Search

Supplementary Tables 1,2,3 - PDF file 283K, Details of cell lines included in siRNA screen and processed data from screen

Investigation of PI3K-AKT signalling in FGFR amplified cell lines.

Supplementary Table 1. Expression of estrogen receptor regulated genes in patient 207 was determined using Nanostring. Data was normalized as described in the Online Methods and is presented as the Log2 ratio. Supplementary Table 2. A list of cell lines including FGFR status. Supplementary Table 3. Copy Number Variation and Gene Expression Assays.

Baseline tissue biomarker analysis

Supplementary Figure 1 - PDF file 573K, Analysis of siRNA screen results

Supplementary Figure 2 - PDF file 649K, Efficacy of combined targeting of EGFR and FGFR3

Results of parallel siRNA screens in FGFR driven cell lines with analysis of ERK and AKT phosphorylation in and panel of FGFR driven cancer cell lines.

Clinical activity of FGFR inhibitor AZD4547 in FGFR amplified breast and gastric cancer.

Supplementary Figure 3 - PDF file 87K, Analysis of cell cycle and apoptosis of FGFR and EGFR combination inhibition

RMH200 panel design

High-level FGFR2 amplified cell lines are highly sensitive to FGFR inhibition.

Supplementary Figure 4 - PDF file 354K, Analysis of the effects on combined EGFR and FGFR3 inhibition, and mechanism of EGFR upregulation by FGFR inhibitors

Severe inflammatory responses are associated with the misbalance of innate and adaptive immunity. TLRs, NLRs, and cytokine receptors play an important role in pathogen sensing and intracellular control, which remains unclear in COVID-19. This study aimed to evaluate IL-8 production in blood cells from COVID-19 patients in a two-week follow-up evaluation. Blood samples were taken at admission (t1) and after 14 days of hospitalization (t2). The functionality of TLR2, TLR4, TLR7/8, TLR9, NOD1, and NOD2 innate receptors and IL-12 and IFN-γ cytokine receptors was evaluated by whole blood stimulation with specific synthetic receptor agonists through the quantification of IL-8, TNF-α, or IFN-γ. At admission, ligand-dependent IL-8 secretion was 6.4, 13, and 2.5 times lower for TLR2, TLR4, and endosomal TLR7/8 receptors, respectively, in patients than in healthy controls. Additionally, IL-12 receptor-induced IFN-γ secretion was lower in COVID-19 patients than in healthy subjects. We evaluated the same parameters after 14 days and observed significantly higher responses for TLR2, TLR4, TLR7/8, TLR9, and NOD1, NOD2, and IFN-γ receptors. In conclusion, the low secretion of IL-8 through stimulation with agonists of TLR2, TLR4, TLR7/8, TLR9, and NOD2 at t1 suggests their possible contribution to immunosuppression following hyperinflammation in COVID-19 disease.

Models of PI3 kinase-AKT signalling in FGFR driven cell lines.

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8–59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3–13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4–19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy.SIGNIFICANCE:The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.This article is highlighted in the In This Issue feature, p. 1

Supplementary Figure 6 - PDF file 123K, Mouse weights from xenograft experiments

Supplementary Table and Figure Legends - PDF file 77K, Supplementary table and figure legends

Supplementary Figure 7 - PDF file 36K, Expression of EGFR and HGF from a publically available bladder cancer gene expression data set

Supplementary Figure 5 - PDF file 243K, Analysis of FGFR3 mRNA and protein in 97-7 cells

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2–mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1–S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1–CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301–13. ©2016 AACR.

Supplementary Materials and Methods

Supplementary Figure Legends

Supplementary Figure 1: Early adaptive resistance limits the efficacy of CDK4/6 inhibition. High-throughput drug screen identified PI3K-mTOR inhibitors as sensitizers to CDK4/6 inhibitors. Supplementary Figure 2: Determinants of sensitivity to the combination CDK4/6 and PI3K inhibition. Supplementary Figure 3: Early adaptation to CDK4/6 inhibition is mediated by non-canonical cyclin D1-CDK2 interaction. IGF1R inhibition increases sensitivity to CDK4/6 inhibition in MCF-7 cells. Supplementary Figure 4: Palbociclib induced senescence like morphology is reversible. Supplementary Figure 5: Acquired palbociclib resistance through RB1 loss or CCNE1 amplification/expression. Supplementary Figure 6: Body weight of mice during vehicle, BYL719, LEE011 or combination treatment. Supplementary Figure 7: The combination LEE011 and BYL719 is more effective in ER positive PDX than single agent treatments.

