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1.  The effect of scan parameters on cone beam CT trabecular bone microstructural measurements of the human mandible 
Dentomaxillofacial Radiology  2013;42(10):20130206.
The objective of this study was to investigate the effect of different cone beam CT scan parameters on trabecular bone microstructure measurements. A human mandibular cadaver was scanned using a cone beam CT (3D Accuitomo 170; J.Morita, Kyota, Japan). 20 cone beam CT images were obtained using 5 different fields of view (4×4 cm, 6×6 cm, 8×8 cm, 10×10 cm and 10×5 cm), 2 types of rotation steps (180° and 360°) and 2 scanning resolutions (standard and high). Image analysis software was used to assess the trabecular bone microstructural parameters (number, thickness and spacing). All parameters were measured twice by one trained observer. Intraclass correlation coefficients showed high intraobserver repeatability (intraclass correlation coefficient, 0.95–0.97) in all parameters across all tested scan parameters. Trabecular bone microstructural measurements varied significantly, especially in smaller fields of view (p = 0.001). There was no significant difference in the trabecular parameters when using different resolutions (number, p = 0.988; thickness, p = 0.960; spacing, p = 0.831) and rotation steps (number, p = 1.000; thickness, p = 0.954; spacing, p = 0.759). The scan field of view significantly influences the trabecular bone microstructure measurements. Rotation steps (180° or 360°) and resolution (standard or high) selections are not relevant.
doi:10.1259/dmfr.20130206
PMCID: PMC3853518  PMID: 24132024
cone beam CT; trabecular bone; diagnostic imaging; scanning parameter
2.  Field-derived Schistosoma mansoni and Biomphalaria pfeifferi in Kenya: a compatible association characterized by lack of strong local adaptation, and presence of some snails able to persistently produce cercariae for over a year 
Parasites & Vectors  2014;7(1):533.
Background
Schistosoma mansoni is widely distributed in sub-Saharan Africa with Biomphalaria pfeifferi being its most widespread and important snail intermediate host. Few studies have examined the compatibility of field-derived B. pfeifferi snails with S. mansoni miracidia derived from human hosts. We investigated compatibility (as defined by shedding of cercariae following exposure to miracidia) of two isolates of S. mansoni from school children from Asao (western Kenya) and Mwea (central Kenya) with B. pfeifferi collected directly from Asao stream or the Mwea rice fields.
Methods
We exposed snails from both regions to four different doses of miracidia (1, 5, 10 and 25) from sympatric or allopatric S. mansoni, and maintained them in a shaded, screened out-of-doors rearing facility in Kisian, in western Kenya. Both snail survival and the number of snails that became infected were monitored weekly. This was done for 25 weeks post-exposure (PE). Those infected snails which survived beyond this period were monitored until they all died.
Results
Although overall survival of Mwea snails maintained in western Kenya was generally low, both sympatric and allopatric combinations of parasites and snails exhibited high compatibility (approximately 50% at a dose of one miracidium per snail), with an increase in infection rates as the miracidial dose was increased (P < 0.002). Schistosomes were no more compatible with sympatric than allopatric snails, nor were snails less compatible with sympatric than allopatric schistosomes. Snail mortality increased significantly with dose of miracidia (P < 0.05). Approximately 3% of Asao snails exposed to a low dose of sympatric miracidia (1 or 5) continued to shed cercariae for as long as 58 weeks post exposure.
