bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Syk in autoimmune diabetes
Authors: Colonna Lucrezia , Ogryzlo‐Harbers Stephanie Natalia , Catalano Geoffrey , Flores Marcella , Chew Claude , Masuda Esteban , Schmitz Jochen , Thomas James , Clynes Raphael 
Published: June 2021

Type I diabetes (T1D) results from autoimmune attack of the pancreatic β cell islet by inflammatory cells, autoreactive T cells being the primary effectors. However, B cells are necessary for disease in nonobese diabetic (NOD) mice, the best studied model of human T1D. B cells may participate pathogenically as antigen presenting cells and/or as producers of autoantibodies (autoAbs). We have shown in the RIP‐mOVA peripheral tolerance model (RO) that auto‐Abs induce a loss of T cell tolerance in a manner dependent on activating Fc receptors on cross‐priming dendritic cells (DCs). Therefore, we have targeted the spleen tyrosine kinase (Syk), which is required for both BCR‐ and FcR‐mediated signaling, in order to broadly inhibit B cell‐mediated as well as autoAb‐enhanced antigen presentation. Using the oral Syk inhibitor R406 (Rigel Pharmaceuticals) we show that Syk blockade abrogates both B cell‐ and DC‐mediated Ag presentation in vitro, as well as effector T cell differentiation and diabetes in RO mice (100% healthy‐treated vs. 20% healthy‐untreated mice, p=0.02). Finally, Syk inhibition decreases autoAb production, prevents diabetes (60% healthy‐treated vs 14% healthy‐untreated mice at 32 weeks, p<0.01) and prolongs survival in NOD mice (p<10−5). Thus pharmacologic blockade of Syk is a promising therapeutic strategy to inhibit the humoral component of autoimmunity and prevent T1D.This work was supported by the training grant of the Integrated Graduate Program in Cellular, Molecular, Structural and Genetic Studies at Columbia University, NY and by the Juvenile Diabetes Research Foundation, NY.
A Chimeric 4‐1BBL as a Potent Adjuvant for Therapeutic Cancer Vaccines
Authors: Sharma Rajesh Kumar , Elpek Kutlu G , Yolcu Esma S , Schabowsky Richard H , Zhao Hong , Bandura Laura L , Shirwan Haval 
Published: June 2021

Objective: Inasmuch as adaptive immune responses are critical to immune surveillance and such responses are regulated by CD28 and TNFR family costimulatory molecules, we herein tested whether 4‐1BBL can serve as an effective adjuvant for therapeutic cancer vaccines. The choice of 4‐1BBL is due to its pleiotropic effect on the cells of innate, adaptive, and regulatory immunity. Inasmuch as 4‐1BBL has no function in soluble form, we generated a chimeric molecule consisting extracellular portions of 4‐1BBL fused C‐terminus to core streptavidin.Methods: Mice were injected with 1×105 TC‐1 cells expressing HPV E7 oncoprotein in the right flank. Once tumor was established, animals were vaccinated s.c. once with 50 μg of an E7 peptide serving as the dominant epitope for CD8+ T cells and 25 μg of SA‐4‐1BBL. The efficacy of vaccine was assed by monitoring animals for tumor growth, in vivo killing response, and intracellular cytokine staining.Results: Vaccination resulted in the eradication of existing tumors as well as prevention of recurrences after surgical removal of the tumors. The efficacy of immunotherapy was correlated with higher CD8+ T cell infiltration into tumors, the generation of robust T cell killing response, higher frequency of IFN‐γ expressing CD8+ T cells, and long‐term memory.Conclusion: This novel form of 4‐1BBL has the potential to serve as an effective adjuvant for the development of therapeutic cancer vaccines because of its role on adaptive, innate, and regulatory immunity.Funded in parts by 1R41AI071618, R43CA109866, R41 CA121665, and JBCC Fellowship
Overcoming brain immune privilege with Flt3L and TK treatment in a recurrent rat glioma model
Authors: King Gwendalyn D. , Muhammad Ghulam , Larocque Daniel , Candolfi Marianela , Bergeron Josee , Liu Chunyan , Kroeger Kurt , Van Rooijen Nico , Lowenstein Pedro R. , Castro Maria G. 
Published: June 2021