En las instituciones educativas de todos los niveles se están implementando estrategias y recursos de innovación educativa en el proceso de enseñanza y aprendizaje, donde las tecnologías de la información, comunicación, conocimiento y aprendizaje digital (TICCAD) conllevan un cambio significativo en el proceso formativo de los estudiantes. Los integrantes del Cuerpo Académico de Tecnología Educativa en la Sociedad del Conocimiento (ITSon CA-27), adscrito al Departamento de Educación del Instituto Tecnológico de Sonora, presentan esta obra coordinada y producida con el propósito de difundir los resultados obtenidos de investigaciones dirigidas y en colaboración con colegas y estudiantes de pre- y posgrado. El libro se conforma de una colección de 12 trabajos teóricos y empíricos divididos en dos partes: la primera, orientada al quehacer docente en cuanto al uso de la tecnología, y la segunda, enfocada al contexto estudiantil y sus experiencias en el aprendizaje. En este juego de roles la integración de las TICCAD hace que los estilos tanto de docentes como de discentes logren enriquecerse y en ocasiones transformarse significativamente hacia un proceso de mejora continua en la creación de materiales dentro del proceso de formación. El libro está dirigido a docentes en formación, investigadores, directivos y personas interesadas en la mejora de los procesos para una educación de calidad en el aprendizaje digital.

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies. This study has been supported by the Susan G. Komen Foundation (CCR15330331) and by the Catalan Agency AGAUR (2017 SGR 540) [to V.S.]. V.S. received funds from the Instituto de Salud Carlos III: grants PI13/01714, CP14/00228, MV15/00041, CPII19/00033 and PI20/00892. M.P. received a Juan de la Cierva Grant from the Ministerio de Economía y Competitividad (FJCI-2015-25412), L.Mo. a grant from FI-AGAUR (2019 FI_B 01199), F.B-M. a grant from the Fundación Científica Asociación Española Contra el Cáncer (AECC_Postdoctoral17-1062) and M.S-G, a Marie Slodowska-Curie Innovative Training Networks PhD fellowship (H2020-MSCA-ITN-2015_675392). This work was supported by Breast Cancer Research Foundation (BCRF-19-08), Instituto de Salud Carlos III Project Reference number AC15/00062 and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181) and Asociación Española Contra el Cáncer (to J.A.). R.B.C. laboratory is supported by Breast Cancer Now (grant numbers: MAN-Q1 and MAN-Q2), NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) and EdiREX Horizon 2020 grant No.731105. The xenograft program in the C.C. laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). This work has been supported by NIH grants P30 CA008748 and RO1CA190642-01, the CDMRP grant BC171535P1, and the Breast Cancer Research Foundation [to M.S.]. A.P. received funds from Instituto de Salud Carlos III—PI16/00904 and PI19/01846, Breast Cancer Now—2018NOVPCC1294, Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT, Fundació La Marató TV3 201935-30, the European Union’s Horizon 2020 research and innovation program H2020-SC1-BHC-2018-2020. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). C. S. Verma reports grants from MSD International and grants from Ipsen outside the submitted work.

Background Emerging literature has documented heat-related impacts on child health, yet few studies have evaluated the effects of heat among children of different age groups and comparing emergency department (ED) and hospitalisation risks. Objectives To examine the differing associations between high ambient temperatures and risk of ED visits and hospitalisations among children by age group in New York City (NYC). Methods We used New York Statewide Planning and Research Cooperative System (SPARCS) data on children aged 0-18 years admitted to NYC EDs (n = 2 252 550) and hospitals (n = 228 006) during the warm months (May-September) between 2005 and 2011. Using a time-stratified, case-crossover design, we estimated the risk of ED visits and hospitalisations associated with daily maximum temperature (Tmax) for children of all ages and by age group. Results The average Tmax over the study period was 80.3°F (range 50°, 104°F). Tmax conferred the greatest risk of ED visits for children aged 0-4, with a 6-day cumulative excess risk of 2.4% (95% confidence interval [CI] 1.7, 3.0) per 13°F (ie interquartile range) increase in temperature. Children and adolescents 5-12 years (0.8%, 95% CI 0.1, 1.6) and 13-18 years (1.4%, 95% CI 0.6, 2.3) are also sensitive to heat. For hospitalisations, only adolescents 13-18 years had increased heat-related risk, with a cumulative excess risk of 7.9% (95% CI 2.0, 14.2) per 13°F increase in Tmax over 85°F. Conclusions This urban study in NYC reinforces that young children are particularly vulnerable to effects of heat, but also demonstrates the sensitivity of older children and adolescents as well. These findings underscore the importance of focussing on children and adolescents in targeting heat illness prevention and emergency response activities, especially as global temperatures continue to rise.

Mycobacterium tuberculosis, the causal agent of one of the most devastating infectious diseases worldwide, can evade or modulate the host immune response and remain dormant for many years. In this review, we focus on identifying the local immune response induced in vivo by M. tuberculosis in the lungs of patients with active tuberculosis by analyzing data from untouched cells from bronchoalveolar lavage fluid (BALF) or exhaled breath condensate (EBC) samples. The most abundant resident cells in patients with active tuberculosis are macrophages and lymphocytes, which facilitate the recruitment of neutrophils. The cellular response is characterized by an inflammatory state and oxidative stress produced mainly by macrophages and T lymphocytes. In the alveolar microenvironment, the levels of cytokines such as interleukins (IL), chemokines, and matrix metalloproteinases (MMP) are increased compared with healthy patients. The production of cytokines such as interferon (IFN)-γ and IL-17 and specific immunoglobulin (Ig) A and G against M. tuberculosis indicate that the adaptive immune response is induced despite the presence of a chronic infection. The role of epithelial cells, the processing and presentation of antigens by macrophages and dendritic cells, as well as the role of tissue-resident memory T cells (Trm) for in situ vaccination remains to be understood.