Conclusions
There were no significant local adaptation effects for either schistosomes or snails. Also, the existence of “super-survivor” snails is noteworthy for its implications for current control initiatives that mostly rely on mass drug administration (MDA). Long-term shedders could provide an ongoing source of cercariae to initiate human infections for many months, suggesting care is required in considering how human MDA treatments are timed. Future control programs should incorporate means to eliminate infected snails to complement chemotherapy interventions in controlling schistosomiasis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-014-0533-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13071-014-0533-3
PMCID: PMC4253995  PMID: 25425455
Schistosomiasis; Host-parasite interactions; Compatibility; Biomphalaria pfeifferi; Schistosoma mansoni; Super-sursvivor snails; Local adaptation; Parasite transmission
3.  No Apparent Reduction in Schistosome Burden or Genetic Diversity Following Four Years of School-Based Mass Drug Administration in Mwea, Central Kenya, a Heavy Transmission Area 
Background
Schistosomiasis is a debilitating neglected tropical disease that infects over 200 million people worldwide. To combat this disease, in 2012, the World Health Organization announced a goal of reducing and eliminating transmission of schistosomes. Current control focuses primarily on mass drug administration (MDA). Therefore, we monitored transmission of Schistosoma mansoni via fecal egg counts and genetic markers in a typical school based MDA setting to ascertain the actual impacts of MDA on the targeted schistosome population.
Methods
For 4 years, we followed 67 children enrolled in a MDA program in Kenya. Infection status and egg counts were measured each year prior to treatment. For 15 of these children, for which there was no evidence of acquired resistance, meaning they became re-infected following each treatment, we collected microsatellite genotype data from schistosomes passed in fecal samples as a representation of the force of transmission between drug treatments. We genotyped a total of 4938 parasites from these children, with an average of 329.2 parasites per child for the entire study, and an average of 82.3 parasites per child per annual examination. We compared prevalence, egg counts, and genetic measures including allelic richness, gene diversity (expected heterozygosity), adult worm burdens and effective number of breeders among time points to search for evidence for a change in transmission or schistosome populations during the MDA program.
Findings
We found no evidence of reduced transmission or schistosome population decline over the course of the program. Although prevalence declined in the 67 children as it did in the overall program, reinfection rates were high, and for the 15 children studied in detail, schistosome egg counts and estimated adult worm burdens did not decline between years 1 and 4, and genetic diversity increased over the course of drug treatment.
Interpretation
School based control programs undoubtedly improve the health of individuals; however, our data show that in an endemic area, such a program has had no obvious effect on reducing transmission or of significantly impacting the schistosome population as sampled by the children we studied in depth. Results like these, in combination with other sources of information, suggest more integrated approaches for interrupting transmission and significantly diminishing schistosome populations will be required to achieve sustainable control.
Author Summary
Schistosomiasis is a chronic and debilitating disease. Current control focuses primarily on mass drug administration (MDA). We monitored schistosome transmission via fecal egg counts and genetic markers in a school based MDA setting to learn how the intervention was influencing transmission or the targeted schistosome population. For 4 years, we followed 67 children enrolled in a MDA program in Kenya, and for 15 of these, we repeatedly acquired in depth genetic data regarding the schistosome populations they harbored. Although prevalence declined in the 67 children, we found no evidence of reduced egg counts/worm burdens in those that reacquired infections and genetic diversity of schistosomes increased over the course of treatment. Our data indicate that this school based MDA program had a strong benefit to individual health as fewer children were infected over time. However, this decline does not appear to be due to schistosome population reduction, and may be caused by either acquired resistance or behavioral changes of the children. In conclusion, control programs based on chemotherapy alone or based on only a subset of the population will need to be supplemented with additional approaches if we are to achieve the WHO goal of eliminating human schistosomiasis by 2025.
doi:10.1371/journal.pntd.0003221
PMCID: PMC4191953  PMID: 25299057
4.  Praziquantel sensitivity of Kenyan Schistosoma mansoni isolates and the generation of a laboratory strain with reduced susceptibility to the drug 
Highlights
•We isolated S. mansoni miracidia from 72 Kenyan adults and children.•We found no evidence of S. mansoni with reduced praziquantel sensitivity.•An S. mansoni lab isolate with reduced praziquantel sensitivity was established.•The potential for the emergence of praziquantel resistance remains.
