The Genomic and Proteomic Content of Cancer Cell-Derived Exosomes

Exosomes are secreted membrane vesicles that have been proposed as an effective means to detect a variety of disease states, including cancer. The properties of exosomes, including stability in biological fluids, allow for their efficient isolation and make them an ideal vehicle for studies on early disease detection and evaluation. Much data has been collected over recent years regarding the messenger RNA, microRNA, and protein contents of exosomes. In addition, many studies have described the functional role that exosomes play in disease initiation and progression. Tumor cells have been shown to secrete exosomes, often in increased amounts compared to normal cells, and these exosomes can carry the genomic and proteomic signatures characteristic of the tumor cells from which they were derived. While these unique signatures make exosomes ideal for cancer detection, exosomes derived from cancer cells have also been shown to play a functional role in cancer progression. Here, we review the unique genomic and proteomic contents of exosomes originating from cancer cells as well as their functional effects to promote tumor progression

Propuesta de automatización de la máquina envasadora Mainar M-600 en la empresa Lopesa Industrial de Huancayo, 2023

La investigación responde al problema ¿Cómo influye la automatización de la máquina envasadora Mainar-600 en la empresa Lopesa Industrial de Huancayo, 2023? , como objetivo pretende determinar la influencia de automatizar la máquina envasadora Mainar-600 en la empresa Lopesa Industrial de Huancayo, 2023; en la muestra investigada y como hipótesis se asume que la automatización de la máquina envasadora Mainar-600 influye positivamente en la producción de sachets en la empresa Lopesa Industrial de Huancayo, 2023. El diseño fue descriptivo correlacional, en la muestra unitaria en la automatización de la máquina Mainar-600. Concluyendo que, la media de la producción de sachets con la máquina envasadora M-600 Mainar es superior a la producción con la máquina envasadora Valpack. Dicho de otra manera, la máquina envasadora M-600 Mainar produce significativamente más sachets que la máquina envasadora Valpack en relación con los 15 verificaciones y mediciones y, por ende, hay una mayor producción. Así también, se concluye que la media del consumo de potencia eléctrica con la máquina envasadora M-600 Mainar no es significativamente superior al consumo de potencia eléctrica con la máquina envasadora Valpack. Dicho de otra manera, la máquina envasadora M-600 Mainar consume menos o igual potencia que la máquina envasadora Valpack con relación a los 15 verificaciones y mediciones y, por ende, están igualados en eficiencia

Cultura de la dependencia en los programas del desarrollo social del distrito de Chinchaypujio, provincia de Anta, Cusco en el 2018

El presente estudio se enfoca en adentrarse en la cultura de la dependencia y su relación en los programas del desarrollo social tomando como caso el distrito de Chinchaypujio de la Provincia de Anta, Cusco en el año 2018. Para ello primero enfocaremos nuestro estudio a los programas de desarrollo social como una alternativa para otros países en donde se implementaron diferentes programas sociales que ayudaron a desarrollarse humanamente, según los datos del desarrollo humano del PNUD, los programas focalizados se empezaron a implementar desde los años 90tas para ajustar económicamente al Estado y son focalizados en vista que no tienen alcance mundial y se establecen en base a las ofertas teniendo como beneficiarios a poblaciones de pobreza y extrema pobreza. Se estima que dentro de la región se benefició a 34 252 familias representada en 8.1 por ciento de lo cubierto. Es así, que, el estudio se enfoca en demostrar lo fundamental de los programas para combatir la pobreza en sectores como Anta y así contribuir al desarrollo humano, sin embargo el problema que aún se evidencia es que los indicadores económicos, aún son un problema de observar a la pobreza como un problema social, ya que, en sí, el problema está en el modo de vida que llevan las familias de estos sectores que en vez de empoderarse en sus capacidades y tengan una libertad en ello, a través de los programas se convierten en asistencialistas, lo que preocupa a la sociedad ya que no se evidencia un crecimiento en su desarrollo humano desde una visión integral sino como elementos económicos vacíos en promesas

Obtencion de Fibra Dietetica a Partir de Bagazo de Zea Mayz l. Caña de Maiz” Como Ingrediente Funcional por Medios Enzimaticos

Se evaluó la composición químico proximal del bagazo de caña de maíz, el contenido de humedad es de 74,49%, de fibra se obtuvo 17,65%, grasa 0,105%, Proteína 1,19% cenizas 1,21% y carbohidratos 5,31%. Las características fisicoquímicas de caña de maíz como la acidez es de 0,14% expresado como ácido sulfúrico y un valor de pH de 6,02 y los sólidos solubles se encontraron un valor de 14,41 %. En cuanto al tamaño se trabajó a un tamaño de partículas homogéneo de 250 μm. Los componentes bioactivos, vitamina C de 34,78 mg de ácido ascórbico por 100 g de muestra, polifenoles totales 796,09 mg-Eq ácido gálico/ g m.s. y flavonoides 12,73 mg-Eq de quercetina por 100 g y una actividad antioxidante de 58,36% de inhibición. Los azucares reductores mantienen su contenido a través del tiempo y las propiedades funcionales de la fibra dietética obtenida como la retención de agua (CRA) de las fibras dietéticas solubles (FDS) obtenidas a 0 min, 20 min y 60 min, observándose que presentan 8,80 ; 17,33 y 15,14 g de agua / g de fibra, capacidad de retención de aceite (CRAceite) de las fibras dietéticas solubles presentan 1,98 ; 4,44 y 3,77 g de aceite/g de fibra, respetivamente, capacidad de hinchamiento (CH) 7,13; 12,23 y 9,70 mL de agua / g de fibra, respectivamente, adsorción de agua (CAdA) presentan 42,53; 26,21 y 80,93 mL de agua / g de fibra, respectivamente, capacidad de absorción de agua (CAA) presentan 1,85; 2,32 y 1,98 g de agua / g de fibra respectivamente.Tesi

