Karla Castellanos - Academia.edu (original) (raw)
Papers by Karla Castellanos
PLOS ONE
Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distin... more Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distinct from healthy individuals, but this has only been shown in healthy individuals, not in those exhibiting several risk factors for dementia. Using amplicon 16S rRNA gene sequencing in a case-control study of 60 older (ages 55–76), obese, predominately female, African American adults, those with MCI (cases) had different gut microbiota profiles than controls. While microbial community diversity was similar between cases and controls, the abundances of specific microbial taxa weren’t, such as Parabacteroides distasonis (lower in cases) and Dialister invisus (higher in cases). These differences disappeared after adjusting for markers of oxidative stress and systemic inflammation. Cognitive scores were positively correlated with levels of Akkermansia muciniphila, a bacterium associated with reduced inflammation. Our study shows that gut microbial composition may be associated with inflammati...
Nutrients, 2020
(1) Background: There are currently very few interventions performed within a community setting t... more (1) Background: There are currently very few interventions performed within a community setting that compare the effects of physical activity (PA) versus PA plus weight loss on cancer and chronic disease risk in older African Americans. Therefore, we investigated the impact of an 8 week (24 session) PA intervention compared to a PA plus weight loss intervention on fat mass, glucose metabolism, and markers of inflammation in older, overweight and obese African Americans. (2) Methods: Subjects were randomized to a PA (n = 83) or PA plus weight loss (n = 72) intervention that met three times weekly for 8 weeks. At baseline and post-intervention, anthropometrics, body composition, systemic inflammation (high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin 6), fasting glucose, insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were determined. (3) Results: Subjects had a mean age of 67 years (SD = 5.3) and were mostly women (88%). The PA plus weight loss group lost more total and visceral fat than the PA group (−4.0% vs. +0.6% and −4.1% vs. +3.7%, respectively, p < 0.01 for both). Changes in inflammation and glucose metabolism were similar between groups post-intervention. Within the PA plus weight loss group only, serum insulin and HOMA-IR decreased significantly. (4) Conclusions: PA combined with weight loss can decrease total and visceral fat mass and improve insulin sensitivity, confirming that these cancer-and chronic disease-related risk factors are influenced by relatively modest lifestyle changes in the short term.
Talento - Revista de Administración, 2021
El objetivo fue analizar el proceso de organización logística en las empresas distribuidoras de p... more El objetivo fue analizar el proceso de organización logística en las empresas distribuidoras de productos lácteos. La investigación se consideró de tipo descriptiva utilizando para ello un diseño no experimental, de campo y transeccional. La población estuvo conformada por nueve personas que ocupan los cargos de gerentes en las empresas de productos lácteos ubicadas en el municipio Cabimas y que se encontraron activas al momento de la investigación. Para el tratamiento de la información se estructuró un cuestionario conformado por nueve ítems con cinco alternativas de respuestas, validado por el juicio de expertos y cuya confiabilidad fue calculada a través del coeficiente de Alfa Cronbach, obteniéndose 0,949. Para el análisis estadístico, se aplicó la estadística descriptiva, a través de las frecuencias y la media aritmética. Se concluye que las empresas manejan una alta utilización de la estructura organizacional, división del trabajo, jerarquización y opciones organizacionales co...
Dilemas contemporáneos: Educación, Política y Valores, 2021
En este trabajo presentamos el diseño estructural e integral de un Plan estratégico al cual denom... more En este trabajo presentamos el diseño estructural e integral de un Plan estratégico al cual denominamos “A un paso de graduarte”, y cuyo objetivo principal consiste en desarrollar, promover, gestionar e impulsar, de manera coordinada con todas las partes involucradas, las competencias transversales para la empleabilidad y la ocupabilidad de los estudiantes de la carrera de Ingeniería Química de la Facultad de Ciencias Químicas de la Universidad Veracruzana en Orizaba, Veracruz. Este plan estratégico va dirigido a los estudiantes que se encuentran en el último tercio de su carrera y su etapa inicial ya se encuentra en marcha. Los resultados obtenidos hasta este momento son halagadores, lo cual indica, que en un futuro, estará dando los frutos esperados.
Scientific Reports, 2021
Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the ... more Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor...
The Journal of Nutrition, 2021
Background Iron is critical for fetal development. Neonates of obese women may be at risk for poo... more Background Iron is critical for fetal development. Neonates of obese women may be at risk for poor iron status at birth as a result of maternal inflammation-driven overexpression of hepcidin. Objectives The objective of this study was to determine differences in placental transfer of oral iron (57Fe) and expression of placental transferrin receptor 1 (TFR1) and ferroportin (FPN) mRNA and protein and their association with maternal and neonatal iron-related parameters, including maternal hepcidin, among women with and without prepregnancy (PP) obesity. Methods 57Fe ingested during the third trimester of pregnancy was recovered in venous umbilical cord blood among 20 PP obese [BMI (in kg/m2): 30.5–43.9] and 22 nonobese (BMI: 18.5–29.0) women aged 17–39 y. Placental TFR1 and FPN mRNA and protein expression were quantified via qPCR and Western blot. Maternal and neonatal markers of iron status and regulation, as well as inflammation, were measured. Descriptive and inferential statistica...
Cancer Research, 2021
Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to ri... more Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs ...
Clinical and Translational Gastroenterology, 2020
INTRODUCTION: Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Trea... more INTRODUCTION: Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response. METHODS: We assessed whether BMI and serum activin A levels are independent markers to determine disease severity in a cohort of patients with AP. To evaluate activin A inhibition as a therapeutic, we used a cerulein-induced murine model of AP and treated mice with activin A-specific neutralizing antibody or immunoglobulin G control, both before and during the development of AP. We measured the production and release of activin A by pancreas and macrophage cell lines and observed the activation of macrophages after activin A treatment. RESULTS: BMI and activin A independently predicted severe AP in patients. Inhibiting activin A in AP mice reduced disease severity and local immune cell infiltration. Inflammatory stimulation led to activin A production and release by pancreas cells but not by macrophages. Macrophages were activated by activin A, suggesting activin A might promote inflammation in the pancreas in response to injury. DISCUSSION: Activin A provides a promising therapeutic target to interrupt the cycle of inflammation and tissue damage in AP progression. Moreover, assessing activin A and BMI in patients on hospital admission could provide important predictive measures for screening patients likely to develop severe disease.
Current Developments in Nutrition, 2019
Objectives Obese women may be at risk for poor iron status in pregnancy due to pro-inflammatory d... more Objectives Obese women may be at risk for poor iron status in pregnancy due to pro-inflammatory driven overexpression of hepcidin that leads to decreased iron bioavailability. Our objective was to determine the impact of pre-pregnancy (PP) obesity on maternal iron utilization in the third trimester of a singleton pregnancy. Methods Using the stable isotope 57Fe prepared as an oral ferrous sulfate solution, we measured iron absorption based on red blood cell incorporation in 50 adult (mean age: 27.6 ± 6.8 years) pregnant women [n = 29 PP non-obese (body mass index (BMI) 18.5–29.9 kg/m2) and n = 21 PP obese (BMI ≥ 30.0 kg/m2] at the 32nd-34th gestational week (mean 32.7 ± 0.7 weeks). We also assessed maternal iron status, hepcidin, inflammation, erythropoietin, dietary iron intake and gestational weight gain. Results Iron deficiency defined as hemoglobin < 11.0 g/dL was highly prevalent (PP obese 67% vs. PP non-obese 48%, P = 0.19). 57Fe utilization (PP non-obese 11.2% (interquarti...
Tumor Biology, 2019
A significant clinical need exists for understanding the early changes in pancreatic cancer (PC) ... more A significant clinical need exists for understanding the early changes in pancreatic cancer (PC) progression and employing imaging of cellular and tissue phenotypes to detect neoplasia. We have investigated the development of early pathology in EL- Kras and p48-Cre/LSL- Kras (EK and KC, respectively) mice using diffusion MR imaging. These models express mutant Kras via different mechanisms yet recapitulate pancreatic precursor lesions seen in human PC. Our ex vivo investigation shows that diffusion MR imaging based only on endogenous contrast not only detects pre-neoplastic pathology in EK and KC mice, but also differentiates the progression of pathology in these mouse models. Fixed pancreata from EK and KC mice at 4M, 8M and 12M (n=4/group) were examined by diffusion imaging on a 14.1T MR microimager. Mean diffusivity was calculated for acinar lobules and lesions. Pancreata evaluated by MRI were processed for histology (HE 12M: 0.59x10 -3 mm 2 /s) indicating a later onset, but more advancing pathology. Changes in tissue diffusivity arise from a complex combination of cytological changes induced by pathology. Lower diffusivity in EK mice at 4M probably arises from higher levels of ADM (31.7%) compared to 4M KC mice (ADM 11.7%). Reduced diffusivity in KC mice at 8 and 12M most likely is related to elevated fibrosis in those mice (60.0-62.5%) which is relatively low in EK mice (13.3-18.3%). While diffusion MR images revealed the presence of fluid-filled cysts in both models, only KC mice showed lesions with much lower diffusivity (0.55-0.39x10 -3 mm 2 /s). Lower diffusivity indicates high cellularity in these neoplastic lesions which are likely mPanINs. Histology revealed that mPanINs which occupied 11.7-18.8% of the tissue in the KC mouse pancreas, are mostly absent in EK mice. Based on our imaging and histology results, MR-measured diffusivity might be a useful marker to assess the onset and progression of PanIN and cystic disease in PC. Citation Format: Palamadai N. Venkatasubramanian, Matthew Smith, Emman Mascrinas, Andrew Diaz, Karla Castellanos, Brian DeCant, Ron McKinney, Paul J. Grippo, Alice M. Wyrwicz. Diffusion MR imaging detects differential progression of pathology in two mutant KRas mouse models of pancreatic neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1960.
Proceedings of the National Academy of Sciences, 2019
Significance Although activation of PI3K p110α appears to promote pancreatic cancer development v... more Significance Although activation of PI3K p110α appears to promote pancreatic cancer development via canonical AKT signaling, in the setting of a high-fat diet (enriched in ω−6 fatty acids), unopposed p110γ inhibition poses a risk for severe hepatic damage. Considering that obesity is a risk factor for pancreatic cancer, these observations suggest the need for caution when translating drugs targeting p110γ to the clinic.
Journal of Clinical Oncology, 2019
e15150 Background: Insulin growth factor-1 (IGF1) and inflammatory biomarkers such as interleukin... more e15150 Background: Insulin growth factor-1 (IGF1) and inflammatory biomarkers such as interleukin-6 (IL6) play a role in early carcinogenesis, predict prognosis and response to some therapies in colorectal cancer (CRC), and are altered in patients with sarcopenia. This study examines the association of IGF-1 and IL-6 with sarcopenia in patients with CRC. Methods: Fasting blood samples were collected at diagnosis of non-metastatic CRC (N = 59) and analyzed for serum IGF-1 and IL-6 by ELISA. Skeletal Muscle Index (SMI) was calculated from cross-sectional image at L3 from computed tomography. Sarcopenia was defined based on published cut points for adults with cancer stratified by body mass index (BMI) as: SMI < 43 cm2/m2 for men and < 41 cm2/m2 for women for normal and underweight; and SMI < 53 cm2/m2 for men and < 41 cm2/m2 for women for overweight and obese. Median and interquartile range (IQR) were reported for patients with sarcopenia versus those without sarcopenia. S...
Translational Cancer Research, 2019
![Research paper thumbnail of {"__content__"=>"KRAS and TP53 Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs.", "sup"=>[{"__content__"=>"G12D"}, {"__content__"=>"R167H"}]}](https://attachments.academia-assets.com/102794880/thumbnails/1.jpg)
](Scientific reports, Jan 22, 2018
Although survival has improved in recent years, the prognosis of patients with advanced pancreati... more Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRAS-TP53 cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreatic duct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight ...
Obesity (Silver Spring, Md.), Jan 6, 2015
In this study, the associations between vitamin D, insulin sensitivity, and inflammation and thei... more In this study, the associations between vitamin D, insulin sensitivity, and inflammation and their relationships with adipose tissue expression of vitamin D receptor (VDR) and inflammatory markers in women with morbid obesity were determined. An oral glucose tolerance test prior to surgery was completed by healthy premenopausal women (n = 76) seeking bariatric surgery. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were collected during surgery. Approximately, 70% of our subjects were vitamin D sufficient or optimal, and 80% had normal glucose tolerance. No significant association between serum 25-hydroxyvitamin D [25(OH)D] with circulating inflammatory markers or insulin sensitivity was identified. In subjects with waist circumference of <139 cm (n = 42), log25(OH)D positively predicted VAT logIL-6 mRNA expression (P = 0.003). LogVDR expression was positively correlated with the expression of inflammatory markers in both SAT (logIL-1β mRNA: r = 0.95,…
PLOS ONE
Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distin... more Those with mild cognitive impairment (MCI), a precursor to dementia, have a gut microbiome distinct from healthy individuals, but this has only been shown in healthy individuals, not in those exhibiting several risk factors for dementia. Using amplicon 16S rRNA gene sequencing in a case-control study of 60 older (ages 55–76), obese, predominately female, African American adults, those with MCI (cases) had different gut microbiota profiles than controls. While microbial community diversity was similar between cases and controls, the abundances of specific microbial taxa weren’t, such as Parabacteroides distasonis (lower in cases) and Dialister invisus (higher in cases). These differences disappeared after adjusting for markers of oxidative stress and systemic inflammation. Cognitive scores were positively correlated with levels of Akkermansia muciniphila, a bacterium associated with reduced inflammation. Our study shows that gut microbial composition may be associated with inflammati...
Nutrients, 2020
(1) Background: There are currently very few interventions performed within a community setting t... more (1) Background: There are currently very few interventions performed within a community setting that compare the effects of physical activity (PA) versus PA plus weight loss on cancer and chronic disease risk in older African Americans. Therefore, we investigated the impact of an 8 week (24 session) PA intervention compared to a PA plus weight loss intervention on fat mass, glucose metabolism, and markers of inflammation in older, overweight and obese African Americans. (2) Methods: Subjects were randomized to a PA (n = 83) or PA plus weight loss (n = 72) intervention that met three times weekly for 8 weeks. At baseline and post-intervention, anthropometrics, body composition, systemic inflammation (high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin 6), fasting glucose, insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were determined. (3) Results: Subjects had a mean age of 67 years (SD = 5.3) and were mostly women (88%). The PA plus weight loss group lost more total and visceral fat than the PA group (−4.0% vs. +0.6% and −4.1% vs. +3.7%, respectively, p < 0.01 for both). Changes in inflammation and glucose metabolism were similar between groups post-intervention. Within the PA plus weight loss group only, serum insulin and HOMA-IR decreased significantly. (4) Conclusions: PA combined with weight loss can decrease total and visceral fat mass and improve insulin sensitivity, confirming that these cancer-and chronic disease-related risk factors are influenced by relatively modest lifestyle changes in the short term.