Schistosomiasis is a neglected tropical disease caused by blood-dwelling flukes of the genus Schistosoma. While the disease may affect as many as 249 million people, treatment largely relies on a single drug, praziquantel. The near exclusive use of this drug for such a prevalent disease has led to concerns regarding the potential for drug resistance to arise and the effect this would have on affected populations. In this study, we use an in vitro assay of drug sensitivity to test the effect of praziquantel on miracidia hatched from eggs obtained from fecal samples of Kenyan adult car washers and sand harvesters as well as school children. Whereas in a previous study we found the car washers and sand harvesters to harbor Schistosoma mansoni with reduced praziquantel sensitivity, we found no evidence for the presence of such strains in any of the groups tested here. Using miracidia derived from seven car washers to infect snails, we used the shed cercariae to establish a strain of S. mansoni with significantly reduced praziquantel sensitivity in mice. This was achieved within 5 generations by administering increasing doses of praziquantel to the infected mice until the parasites could withstand a normally lethal dose. This result indicates that while the threat of praziquantel resistance may have diminished in the Kenyan populations tested here, there is a strong likelihood it could return if sufficient praziquantel pressure is applied.
doi:10.1016/j.ijpddr.2014.09.006
PMCID: PMC4266778  PMID: 25516840
Praziquantel; Schistosoma; Drug resistance; Miracidia; Schistosomiasis; Helminths
5.  Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations 
Clinical & experimental metastasis  2013;30(5):10.1007/s10585-013-9567-8.
The aim of this study was to compare the time-to progression and overall survival (OS) in patients with metastatic breast cancer (MBC) with and without deleterious BRCA1/2 mutations. 195 women with MBC who were referred for BRCA genetic testing between 1997 and 2011 were included in the study. Logistic regression models and Cox proportional hazards models were fit to determine the associations between clinical variables and outcomes. Of 195 women with MBC, 21 % (n = 41) were positive for BRCA1/2 mutations. The number of metastatic sites at the time of metastatic disease was not different between BRCA1 versus BRCA2 carriers versus non-carriers (P = 0.77). The site of first metastasis was visceral-only in 70 % of BRCA1 carriers compared to 9 % in BRCA2 carriers and 37 % in non-carriers (P = 0.001). Median follow-up was 2.8 years. BRCA non-carriers and BRCA2 carriers had a longer time-to progression and OS compared to BRCA1 carriers (median time-to progression = 1.3 vs. 0.9 vs. 0.7 years; P = 0.31, and median OS = 4.88 vs. 4.94 vs. 1.34 years; P = 0.0065). In a multivariate model, no association was identified between BRCA positivity and time-to-event outcomes (P > 0.28). In addition, patients with triple-negative MBC carried a poorer prognosis irrespective of their BRCA status (P = 0.058 and P = 0.15 for the interaction term of BRCA status and triple-negative for time-to progression and OS, respectively). Our data indicate that BRCA1 carriers diagnosed with MBC have worse outcomes compared to BRCA2 carriers and non-carriers. However, the differences in outcome did not reach statistical significance likely due to small sample sizes.
doi:10.1007/s10585-013-9567-8
PMCID: PMC3857726  PMID: 23370825
BRCA mutation; Chemotherapy; Metastatic breast cancer; Recurrence; Survival
6.  Diagnostic imaging of trabecular bone microstructure for oral implants: a literature review 
Dentomaxillofacial Radiology  2013;42(3):20120075.
Several dental implant studies have reported that radiographic evaluation of bone quality can aid in reducing implant failure. Bone quality is assessed in terms of its quantity, density, trabecular characteristics and cells. Current imaging modalities vary widely in their efficiency in assessing trabecular structures, especially in a clinical setting. Most are very costly, require an extensive scanning procedure coupled with a high radiation dose and are only partially suitable for patient use. This review examines the current literature regarding diagnostic imaging assessment of trabecular microstructure prior to oral implant placement and suggests cone beam CT as a method of choice for evaluating trabecular bone microstructure.
doi:10.1259/dmfr.20120075
PMCID: PMC3667540  PMID: 23420864
dental implants; cone beam CT; microstructure
7.  Influence of cone beam CT scanning parameters on grey value measurements at an implant site 
Dentomaxillofacial Radiology  2013;42(3):79884780.