GBM is an invasive primary brain cancer which invariably recurs. Intratumoral treatment of a large syngeneic rat model of GBM with AdFlt3L and AdTK induce ~70% long term survival. Here we evaluated Flt3L and TK treatment in a model of recurrence. Long term GBM survivors post‐therapy were rechallenged with GBM in the contralateral striatum. 100% of animals survived to ~200 days post‐GBM rechallenge. In vitro elispot assays detected tumor specific circulating T cells; in vivo DTH was detected in all long term survivors. Depletion of CD8+ cells but not CD4+ or macrophages abrogated survival of GBM rechallenged animals. To model neo‐antigen expression as a means of tumor escape, we generated CNS‐1 cells stably expressing hemagglutinin CNS1‐HA cells grew similarly in vitro and in vivo and responded to Ad‐Flt3L/Ad‐TK treatment in an indistinguishable fashion from CNS1 tumors. When long term survivors were rechallenged with CNS‐1HA cells, INF γ secreting T‐cells were detected against HA. We conclude that Ad‐Flt3L/Ad‐TK treatment induces immunological memory that protects against recurrence and tumor escape by overcoming brain immune privilege.Funding: NIH/NINDS Grant 1R01 NS44556.01; 1R21‐NSO54143.01; 1UO1 NS052465.01; 1RO1 NS 054193.01; RO1 NS 42893.01, U54 NS045309‐01 and 1R21 NS047298‐01 to P.R.L. GDK and MC are supported by NIH/NINDS 1F32 N50503034‐01 and 1F32 NS058156.01 respectively.
Gadd45β Is Important for CD8+T Cell Mediated Tumor Surveillance
Authors: Ju Songguang , Li Changyou , Zhao Yani , He Yukai , Gu Qin , Liu Lin , Zhang Xueguang , Lu Binfeng 
Published: June 2021

Recent studies have shown that growth arrest and DNA damage‐inducible protein 45β (Gadd45β) plays an important role in Th1 responses in the acute infectious model and promotes Th1‐mediated autoimmune diseases in experimental allergic encephalomyelitis (EAE). However, the function of Gadd45β in CD8+T cells is unclear. In this study, it is shown that Gadd45β deletion results in decreased IFNγ production and reduced levels of activated p38 MAP kinase in CD8+T cells upon TCR or IL12/IL18 stimulation. Gadd45β−/− mice are more susceptible to tumor development. The compromised CD8 T cell function caused by Gadd45b deletion is mainly responsible for the failure of tumor immunosurveillance. Taken together, our study demonstrated that Gadd45β plays an important role in tumor surveillance by promoting t tumor suppression by CD8+T cells.Grant support: Cancer Research Institute Investigator award to Binfeng Lu; Pittsburgh Cancer and Aging Program (NIH grant #P20 CA103730) to Binfeng Lu. National Natural Science Foundation of China (No. 30400394) to Songguang Ju.
MCF7 Side Population (SP) cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1
Authors: Engelmann Katja , Shen Hongmei , Finn Olivera J 
Published: June 2021

Cancer stem and progenitor cells, which are resistant to standard cancer therapy, are suspected to initiate tumor growth and cause tumor relapse. Our study aimed to characterize expression of MUC1 tumor antigen at various stages during tumor progression and to validate MUC1 as immunotherapy target on cancer stem/progenitor cells.We isolated a population of stem/progenitor cells, the so‐called Side Population (SP), from MCF7 cell line, assessed expression of proposed cancer stem cell markers and studied MUC1 expression and in vivo tumorigenicity.About 80% of MCF7 SP cells (7.5% ±1.19 SD) showed a CD44+/CD24−/low phenotype. Microarray analysis confirmed expression of stem/progenitor genes in SP cells; cell morphology and growth supported their stem/progenitor cell phenotype. For the first time we show expression of MUC1 on SP cells (77.8% ±6.9 SD) that was similar to that on mature tumor cells. The minor MUC1− subpopulation accumulated MUC1 protein intracellularly. In vivo injected MUC1+ and MUC1− MCF7 SP cells gave rise to MUC1+ tumors that maintained MUC1+ SP.We conclude that MUC1 is aberrantly expressed not only on mature cancer cells, but also on cancer stem/progenitor cells and suggest that epithelial cancer stem/progenitor cells could be targets of MUC1‐specific tumor immunotherapy.Support: Human Immunology Grant Irvington Institute/Dana Foundation, NIH grants 5P01 CA73743‐07 and 2R01 CA56103‐13.
The effects of exercise on bone density and hormones in lactating women
Authors: Colleran Heather L , Bopp Melanie , Mackie Heather , Wideman Laurie , Lovelady Cheryl 
Published: June 2021

