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CRISPR/Cas9 allows the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons.

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence. Chaib et al. find that therapy-induced senescent cells have high programmed cell death 1 ligand 2 (PD-L2), contributing to recurrence. They show that PD-L2 blocking combined with chemotherapy is therapeutically beneficial because it reduces senescent cells and immunosuppressive cell recruitment.

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors. Chimeric antigen receptor T (CAR-T) cell therapy is efficient in certain haematologic malignancies, but clinical success in solid tumours has been hampered by scarcity of tumour-specific antigens. Here authors show that combination therapy using CAR T cells targeting p95HER2 and bispecific antibodies against HER2 and CD3 consistently leads to complete regression in HER2-positive, patient-derived xenografts tumours in mouse models.

Background: Studies focusing on the effects of lifestyle strategies on patients with obstructive sleep apnea (OSA) that go beyond body weight and explore body composition are currently scarce and inconclusive. Objectives/Methods: The aim of this study was to evaluate the effects of a 12-month intensive life intervention program (ILI), based on a hypocaloric Mediterranean diet, on changes in the body composition parameters as assessed by abdominal computed tomography (CT) and the cardiorespiratory profile of patients with severe OSA and grade I–II obesity, compared to patients receiving standard care. Resultts:Thirty-four patients (30 males and four females) were randomly assigned to an intervention group (IG) (n = 18) or a control group (CG) (n = 16). We observed an improvement in OSA severity following the intervention. Patients in the IG lost 8.2% of their body weight compared to 0.1% of the patients in the CG (p < 0.001), and this loss was primarily due to reductions in total body fat, visceral adipose tissue index (VATI) [IG −19.4 (18.1) cm2/m2 versus CG 2.32 (11.6) cm2/m2, p < 0.001], and a tendency toward lower intramuscular adipose tissue index (IMATI) [IG −0.69 (0.85) cm2/m2 versus CG 0.04 (1.3) cm2/m2, p = 0.098]. These changes were associated with an improvement in patients’ metabolic and inflammatory profile. Younger age and a higher degree of obesity at baseline were associated with greater weight loss. Conslusions: In conclusion, the ILI was effective in reducing 8.2% of body weight at 12 months, leading to favorable changes in patients’ body composition profile that resulted in healthier metabolic and inflammatory parameters.

Study Objectives: To determine whether an intensive weight-loss program (IWLP) is effective for reducing weight, the severity of obstructive sleep apnea (OSA), and metabolic variables in patients with obesity and severe OSA undergoing continuous positive airway pressure treatment. Methods: Forty-two patients were randomized to the control (CG, n = 20) or the intervention group (IG, n = 22), who followed a 12-month IWLP. The primary outcome was a reduction in the apnea-hypopnea index (AHI) as measured at 3 and 12 months by full polysomnography. Metabolic variables, blood pressure, body fat composition by bioimpedance, carotid intima media thickness, and visceral fat by computed tomography were also assessed. Results: Mean age was 49 (6.7) years, body mass index 35 (2.7) kg/m 2 , and AHI 69 (20) events/h. Weight reduction was higher for the IG than the CG at 3 and 12 months, −10.5 versus −2.3 kg ( P < .001), and −8.2 versus −0.1 kg ( P < .001), respectively, as was loss of visceral fat at 12 months. AHI decreased more in the IG at 3 months (−23.72 versus −9 events/h) but the difference was not significant at 12 months, though 28% of patients from the IG had an AHI < 30 events/h compared to none in the CG ( P = .046). At 12 months, the IG showed a reduction in C-reactive protein ( P = .013), glycated hemoglobin ( P = .031) and an increase in high density lipoprotein cholesterol ( P = .027). Conclusions: An IWLP in patients with obesity and severe OSA is effective for reducing weight and OSA severity. It also results in an improvement in lipid profiles, glycemic control, and inflammatory markers. Clinical Trial Registration: Registry: ClinicalTrials.gov ; Title: Effectiveness of an Intensive Weight Loss Program for Obstructive Sleep Apnea Syndrome (OSAS) Treatment; Identifier: NCT02832414; URL: https://clinicaltrials.gov/ct2/show/record/NCT02832414 Citation: López-Padrós C, Salord N, Alves C, et al. Effectiveness of an intensive weight-loss program for severe OSA in patients undergoing CPAP treatment: a randomized controlled trial. J Clin Sleep Med . 2020;16(4):503–514.

Au XIXe siede, période historique d'avancées scientifiques ayant fait suite aux Lumieres, les Sciences et les Lettres étaient des métiers réservés au genre masculin ; la traduction spécialisée n'y fit pas exception. De façon quelque peu fortuite, María Antonia Gutiérrez Bueno y Ahoiz (1781-1874), fille du chimiste et pharmacien Pedro Gutiérrez Bueno, commence sa carriere de traductrice avec la publication d'un recueil d'articles sur la maladie appelée « choléra-morbus » sous son pseudonyme masculin. Elle traduit du français vers l'espagnol et la plupart de ses traductions traitent des problemes médicaux. Å travers l'analyse des textes originaux et de ses traductions, on observe l'utilisation des techniques traductologiques habituelles au XIXe siecle. De meme, elle assume son statut de « médiateur linguistique » afin de transférer les connaissances médicales de France en Espagne.

En Feminismes i Traducció (1965-1990), Pilar Godayol demuestra fehacientemente que la traducción se convirtió en un vector fundamental para promover la acción política que dio fuerza a la lucha feminista correspondiente a la segunda ola en Cataluña durante las etapas del tardofranquismo y el postfranquismo.

El presente capítulo se inserta en el marco de los estudios históricos de género. Mediante esta investigación pretendemos, en primer lugar, presentar sucintamente la vida de María Antonia Gutiérrez Bueno y Ahoiz, poco conocida hasta el momento. En segundo lugar, nos centraremos en su obra, titulada Diccionario histórico y biográfico de mugeres [sic] célebres (1835), para analizar cómo fue confeccionada y redactada. A nivel metodológico, hemos empleado el método analíticosintético a través del cual hemos descompuesto los diferentes elementos relativos a su vida y a su obra para analizarlos particularmente y, posteriormente, hemos procedido a unificar los datos para establecer

CRISPR/Cas9 enables the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons.

En Feminismes i Traducció (1965-1990), Pilar Godayol demuestra fehacientemente que la traducción se convirtió en un vector fundamental para promover la acción política que dio fuerza a la lucha feminista correspondiente a la segunda ola en Cataluña durante las etapas del tardofranquismo y el postfranquismo.