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Modeling Macrophage Polarization and Its Effect on Cancer Treatment Success  [PDF]
Valentin Morales, Luis Soto-Ortiz
Open Journal of Immunology (OJI) , 2018, DOI: 10.4236/oji.2018.82004
Abstract: Positive feedback loops drive immune cell polarization toward a pro-tumor phenotype that accentuates immunosuppression and tumor angiogenesis. This phenotypic switch leads to the escape of cancer cells from immune destruction. These positive feedback loops are generated by cytokines such as TGF-β, Interleukin-10 and Interleukin-4, which are responsible for the polarization of monocytes and M1 macrophages into pro-tumor M2 macrophages, and the polarization of naive helper T cells intopro-tumor Th2 cells. In this article, we present a deterministic ordinary differential equation (ODE) model that includes key cellular interactions and cytokine signaling pathways that lead to immune cell polarization in the tumor microenvironment. The model was used to simulate various cancer treatments in silico. We identified combination therapies that consist of M1 macrophages or Th1 helper cells, coupled with an anti-angiogenic treatment, that are robust with respect to immune response strength, initial tumor size and treatment resistance. We also identified IL-4 and IL-10 as the targets that should be neutralized in order to make these combination treatments robust with respect to immune cell polarization. The model simulations confirmed a hypothesis based on published experimental evidence that a polarization into the M1 and Th1 phenotypes to increase the M1-to-M2 and Th1-to-Th2 ratios plays a significant role in treatment success. Our results highlight the importance of immune cell reprogramming as a viable strategy to eradicate a highly vascularized tumor when the strength of the immune response is characteristically weak and cell polarization to the pro-tumor phenotype has occurred.
A Computational Assessment of the Robustness of Cancer Treatments with Respect to Immune Response Strength, Tumor Size and Resistance
Luis Soto-Ortiz
- , 2018, DOI: 10.5923/j.ijtt.20180701.01
Abstract: The emergence of bioengineering has paved the way for the in vitro design of immune cells that can detect and destroy tumor cells of low antigenicity. However, the results of clinical trials involving cancer treatments have not matched the success in the lab. A reason for treatment failure is the presence of patient-specific genetic biomarkers that affect long-term effectiveness. The cross-talk between multiple signaling pathways involved in tumor cell survival, the existence of redundant pathways with similar functions, and the intrinsic genetic instability of tumor cells also contribute to treatment failure. With the advent of novel cancer treatments, a need has arisen to undertake a computational approach to identify treatment combinations that maximize long-term effectiveness while minimizing the risk of serious side effects. In the present work, mathematical modeling was used to track the time-varying concentrations of pro- and anti-tumor cells and cytokines after a cancer treatment is administered. The simulations demonstrated the importance of treatment timing and frequency to achieve synergy. A combination therapy based on sunitinib and fresolimumab was found to be robust in reducing tumor size with respect to the strength of a patient’s anti-tumor immune response, the size of the tumor at the start of treatment, and with respect to mutations that can make cancer cells become refractory to the first-line treatment. The robustness of the identified sunitinib + fresolimumab combination therapy confers it with the capability to eliminate heterogeneous tumors made up of sensitive and resistant cells, in a patient whose anti-tumor immune response has become suppressed due to advanced age, chronic inflammation or a prior medical treatment. The model simulations highlight the superiority of combination therapy over monotherapy, and provide guidance to identify protocols that have the greatest potential to eliminate a tumor
A theory of the cancer age-specific incidence data based on extreme value distributions
Luis Soto-Ortiz,James P. Brody
AIP Advances , 2012, DOI: 10.1063/1.3699050
Abstract: The incidence of cancers varies with age, if normalized this is called the age-specific incidence. A mathematical model that describes this variation should provide a better understanding of how cancers develop. We suggest that the age-specific incidence should follow an extreme value distribution, based on three widely accepted assumptions: (1) a tumor develops from a single cell, (2) many potential tumor progenitor cells exist in a tissue, and (3) cancer is diagnosed when the first of these many potential tumor cells develops into a tumor. We tested this by comparing the predicted distribution to the age-specific incidence data for colon and prostate carcinomas collected by the Surveillance, Epidemiology and End Results network of 17 cancer registries. We found that colon carcinoma age-specific incidence data is consistent with an extreme value distribution, while prostate carcinomas age-specific incidence data generally follows the distribution. This model indicates that both colon and prostate carcinomas only occur in a subset of the population (22% for prostate and 13.5% for colon.) Because of their very general nature, extreme value distributions might be applicable to understanding other chronic human diseases.
Similarities in the Age-Specific Incidence of Colon and Testicular Cancers
Luis Soto-Ortiz, James P. Brody
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066694
Abstract: Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thought to develop in only a small fraction of men, beginning in utero. These models of carcinogenesis are, in part, based upon age-specific incidence data. The specific incidence for colon cancer appears to monotonically increase with age, while that of testicular cancer increases to a maximum value at about 35 years of age, then declines to nearly zero by the age of 80. We hypothesized that the age-specific incidence for these two cancers is similar; the apparent difference is caused by a longer development time for colon cancer and the lack of age-specific incidence data for people over 84 years of age. Here we show that a single distribution can describe the age-specific incidence of both colon carcinoma and testicular cancer. Furthermore, this distribution predicts that the specific incidence of colon cancer should reach a maximum at about age 90 and then decrease. Data on the incidence of colon carcinoma for women aged 85–99, acquired from SEER and the US Census, is consistent with this prediction. We conclude that the age specific data for testicular cancers and colon cancers is similar, suggesting that the underlying process leading to the development of these two forms of cancer may be similar.
