BackgroundObesity has reached epidemic proportions in the United States. It is implicated in the development of a variety of chronic disease states and is associated with increased levels of inflammation and oxidative stress. The objective of this study is to examine the effect of Medifast's meal replacement program (MD) on body weight, body composition, and biomarkers of inflammation and oxidative stress among obese individuals following a period of weight loss and weight maintenance compared to a an isocaloric, food-based diet (FB).MethodsThis 40-week randomized, controlled clinical trial included 90 obese adults with a body mass index (BMI) between 30 and 50 kg/m2, randomly assigned to one of two weight loss programs for 16 weeks and then followed for a 24-week period of weight maintenance. The dietary interventions consisted of Medifast's meal replacement program for weight loss and weight maintenance, or a self-selected, isocaloric, food-based meal plan.ResultsWeight loss at 16 weeks was significantly better in the Medifast group (MD) versus the food-based group (FB) (12.3% vs. 6.9%), and while significantly more weight was regained during weight maintenance on MD versus FB, overall greater weight loss was achieved on MD versus FB. Significantly more of the MD participants lost ≥ 5% of their initial weight at week 16 (93% vs. 55%) and week 40 (62% vs. 30%). There was no difference in satiety observed between the two groups during the weight loss phase. Significant improvements in body composition were also observed in MD participants compared to FB at week 16 and week 40. At week 40, both groups experienced improvements in biochemical outcomes and other clinical indicators.ConclusionsOur data suggest that the meal replacement diet plan evaluated was an effective strategy for producing robust initial weight loss and for achieving improvements in a number of health-related parameters during weight maintenance, including inflammation and oxidative stress, two key factors more recently shown to underlie our most common chronic diseases.Trial RegistrationClinicalTrials.gov NCT01011491
To define the role of the ␣21 integrin in pathologic angiogenesis, we investigated tumor-associated growth and angiogenesis in wild-type and ␣2-null mice. Our findings reveal that the ␣21 integrin plays an important role in angiogenesis via regulation of VEGFR1 expression. When challenged with B16F10 melanoma cells, mice lacking ␣21 integrin expression exhibit increased tumor angiogenesis associated with up-regulated VEGFR1 expression. In contrast, there was no ␣21 integrin-dependent difference in the angiogenic response to Lewis lung carcinoma (LLC) cells. Interestingly, whereas B16F10 cells secrete high levels of placental growth factor (PLGF), LLC cells produce high levels of VEGF, but low levels of PLGF. The ␣21 integrindependent difference in angiogenesis was restored to LLC cells by expression of PLGF, strongly suggesting that the angiogenic phenotype and tumor growth in the ␣2-null host is dependent on specific interactions between the tumor cell and the genetically defined integrin repertoire of the host microenvironment. Thus integrin ␣2-null mice represent an example of genetic alterations of "the soil" determining response to the "seed." (Blood. 2008; 111:1980-1988 © 2008 by The American Society of Hematology IntroductionTumor initiation and progression involve complex interactions between tumor cells and their microenvironment. 1 Integrins are expressed on both tumor cells and cells of the microenvironment where they modulate tumor initiation, progression, and angiogenesis. [2][3][4][5] Several integrins, including the ␣v3, ␣v5, ␣41, and ␣51 have been implicated in angiogenesis. [6][7][8][9] The ␣11 and ␣21 integrins, the 2 major collagen receptors, have also been implicated in the pathobiology of tumor angiogenesis. [10][11][12][13][14][15][16][17] Genetic deletion of the ␣11 integrin supported the concept that the ␣11 integrin was proangiogenic. 16,17 The ␣1-deficient mice demonstrate decreased tumor growth and angiogenesis, a finding consistent with the ␣11 integrin serving a proangiogenic function. Recent wound healing studies in wild-type and ␣21 integrin-deficient mice demonstrated that deletion of the ␣21 integrin resulted in increased neoangiogenesis, suggesting that the ␣21 integrin plays a negative role in regulating neoangiogenesis within the wounded microenvironment. 18,19 In this present study we investigated the molecular mechanisms whereby loss of the ␣21 integrin leads to increased neovascularization, particularly in the context of tumor-associated angiogenesis. We show that the ␣21 integrin plays an unexpected role in regulating tumor neoangiogenesis in vivo. Expression of the ␣21 integrin is up-regulated on endothelium within the tumor microenvironment. Unlike ␣1-null mice, ␣2-null mice exhibit increased tumor angiogenesis and consequent increased tumor growth when challenged with B16F10 melanoma cells. Increased expression of vascular endothelial cell growth factor receptor 1 (VEGFR-1) on ␣2-null endothelial cells within the tumor microenvironment is in part re...