Objectives:
The aim of this study was to determine the grey value variation at the implant site with different scan settings, including field of view (FOV), spatial resolution, number of projections, exposure time and dose selections in two cone beam CT (CBCT) systems and to compare the results with those obtained from a multislice CT system.
Methods:
A partially edentulous human mandibular cadaver was scanned by three CT modalities: multislice CT (MSCT) (Philips, Best, the Netherlands), and two CBCT systems: (Accuitomo 170®, Morita, Japan) and (NewTom 5G®, QR, Verona, Italy). Using different scan settings 36 and 24 scans were obtained from the Accuitomo and the NewTom, respectively. The scans were converted to digital imaging and communications in medicine 3 format. The analysis of the data was performed using 3Diagnosys® software (v. 3.1, 3diemme, Cantù, Italy) and Geomagic studio® 2012 (Morrisville, NC). On the MSCT scan, one probe designating the site for pre-operative implant placement was inserted. The inserted probe on MSCT was transformed to the same region on each CBCT scan using a volume-based three-dimensional registration algorithm. The mean voxel grey value of the region around the probe was derived separately for each CBCT. The influence of scanning parameters on the measured mean voxel grey values was assessed.
Results:
Grey values in both CBCT systems significantly deviated from Hounsfield unit values measured with MSCT (p = 0.0001). In both CBCT systems, scan FOV and spatial resolution selections had a statistically significant influence on grey value measurements (p = 0.0001). The number of projections selection had a statistically significant influence in the Accuitomo system (p = 0.0001) while exposure time and dose selections had no statistically significant influence on grey value measurements in the NewTom (p = 0.43 and p = 0.37, respectively).
Conclusions:
Grey-level values from CBCT images are influenced by device and scanning settings.
doi:10.1259/dmfr/79884780
PMCID: PMC3667541  PMID: 22933535
cone beam CT; registration; grey values; bone density
8.  Multiplex PCR in Determination of Opiinae Parasitoids of Fruit Flies, Bactrocera sp., Infesting Star Fruit and Guava 
Malaysia is a tropical country that produces commercial fruits, including star fruits, Averrhoa carambola L. (Oxalidales: Oxalidaceae), and guavas, Psidium guajava L. (Myrtales: Myrtaceae). There is a high demand for these fruits, and they are planted for both local consumption and export purposes. Unfortunately, there has been a gradual reduction of these fruits, which has been shown to be related to fruit fly infestation, especially from the Bactrocera species. Most parasitic wasps (Hymenoptera: Braconidae: Opiinae) are known as parasitoids of fruit fly larvae. In this study, star fruits and guavas infested by fruit fry larvae were collected from the Malaysian Agricultural Research and Development Institute. The parasitized larvae were reared under laboratory conditions until the emergence of adult parasitoids. Multiplex PCR was performed to determine the braconid species using two mitochondrial DNA markers, namely cytochrome oxidase subunit I and cytochrome b. Two benefits of using multiplex PCR are the targeted bands can be amplified simultaneously using the same reaction and the identification process of the braconid species can be done accurately and rapidly. The species of fruit flies were confirmed using the COI marker. The results obtained from our study show that Diachasmimorpha longicaudata (Ashmead) (Hymenoptera: Braconidae), Fopius arisanus (Sonan), and Pysttalia incisi (Silvestri) were parasitoids associated with Bactrocera carambolae (Drew and Hancock) (Diptera: Tephritidae) infested star fruits. Fopius arisanus was also the parasitoid associated with Bactrocera papayae (Drew and Hancock) infested guavas. Maximum parsimony was been constructed in Opiinae species to compare tree resolution between these two genes in differentiating among closely related species. The confirmation of the relationship between braconids and fruit fly species is very important, recognized as preliminary data, and highly necessary in biological control programs.
