Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a chromatin modifying enzyme playing a key role in the cell cycle and cell differentiation and proliferation through the demethylation of histones and nonhistone substrates. In addition to its enzymatic activity, LSD1 plays a fundamental scaffolding role as part of transcription silencing complexes such as rest co-repressor (CoREST) and nucleosome remodeling and deacetylase (NuRD). A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat). Despite this, no single study exists that characterizes them all under the same experimental conditions, preventing a clear interpretation of published results. Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds have very low activity and selectivity, suggesting some conclusions derived from their use should be taken with caution.

Spanish home enteral nutrition registry of the year 2014 and 2015 from the NADYA-SENPE Group / Registro del Grupo NADYA-SENPE de nutrición enteral domiciliaria en España, años 2014 y 2015.

Objective: To present the results of the Spanish home enteral nutrition (HEN) registry of the NADYA-SENPE group for the years 2014 and 2015. Methods: From January 1st 2014 to December 31st 2015 the HEN registry was recorded and afterwards a further descriptive and analytical analysis was done. Results: In 2014, 3749 patients were recorded, and 4202 in 2015; prevalence was 80.58 patients/one million inhabitants in Spain in 2014 and 90.51 in 2015. There were 49.9% females in 2014 and 50.3% in 2015. Median age was 73 years (IQI 59-83) in 2014 as well as in 2015. 684 episodes finished in 2014 and 631 in 2015, with death as the main cause, in 54.9% and 50.4%, respectively. The ones who were fed through nasogastric tube had a mean age higher than the ones fed by any other route (p-value < 0.001). Sisty-seven paediatric patients were recorded in 2014 (56.7% females) and 77 in 2015 (55.8% females). Median age at the beginning of HEN among children was 5 months in 2014 and 5 months in 2015. The main route of administration was gastrostomy, in 52.5% in 2014 and nasogastric tube in 50.8% in 2015. 7 episodes finished in 2014 and 13 in 2015, having death as the main cause (57.1% in 2014 and 38.5% in 2015). It was found that were younger children the ones who were mainly fed by nasogastric tubes (p-value 0.004 vs. 0.002). Among paediatric patients as well as adults, the main diagnosis leading to HEN was neurological disease which gives aphagia or severe dysphagia. Conclusions: There has been an increase in the number of patients in the registry as well as the participating centers and the number of patients per center, without any significant change in the characteristics of the patients other than longer duration of the episodes.

Objetivo: exponer los resultados del registro de nutrición enteral domiciliaria (NED) del año 2014 y 2015 del Grupo NADYA-SENPE. Métodos: se recopilaron los pacientes introducidos en el registro desde el 1 de enero al 31 de diciembre de 2014 y la mismas fechas de 2015, y se procedió al análisis descriptivo y analítico de los datos. Resultados: en el año 2014, se registraron 3.749 pacientes y en 2015, 4.202; la prevalencia fue de 80,58 pacientes/millón de habitantes en el año 2014 y de 90,51 en 2015. Por sexos, hubo un 49,9% de mujeres en 2014 y un 50,3% en 2015. La edad media fue de 73 años (IIQ 59-83) en ambos años. Finalizaron 684 episodios de NED en 2014 y 631 en 2015, la causa principal fue el fallecimiento en el 54,9% y 50,4% de los casos, respectivamente. Los portadores de sonda nasogástrica presentan una edad media superior a los pacientes con cualquier otra vía (p < 0,001). Se registraron 67 pacientes pediátricos en 2014 (56,7% niñas) y 77 en 2015 (55,8% niñas). La vía principal de administración fue la gastrostomía en el 52,0% de los casos de 2014 y sonda nasogástrica en el 50,8% de los casos de 2015. La causa principal de finalización de la nutrición fue el fallecimiento (57,1% en 2014 y 38,5% en 2015). Se observó que los niños más pequeños eran los que se alimentaban preferentemente por SNG (p 0,004 vs.0,002).Tanto en pacientes pediátricos como en adultos el diagnóstico principal que motivó la necesidad de NED fue la enfermedad neurológica que cursa con afagia o disfagia severa. Conclusiones: se ha incrementado el número de pacientes del registro, así como el número de centros participantes y el número medio de pacientes comunicados por cada centro respecto a años anteriores, sin que se hayan modificado sustancialmente las características de los pacientes, salvo mayor duración de los episodios.

