canine parvovirus 2c (CPV-2c) (one guigna and one cat), feline panleukopenia virus (FPV) (one cat), CPV-2 (no subtype identified) (two cats), CPV-2a (one cat). The CVP-2c-like sequence found in a guigna clustered together with domestic cat and dog CPV-2c sequences from South America, suggesting possible spillover from a domestic to a wild species as the origin of infection in guigna. No clinical signs of disease were found in PCR-positive animals except for a CPV-2c-infected guigna, which had haemorrhagic diarrhoea and died a few days after arrival at a wildlife rescue centre. Our findings reveal widespread presence of Carnivore protoparvovirus-1 across the guigna distribution in Chile and suggest that virus transmission potentially occurs from domestic to wild carnivores, causing severe disease and death in susceptible wild guignas

Chemical composition, mineral content and antioxidant activity of Verbena officinalis L.

Aqueous and hydroalcoholic extracts from Verbena officinalis L. were obtained and characterised. The analysis by HPLC-DAD and LC–MS allowed the detection and identification of three iridoids, fifteen flavonoids and four phenolic acid derivatives. Four flavonoids, scutellarein 7-diglucuronide (9), scutellarein 7-glucuronide (13), pedalitin 6-galactoside (15) and scutellarein 7-glucoside (19) are reported for the first time from this plant. In addition, three new flavonoids have been isolated: scutellarein 7-O-(2-O-feruloyl)-diglucuronide (5), pedalitin 6-O-diglucuronide (6) and pedalitin 6-O-(2-O-feruloyl)-diglucuronide (13). To our knowledge, these flavonoids have not been reported as natural products. Both extracts showed significant antioxidant activity using three in vitro model systems and the results have been correlated with total phenolic and total flavonoid contents. The results have allowed establishing an important relation structure–activity and significant correlations have also been found between the mineralcontent and the flavonoids present in both extracts