doi:10.1673/031.014.07
PMCID: PMC4199358  PMID: 25373154
biological control programs; braconids; parasitic wasps
9.  Non-Invasive Sampling of Schistosomes from Humans Requires Correcting for Family Structure 
For ethical and logistical reasons, population-genetic studies of parasites often rely on the non-invasive sampling of offspring shed from their definitive hosts. However, if the sampled offspring are naturally derived from a small number of parents, then the strong family structure can result in biased population-level estimates of genetic parameters, particularly if reproductive output is skewed. Here, we document and correct for the strong family structure present within schistosome offspring (miracidia) that were collected non-invasively from humans in western Kenya. By genotyping 2,424 miracidia from 12 patients at 12 microsatellite loci and using a sibship clustering program, we found that the samples contained large numbers of siblings. Furthermore, reproductive success of the breeding schistosomes was skewed, creating differential representation of each family in the offspring pool. After removing the family structure with an iterative jacknifing procedure, we demonstrated that the presence of relatives led to inflated estimates of genetic differentiation and linkage disequilibrium, and downwardly-biased estimates of inbreeding coefficients (FIS). For example, correcting for family structure yielded estimates of FST among patients that were 27 times lower than estimates from the uncorrected samples. These biased estimates would cause one to draw false conclusions regarding these parameters in the adult population. We also found from our analyses that estimates of the number of full sibling families and other genetic parameters of samples of miracidia were highly intercorrelated but are not correlated with estimates of worm burden obtained via egg counting (Kato-Katz). Whether genetic methods or the traditional Kato-Katz estimator provide a better estimate of actual number of adult worms remains to be seen. This study illustrates that family structure must be explicitly accounted for when using offspring samples to estimate the genetic parameters of adult parasite populations.
Author Summary
Genetic epidemiology uses genetic data to uncover patterns of disease processes. To acquire data for these analyses, individual pathogens are collected and scored at genetic markers, and the resultant data are analyzed to infer biological patterns about the pathogen populations. In lieu of invasive sampling of adult pathogens in humans, researchers have relied on non-invasive sampling of parasite offspring (often shed in fecal samples). One potential problem with this approach is that analyses using the offspring data will be biased because many of the offspring are related and family sizes are likely to be unequal. We show that this sampling issue is relevant in a natural transmission zone in western Kenya and that it yields biases in three important parameters: genetic differentiation, inbreeding coefficients, and estimates of the amount of non-random association between loci (linkage disequilibrium). We also develop a method to remove these biases by removing the sibling structure present in the dataset. Finally, we suggest that our measure of family number, as well as other genetic measures, may be useful measures of the worm burdens in patients.
doi:10.1371/journal.pntd.0002456
PMCID: PMC3777896  PMID: 24069499
10.  Polymorphism associated with the Schistosoma mansoni tetraspanin-2 gene 
International journal for parasitology  2011;41(12):1249-1252.
A vaccine against schistosomiasis would contribute significantly to reducing the 3-70 million disability-adjusted life years lost annually to the disease. Towards this end, inoculation with the large extracellular loop (EC-2) of Schistosoma mansoni tetraspanin-2 protein (Sm-TSP-2) has proved effective in reducing worm and egg burdens in S. mansoni-infected mice. The EC-2 loop of S. japonicum TSP-2, however, has been found to be highly polymorphic, perhaps diminishing the likelihood that this antigen can be used for vaccination against this species. Here, we examine polymorphism of the EC-2 of Sm-TSP-2 in genetically unique worms derived from six individuals from Kisumu, Kenya.
doi:10.1016/j.ijpara.2011.07.007
PMCID: PMC3188324  PMID: 21889508
Schistosoma; Polymorphism; Tetraspanin-2; Genotype; Kozak sequence; Vaccine
11.  Effect of novel water soluble curcumin derivative on experimental type- 1 diabetes mellitus (short term study) 
Background
Diabetes mellitus type 1 is an autoimmune disorder caused by lymphocytic infiltration and beta cells destruction. Curcumin has been identified as a potent inducer of heme-oxygenase-1 (HO-1), a redoxsensitive inducible protein that provides protection against various forms of stress. A novel water soluble curcumin derivative (NCD) has been developed to overcome low in vivo bioavailability of curcumin. The aim of the present work is to evaluate the anti diabetic effects of the “NCD” and its effects on diabetes-induced ROS generation and lipid peroxidation in experimental type- 1 diabetes mellitus. We also examine whether the up regulation of HO-1 accompanied by increased HO activity mediates these antidiabetic and anti oxidant actions.
