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Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis. PLK1 is a mitotic regulator overexpressed in cancer; however, whether this overexpression causally contributes to tumor development is unclear. Here the authors produce an inducible mouse model to overexpress PLK1 and show that actually this can act as a tumor suppressor by perturbing mitotic progression and cytokinesis.

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.

RAF kinases are RAS-activated enzymes that initiate signalling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryo-electron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities to attempt the pharmacological degradation of RAF1 for therapeutic purposes. Competing Interest Statement The authors have declared no competing interest.

Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by KrasG12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.

Background Unprotected and fragile elderly people in nursing homes experienced the highest mortality rates during the initial coronavirus disease 2019 (COVID-19) pandemic. Objective Our aim was to study the role of two oral anti-inflammatory drugs, colchicine and prednisone, in elderly patients with COVID-19 in geriatric centers. Methods A phase II/III, randomized, controlled, multicenter clinical trial was performed in a geriatric population comparing the efficacy and safety of an oral combination of prednisone (60 mg/day for 3 days) and colchicine (at loading doses of 1–1.5 mg/day for 3 days, followed by 0.5 mg/day for 11 days) with the standard treatment, based on intravenous dexamethasone. Primary endpoints assessed the efficacy in reducing death or the modified endpoint death/therapeutic failure to the study drugs over a 28-day period, while secondary endpoints included safety, laboratory changes, and additional therapies used. Results Fifty-four patients (35 female/19 male) were enrolled, 25 (46.3%) of whom were allocated to the experimental arm and 29 (53.7%) to the control arm. At day 28, no differences in deaths were observed. The combination of mortality or therapeutic failure occurred in 12 (45.13%) patients receiving dexamethasone and 6 (28.13%) patients receiving colchicine/prednisone, resulting in a reduction of risk difference (RD) of − 17% ( p  = 0.17), with an average reduction of 39% (risk ratio [RR] 0.61) in patients receiving colchicine/prednisone ( p  = 0.25). Control patients received higher amounts of additional glucocorticoids ( p  = 0.0095) over a longer time frame ( p  = 0.0003). Colchicine/prednisone significantly reduced ferritin levels at day 14, as well as d -dimer and lactate dehydrogenase (LDH) levels at day 28. Adverse events were similar in both groups. Conclusions The combination colchicine/prednisone compared with intravenous dexamethasone has shown a remarkable trend to increase disease survival over a 28-day period in elderly patients requiring oxygen therapy in geriatric centers, without safety issues. Clinical Trial Registry Clinical Trials Registration Number: NCT04492358.