The objective of this study was to determine the effects of exercise on bone‐related hormones in lactating women. At 4wks postpartum (PP) women were randomized to either exercise group (EX, n=10) [weight bearing aerobic exercise (3d/wk, 45 min/d) and 3d/wk of resistance exercise] or control group (C, no exercise, n=10) for 16 wks with a 1‐yr PP follow‐up. Lumbar spine (LS) and hip bone mineral densities (BMD) were measured by DXA. Prolactin (Prl), estradiol (E2), growth hormone (GH), insulin‐like growth factor (IGF‐1), and its associated binding protein‐3 (IGFBP‐3) were analyzed using ELISA. RMANOVA was used to determine differences between groups. During the intervention, C lost significantly more LS BMD then EX (−7 ± 2% vs −5 ± 1%, p < 0.01), but not hip BMD (−2 ± 3% vs −3 ± 2%). GH levels decreased in the C (2.2 ± 2.7 to 1.0 ± 1.6 μg/L) and increased in the EX (2.0 ± 2.7 to 4.0 ± 4.7 μg/L), p=0.1, with no change in IGF‐1 and IGFBP‐3. Prl levels declined in both groups during 1‐yr PP, whereas E2, GH, IGF‐1 and IGFBP‐3 levels remained stable in both groups. At 1‐yr PP, controlling for Prl levels, LS and hip BMD were within baseline values for EX (−1% and +0.4%, respectively) vs C (−4% and −2%), p=0.1. These results suggest exercise during lactation affects GH levels and given the role of GH in bone metabolism, may ultimately influence BMD.Supported by NC Agricultural Research Services
Complementary feeding practices in contemporary Guatemalan infants: zinc (Zn) and iron (Fe) intakes
Authors: Mazariegos Manolo , Westcott Jamie , Krebs Nancy F. , Goco Norman , Gonzalez Michelle , Kraushaar Hatai , Wright Linda , Solomons Noel W , Hambidge K Michael 
Published: June 2021

Background:The lack of adequate complementary feeding (CF) practices in the infants of developing countries is a major contributor to morbidity in young children. Objective: In the context of a community nutrition trial in the Western Highlands of Guatemala, the nutrient content of Fe and Zn in diets of older infants was assessed. Methods: Cross‐sectional 24h‐interactive dietary recalls were obtained at 6 (n=78), 9 (130) and 12 (110) mo. Nutrient values were estimated by WFS (Berkeley, CA) and INCAP food composition tables. Results: Breastfeeding was reported in 100% of infants, with 90% having >6 feeds/d at each timepoint. Mean ± SD intakes/d at 6, 9 and 12 mo were: energy (kcal) 146±139 (min‐max, 0–848), 344±209 (29–1102), 359±198 (52–1130); protein (g) 4.2±5.0, 11.8±9.1, 12.0±7.8; animal protein (% of total) 35±34, 36±26, 34±25; Fe (mg) 1.1±1.6, 2.7±2.8, 3.3±3.5; Zn (mg) 0.7±1.0, 1.5±1.2, 1.5±0.9; animal source Zn (%) 26±37, 28±27, 24±24; phytate (mg) 119±172, 338±252, 413±283; phytate:Zn molar ratios 26±26, 24±14, 28±12. Conclusion: Infants’ plant‐based CF diets are low in Zn and Fe and have a high content of an absorption inhibitor. This suggests an increased risk of mineral deficiencies in this population.Supported by Global Network for Women's and Children's Health Research, Bill and Melinda Gates Foundation, and NIH Office of Dietary Supplements.
Childhood Overweight and Obesity in China
Authors: Lum Jessica May , Wang May Choo 
Published: June 2021

