CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to c-secretase inhibitors

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with c-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to c-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs. Leukemia (2006) 20, 1279–1287. doi:10.1038/sj.leu.2404258; published online 11 May 200

Marketing digital y fidelización de clientes en el desarrollo de la sostenibilidad comercial de la región Junín

Objective. To determine the relationship between digital marketing and customer loyalty in the development of commercial sustainability in the province of Tarma, Junín region (Peru). Methods. The research had a quantitative approach and was of basic type, correlational level and non-experimental-cross-sectional design; two instruments were used: the digital marketing questionnaire and the customer loyalty questionnaire. The first questionnaire consisted of 12 items referring to the dimensions of digital marketing and the second consisted of 15 items referring to the dimensions of customer loyalty. The sample consisted of 120 customers of commercial establishments in the province of Tarma. Results. 47.5 % of respondents considered that the implementation of digital marketing in commercial establishments is regular, 36.7 % considered that there is a low implementation and only 15.8 % considered that there is a high implementation of digital marketing. Referring to the customer loyalty questionnaire, 63.3 % considered that customer loyalty in commercial establishments occurs regularly, 21.7 % considered that customer loyalty is high and 15 % considered that customer loyalty is low. Conclusion. There is a direct and statistically significant relationship between digital marketing and customer loyalty in the development of sustainability in the province of Tarma, Junín region.Objetivo. Determinar la relación entre marketing digital y fidelización de clientes en el desarrollo de la sostenibilidad comercial de la provincia de Tarma, región Junín (Perú). Métodos. La investigación tuvo un enfoque cuantitativo y fue de tipo básico, nivel correlacional y diseño no experimental-transversal; se emplearon dos instrumentos: el cuestionario de marketing digital y el cuestionario de fidelización de clientes. El primer cuestionario constó de 12 ítems referidos a las dimensiones de marketing digital y el segundo constó de 15 ítems referidos a las dimensiones de la fidelización de clientes. La muestra estuvo conformada por 120 clientes de establecimientos comerciales de la provincia de Tarma. Resultados. El 47,5 % de encuestados consideró que la implementación del marketing digital en los establecimientos comerciales se da de forma regular, el 36,7% consideró que hay una baja implantación y solo el 15,8 % consideró que hay una alta implantación del marketing digital. Referente al cuestionario de fidelización de clientes, el 63,3 % consideró que la fidelización de clientes en los establecimientos comerciales se da de forma regular, el 21,7 % consideró que la fidelización de clientes es alta y el 15% considera que la fidelización de clientes es baja. Conclusión. Existe relación directa y estadísticamente significativa entre marketing digital y fidelización de clientes en el desarrollo de la sostenibilidad de la provincia de Tarma, región Junín

Pleiotropic functions of the tumor- and metastasis-suppressing Matrix Metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity which has onco-suppressive actions in numerous tumor types

Generating Random Logic Programs Using Constraint Programming

Testing algorithms across a wide range of problem instances is crucial to ensure the validity of any claim about one algorithm's superiority over another. However, when it comes to inference algorithms for probabilistic logic programs, experimental evaluations are limited to only a few programs. Existing methods to generate random logic programs are limited to propositional programs and often impose stringent syntactic restrictions. We present a novel approach to generating random logic programs and random probabilistic logic programs using constraint programming, introducing a new constraint to control the independence structure of the underlying probability distribution. We also provide a combinatorial argument for the correctness of the model, show how the model scales with parameter values, and use the model to compare probabilistic inference algorithms across a range of synthetic problems. Our model allows inference algorithm developers to evaluate and compare the algorithms across a wide range of instances, providing a detailed picture of their (comparative) strengths and weaknesses.Comment: This is an extended version of the paper published in CP 202

Experiencia subjetiva del empleado en colaboradores de establecimientos hoteleros de la región Junín

Objective: To determine the characteristics of the employee experience in employees of hotel establishments in the Junín region. Methods. The type of research was basic, descriptive level, simple descriptive design and non-experimental-transectional. The methods used were observation, analysis and synthesis and inductive-deductive, while the instrument applied was the questionnaire and the technique was the survey. The sample consisted of 320 employees of hotel establishments in the Junín region and the sample selection criterion was non-probabilistic by convenience. Results. The main results were that the levels of employee experience at the subjective level were regular in its physical and technological dimensions, and high in its cultural dimension; which reflects that, despite the adverse conditions due to the covid-19 pandemic, the collaborators performed their tasks with appropriateness and assertiveness. Conclusion. Companies in the hotel sector should implement programs that reinforce and establish the objective conditions of their work environment in order to generate profitable and positive subjective experiences in favor of their employees and the productivity of the organization.Objetivo. Determinar las características del employee experience en colaboradores de establecimientos hoteleros de la región Junín. Métodos. El tipo de investigación fue básica, de nivel descriptivo, diseño descriptivo simple y no experimental-transeccional. Los métodos fueron la observación, el análisis y síntesis y el inductivo-deductivo, mientras que el instrumento aplicado fue el cuestionario y la técnica la encuesta. La muestra estuvo conformada por 320 colaboradores de establecimientos hoteleros de la región Junín y el criterio de selección de la muestra fue no probabilístico por conveniencia. Resultados. Los principales resultados fueron que los niveles de experiencia del empleado a nivel subjetivo fueron regulares en sus dimensiones física y tecnológica, y de nivel alto en su dimensión cultural; lo que refleja que, pese a las condiciones adversas por pandemia de la covid-19, los colaboradores desarrollaron labores con propiedad y asertividad. Conclusión. Las empresas del sector hotelero deben implementar programas que refuercen y establezcan las condiciones objetivas de su entorno laboral a fin de generar experiencias subjetivas redituables y positivas en favor de sus colaboradores y la productividad de la organización

