A functional genetic screen defines the AKT-induced senescence signaling network

Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.Peer reviewe

Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10-8 and 6.4 × 10-4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories

Vitrification of kidney precursors as a new source for organ transplantation

[EN] Kidney transplantation from deceased or living human donors has been limited by donor availability as opposed to the increasing demand, and by the risk of allograft loss rejection and immunosuppressive therapy toxicity. In recent years, xenotransplantation of developed kidney precursor cells has offered a novel solution for the unlimited supply of human donor organs. Specifically, transplantation of kidney precursors in adult hosts showed that intact embryonic kidneys underwent maturation, exhibiting functional properties, and averted humoural rejection post-transplantation from non-immunosuppressed hosts. Even if supply and demand could be balanced using xenotransplants or lab-grown organs from regenerative medicine, the future of these treatments would still be compromised by the ability to physically distribute the organs to patients in need and to produce these products in a way that allows adequate inventory control and quality assurance. Kidney precursors originating from fifteen-day old rabbit embryos were vitrified using Cryotop® as a device and VM3 as vitrification solution. After 3 months of storage in liquid nitrogen, 18 kidney precursors were transplanted into non-immunosuppressed adult hosts by laparoscopy surgery. Twenty-one days after allotransplantation, 9 new kidneys were recovered. All the new kidneys recovered exhibited significant growth and mature glomeruli. Having achieved these encouraging results, we report, for the first time, that it is possible to create a long-term biobank of kidney precursors as an unlimited source of organs for transplantation, facilitating the inventory control and distribution of organs.This work was supported by funds from the Generalitat Valenciana Research Programme (PrometeoII 2014/036).Marco Jiménez, F.; Garcia-Dominguez, X.; Jiménez Trigos, ME.; Vera Donoso, CD.; Vicente Antón, JS. (2015). Vitrification of kidney precursors as a new source for organ transplantation. Cryobiology. 70(3):278-282. https://doi.org/10.1016/j.cryobiol.2015.04.007S27828270

Combinación de estrategias de innovación docente para la enseñanza de asignaturas de Ciencias de la Tierra: aprendizaje colaborativo y basado en proyectos como fuente de material para el aula invertida

Se han combinado diferentes estrategias de innovación docente para la creación de material de uso en el aula invertida. Grupos de alumnos han realizado micro-videotutoriales para la resolución de problemas básicos de cortes geológicos, realizando ellos mismos desde el guion hasta la edición, pasando por la grabación. Mediante esta actividad han tenido que desarrollar un proyecto y trabajar de forma colaborativa. El resultado de este trabajo ha sido una colección de microvideos que están siendo empleados en la formación de otros alumnos mediante el aula invertida en varias asignaturas de Ciencias de la Tierra. Los videos se han puesto a disposición de los alumnos a través de la plataforma Moodle de la UPM para que puedan aprender y repasar las técnicas de resolución de problemas de forma autónoma

EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris - Part 2 : specific clinical and comorbid situations

This evidence- and consensus-based guideline on the treatment of psoriasis vulgaris was developed following the EuroGuiDerm Guideline and Consensus Statement Development Manual. The second part of the guideline provides guidance for specific clinical and comorbid situations such as treating psoriasis vulgaris patient with concomitant psoriatic arthritis, concomitant inflammatory bowel disease, a history of malignancies or a history of depression or suicidal ideation. It further holds recommendations for concomitant diabetes, viral hepatitis, disease affecting the heart or the kidneys as well as concomitant neurological disease. Advice on how to screen for tuberculosis and recommendations on how to manage patients with a positive tuberculosis test result are given. It further covers treatment for pregnant women or patients with a wish for a child in the near future. Information on vaccination, immunogenicity and systemic treatment during the COVID-19 pandemic is also provided.Peer reviewe

EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris – : Part 1: treatment and monitoring recommendations

Peer reviewe

Gene family expansions and contractions are associated with host range in plant pathogens of the genus Colletotrichum

Background: Many species belonging to the genus Colletotrichum cause anthracnose disease on a wide range of plant species. In addition to their economic impact, the genus Colletotrichum is a useful model for the study of the evolution of host specificity, speciation and reproductive behaviors. Genome projects of Colletotrichum species have already opened a new era for studying the evolution of pathogenesis in fungi. Results: We sequenced and annotated the genomes of four strains in the Colletotrichum acutatum species complex (CAsc), a clade of broad host range pathogens within the genus. The four CAsc proteomes and secretomes along with those representing an additional 13 species (six Colletotrichum spp. and seven other Sordariomycetes) were classified into protein families using a variety of tools. Hierarchical clustering of gene family and functional domain assignments, and phylogenetic analyses revealed lineage specific losses of carbohydrate-active enzymes (CAZymes) and proteases encoding genes in Colletotrichum species that have narrow host range as well as duplications of these families in the CAsc. We also found a lineage specific expansion of necrosis and ethylene-inducing peptide 1 (Nep1)-like protein (NLPs) families within the CAsc. Conclusions: This study illustrates the plasticity of Colletotrichum genomes, and shows that major changes in host range are associated with relatively recent changes in gene content

How do patient-reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients

Objectives The AsseSSing Impact in pSoriatic Treatment (ASSIST) study investigated prescribing in routine PsA care and whether the patient-reported outcome—PsA Impact of Disease questionnaire (PsAID-12)—impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. Methods Patients with PsA were selected across the UK and Europe between July 2021 and March 2022. Patients completed the PsAID questionnaire and the results were shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. Results A total of 503 patients were recruited. Some 36.2% had changes made to treatment, and 88.8% of these had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; increase in PSAID-12 score is associated with increased odds of treatment escalation (odds ratio 1.58; P < 0.0001). However, most clinicians reported that PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician’s assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation (odds ratio 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. Conclusion This study highlights multiple factors impacting treatment decision-making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported that the PsAID-12 did not influence treatment escalation decisions. Psoriatic Arthritis Impact of Disease (PsAID) scoring could be used to increase confidence in treatment de-escalation