Disulfiram overcomes bortezomib and cytarabine resistance in Down-syndrome-associated acute myeloid leukemia cells

Background Children with Down syndrome (DS) have increased risk for developing AML (DS-AMKL), and they usually experience severe therapy-related toxicities compared to non DS-AMKL. Refractory/relapsed disease has very poor outcome, and patients would benefit from novel, less toxic, therapeutic strategies that overcome resistance. Relapse/resistance are linked to cancer stem cells with high aldehyde dehydrogenase (ALDH) activity. The purpose of the present work was to study less toxic alternative therapeutic agents for relapsed/refractory DS-AMKL. Methods Fourteen AML cell lines including the DS-AMKL CMY and CMK from relapsed/refractory AML were used. Cytarabine (Ara-C), bortezomib (BTZ), disulfiram/copper (DSF/Cu2+) were evaluated for cytotoxicity, depletion of ALDH-positive cells, and resistance. BTZ-resistant CMY and CMK variants were generated by continuous BTZ treatment. Cell viability was assessed using CellTiter-Glo®, ALDH activity by ALDELUORTM, and proteasome inhibition by western blot of ubiquitinated proteins and the Proteasome-Glo™ Chymotrypsin-Like (CT-like) assay, apoptosis by Annexin V Fluos/Propidium iodide staining, and mutations were detected using PCR, cloning and sequencing. Results Ara-C-resistant AML cell lines were sensitive to BTZ and DSF/Cu2+. The Ara-C-resistant DS-AMKL CMY cells had a high percentage of ALDHbright “stem-like” populations that may underlie Ara-C resistance. One percent of these cells were still resistant to BTZ but sensitive to DSF/Cu2+. To understand the mechanism of BTZ resistance, BTZ resistant (CMY-BR) and (CMK-BR) were generated. A novel mutation PSMB5 Q62P underlied BTZ resistance, and was associated with an overexpression of the β5 proteasome subunit. BTZ-resistance conferred increased resistance to Ara-C due to G1 arrest in the CMY-BR cells, which protected the cells from S-phase damage by Ara-C. CMY-BR and CMK-BR cells were cross-resistant to CFZ and MG-132 but sensitive to DSF/Cu2+. In this setting, DSF/Cu2+ induced apoptosis and proteasome inhibition independent of CT-like activity inhibition. Conclusions We provide evidence that DSF/Cu2+ overcomes Ara-C and BTZ resistance in cell lines from DS-AMKL patients. A novel mutation underlying BTZ resistance was detected that may identify BTZ-resistant patients, who may not benefit from treatment with CFZ or Ara-C, but may be responsive to DSF/Cu2+. Our findings support the clinical development of DSF/Cu2+ as a less toxic efficacious treatment approach in patients with relapsed/refractory DS-AMKL

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma

<p>Abstract</p> <p>Background</p> <p>Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to identify kinase targets involved in growth and survival of Ewing's sarcoma cells.</p> <p>Results</p> <p>Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis.</p> <p>Conclusion</p> <p>In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.</p

High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation

<p>Abstract</p> <p>Background</p> <p>Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments.</p> <p>Results</p> <p>We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.</p> <p>Conclusions</p> <p>These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.</p

Hematopoietic gene promoters subjected to a group-combinatorial study of DNA samples: identification of a megakaryocytic selective DNA signature

Identification of common sub-sequences for a group of functionally related DNA sequences can shed light on the role of such elements in cell-specific gene expression. In the megakaryocytic lineage, no one single unique transcription factor was described as linage specific, raising the possibility that a cluster of gene promoter sequences presents a unique signature. Here, the megakaryocytic gene promoter group, which consists of both human and mouse 5′ non-coding regions, served as a case study. A methodology for group-combinatorial search has been implemented as a customized software platform. It extracts the longest common sequences for a group of related DNA sequences and allows for single gaps of varying length, as well as double- and multiple-gap sequences. The results point to common DNA sequences in a group of genes that is selectively expressed in megakaryocytes, and which does not appear in a large group of control, random and specific sequences. This suggests a role for a combination of these sequences in cell-specific gene expression in the megakaryocytic lineage. The data also point to an intrinsic cross-species difference in the organization of 5′ non-coding sequences within the mammalian genomes. This methodology may be used for the identification of regulatory sequences in other lineages

Hematopoietic gene promoters subjected to a group-combinatorial study of DNA samples: identification of a megakaryocytic selective DNA signature

Identification of common sub-sequences for a group of functionally related DNA sequences can shed light on the role of such elements in cell-specific gene expression. In the megakaryocytic lineage, no one single unique transcription factor was described as linage specific, raising the possibility that a cluster of gene promoter sequences presents a unique signature. Here, the megakaryocytic gene promoter group, which consists of both human and mouse 5′ non-coding regions, served as a case study. A methodology for group-combinatorial search has been implemented as a customized software platform. It extracts the longest common sequences for a group of related DNA sequences and allows for single gaps of varying length, as well as double- and multiple-gap sequences. The results point to common DNA sequences in a group of genes that is selectively expressed in megakaryocytes, and which does not appear in a large group of control, random and specific sequences. This suggests a role for a combination of these sequences in cell-specific gene expression in the megakaryocytic lineage. The data also point to an intrinsic cross-species difference in the organization of 5′ non-coding sequences within the mammalian genomes. This methodology may be used for the identification of regulatory sequences in other lineages