Successful experiences in the application of Concept Maps in Engineering in Computing, Mexico
Beatriz Guardian Soto,Jorge F. Veloz Ortiz,Iovanna A. Rodríguez Moreno,Luis E. Veloz Ortiz
Journal for Educators, Teachers and Trainers , 2013,
Abstract: Today there is an enormous amount of work related to new models and styles of learning and instruction in the field of engineering. In the case of the engineering degree in computing that is taught in the Mexico National Polytechnic Institute (IPN), there is a working group led by an expert of international waisted whose success and work thereon, processes are reflected in this text through experiences gained in the last 8 years with students and teachers, thus generatingthe requirements and tools for the globalised world and the knowledge society in which we find ourselves. Lessons learned are in subjects as the theory of automata (TA), compilers (Cs), analysis of algorithms (AA), (R), Artificial Intelligence (AI), computer programming (P) networks, degree project (PT) and strategic planning (PE) mainly, among others to facilitate the understanding of concepts and applications by the student and believe that through the teaching strategy using concept maps developed by j. Novak results have been favorable in dynamism, understanding and generating meaningful learning in the long term, providing well, solid elements for your professional practice. Listed proposals obtained by teachers and exercises developed by teachers and students.
Histoplasma panniculitis in a patient with systemic lupus erythematosus
Edgar Ortiz-Brizuela,Luis Enrique Soto-Ramírez,Luis Rodrigo Flores-Bozo
- , 2019, DOI: 10.1590/abd1806-4841.20197636
Abstract: Histoplasmosis usually presents primarily as lung infection. Occasionally, mainly in immunocompromised hosts, it can spread and cause systemic manifestations. Skin lesions have been reported in 10 to 15 percent of cases of disseminated histoplasmosis, and panniculitis has been described as an unusual form of presentation in affected patients. We present the case of a patient with systemic lupus erythematosus who presented cellulitis due to disseminated histoplasmosis
Frecuencia de las cosechas en Cymbopogon citratus Stapf en las condiciones edafoclimáticas de La Habana
Soto Ortiz,Rafaela; Vega Marrero,Gilbero; Tamajón Navarro,Aldo Luis;
Revista Cubana de Plantas Medicinales , 2003,
Abstract: the effect of 3 crop frequencies - three, four and five annual crops - was evaluated on a ferriferous red soil of havana province by a field experiment. the studied variables were: height and number of offspring per plant, dead plants per parcel, plant masss yielding, and content and quality of the essential oil. the results showed that 4 crops a year, every 3 months, proved to be convenient for cymbopogon citratus stapf, since the highest yieldings were obtained without affecting the quality of the essential oil.
Efecto de diferentes densidades de plantación en Cymbopogon citratus Stapf
Soto Ortiz,Rafaela; Vega Marrero,Gilberto; Tamajón Navarro,Aldo Luis;
Revista Cubana de Plantas Medicinales , 2003,
Abstract: the effect of different plantation densities on the growth, development and plant mass yielding of cymbopogon citratus was evaluated.to this end, an experiment was made on a red ferriferous soil at the experimental station of essential oils of suchel enterprise union between 1990 and 1991. the following densities were studied: 37 037, 22 222, 12 345, 6 172 and 3 082 plants per hectare. a design of blocks at random was used. it was finally observed that the plantation densities of 37 037 and 22 222 had the highest yieldings of plant mass.
Efecto de diferentes densidades de plantación en Cymbopogon citratus Stapf
Rafaela Soto Ortiz,Gilberto Vega Marrero,Aldo Luis Tamajón Navarro
Revista Cubana de Plantas Medicinales , 2003,
Abstract: Se evaluó el efecto de diferentes densidades de plantación sobre el crecimiento, desarrollo y rendimiento en masa vegetal de Cymbopogon citratus. Para ello se realizó un experimento en la Estación Experimental de Aceites Esenciales de la Unión de Empresas Suchel, sobre un suelo ferralítico rojo entre 1990 y 1991. Se estudiaron las siguientes densidades: 37 037, 22 222, 12 345, 6 172 y 3 082 plantas por hectárea. Se empleó un dise o de bloques al azar. Se pudo concluir que las densidades de plantación de 37 037 y 22 222, dieron los mayores rendimientos de masa vegetal. The effect of different plantation densities on the growth, development and plant mass yielding of Cymbopogon citratus was evaluated.To this end, an experiment was made on a red ferriferous soil at the Experimental Station of Essential Oils of Suchel Enterprise Union between 1990 and 1991. The following densities were studied: 37 037, 22 222, 12 345, 6 172 and 3 082 plants per hectare. A design of blocks at random was used. It was finally observed that the plantation densities of 37 037 and 22 222 had the highest yieldings of plant mass.
Instructivo técnico del cultivo de Cymbopogon citratus (D.C) Stapf (ca a santa)
Rafaela Soto Ortiz,Gilberto Vega Marrero,Aldo Luis Tamajón Navarro
Revista Cubana de Plantas Medicinales , 2002,
Abstract:
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