The 2,4-D choline/glyphosate DMA formulation has reduced drift and volatility compared to the amine or ester formulation of 2,4-D and therefore is advantageous compared to a tank mix of 2,4-D amine or ester with glyphosate. The objective of this research was to compare the control of glyphosate susceptible and glyphosate resistant Canada fleabane with 2,4-D choline/glyphosate DMA with 2,4-D amine, glyphosate, and a tank mix of 2,4-D amine and glyphosate. Ten rates of 2,4-D amine (0-6708 g•ae•ha⁻¹), glyphosate (0-7052 g•ae•ha⁻¹), a tank mix of glyphosate plus 2,4-D amine (0-7052 g•ae•ha⁻¹ + 0-6708), and 2,4-D choline/glyphosate DMA (0-13760 g•ae•ha⁻¹) were examined in the greenhouse for the control of two susceptible (GS) and two resistant to glyphosate (GR) Canada fleabane biotypes. The tank mix of 2,4-D amine plus glyphosate and 2,4-D choline/glyphosate DMA provided equivalent control of the GR Canada fleabane biotypes at 35 days after the application (DAA). The 2,4-D choline/glyphosate DMA treatment was more efficacious than the tank mix on the GS biotypes. Glyphosate (880 g•ae•ha⁻¹) provided 50% and 100% control of the resistant and susceptible biotypes, respectively. The 2,4-D choline/glyphosate DMA formulation and the tankmix of 2,4-D amine and glyphosate provided similar control of GR Canada fleabane.
Glyphosate resistant (GR) Canada fleabane (horseweed) has quickly spread across southwestern Ontario and is a difficult weed to control in GR crops. Glyphosate dimethylamine (DMA)/2,4-D choline (Enlist Duo ® ™ Dow AgroSciences LLC), a new herbicide premix developed by Dow Agro Sciences, provides control of GR and other problematic weeds. The objective of this study was to compare single and sequential applications of glyphosate DMA/2,4-D choline for the control of GR Canada fleabane in GR corn. Three single applications of glyphosate (DMA)/2,4-D choline (1720 g•ae•ha −1) were evaluated: 1) preplant (PP) applied to Canada fleabane up to 10 cm diameter/height, 2) postplant 1 (POST 1) applied when Canada fleabane was up to 20 cm tall and 3) postplant 2 (POST 2) applied up to 30 cm tall Canada fleabane. Four sequential applications were also examined:1) PP followed by (fb) POST 1, 2) PP fb POST 2, 3) POST 1 fb POST 2 and 4) PP fb POST 1 fb POST 2. The single applications provided 69%-86% control of the GR Canada fleabane while the sequential applications increased control to 92%-100%. Three applications did not provide an increase in control over a sequential two-pass application at 8 weeks after the application (WAA). Results from this research indicate that a sequential 2-pass application of glyphosate DMA/2,4-D choline provided acceptable control of GR Canada fleabane in corn.
Autologous ex vivo hematopoietic stem cell gene therapy is particularly relevant in lysosomal storage diseases (LSD) as it offers the prospect of both a safe transplant, as observed in immune deficiency and hematologic illness, and an effective transplant, since it delivers greater enzyme levels to host tissues than is possible in allogeneic transplant. We report early data from such an approach in an allogeneic transplant refractory LSD, Mucopolysaccharidosis type IIIA (MPSIIIA, Sanfilippo syndrome). Background: MPSIIIA is a LSD caused by mutations in the SGSH gene leading to a deficiency of the enzyme N-sulfoglucosamine sulfohydrolase. As a result there is accumulation of heparan sulfate, with clinical manifestations of developmental delay, regression of previously acquired skills, hyperactivity, seizures and progressive cognitive decline leading to an early death at the end of the second decade of life. Unlike some other LSDs, MPSIIIA is unresponsive to allogeneic stem cell transplant (Hoogerbrugge et al., The Lancet 1995; Sivakumur & Wraith, Journal of inherited metabolic disease 1999), with the donor cells unable to deliver enough enzyme for clinically meaningful cross-correction. Significant pre-clinical work undertaken at the University of Manchester led to the design of the lentiviral vector containing the SGSH gene and a CD11b (myeloid) promoter. In murine studies MPSIIIA mice underwent stem cell mobilization and collection and stem cells were transduced with the lentiviral vector ex vivo. The mice received myeloablative busulfan before being infused with the autologous transduced stem cells. Enzyme expression in the brain was high with normalised heparan sulfate and improvement in the behavior of the mice (Sergijenko et al., Molecular Therapy 2013). Transduction and transplant of human CD34+ stem cells to humanized NSG mice demonstrated stable engraftment with no evidence of viral shedding or transformational potential (Ellison et al., Molecular Therapy-Methods & Clinical Development 2019), further adding to the safety profile and the translation of this work to the clinic. Study Design and Methods: This is a phase I/II safety and tolerability study. It is open-label and aims to recruit up to 5 patients. Patients enrolled into the trial are between the age of 3 and 24 months, have confirmed classical MPSIIIA (either by known genotypes, somatic features or family history) and have preserved neurocognitive function (DQ ≥80) before commencing the trial. Patients undergo stem cell mobilization and peripheral collection of CD34+ cells. The SGSH gene under the CD11b promoter is introduced by the lentiviral vector. Patients then receive myeloablative busulfan before infusion of the autologous transduced stem cells. Follow up takes place over 3 years. The primary end point is to assess the safety and tolerability of the transduced stem cell product. The primary efficacy endpoint is SGSH activity in leukocytes at 12 months. Several secondary and exploratory end points are also to be reported including neurocognitive outcomes. Current trial status: We report the preliminary data of the first treated patient recruited to the trial including the mobilization, transplant and sustained engraftment of gene-modified cells by vector copy number. Supra-physiological enzyme expression in multiple lineages - 150 fold increase above median in leukocytes and 200 fold increase above control in myeloid lineage - and substrate reduction in plasma, CSF and urine - reduced in urine to normal range by 3 months - has been observed. Disclosures Bigger: Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thrasher:Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jones:Orchard Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.
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