PURPOSE: This study examines the published literature on trends, risk factors, and emerging directions for intervention regarding childhood overweight and obesity in China.METHODS: Literature searches were conducted via Pub Med with the key words “childhood overweight China” and “risk factors obesity China.” Only articles featuring ethnically Chinese children, ages 0.1–18 years, in China were used for analysis. Approximately 40 articles were reviewed in this study.RESULTS: The prevalence of overweight has increased significantly in China since the late 1980s. Studies consistently report higher prevalence rates in urban versus rural areas. For example, in the capital city of Beijing, the overall prevalence of obesity in children ages 6–12 years increased from 10.9% in 1990 to 17.2% in 1993. Multiple studies also indicate that that there are higher rates in boys than in girls. Additionally, several studies report that household socioeconomic status (SES) is positively associated with BMI. Possible etiological factors that have been identified include low physical activity, parental overweight, and increasing consumption of high‐fat, Westernized diets.CONCLUSIONS: Further research is needed on the effects of the nutrition transition on children's health status in developing countries. With China's distinct patterns of higher rates of obesity in boys and in urban areas, cultural and environmental factors must be considered a part of the etiology. As diets become westernized, the values and norms of local communities are also influenced. These relations must be analyzed to yield the most effective interventions to counter childhood obesity.
Dietary habits and cardiovascular disease risk factors in Hispanics with type 2 diabetes mellitus enrolled in the DIALBEST trial. Preliminary results
Authors: Calle Mariana C , Vega‐López Sonia , Pérez‐Escamilla Rafael , Chhabra Jyoti , D’Agostino Darrin , Damio Grace , Fernandez Maria Luz 
Published: June 2021

Anthropometrics, plasma lipids, glucose, glycosylated hemoglobin (HbA1C) and 24h recalls were analyzed for Hispanic subjects diagnosed with type 2 diabetes at the time of enrollment in the DIALBEST trial (n = 15 men and 65 women) aged 32–76 y. Plasma glucose levels were 187.2 ± 68.4 mg/dL for men and 204.8 ± 90 mg/dL for women with a range of 113–542 mg/dL. HbA1C values were 10.4% for men and 11.4 % for women. Mean BMI and waist circumference (WC) for women were 33.7 and 106.3 cm, respectively while men had a BMI = 33 and WC = 109.6 cm. Self reports of activity levels suggested little or no physical activity at baseline evaluation. Plasma LDL cholesterol concentrations were 110.2 ± 43.2 mg/dL for women and 84.8 ± 26.0 mg/dL for men (P <0.05). Mean plasma triglycerides were above 150 mg/dL for both men and women. Plasma HDL cholesterol was 51.6 ± 14.2 mg/dL for women and 47.0 ± 18.5 mg/dL for men. There was a significant positive correlation of plasma glucose with plasma TG (r = 0.504, P < 0.0001), and between WC and diastolic blood pressure (r = 0.350, P < 0.01). Dietary analysis indicated that carbohydrate represented the major source of energy ranging from 23 to 94% with a mean of 55% of total energy intake. Mean total sugar consumption was 60 g/d. These results indicate that this population is at high risk for cardiovascular disease and other complications associated with diabetes. In addition, the anthropometric parameters, plasma glucose and plasma lipids suggest that women are at a higher risk than men.[Supported by NIH‐NCMHD EXPORT Center grant P20MD001765].
Quantitative ultrasound (QUS) measurements in small versus appropriate birth weight for gestation neonates
Authors: Koo Winston 
Published: June 2021

