Biodiversidad y especiación críptica en los caprélidos (Crustacea: Amphipoda): ¿cuánto falta por descubrir?

La biodiversidad en el medio marino está subestimada, particularmente en el caso de los invertebrados donde la presencia de especies crípticas es más frecuente de lo que se pensaba. Los anfípodos caprélidos, a pesar de su importancia en el medio marino, han sido muy poco estudiados, y esto se debe, en gran parte, a su complicada taxonomía. Así mismo, la tradicional identificación taxonómica basada en caracteres morfológicos sigue siendo la más empleada para identificar y describir las especies de caprélidos, y, dado que la especiación no siempre va acompañada de cambio morfológico (especies crípticas), el uso exclusivo de estos caracteres puede conllevar a una subestimación de su diversidad real. El empleo de metodologías complementarias es, por tanto, necesario. Y, en este sentido, las herramientas moleculares han resultado eficaces y útiles para identificar especies y resolver problemas taxonómicos en estos pequeños crustáceos marinos. En el presente trabajo se muestra una pequeña revisión de los resultados obtenidos para diferentes especies del género Caprella. Estos resultados, que muestran la existencia de nuevas especies, muchas de ellas crípticas, indican que la diversidad de los caprélidos está subestimada, y que la especiación críptica parece ser un fenómeno muy importante y frecuente en estos organismos.Fondo Europeo de Desarrollo Regional POCTI/BSE/42300/2001, FCOMP-01- 0124-FEDER-PTDC/MAR/118205/201

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines

Evaluación y resultados de la instauración de un programa de terapia de grupo dirigido a un colectivo de cuidadores familiares de enfermos de Alzheimer

[Resumen] La terapia de grupo es una de las actividades que se han mostrado más positivas como apoyo a los cuidadores familiares de enfermos de Alzheimer; por ello, en este trabajo pre - sentamos un programa de ayuda a cuidadores de enfermos de Alzheimer, en donde la terapia de grupo es una de las actividades establecidas con dos funciones; por un lado contrarrestar el aislamiento de los cuidadores; mientras que por el otro será ayudarlos a superar los sentimientos negativos que suscitan su situación. Los resultados que presentamos, corresponden a un periodo de intervención de seis meses, valorados mediante el STAI; en ellos se muestra como muy afectiva tanto para la reducción de la ansiedad como para el establecimiento de un sistema de comunicación acerca de la problemática común y de la búsqueda de soluciones percibiendo los cuidado - res estas actuaciones como excelentes para su bienestar.[Abstract] The group therapy is one of the activities that have been shown more positive as sup - port to the family caregivers of AD; for it, in this work we introduce a program of help to caregivers; where the group therapyl is one of the established activities with two functions: counteracting the isolation of the caregivers and helping them to overcome the negative fee - lings that raise their situation. The results that we present, correspond to a period of intervention of six months, valued by the STAI. Results point out to be very effective for the reduction of the anxiety like for the establishment of a communication system about the common problem and the search of solutions, perceiving the caregivers these performances as excellent for their wellfare

Connecting the chemical and biological reactivity of epoxides

The chemical reactivity of the mutagenic epoxides (EP) propylene oxide (PO), 1,2-epoxybutane (1,2-EB), and cis- and trans-2,3-epoxybutane (cis- and trans-2,3-EB) with 4-(p-nitrobenzyl)pyridine (NBP), a bionucleophile model for S(N)2 alkylating agents with high affinity for the guanine-N7 position, was investigated kinetically. It was found that three reactions are involved simultaneously: the alkylation reaction of NBP by EP, which yields the corresponding NBP-EP adducts through an S(N)2 mechanism, and EP and NBP-EP hydrolysis reactions. PO and 1,2-EB were seen to exhibit a higher alkylating potential than cis- and trans-2,3-EB. From a study of the correlations between the chemical reactivity (kinetic parameters) and the biological effectiveness of oxiranes, the following conclusions can be drawn: (i) the hydrolysis reactions of epoxides must be taken into account to understand their bioactivity. (ii) The fraction (f) of the alkylating oxirane that forms the adduct and the adduct life (AL) permit the potential of epoxides as bioactive molecules to be rationalized even semiquantitatively; and (iii) alkylation of DNA by epoxides and the O-6-/N7-guanine adduct ratio are directly related to their mutagenicity in vitro.Publicad