Registro del Grupo NADYA-SENPE de nutrición enteral domiciliaria en España, años 2014 y 2015 / Spanish home enteral nutrition registry of the year 2014 and 2015 from the NADYA-SENPE Group

Objetivo: exponer los resultados del registro de nutrición enteral domiciliaria (NED) del año 2014 y 2015 del Grupo NADYA-SENPE. Métodos: se recopilaron los pacientes introducidos en el registro desde el 1 de enero al 31 de diciembre de 2014 y la mismas fechas de 2015, y se procedió al análisis descriptivo y analítico de los datos. Resultados: en el año 2014, se registraron 3.749 pacientes y en 2015, 4.202; la prevalencia fue de 80,58 pacientes/millón de habitantes en el año 2014 y de 90,51 en 2015. Por sexos, hubo un 49,9% de mujeres en 2014 y un 50,3% en 2015. La edad media fue de 73 años (IIQ 59-83) en ambos años. Finalizaron 684 episodios de NED en 2014 y 631 en 2015, la causa principal fue el fallecimiento en el 54,9% y 50,4% de los casos, respectivamente. Los portadores de sonda nasogástrica presentan una edad media superior a los pacientes con cualquier otra vía (p < 0,001). Se registraron 67 pacientes pediátricos en 2014 (56,7% niñas) y 77 en 2015 (55,8% niñas). La vía principal de administración fue la gastrostomía en el 52,0% de los casos de 2014 y sonda nasogástrica en el 50,8% de los casos de 2015. La causa principal de finalización de la nutrición fue el fallecimiento (57,1% en 2014 y 38,5% en 2015). Se observó que los niños más pequeños eran los que se alimentaban preferentemente por SNG (p 0,004 vs. 0,002).Tanto en pacientes pediátricos como en adultos el diagnóstico principal que motivó la necesidad de NED fue la enfermedad neurológica que cursa con afagia o disfagia severa. Conclusiones: se ha incrementado el número de pacientes del registro, así como el número de centros participantes y el número medio de pacientes comunicados por cada centro respecto a años anteriores, sin que se hayan modificado sustancialmente las características de los pacientes, salvo mayor duración de los episodios (AU)

Objective: To present the results of the Spanish home enteral nutrition (HEN) registry of the NADYA-SENPE group for the years 2014 and 2015. Methods: From January 1st 2014 to December 31st 2015 the HEN registry was recorded and afterwards a further descriptive and analytical analysis was done. Results: In 2014, 3749 patients were recorded, and 4202 in 2015; prevalence was 80.58 patients/one million inhabitants in Spain in 2014 and 90.51 in 2015. There were 49.9% females in 2014 and 50.3% in 2015. Median age was 73 years (IQI 59-83) in 2014 as well as in 2015. 684 episodes finished in 2014 and 631 in 2015, with death as the main cause, in 54.9% and 50.4%, respectively. The ones who were fed through nasogastric tube had a mean age higher than the ones fed by any other route (p-value < 0.001). Sixty-seven paediatric patients were recorded in 2014 (56.7% females) and 77 in 2015 (55.8% females). Median age at the beginning of HEN among children was 5 months in 2014 and 5 months in 2015. The main route of administration was gastrostomy, in 52.5% in 2014 and nasogastric tube in 50.8% in 2015. 7 episodes finished in 2014 and 13 in 2015, having death as the main cause (57.1% in 2014 and 38.5% in 2015). It was found that were younger children the ones who were mainly fed by nasogastric tubes (p-value 0.004 vs. 0.002). Among paediatric patients as well as adults, the main diagnosis leading to HEN was neurological disease which gives aphagia or severe dysphagia. Conclusions: There has been an increase in the number of patients in the registry as well as the participating centers and the number of patients per center, without any significant change in the characteristics of the patients other than longer duration of the episodes (AU)

Advances in the development of histone lysine demethylase inhibitors.