Background: Small for gestation (SGA) neonates have lower birth weight (<10th percentile) and lower bone mass compared to those born with appropriate birth weights (AGA, 10th to 90th percentile). QUS measurements are thought to reflect multiple parameters in addition to bone mass which contributed to bone strength and there are limited data on QUS measurements in SGA infants.Hypothesis: SGA infants will have lower QUS measurements compared to AGA neonates.Methods: Speed of sound (SOS) measurements were obtained at left tibia with a commercial axial transmission QUS device using manufacturer (Sunlight Omnisense 7000S Bone Sonometer) supplied neonatal software and CR and/or CS probes. CV of duplicate measurement was 0.6% of mean. None of the SGA infants had any known intrauterine infectious or genetic disorders. All measurements were performed within a few days after birth. Based on the expected lower birth weight and bone mass of SGA infants, this study was powered to detect a 10% difference in SOS between AGA and SGA neonates.Results:Conclusion: There were no significant differences in QUS SOS measurements between SGA and AGA neonates.
Carnitine compartmentalization in surgery patients
Authors: George Wesley , Borum. FSHN Peggy R. 
Published: June 2021

Carnitine, an amino acid derivative, is involved in the transport of fatty acids into the mitochondrial matrix for βoxidation. Plasma carnitine is often used as a clinical indicator of the carnitine status throughout the body, but the carnitine concentration in organs and the relationship of carnitine compartments within the body are usually not known. We measured plasma carnitine collected before (PC) and during anesthesia (Surg‐PC), red blood cell carnitine collected before (RC) and during anesthesia (Surg‐RC), muscle carnitine (MuC) collected during general anesthesia, and in approximately half of the patients liver carnitine (LC) collected during general anesthesia. Total carnitine values of the various compartments are shown in the table below.Surg‐PC was lower than PC (p<.05), but RC and Surg‐RC did not differ. Correlations of MuC or LC with any of the blood carnitine parameters indicated that less than 15 percent of the tissue carnitine concentration could be predicted by the blood carnitine parameters. Neither plasma carnitine nor red blood cell carnitine appears to be a strong predictor of carnitine status in tissue compartments.
Evaluation of dyslipidemia and diet prescription of patients on ketogenic therapy for seizures
Authors: Little Lauren E. , Borum Peggy R. 
Published: June 2021

Ketogenic therapy (KT) has been shown to be effective against seizures, but requires a fat intake (80–90% of calories) much higher than is recommended by the American Heart Association (AHA). There is conflicting evidence in the literature as to whether or not dyslipidemia is an adverse effect of KT. Currently there are no available feeding options that provide a balanced fatty acid profile similar to what is recommended by the AHA. KT prescription is designated as a ratio of grams of fat to grams of carbohydrate plus protein. 76 patients who had been on KT for at least 1 year were stratified according to fat ratio and no effect of ratio on blood lipids was observed. During therapy, oral fed patients usually receive a diet high in saturated fatty acids (SF) and tube fed patients usually receive a diet high in omega 6 fatty acids (w6). When the patients were stratified between the high SF oral diet and the high w6 tube‐fed diet, the following data were obtained using a t‐test assuming unequal variances.The type of fat appears to be more important than the amount of fat for increasing the risk of dyslipidemia on patients receiving KT for seizures.
“WESTERN” DIET INDUCES APOPTOSIS IN THE HEART OF A RAT MODEL WITH DIET‐INDUCED OBESITY
Authors: BALLAL KALPANA , WILSON CHRISTOPHER ROBERT , SALAZAR REBECCA LYNN , TAEGTMEYER HEINRICH 
Published: June 2021

Background: We proposed that excess fuel supply in a rat model of diet‐induced obesity leads to cell damage due to increased oxidative stress and apoptosis.Methods and Results: Male Wistar rats (n=8/group) were fed either low fat, western or high fat diets (10%, 45%, or 60% calories from fat, respectively) for acute, short, intermediate, or long term. Hearts were treated with 2, 4‐dinitrophenylhydrazine, and protein carbonyl formation was measured spectrophotometrically. Increased protein carbonylation was discovered with all diets in the intermediate term, but was reduced in the long term, which suggests upregulation of antioxidant defense mechanisms. Antiapoptotic BCl‐2 protein expression in the heart was markedly reduced with western diet, (85%, p<0.0001), but not with high fat diet. Decrease in BCl2 was associated with an increase of the mitochondrial transcription factor A (mtTFA) with western diet. Induction of mtTFA suggests compensatory mitochondrial biogenesis in the face of increased mitochondrial damage due to oxidative stress with western diet. Lastly, we also observed decreased expression of cardiac SERCA2a protein with western diet confirming similar observations in animal models of diabetes.Conclusion: Downregulation of BCl2 and increased mitochondrial biogenesis are mediators of oxidative stress‐induced apoptosis in hearts of obese animals fed a western diet.
Application of the Hegsted Equation to Low Carbohydrate‐Low Fat Diet Comparisons
Authors: Volk Brittanie M , Feinman Richard D , Quann Erin E , Puglisi Michael J , Forsythe Cassandra E , Labonte Cherise C , Fernandez Maria‐Luz , Kraemer William J , Volek Jeff S 
Published: June 2021