Effect of different media additives on capacitation of frozen-thawed ram spermatozoa as a potential replacement for estrous sheep serum

Capacitation is a key process through which spermatozoa acquire their fertilizing ability. This event is required for the successful application of assisted reproductive technologies such as IVF. The aim of the present study was to investigate the effect of using a synthetic oviductal fluid medium supplemented with either heparin–hypotaurine alone, in combination with progesterone (P4), 17β-estradiol (E2), or BSA, or just β-cyclodextrin, in replacement for estrous sheep serum (ESS) for ram sperm capacitation. After incubation in the corresponding media for 15 (time 0) or 60 minutes, sperm function was evaluated by computerized sperm motility analysis and flow cytometry (plasma membrane status and fluidity). Treatments rendering the best results in regards to sperm function parameters related to capacitation were used for an IVF test. Herein, neither heparin–hypotaurine (alone), or in combination with P4, or E2, nor β-cyclodextrin induced capacitation-related changes in frozen–thawed ram spermatozoa. Only the medium supplemented with heparin–hypotaurine–BSA was able to induce changes compatible with in vitro capacitation relating to sperm motility pattern and plasma membrane fluidity, comparable to those in ESS-containing medium. Both media yielded sperm parameter values that differed (P < 0.05) from those obtained in the rest of the media tested. However, after the IVF trial, BSA was unable to support cleavage rates (21.80%) comparable to those obtained with ESS (52.60%; P < 0.05). We conclude that heparin–hypotaurine, P4, E2, β-cyclodextrin, or BSA is not suitable for replacing ESS in capacitation and fertilization media for ram spermatozoa.M. Ramón was supported by the Research Recruitment Program from the National Institute for Agricultural and Food Research program.Peer Reviewe

The nuclear and extended infrared emission of the Seyfert galaxy NGC 2992 and the interacting system Arp 245

We present subarcsecond resolution infrared (IR) imaging and mid-IR (MIR) spectroscopic observations of the Seyfert 1.9 galaxy NGC 2992, obtained with the Gemini North Telescope and the Gran Telescopio CANARIAS (GTC). The N-band image reveals faint extended emission out to ∼3 kpc, and the polycyclic aromatic hydrocarbon features detected in the GTC/CanariCam 7.5–13 μm spectrum indicate that the bulk of this extended emission is dust heated by star formation. We also report arcsecond resolution MIR and far-IR imaging of the interacting system Arp 245, taken with the Spitzer Space Telescope and the Herschel Space Observatory. Using these data, we obtain nuclear fluxes using different methods and find that we can only recover the nuclear fluxes obtained from the subarcsecond data at 20–25 μm, where the active galactic nuclei (AGN) emission dominates. We fitted the nuclear IR spectral energy distribution of NGC 2992, including the GTC/CanariCam nuclear spectrum (∼50 pc), with clumpy torus models. We then used the best-fitting torus model to decompose the Spitzer/IRS 5–30 μm spectrum (∼630 pc) in AGN and starburst components, using different starburst templates. We find that, whereas at shorter MIR wavelengths the starburst component dominates (64 per cent at 6 μm), the AGN component reaches 90 per cent at 20 μm. We finally obtained dust masses, temperatures and star formation rates for the different components of the Arp 245 system and find similar values for NGC 2992 and NGC 2993. These measurements are within those reported for other interacting systems in the first stages of the interaction.IGB acknowledges financial support from the Instituto de Astrofísica de Canarias through Fundacion La Caixa. This research was partly supported by a Marie Curie Intra European Fellowship within the 7th European Community Framework Programme (PIEF-GA-2012-327934). CRA and IGB acknowledge financial support from the Spanish Ministry of Science and Innovation (MICINN) through project PN AYA2013-47742-C4-2-P. AAH acknowledges funding from the Spanish Ministry of Economy and Competitiveness under grant AYA2012-31447, which is party funded by the FEDER program. PE acknowledges support from the Spanish Plan Nacional de Astronomía y Astrofísica under grant AYA2012-31277. OGM acknowledges support from grant AYA2012-39168-C03-01. TDS was supported by ALMA-CONICYT grant number 31130005.Peer Reviewe

Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial

Background: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. Patients and methods: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. Results: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. Conclusions: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations

Differential role of the RasGEFs Sos1 and Sos2 in mouse skin homeostasis and carcinogenesis

Using Sos1 knockout (Sos1-KO), Sos2-KO, and Sos1/2 double-knockout (Sos1/2-DKO) mice, we assessed the functional role of Sos1 and Sos2 in skin homeostasis under physiological and/or pathological conditions. Sos1 depletion resulted in significant alterations of skin homeostasis, including reduced keratinocyte proliferation, altered hair follicle and blood vessel integrity in dermis, and reduced adipose tissue in hypodermis. These defects worsened significantly when both Sos1 and Sos2 were absent. Simultaneous Sos1/2 disruption led to severe impairment of the ability to repair skin wounds, as well as to almost complete ablation of the neutrophil-mediated inflammatory response in the injury site. Furthermore, Sos1 disruption delayed the onset of tumor initiation, decreased tumor growth, and prevented malignant progression of papillomas in a DMBA (7,12-dimethylbenz[α]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate)-induced skin carcinogenesis model. Finally, Sos1 depletion in preexisting chemically induced papillomas resulted also in decreased tumor growth, probably linked to significantly reduced underlying keratinocyte proliferation. Our data unveil novel, distinctive mechanistic roles of Sos 1 and Sos2 in physiological control of skin homeostasis and wound repair, as well as in pathological development of chemically induced skin tumors. These observations underscore the essential role of Sos proteins in cellular proliferation and migration and support the consideration of these RasGEFs as potential biomarkers/therapy targets in Ras-driven epidermal tumors.This study was supported by grants FIS PI16/02137 from ISCIII (MINECO), SA043U16 (UIC 076) from JCyL, and AECC Spain (to E.S.); by MINECO grant SAF2015-66015-R; and by MSyC grants ISCIII-RETIC RD12/0036/0009, PIE 15/00076, and CB/16/00228 (to J.M.P.). This research was cofinanced by FEDER fund

Revealing prevalent cancers by interrogating glycoproteins with sustainable immunoelectrochemical tools

Trabajo presentado en el 4th European Biosensor Symposium, celebrado en Aquisgrán (Alemania), del 27 al 30 de agosto de 2023Introduction. The worldwide incidence and death toll of colorectal and pancreatic cancers (CRC and PDAC) have increased considerably since 1990. For this reason, both early detection and regular follow-up are considered key factors in improving patient prognosis. In this sense, the determination of the total content of specific proteins and their aberrantly glycosylated fraction in oncologic processes could help to achieve the proposed goals. Results and Discussion. In this work, two simple but highly competitive electrochemical immunoplatforms for the determination of total and glycosylated post-translational modified haptoglobin (Hp) [1], and CA19-9 [2] (candidate biomarkers associated with colorectal and pancreatic cancer, respectively) are presented. As seen in Figure 1, these biotools are uplifted in the use of magnetic immunocaptors and another antibody or a lectin as detector elements lastly labeled with HRP, which enables subsequent amperometric detection. The presented bioplatforms exhibit attractive characteristics in terms of simplicity, affordability, and point-of-care application compared to the conventional available methodologies, highlighting low detection limits (0.07 and 0.46 ng mL¿1 for total and glycosylated Hp, respectively, and 1.5 U mL¿1 for CA19-9), and short assay times (< 2 h). The workability of these quantitative bioplatforms for the analysis of secretomes from cultured CRC cells with the distinct potential to metastasize (Hp) or serum samples from healthy and PDAC-diagnosed subjects (CA19-9) was assessed to definitely confirm full exploitation of all the above exposed enticing attributes. Conclusions. Our findings clearly revealed the unquestionable ability of these modern electrochemical immunoplatforms to discriminate between healthy and cancer-diagnosed subjects, as well as to assess disease progression, positioning these simple but effective methodologies as advanced electroanalytical tools with proven real biomedical applications, and the hope of aiding in the accurate diagnosis of prevalent and high mortality cancers

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients.Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm.Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: pop-ulation for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 pa-tients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C.Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher nu-merical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles