Human embryonic stem cells: A potential source for cellular therapy

Many degenerative human diseases reflect damage to cells that are not normally repaired or replaced, such as diabetes, Parkinson's disease, hepatic failure and congestive heart failure. Preliminary studies in animals and humans have suggested that these diseases may be treatable by transplantation of healthy cells. Such cells may be obtained by in vitro culture of embryonic stem cells, which are capable of differentiating into many cell types. This review discusses applicative approaches for the derivation, maintenance and safety of human embryonic stem (hES) cells as well as ethical concerns surrounding their possible source for cellular therapy. hES cells offer broad application in cellular therapy; however, this review specifically emphasizes on cardiovascular repair, generation and characterization of hES cell-derived cardiomyocytes, vascular progenitors and differentiation of derivatives.     

Pharmacological evidence, using in vivo dialysis, that substances additional to ascorbic acid, uric acid and homovanillic acid contribute to the voltammetric signals obtained in unrestrained rats from chronically implanted carbon paste electrodes

In vivo voltammetry at chronically implanted carbon paste electrodes in unrestrained rats is a particularly useful technique for evaluating neurochemical changes during spontaneous behaviour, or behaviour under experimental control. A 3 peak signal is observed in the striatum; most recently the consensus view has attributed these peaks to ascorbic acid (AA), uric acid (UA) and homovanillic acid (HVA) in ascending order of oxidation potential. We have used a pharmacological approach, combined with in vivo dialysis, to further elucidate the nature of the contributing species. Allopurinol, an inhibitor of xanthine oxidase, and thus of uric acid production, has previously been reported to abolish peak 2. We now report, using dialysis, that it selectively depletes UA in the extracellular fluid (ECF). Pargyline, a monoamine oxidase inhibitor, reduces peak 3 transiently (max. 60%) as expected, however it results in a more sustained reduction in ECF HVA (max. 100%). It also increases peak 1 (max. 75%) and decreases peak 2 (max. 40%), although changes in ECF AA and UA measured by dialysis and HPLC are minimal. Pargyline does however reduce ECF 5-hydroxyindoleacetic acid by 65%. We conclude that, using linear sweep voltammetry at chronically implanted paste electrodes: (a) one or more substances in addition to AA can contribute to peak 1; dopamine can do so in some situations; (b) 5-hydroxyindoleacetic acid, as well as UA, contributes to peak 2; its contribution is about one third that of the latter; and (c) one or more substances in addition to HVA can contribute to peak 3. 3-Methoxytyramine can do so. Since this is another methylated metabolite of dopamine, this does not prevent the use of peak 3 as an index of dopamine metabolism, and may extend its usefulness to situations where monoamine oxidase is inhibited.     

Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

Economics in pediatric type 1 diabetes - results from recently published studies.

OBJECTIVE: Type 1 diabetes in childhood is increasing worldwide. Several therapy components and models of pediatric diabetes care have been introduced. Economic aspects are of increasing interest to decide appropriate strategies in clinical practice. However, knowledge in pediatric diabetes is limited. METHODS: We conducted a literature research to identify and describe systematically recently published analyses on the economics of pediatric diabetes. RESULTS: We substracted ten analyses. Four were cost of illness studies. The main result is that hospitalization, mainly due to metabolic control, education, and acute complications, seems to be a large cost component. Only one study took the perspective of society, including indirect costs. Four of the six studies which evaluated interventions in pediatric diabetes care focussed on ambulatory or home care strategies. Detailed evaluation of new technologies, pharmacotherapy, or screening for late complications is lacking. Except one, all studies performed cost comparison analyses. Evidence is limited, however, diabetes care models may be effective and, possibly, cost saving compared to routine care. CONCLUSIONS: Health economic studies in pediatric diabetes are scarse and limited with respect to topics and quality. Hospitalization has a large impact on health care costs in diabetic children and adolescents. Models in pediatric diabetes care like home intervention may be cost effective compared to more traditional strategies of care. However, further studies are warranted which evaluate clinical and cost effectiveness in pediatric diabetes.     

Carcinoma of the breast

In the differential clinical diagnosis of mammary neoplasms, adenocarcinoma can safely be excluded only after biopsy and microscopic study.In a series of 177 cases of mammary cancer treated by surgery with x-ray therapy, 30.4 per cent of the patients are alive three years or more after treatment; 18 per cent five years or longer.Only one of every four patients presents herself with a lesion still within the breast. Exclusive of Group I this results in a cure in 86.1 per cent in Group II and 15.4 per cent in Group III. The mortality rate then increases five and one-half times as spread occurs beyond the breast.The results of irradiation therapy for curative purposes in recurrent or metastatic mammary adenocarcinoma are poor.

Percentage of cure by stages.

     

48.

Radical prostatectomy versus watchful waiting in early prostate cancer: Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Bratell S, Spangberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlen BJ, Johansson JE, Scandinavian Prostate Cancer Group Study No. 4, Department of Urology, University Hospital, Uppsala, Sweden     

Joseph A. Smith M.D. 《Urologic oncology》2005,23(6):1291

     

49.

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.   总被引：4，自引：0，他引：4  

Daniel A Hamstra  Kuei C Lee  Joseph M Tychewicz  Victor D Schepkin  Bradford A Moffat  Mark Chen  Kenneth J Dornfeld  Theodore S Lawrence  Thomas L Chenevert  Brian D Ross  Juri T Gelovani  Alnawaz Rehemtulla 《Molecular therapy》2004,10(5):916-928

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

50.

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.     

Nathan J Koewler  Katie T Freeman  Ryan J Buus  Monica B Herrera  Juan M Jimenez-Andrade  Joseph R Ghilardi  Christopher M Peters  Lucy J Sullivan  Michael A Kuskowski  Jack L Lewis  Patrick W Mantyh 《Journal of bone and mineral research》2007,22(11):1732-1742

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.     

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Stage	Patients Treated	Per Cent Cures
I	1	100.0
II and IIa	40	86.1
III and IIIa	130	15.4

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.     

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.