New GOLD classification: Longitudinal data on group assignment

Rationale: Little is known about the longitudinal changes associated with using the 2013 update of the multidimensional GOLD strategy for chronic obstructive pulmonary disease (COPD). Objective: To determine the COPD patient distribution of the new GOLD proposal and evaluate how this classification changes over one year compared with the previous GOLD staging based on spirometry only. Methods: We analyzed data from the CHAIN study, a multicenter observational Spanish cohort of COPD patients who are monitored annually. Categories were defined according to the proposed GOLD: FEV1%, mMRC dyspnea, COPD Assessment Test (CAT), Clinical COPD Questionnaire (CCQ), and exacerbations-hospitalizations. One-year follow-up information was available for all variables except CCQ data. Results: At baseline, 828 stable COPD patients were evaluated. On the basis of mMRC dyspnea versus CAT, the patients were distributed as follows: 38.2% vs. 27.2% in group A, 17.6% vs. 28.3% in group B, 15.8% vs. 12.9% in group C, and 28.4% vs. 31.6% in group D. Information was available for 526 patients at one year: 64.2% of patients remained in the same group but groups C and D show different degrees of variability. The annual progression by group was mainly associated with one-year changes in CAT scores (RR, 1.138; 95%CI: 1.074-1.206) and BODE index values (RR, 2.012; 95%CI: 1.487-2.722). Conclusions: In the new GOLD grading classification, the type of tool used to determine the level of symptoms can substantially alter the group assignment. A change in category after one year was associated with longitudinal changes in the CAT and BODE index

A strategy to incorporate prior knowledge into correlation network cutoff selection

Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization

Cell biological analysis reveals an essential role for Pfcerli2 in erythrocyte invasion by malaria parasites

Merozoite invasion of host red blood cells (RBCs) is essential for survival of the human malaria parasite Plasmodium falciparum. Proteins involved with RBC binding and invasion are secreted from dual-club shaped organelles at the apical tip of the merozoite called the rhoptries. Here we characterise P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 2 (PfCERLI2), as a rhoptry bulb protein that is essential for merozoite invasion. Phylogenetic analyses show that cerli2 arose through an ancestral gene duplication of cerli1. We show that PfCERLI2 is essential for blood-stage growth and localises to the cytosolic face of the rhoptry bulb. Inducible knockdown of PfCERLI2 led to a proportion of merozoites failing to invade and was associated with elongation of the rhoptry organelle during merozoite development and inhibition of rhoptry antigen processing. These findings identify PfCERLI2 as a protein that has key roles in rhoptry biology during merozoite invasion.Benjamin Liffner, Juan Miguel Balbin, Gerald J. Shami, Ghizal Siddiqui, Jan Strauss, Sonja Frölich, Gary K. Heinemann, Ella May Edwards, Arne Alder, Jan Stephan Wichers, Darren J. Creek, Leann Tilley, Matthew W.A. Dixon, Tim-Wolf Gilberger, Danny W. Wilso

CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion

<p>Abstract</p> <p>Background</p> <p>Ovarian carcinoma (OvCa) is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells and its only natural ligand, CCL25, is largely expressed in the thymus, which involutes with age. Other than the thymus, CCL25 is expressed by the small bowel. Interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for OvCa cells. The current study shows OvCa tissue and cells significantly express CCR9, which interacts with CCL25 to support carcinoma cell migration and invasion.</p> <p>Methods</p> <p>RT-PCR and flow cytometry techniques were used to quantify the expression CCR9 by OvCa cells. OvCa tissue microarrays (TMA) was used to confirm CCR9 expression in clinical samples. The Aperio ScanScope scanning system was used to quantify immunohistochemical staining. Cell invasion and migration assays were performed using cell migration and matrigel invasion chambers. Matrix metalloproteinase (MMP) mRNAs were quantified by RT-PCR and active MMPs were quantified by ELISA.</p> <p>Results</p> <p>Our results show significantly (<it>p </it>< 0.001) higher expression of CCR9 by mucinous adenocarcinoma, papillary serous carcinoma, and endometriod ovarian carcinoma cases, than compared to non-neoplastic ovarian tissue. Furthermore, CCR9 expression was significantly elevated in OvCa cell lines (OVCAR-3 and CAOV-3) in comparison to normal adult ovarian epithelial cell mRNA. OvCa cells showed higher migratory and invasive potential towards chemotactic gradients of CCL25, which was inhibited by anti-CCR9 antibodies. Expression of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), and stromelysins (MMP-3, -10, and -11) by OvCa cells were modulated by CCL25 in a CCR9-dependent fashion.</p> <p>Conclusions</p> <p>These results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.</p

Distribution and outcomes of a phenotype-based approach to guide COPD management: Results from the CHAIN cohort

Rationale: The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes. Objective: We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. Methods: We followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes. Results: Overall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year. Conclusions: There is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use