Talento - Revista de Administración, 2021
El objetivo fue analizar el proceso de organización logística en las empresas distribuidoras de p... more El objetivo fue analizar el proceso de organización logística en las empresas distribuidoras de productos lácteos. La investigación se consideró de tipo descriptiva utilizando para ello un diseño no experimental, de campo y transeccional. La población estuvo conformada por nueve personas que ocupan los cargos de gerentes en las empresas de productos lácteos ubicadas en el municipio Cabimas y que se encontraron activas al momento de la investigación. Para el tratamiento de la información se estructuró un cuestionario conformado por nueve ítems con cinco alternativas de respuestas, validado por el juicio de expertos y cuya confiabilidad fue calculada a través del coeficiente de Alfa Cronbach, obteniéndose 0,949. Para el análisis estadístico, se aplicó la estadística descriptiva, a través de las frecuencias y la media aritmética. Se concluye que las empresas manejan una alta utilización de la estructura organizacional, división del trabajo, jerarquización y opciones organizacionales co...
Dilemas contemporáneos: Educación, Política y Valores, 2021
En este trabajo presentamos el diseño estructural e integral de un Plan estratégico al cual denom... more En este trabajo presentamos el diseño estructural e integral de un Plan estratégico al cual denominamos “A un paso de graduarte”, y cuyo objetivo principal consiste en desarrollar, promover, gestionar e impulsar, de manera coordinada con todas las partes involucradas, las competencias transversales para la empleabilidad y la ocupabilidad de los estudiantes de la carrera de Ingeniería Química de la Facultad de Ciencias Químicas de la Universidad Veracruzana en Orizaba, Veracruz. Este plan estratégico va dirigido a los estudiantes que se encuentran en el último tercio de su carrera y su etapa inicial ya se encuentra en marcha. Los resultados obtenidos hasta este momento son halagadores, lo cual indica, que en un futuro, estará dando los frutos esperados.
Scientific Reports, 2021
Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the ... more Pancreatic ductal adenocarcinoma (PDAC) has extensive stromal involvement and remains one of the cancers with the highest mortality rates. Activin A has been implicated in colon cancer and its stroma but its role in the stroma of PDAC has not been elucidated. Activin A expression in cancer and stroma was assessed in human PDAC tissue microarrays (TMA). Activin A expression in human TMA is significantly higher in cancer samples, with expression in stroma correlated with shorter survival. Cultured pancreatic stellate cells (PSC) were found to secrete high levels of activin A resulting in PDAC cell migration that is abolished by anti-activin A neutralizing antibody. KPC mice treated with anti-activin A neutralizing antibody were evaluated for tumors, lesions and metastases quantified by immunohistochemistry. KPC mice with increased tumor burden express high plasma activin A. Treating KPC mice with an activin A neutralizing antibody does not reduce primary tumor size but decreases tumor...
The Journal of Nutrition, 2021
Background Iron is critical for fetal development. Neonates of obese women may be at risk for poo... more Background Iron is critical for fetal development. Neonates of obese women may be at risk for poor iron status at birth as a result of maternal inflammation-driven overexpression of hepcidin. Objectives The objective of this study was to determine differences in placental transfer of oral iron (57Fe) and expression of placental transferrin receptor 1 (TFR1) and ferroportin (FPN) mRNA and protein and their association with maternal and neonatal iron-related parameters, including maternal hepcidin, among women with and without prepregnancy (PP) obesity. Methods 57Fe ingested during the third trimester of pregnancy was recovered in venous umbilical cord blood among 20 PP obese [BMI (in kg/m2): 30.5–43.9] and 22 nonobese (BMI: 18.5–29.0) women aged 17–39 y. Placental TFR1 and FPN mRNA and protein expression were quantified via qPCR and Western blot. Maternal and neonatal markers of iron status and regulation, as well as inflammation, were measured. Descriptive and inferential statistica...
Cancer Research, 2021
Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to ri... more Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs ...
Clinical and Translational Gastroenterology, 2020
INTRODUCTION: Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Trea... more INTRODUCTION: Acute pancreatitis (AP) is a healthcare challenge with considerable mortality. Treatment is limited to supportive care, highlighting the need to investigate disease drivers and prognostic markers. Activin A is an established mediator of inflammatory responses, and its serum levels correlate with AP severity. We hypothesized that activin A is independent of body mass index (BMI) and is a targetable promoter of the AP inflammatory response. METHODS: We assessed whether BMI and serum activin A levels are independent markers to determine disease severity in a cohort of patients with AP. To evaluate activin A inhibition as a therapeutic, we used a cerulein-induced murine model of AP and treated mice with activin A-specific neutralizing antibody or immunoglobulin G control, both before and during the development of AP. We measured the production and release of activin A by pancreas and macrophage cell lines and observed the activation of macrophages after activin A treatment. RESULTS: BMI and activin A independently predicted severe AP in patients. Inhibiting activin A in AP mice reduced disease severity and local immune cell infiltration. Inflammatory stimulation led to activin A production and release by pancreas cells but not by macrophages. Macrophages were activated by activin A, suggesting activin A might promote inflammation in the pancreas in response to injury. DISCUSSION: Activin A provides a promising therapeutic target to interrupt the cycle of inflammation and tissue damage in AP progression. Moreover, assessing activin A and BMI in patients on hospital admission could provide important predictive measures for screening patients likely to develop severe disease.
Current Developments in Nutrition, 2019
Objectives Obese women may be at risk for poor iron status in pregnancy due to pro-inflammatory d... more Objectives Obese women may be at risk for poor iron status in pregnancy due to pro-inflammatory driven overexpression of hepcidin that leads to decreased iron bioavailability. Our objective was to determine the impact of pre-pregnancy (PP) obesity on maternal iron utilization in the third trimester of a singleton pregnancy. Methods Using the stable isotope 57Fe prepared as an oral ferrous sulfate solution, we measured iron absorption based on red blood cell incorporation in 50 adult (mean age: 27.6 ± 6.8 years) pregnant women [n = 29 PP non-obese (body mass index (BMI) 18.5–29.9 kg/m2) and n = 21 PP obese (BMI ≥ 30.0 kg/m2] at the 32nd-34th gestational week (mean 32.7 ± 0.7 weeks). We also assessed maternal iron status, hepcidin, inflammation, erythropoietin, dietary iron intake and gestational weight gain. Results Iron deficiency defined as hemoglobin < 11.0 g/dL was highly prevalent (PP obese 67% vs. PP non-obese 48%, P = 0.19). 57Fe utilization (PP non-obese 11.2% (interquarti...
Tumor Biology, 2019
A significant clinical need exists for understanding the early changes in pancreatic cancer (PC) ... more A significant clinical need exists for understanding the early changes in pancreatic cancer (PC) progression and employing imaging of cellular and tissue phenotypes to detect neoplasia. We have investigated the development of early pathology in EL- Kras and p48-Cre/LSL- Kras (EK and KC, respectively) mice using diffusion MR imaging. These models express mutant Kras via different mechanisms yet recapitulate pancreatic precursor lesions seen in human PC. Our ex vivo investigation shows that diffusion MR imaging based only on endogenous contrast not only detects pre-neoplastic pathology in EK and KC mice, but also differentiates the progression of pathology in these mouse models. Fixed pancreata from EK and KC mice at 4M, 8M and 12M (n=4/group) were examined by diffusion imaging on a 14.1T MR microimager. Mean diffusivity was calculated for acinar lobules and lesions. Pancreata evaluated by MRI were processed for histology (HE 12M: 0.59x10 -3 mm 2 /s) indicating a later onset, but more advancing pathology. Changes in tissue diffusivity arise from a complex combination of cytological changes induced by pathology. Lower diffusivity in EK mice at 4M probably arises from higher levels of ADM (31.7%) compared to 4M KC mice (ADM 11.7%). Reduced diffusivity in KC mice at 8 and 12M most likely is related to elevated fibrosis in those mice (60.0-62.5%) which is relatively low in EK mice (13.3-18.3%). While diffusion MR images revealed the presence of fluid-filled cysts in both models, only KC mice showed lesions with much lower diffusivity (0.55-0.39x10 -3 mm 2 /s). Lower diffusivity indicates high cellularity in these neoplastic lesions which are likely mPanINs. Histology revealed that mPanINs which occupied 11.7-18.8% of the tissue in the KC mouse pancreas, are mostly absent in EK mice. Based on our imaging and histology results, MR-measured diffusivity might be a useful marker to assess the onset and progression of PanIN and cystic disease in PC. Citation Format: Palamadai N. Venkatasubramanian, Matthew Smith, Emman Mascrinas, Andrew Diaz, Karla Castellanos, Brian DeCant, Ron McKinney, Paul J. Grippo, Alice M. Wyrwicz. Diffusion MR imaging detects differential progression of pathology in two mutant KRas mouse models of pancreatic neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1960.