The Keys and Hegsted equations continue to be used to predict serum total cholesterol (TC) or LDL‐C based on dietary saturated fat (SFA), polyunsaturated fat (PUFA) and cholesterol (Chol). The equations frequently give good fit but are limited in that they are primarily descriptive without an underlying mechanism. As predictors of CVD risk, TC and LDL‐C are also not optimal: LDL particle size (and its surrogate TG/HDL‐C) are generally better. Carbohydrate restricted diets (CRD) effectively reduce the more atherogenic small LDL, due to the role of insulin in lipid metabolism. Because the Hegsted equations are still used, we evaluated their predictive value in subjects who consumed a CRD (n = 16: 1504 kcal, %CHO:fat:protein=12:59:28) and a low‐fat diet (n = 18: 1478 kcal,%CHO:fat:protein=56:24:20). The actual change in fasting serum lipid values after 12 weeks of diet was compared to predicted values using recent versions of the Hegsted equation:[ΔTC = 2.10 ΔSFA − 1.16 ΔPUFA + 0.067 ΔChol and LDL‐C = 1.74 ΔSFA − 0.766 ΔPUFA + 0.0439 ΔChol]TC and LDL‐C were weakly predicted for low‐fat diets (R = 0.22, 0.10) but not CRD (R = −0.12, 0.01). In distinction, we found that dietary carbohydrate was a good predictor of LDL particle size or TG/HDL‐C (R = 0.52, 0.51) and may be more generally useful in the assessment of the influence of diet on CVD risk than those indicators, like the Hegsted equations, based primarily on lipid components.
Dietary docosahexaenoic acid modulates hippocampal development in mouse
Authors: Rai Kiranmai Sesappa , Sanders Lisa Merle , Parikh Komal , Zeisel Steven H 
Published: June 2021

Dietary docosahexaenoic acid modulates hippocampal development in the mousePhosphatidyl‐N‐methyl transferase (PEMT) catalyzes the biosynthesis of phosphatidyl choline (PtdCho), and prefers incorporation of docosahexaenoic acid (DHA) into PtdCho. We previously reported that the PEMT knock out mouse has altered hippocampal development. The present study explores if changes in membrane DHA species of PtdCho mediate the observed effects on brain development. Timed pregnant CBL57 wild type (WT) mice and PEMT knock‐out (KO) mice were kept on control diet. A subgroup of dams, were given DHA, from embryonic day E11 to E17.Brains of fetuses collected on E17 were processed for immunohistochemistry. Results show increased neural progenitor cell proliferation in the ventricular lining of the developing hippocampus in fetuses from WT dams (92± 29 mitotic cells in DHA treated vs 33±11on control diet, p<0.05), but no change seen in calretenin expressing neurons in the dentate gyrus (DG). In addition, while fetuses of KO dams versus WT dams on control diet showed increased cell proliferation (144± 21 mitotic cells in KO vs 33±11 in WT, p<0.001), fetuses of KO dams on DHA diet did not.In addition, fetuses from KO dams on DHA diet had increased calretenin neurons in DG (3± 0.4 mean optical density in DHA treated vs −0.1 ± 0.2 on control diet, p<0.05) while fetuses from WT dams on DHA diet did not. These data suggest that, maternal dietary DHA, and PEMT‐mediated PtdCho‐DHA in brain can alter hippocampal development.