The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes. Initially thought to be an irreversible process, histone methylation is now known to be reversed by demethylases, FAD dependent amineoxidases and by iron(II)-alpha-ketoglutarate dependent deoxygenases of the Jumonji family. Altered histone demethylase activities have been associated with human disease, including cancer. The first wave of novel investigational drugs directed against KDM1A has recently entered the clinic, and the first specific inhibitor targeting a Jumonji KDM is advancing in preclinical regulatory studies.

Hospital de día de enfermedades respiratorias: impacto sobre la tasa de ingresos hospitalarios por exacerbaciones de la enfermedad pulmonar obstructiva crónica / Respiratory day hospital: Impact on the rate of hospital admissions due to chronic obstructive pulmonary disease exacerbations

Fundamento y objetivo: Las exacerbaciones de la enfermedad pulmonar obstructiva crónica (EA-EPOC) constituyen un factor determinante en el deterioro de los pacientes, con gran repercusión sobre el gasto sanitario. El objetivo de este estudio fue evaluar el impacto de la atención de las EA-EPOC en un hospital de día de enfermedades respiratorias (HDER) sobre la tasa de ingresos hospitalarios. Pacientes y método:Durante 14 meses se recogieron prospectivamente todos los episodios de EA-EPOC atendidos en el HDER y en el Servicio de Urgencias, excluyendo a los pacientes con otra causa de agudización o necesidad de ventilación mecánica invasiva.Resultados: Se incluyeron 226 episodios (173 pacientes, edad media [DE] de 72 [8] años). En el HDER se atendieron 121 (53,5%). El número de ingresos en el grupo del HDER fue claramente inferior (32,2 frente a 66,7%, p<0,001), incluso en pacientes con más ingresos el año previo. No hubo diferencias en la gravedad de la exacerbación ni en la tasa de reingresos ni de mortalidad en el seguimiento.Conclusiones: El manejo de las EA-EPOC en el HDER parece reducir el número de ingresos hospitalarios en comparación con un Servicio de Urgencias (AU)

Background and objective: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are considered to be the most important factor in determining the course of the disease, and have great impact on the health care system. We evaluated the effects of a Respiratory Day Hospital (RDH) on the rate of hospital admissions due to AE-COPD. Patients and methods:During 14 months, every case of AE-COPD seen at the RDH and emergency services was recruited prospectively. Patients were excluded when another known cause of exacerbation was present and/or when they required invasive mechanical ventilation. Results:226 episodes (173 patients) were included (72, SD 8years old). One hundred and twenty one cases received treatment at the RDH (53.5%). Admissions from the RDH group were noticeably lower (32.2 vs. 66.7%, p<0.001), even in patients with more admissions due to AE-COPD the year before the study. There were no differences either in terms of AE-COPD severity or in readmissions and mortality rates during the follow up.Conclusions: Management of AE-COPD in a RDH seems to be associated with a lower rate of hospital admissions in comparison with an emergency department (AU)

[Respiratory day hospital: Impact on the rate of hospital admissions due to chronic obstructive pulmonary disease exacerbations]. / Hospital de día de enfermedades respiratorias: impacto sobre la tasa de ingresos hospitalarios por exacerbaciones de la enfermedad pulmonar obstructiva crónica.

BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are considered to be the most important factor in determining the course of the disease, and have great impact on the health care system. We evaluated the effects of a Respiratory Day Hospital (RDH) on the rate of hospital admissions due to AE-COPD. PATIENTS AND METHODS: During 14 months, every case of AE-COPD seen at the RDH and emergency services was recruited prospectively. Patients were excluded when another known cause of exacerbation was present and/or when they required invasive mechanical ventilation. RESULTS: 226 episodes (173 patients) were included (72, SD 8 years old). One hundred and twenty one cases received treatment at the RDH (53.5%). Admissions from the RDH group were noticeably lower (32.2 vs. 66.7%, p<0.001), even in patients with more admissions due to AE-COPD the year before the study. There were no differences either in terms of AE-COPD severity or in readmissions and mortality rates during the follow up. CONCLUSIONS: Management of AE-COPD in a RDH seems to be associated with a lower rate of hospital admissions in comparison with an emergency department.

Minimum data set for nutritional intervention studies in elderly people.

Malnutrition, considered for the purpose of the present data set as undernutrition, is a major risk factor of mortality in elderly people. Such protein-energy malnutrition should be detected as soon as possible. Once established, this malnutrition state must be corrected by appropriate diet, supplementation, artificial nutrition, or therapeutic treatment. If carried out well, these interventions should reduce the risk of mortality and, for some diseases such as degenerative diseases, may postpone morbidity and dependence. The efficiency of nutritional interventions has already been evaluated by different means including the measurement of anthropometric and laboratory parameters. However, in the absence of a consensus on the use of these parameters, comparison between studies and even effectiveness of the proposed treatment are frequently unconvincing. The relevance of the most common markers used in epidemiologic studies on malnutrition and nutritional interventions in elderly persons was studied for establishing a minimum data set. The aim of this task force was to provide investigators and operators in the field of clinical nutrition with clear and expert validated clinical outcomes allowing them to design and set up conclusive trials.

Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation.

BACKGROUND: The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer (CRC) led us to examine the possible association between dietary factors and mutations, such as Ki-ras mutations, in genes implicated in the pathogenesis of these neoplasms. PATIENTS AND METHODS: The study was based on 246 cases and 296 controls. For the molecular study only 117 patients with Ki-ras tumor expression were included. Dietary patterns were assessed using a semi-quantitative food frequency questionnaire. RESULTS: Patients with Ki-ras mutations in codon 12 (K12) consumed significantly less vitamin A (p=0.02), B1 (p=0.01), D (p=0.02) and iron (p=0.03) than controls, whereas patients without these mutations had similar intakes of these nutrients to controls. The consumption of fiber, folate, vitamin E and potassium was lower in the two subgroups of patients (K12-positive or -negative) than in controls. Mutation in codon 13 was not associated with any nutrient deficit. CONCLUSION: These results support previous findings that certain micronutrients protect against colorectal neoplasia and emphasize the importance of considering the different molecular forms of CRC as etiologically distinct diseases.

Estimate of specific energy expenditure of fat-free mass and fat mass in children receiving total parenteral nutrition.

OBJECTIVES: Simple methods for calculation of the energy expenditure may be useful for clinicians involved in the treatment of nutritional disorders in children. The aims of this study were to (1) estimate the specific energy expenditure (SEE) of fat mass (FM) and fat-free mass (FFM) and (2) determine a sensitive predictive indicator of resting energy expenditure (REE). METHODS: The REE of 26 children receiving longterm TPN, was measured by long-term indirect calorimetry. Body composition was estimated from the sum of four skinfold measurements. RESULTS: The following regression equations were derived: (1) REE (kcal/d) = 56.6 x FFM (kg) + 97.9 (r2 = 0.98, p < 0.001); (2) REE (kcal/d) = 45.6 x BW (kg) + 136 (r2 = 0.92, p < 0.001); (3) REE (kcal/d) = 68.9 x FFM (kg) + 3.3 x FM (kg) (r2 = 0.985, p < 0.001). The results obtained allowed the estimate of K1 and K2 with their respective SEE: K1 = 3.3 +/- 18.0 kcal/kg of FM, K2 = 68.9 +/- 3.1 kcal/kg of FFM. CONClUSIONS Anthropometrically measured FFM is an easily determined predictive factor of REE. The above equations may be used to estimate the REE in stable children receiving TPN.