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Supplementary Tables

Extended Materials and Methods and Supplementary figures with legends

Effect of doxorubicin and Cdk4/6i on cells expressing different levels of HER2.

Antibody–drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression.Significance:Combining ADCs against HER2-positive breast cancers with therapies that induce cellular senescence may improve their therapeutic efficacy by facilitating a bystander effect against antigen-negative tumor cells.

A finales del siglo xviii, centuria de avances médicos, la mujer es puesta en el epicentro de la investigación médica. Por una parte, los estudios se centran en describir a las mujeres como seres enfermizos y débiles. Por otra, los médicos intentan dar una explicación a la atribución del sexo durante el acto reproductor, esforzándose, sobre todo, en la importancia de concebir niños en su sentido estrictamente masculino. Las hipótesis del médico francés Michel Proscope-Couteux (1684-1753) suponen un claro ejemplo de este tipo de teorías erróneas. En L’art de faire des garçons (1755), defiende su tesis sobre la transmisión genética y nuestro objetivo es, por ende, analizar su discurso médico desde una perspectiva de género.

Anti-cancer therapies often result in a subset of surviving cancer cells that undergo therapy-induced senescence (TIS). Senescent cancer cells strongly modify the intratumoural microenvironment favoring immunosuppression and, thereby, tumour growth. An emerging strategy to optimise current therapies is to combine them with treatments that eliminate senescent cells. To this end, we undertook an unbiased proteomics approach to identify surface markers contributing to senescent cells immune evasion. Through this approach, we discovered that the immune checkpoint inhibitor PD-L2, but not PD-L1, is upregulated across multiple senescent human and murine cells. Importantly, blockade of PD-L2 strongly synergises with genotoxic chemotherapy, causing remission of solid tumours in mice. We show that PD-L2 inhibition prevents the persistence of chemotherapy-induced senescent cells, which exert cell-extrinsic immunomodulatory actions. In particular, upon chemotherapy, tumours deficient in PD-L2 fail to produce cytokines of the CXCL family, do not recruit myeloid-derived suppressor cells (MDSCs) and are eliminated in a CD8 T cell-dependent manner. We conclude that blockade of PD-L2 improves chemotherapy efficacy by reducing the intratumoural burden of senescent cells and their associated recruitment of immunosuppressive cells. These findings provide a novel strategy to exploit vulnerabilities arising in tumour cells as a result of therapy-induced damage and cellular senescence.

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.

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.

Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (COXPD1) is a recessive mitochondrial translation disorder caused by mutations in GFM1, a nuclear gene encoding mitochondrial elongation factor G1 (EFG1). Patients with COXPD1 typically present hepatoencephalopathy early after birth with rapid disease progression, and usually die within the first few weeks or years of life. We have generated two different mouse models: a Gfm1 knock-in (KI) harboring the p.R671C missense mutation, found in at least 10 patients who survived more than 1 year, and a Gfm1 knock-out (KO) model. Homozygous KO mice (Gfm1

espanolResena de libro: Hoyos, Juan Carlos de (2018): Lexico economico en la lengua espanola de principios del XIX. El Epitome de Jean-Baptiste Say, La Rioja, Cilengua, Fundacion San Millan de la Cogolla, Instituto Caro y Cuervo, 291 pp. EnglishBook review: Hoyos, Juan Carlos de (2018): Lexico economico en la lengua espanola de principios del XIX. El Epitome de Jean-Baptiste Say, La Rioja, Cilengua, Fundacion San Millan de la Cogolla, Instituto Caro y Cuervo, 291 pp. galegoRecension de libro: Hoyos, Juan Carlos de (2018): Lexico economico en la lengua espanola de principios del XIX. El Epitome de Jean-Baptiste Say, La Rioja, Cilengua, Fundacion San Millan de la Cogolla, Instituto Caro y Cuervo, 291 pp.

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., This work was mainly supported by a grant from the Fondo de Investigaciones Sanitarias (FIS) of the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (ERDF) “Una manera de hacer Europa” [grant PI17/01895 to IGT and MSM.]; Junta de Castilla y León, Fondos FEDER [SA085U16 to JMHR]; Novartis grant; and by the Fundación “Jabones para Daniel”. JM Hernández-Sánchez was supported by a research grant from Fundación Española de Hematología y Hemoterapia (FEHH).

Home respiratory polygraphy may be a simpler alternative to in-laboratory polysomnography for the management of more symptomatic patients with obstructive sleep apnea, but its effectiveness has not been evaluated across a broad clinical spectrum.To compare the long-term effectiveness (6 mo) of home respiratory polygraphy and polysomnography management protocols in patients with intermediate-to-high sleep apnea suspicion (most patients requiring a sleep study).A multicentric, noninferiority, randomized controlled trial with two open parallel arms and a cost-effectiveness analysis was performed in 12 tertiary hospitals in Spain. Sequentially screened patients with sleep apnea suspicion were randomized to respiratory polygraphy or polysomnography protocols. Moreover, both arms received standardized therapeutic decision-making, continuous positive airway pressure (CPAP) treatment or a healthy habit assessment, auto-CPAP titration (for CPAP indication), health-related quality-of-life questionnaires, 24-hour blood pressure monitoring, and polysomnography at the end of follow-up. The main outcome was the Epworth Sleepiness Scale measurement. The noninferiority criterion was -2 points on the Epworth scale.In total, 430 patients were randomized. The respiratory polygraphy protocol was noninferior to the polysomnography protocol based on the Epworth scale. Quality of life, blood pressure, and polysomnography were similar between protocols. Respiratory polygraphy was the most cost-effective protocol, with a lower per-patient cost of 416.7€.Home respiratory polygraphy management is similarly effective to polysomnography, with a substantially lower cost. Therefore, polysomnography is not necessary for most patients with suspected sleep apnea. This finding could change established clinical practice, with a clear economic benefit. Clinical trial registered with www.clinicaltrials.gov (NCT 01752556).