Los miembros y coordinadores de los capítulos nacionales integrantes del Comité Internacional para la Elaboración de Consensos y Estandarización en Nutriología (CIENUT), después de un proceso profundo de discusión y análisis, declaramos lo siguiente: La detección precoz de problemas nutricionales, que pudiesen afectar el estado de salud de las personas o reagudizar una patología, es una parte fundamental del proceso de atención nutricional en todo nivel de atención. Por diversas circunstancias, existe una brecha significativamente grande de atención nutricional no cubierta por parte de profesionales de la nutrición, lo cual se ve reflejado en tasas elevadas de morbi-mortalidad que acarrean daños al paciente y gastos innecesarios a las instituciones, aspectos que pudieron evitarse oportunamente. En este contexto, hemos elaborado el Consenso 2 denominado Tamizaje Nutricional; este consenso busca fijar los criterios técnicos y científicos, por los cuales se logre lo siguiente: La implementación de herramientas de tamizaje nutricional en todo nivel de atención tomando en cuenta tanto su validez interna como externa. La reglamentación básica necesaria para que sea el profesional de nutrición quién, en principio, sea el encargado de llevar a cabo la aplicación de herramientas de tamizaje y que, en caso no pudiese hacerlo por escasez de recurso humano, sea otro profesional de la salud debidamente capacitado tanto en la ejecución como en la importancia de los resultados. Invocamos, además, a todas las instituciones que brindan atención nutricional suscriban este consenso y hagan todo lo necesario para que pueda implementarse en la forma más rápida posible. Firmado el 14 de setiembre de 2019 en Lima, Perú.

Los miembros y coordinadores de los capítulos nacionales integrantes del Comité Internacional para la Elaboración de Consensos y Estandarización en Nutriología (CIENUT), después de un proceso profundo de discusión, declaramos lo siguiente: Como las demás especialidades de la salud, la Ciencia de la Nutrición ha debido recorrer un camino largo de trabajo marcado por un proceso de constante evolución y afianzamiento; se ha beneficiado significativamente del desarrollo de disciplinas complementarias como la Física, la Química o la Bioquímica; ha alcanzado un grado suficiente de madurez científica como para que los profesionales que la ejercemos, nos tomemos el tiempo necesario para reflexionar y re-pensar nuestras definiciones, procesos y todo lo relacionado con nuestro quehacer. En este contexto, hemos elaborado el Consenso 1 denominado Nombre de la Ciencia y denominación del Profesional de Nutrición; este consenso busca fijar los criterios técnicos, científicos y filosóficos, por los cuales se logre lo siguiente: Universalización del término Nutriología Humana para denominar a la Ciencia de la Nutrición que se estudia como carrera profesional. Universalización del término Nutriólogo Humano para denominar al profesional que ha estudiado la carrera de Nutriología Humana y que la ejerce de acuerdo a los estándares que la ciencia y el conocimiento demandan en la actualidad. Invocamos, además, a todas las instituciones que forman y representan a profesionales de la Nutrición a suscribir este consenso y hacer todo lo necesario para que pueda implementarse en la forma más rápida posible. Firmado el 14 de setiembre de 2019 en Lima, Perú.

Los firmantes, coordinadores de los Capítulos nacionales integrantes del Comité Internacional para la Elaboración de Consensos y Estandarización en Nutriología (CIENUT), después de un proceso profundo de discusión y análisis que involucró a la totalidad de nuestros miembros, declaramos lo siguiente: La anemia por deficiencia de hierro es un problema de Nutrición Pública que afecta en grados variables, pero significativos, a la población de todos los países latinoamericanos y presenta algunos factores que vienen contribuyendo a esta situación. La prevalencia de lactancia materna exclusiva, por ejemplo, ha caído sostenidamente en el último quinquenio; la introducción de alimentos diferentes a la leche humana se produce en promedio a partir de los 4 meses y es la leche de vaca uno de los alimentos más empleados como sustituto de la leche humana. Dada las características bioquímico-moleculares de la proteína de la leche de vaca su consumo antes del año de vida contribuye significativamente a agudizar el problema de anemia en poblaciones de riesgo. En este contexto, hemos elaborado la Declaración de Lima sobre el consumo de leche entera de vaca en menores de un año; esta declaración busca generar conciencia entre las autoridades de salud sobre lo siguiente: Difundir que las características bioquímicas de la proteína de la leche entera de vaca pueden generar microsangrados a nivel intestinal cuando es administrada en niños de 0 a 1 año. Promover la lactancia materna exclusiva los primeros 6 meses de vida y la alimentación complementaria a partir de los 6 meses. Promover la lactancia materna hasta los 2 años. Invocamos, además, a todas las instituciones que brindan atención nutricional suscriban este consenso y hagan todo lo necesario para que pueda implementarse en la forma más rápida posible. Firmado el 14 de setiembre de 2019 en Lima, Perú.