Introduction: In a global context of increasing demand for health care and the greater demand on the quality of care, our health systems are being challenged to maintain high quality standards. In order to meet these expectations, it is necessary to apply increasingly efficient management models that safeguard and improve the user’s perception of the attention received.Limited public or private resources in health institutions urge us to seek their optimization by implementing more effective alternative modus operandi. By incorporating technological advances in the sector, particularly through new communication systems, we are given an opportunity to substantially alter doctor-patient or administration-patient relations whilst promoting co responsibility in the health process.With these premises, and a clear commitment to the patient, a project is born focused on the outpatient area of the Hospital Sant Joan de Deu de Martorell in Barcelona. The aim is to simplify the highly complex flow of patients, which increases the cost of the care process due to its numerous associated administrative procedures. This gives rise to a negative impact on the end user’s satisfaction. Using the basic principles of ‘LEAN’ methodology and process reengineering in the areas of surgical scheduling, outpatient visits, admissions and certain outpatient procedures, waiting time targets have been reduced and improved levels of accessibility to specialist consultants were established.Methods: The project is defined initially by focusing on the outpatient area, however with a view to expanding it into other hospital areas. The project has been undertaken in close collaboration with primary care teams resulting in the setting of the main following lines of action:1. Review and redesign of patient care systems, from hospital admission to scheduling consultations and diagnostic tests by applying reduced flow time and optimization of resources.2. Incorporation of non-face-to-face service processes by implementing mobile-phone technology as a way of bi-directional communication with the patient.3. Creation of a preoperative care unit, with a single preoperative interaction as a specific approach in the pre-surgical procedure.4. Application of biometric signatures, with informed consent, and the elimination of paper medical records.Results: In less than a year, after the implementation of the actions described, the results exceeded the expectations created and effected directly and indirectly all influential areas of the organization. There were substantial quantitative and qualitative improvements in the main assessment indicators.A notable 95% reduction of face events (250.000 per year) in the areas of scheduling outpatient visits, diagnostic tests and surgical procedures, through computerization of the requests generated in consultancies, along with the extension and acceptance of the non-contact care program, has been the biggest factor in allowing the users to spend only the minimum time necessary in those activities that add value to the process of health.The bi-directional communication with the patient through mobile messaging for appointments, modification and/or cancellation, has allowed a reduction in the rate of user’s presence. This has produced an 11% increase in accessibility to the agendas and has facilitated meeting current commitments to ‘Maximum Delay’ objectives for first visits in all specialties.The new preoperative care unit, which provides a single time for the patient to take all necessary surgical diagnostic tests has resulted in improvements in the level of patient risk and in the application of complementary diagnostic tests. The prior review of the need to test, avoiding duplication and unnecessary patient radiation, has meant an 8% reduction in electrocardiograms and 56% in chest x-rays.Document scanning, the implementation of the biometric signature and the incorporation of advances in communication, replacing letters and phone calls has reduced by up to 70% office supplies costs (paper, printer toner, labels, ...) and gave over 60% savings in telephone costs.Discussion: Results to date show that the implementation of mobile-phone technology is an essential tool in order to obtain a more effective and higher quality health care.Having noted the acceptance and profitability of the project in the hospital environment, we consider the feasibility of it is exportable to all primary care services, as it has been proven in our area of influence.Conclusion: From the patient's perspective, and the considerable organizational benefits, simplifying the flow of patients, reducing queues and waiting times as well as the reduction of face-to face services has facilitated the meeting of objectives giving rise to an improvement in overall user satisfaction and the perception of health care.

RESUMEN Contextualización: La presente investigación se contextualiza en sistemas de producción campesina de la zona de ladera del municipio de Palmira- Valle del Cauca, caracterizados por presentar pequeñas áreas productivas con especies vegetales perennes, de ciclo corto y sistemas pecuarios con especies menores. Estos sistemas son de gran importancia para la seguridad alimentaria de la población por su diversa oferta en el mercado de la región. Vacío de conocimiento: Los sistemas campesinos son altamente vulnerables ante diversos factores externos como la fluctuación del mercado y la variabilidad climática que los colocan en riesgo. La presente investigación se basó en la siguiente pregunta: ¿qué tan sustentables son los sistemas agropecuarios campesinos de zona de ladera del Municipio de Palmira Valle del Cauca? Propósito: Evaluar la sustentabilidad agropecuaria de sistemas campesinos del corregimiento Ayacucho, municipio de Palmira- Valle del Cauca. Metodología: Se cuantificaron algunos atributos de trece sistemas campesinos priorizados, empleando el Marco de Evaluación de Sistemas de Manejo de recursos naturales incorporando Indicadores de Sostenibilidad- MESMIS. Los datos obtenidos a partir de encuesta y visitas en campo se analizaron mediante estadística descriptiva y multivariada de componentes principales empleando el paquete estadístico R Studio versión 3.0.1. Los atributos productividad, adaptabilidad, estabilidad, confiabilidad y resiliencia, equidad y autogestión, se graficaron mediante diagrama tipo radar, con un rango evaluativo de 0-100%. Los indicadores por atributo se graficaron como eigenvectores para los dos primeros componentes principales, estableciendo su grado de similitud mediante la varianza acumulada. Resultados y conclusiones: El atributo estabilidad registró el valor más alto con 75.15%, indicando fortalezas en tenencia de la tierra y oferta hídrica de la zona para la producción agropecuaria. Los atributos adaptabilidad y autogestión registraron los valores más bajos con 44.90% y 46.15% respectivamente, indicando debilidades como la alta dependencia de insumos externos, desconocimiento técnico para la integración de los componentes animal y vegetal, así como bajo nivel de asociatividad. Los resultados obtenidos a partir de la evaluación MESMIS permitieron valorar de manera holística los sistemas campesinos de la vereda Arenillo- Palmira, identificando los aspectos críticos para establecer oportunidades de mejora con miras de alcanzar la sustentabilidad.