Proceedings of the National Academy of Sciences, 2019
Significance Although activation of PI3K p110α appears to promote pancreatic cancer development v... more Significance Although activation of PI3K p110α appears to promote pancreatic cancer development via canonical AKT signaling, in the setting of a high-fat diet (enriched in ω−6 fatty acids), unopposed p110γ inhibition poses a risk for severe hepatic damage. Considering that obesity is a risk factor for pancreatic cancer, these observations suggest the need for caution when translating drugs targeting p110γ to the clinic.
Journal of Clinical Oncology, 2019
e15150 Background: Insulin growth factor-1 (IGF1) and inflammatory biomarkers such as interleukin... more e15150 Background: Insulin growth factor-1 (IGF1) and inflammatory biomarkers such as interleukin-6 (IL6) play a role in early carcinogenesis, predict prognosis and response to some therapies in colorectal cancer (CRC), and are altered in patients with sarcopenia. This study examines the association of IGF-1 and IL-6 with sarcopenia in patients with CRC. Methods: Fasting blood samples were collected at diagnosis of non-metastatic CRC (N = 59) and analyzed for serum IGF-1 and IL-6 by ELISA. Skeletal Muscle Index (SMI) was calculated from cross-sectional image at L3 from computed tomography. Sarcopenia was defined based on published cut points for adults with cancer stratified by body mass index (BMI) as: SMI < 43 cm2/m2 for men and < 41 cm2/m2 for women for normal and underweight; and SMI < 53 cm2/m2 for men and < 41 cm2/m2 for women for overweight and obese. Median and interquartile range (IQR) were reported for patients with sarcopenia versus those without sarcopenia. S...
Translational Cancer Research, 2019
Scientific reports, Jan 22, 2018
Although survival has improved in recent years, the prognosis of patients with advanced pancreati... more Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRAS-TP53 cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreatic duct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight ...
Obesity (Silver Spring, Md.), Jan 6, 2015
In this study, the associations between vitamin D, insulin sensitivity, and inflammation and thei... more In this study, the associations between vitamin D, insulin sensitivity, and inflammation and their relationships with adipose tissue expression of vitamin D receptor (VDR) and inflammatory markers in women with morbid obesity were determined. An oral glucose tolerance test prior to surgery was completed by healthy premenopausal women (n = 76) seeking bariatric surgery. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were collected during surgery. Approximately, 70% of our subjects were vitamin D sufficient or optimal, and 80% had normal glucose tolerance. No significant association between serum 25-hydroxyvitamin D [25(OH)D] with circulating inflammatory markers or insulin sensitivity was identified. In subjects with waist circumference of <139 cm (n = 42), log25(OH)D positively predicted VAT logIL-6 mRNA expression (P = 0.003). LogVDR expression was positively correlated with the expression of inflammatory markers in both SAT (logIL-1β mRNA: r = 0.95,…