Contextualización: la presente investigación se enfocó en sistemas de producción campesina de la zona de ladera del municipio de Palmira [Valle del Cauca], los cuales se caracterizan por presentar pequeñas áreas productivas con especies vegetales perennes y de ciclo corto, y sistemas pecuarios con especies animales menores. Estos sistemas son de gran importancia para la seguridad alimentaria de la población por su diversa oferta para el mercado de la región. Vacío de conocimiento: los sistemas campesinos son altamente vulnerables ante diversos factores externos, como la fluctuación del mercado y la variabilidad climática que los colocan en riesgo. La presente investigación se basó en la siguiente pregunta: ¿Qué tan sustentables son los sistemas agropecuarios campesinos en la zona de ladera de Palmira Valle del Cauca? Propósito: evaluar la sustentabilidad agropecuaria de sistemas campesinos en el corregimiento de Ayacucho [Palmira, Valle del Cauca]. Metodología: se cuantificaron algunos atributos de trece sistemas campesinos priorizados, empleando el marco de evaluación de sistemas de manejo de recursos naturales e incorporando Indicadores de Sostenibilidad [MESMIS]. Los datos obtenidos a partir de encuestas y visitas en campo se analizaron mediante estadística descriptiva y multivariada de componentes principales, empleando el paquete estadístico R Studio versión 3.0.1. Los atributos de productividad, adaptabilidad, estabilidad, confiabilidad, resiliencia, equidad y autogestión se graficaron mediante diagrama tipo radar, con un rango evaluativo de 0-100 %. Los indicadores por atributo se graficaron como eigenvectores para los dos primeros componentes principales, estableciendo su grado de similitud mediante la varianza acumulada. Resultados y conclusiones: el atributo estabilidad registró el valor más alto con 75.15 %, indicando fortalezas en la tenencia de la tierra y en la oferta hídrica de la zona para la producción agropecuaria. Los atributos adaptabilidad y autogestión registraron los valores más bajos, con 44.90 % y 46.15 % respectivamente, mostrando debilidades como la alta dependencia de insumos externos, desconocimiento técnico para la integración de los componentes animal y vegetal, así como bajo nivel de asociatividad. Los resultados obtenidos, a partir de la evaluación MESMIS, permitieron valorar de manera holística los sistemas campesinos de la vereda Arenillo [ubicada en Palmira], y esto permitió identificar los aspectos críticos para desarrollar mejoras que permitan alcanzar la sustentabilidad de estos sistemas agropecuarios.

Patients with peripheral artery disease (PAD) are at increased risk for subsequent ischemic events. We used data from the FRENA Registry to find predictors of subsequent myocardial infarction (MI), ischemic stroke, and limb amputation in stable outpatients with PAD. As of January 2012, 1,270 patients with PAD were recruited, of whom 1,042 (82 %) had Fontaine stage II; 113 (8.9 %) stage III; and 115 (9.1 %) stage IV. Over a mean follow-up of 14 months, 35 patients developed MI, 25 had stroke, 39 underwent limb amputation, and 91 died. Among patients with Fontaine stage II, the incidence of MI (2.09 events per 100 patient-years; 95 % CI 1.43–2.97) or stroke (0.93; 95 % CI 0.52–1.56) was similar to that of limb amputation (3.22; 95 % CI 2.37–4.29). On multivariate analysis, patients with diabetes [hazard ratio (HR) 2.09; 95 % CI 1.05–4.18], prior coronary disease (HR 5.35; 95 % CI 2.24–12.8), or atrial fibrillation (HR 3.11; 95 % CI 1.52–6.37) were at increased risk for MI; female (HR 2.94; 95 % CI 1.32–6.67), those with prior stroke (HR 5.21; 95 % CI 1.22–22.2) or atrial fibrillation (HR 3.37; 95 % CI 1.45–7.85) at increased risk for stroke; and female (HR 2.38; 95 % CI 1.23–4.55), those with diabetes (HR 3.50; 95 % CI 1.58–7.73) or advanced stages of PAD were at increased risk for limb amputation. Prior coronary artery disease, diabetes and atrial fibrillation predicted subsequent MI; female gender, prior stroke and atrial fibrillation predicted stroke; and female gender, diabetes, and advanced stages of PAD predicted limb amputation.