Materials and methods
Rats were divided into control group, control group receiving curcumin derivative, diabetic group, diabetic group receiving curcumin derivative and diabetic group receiving curcumin derivative and HO inhibitor ZnPP. Type-1 diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin derivative was given orally for 45 days. At the planned sacrification time (after 45 days), fasting blood samples were withdrawn for estimation of plasma glucose, plasma insulin and lipid profile . Animals were sacrificed; pancreas, aorta and liver were excised for the heme oxygenase - 1 expression, activity and malondialdehyde estimation.
Results
NCD supplementation to diabetic rats significantly lowered the plasma glucose by 27.5% and increased plasma insulin by 66.67%. On the other hand, the mean plasma glucose level in the control group showed no significant difference compared to the control group receiving the oral NCD whereas, NCD supplementation to the control rats significantly increased the plasma insulin by 47.13% compared to the control. NCD decreased total cholesterol, triglycerides, LDL cholesterol and increased HDL cholesterol levels. Also, it decreased lipid peroxides (malondialdehyde) in the pancreas, aorta and liver.
Conclusion
The (NCD) by its small dose possesses antidiabetic actions and that heme oxygenase induction seems to play an important role in its anti-diabetic effects. NCD also improves the lipid profile and oxidative status directly, proved by decreasing lipid peroxides (malondialdehyde) in pancreas, liver & aorta. The new water soluble curcumin derivative still retains the essential potencies of natural curcumin.
doi:10.1186/1758-5996-4-30
PMCID: PMC3533893  PMID: 22762693
Diabetes Type 1; Heme oxygenase −1; Curcumin; Insulin secretion; Oxidative stress
12.  Diffuse Large B-Cell Lymphoma Transformed from Mucosa-Associated Lymphoid Tissue Lymphoma Arising in a Female Urethra Treated with Rituximab for the First Time 
Case Reports in Oncology  2012;5(2):238-245.
A 30-year-old female patient presented to the gynecology clinic with a small (painless) swelling at the urethral orifice. She underwent surgical excision of the lesion. Pathological examination revealed non-Hodgkin's lymphoma of diffuse large B-cell type and mucosa-associated lymphoid tissue type, stage IE. The patient refused radiotherapy. Accordingly, we started CHOP-R chemotherapy. She received a total of 6 cycles of CHOP and 8 cycles of rituximab. Patient follow-up was done 3 months later through CT scan and cytoscopy confirming the complete remission. The patient has been disease-free for 4 years. We reviewed 26 cases of this rare entity reported previously.
doi:10.1159/000333357
PMCID: PMC3369256  PMID: 22679430
Urethra; NHL; Chemotherapy; Malignant lymphoma; Female urethra; CHOP-R chemotherapy
13.  (E)-2-(3-Cinnamoyl­thio­ureido)acetic acid dimethyl sulfoxide disolvate 
In the title compound, C12H12N2O3S·2C2H6OS, the acetic acid and cinnamoyl groups adopt Z and E configurations, respectively, with respect to the thio group about the C—N bonds. The components of the asymmetric unit are connected by N—H⋯O and O—H⋯O hydrogen bonds and in the crystal weak inter­molecular C—H⋯O and C—H⋯S hydrogen bonds further connect the components into chains along the b axis. In the main mol­ecule, an intra­molecular N—H⋯O hydrogen bond is also present.
doi:10.1107/S1600536811036750
PMCID: PMC3201284  PMID: 22058788
14.  3-(3-Meth­oxy­benzo­yl)-1,1-diphenyl­thio­urea 
The thiono and carbonyl groups in the title compound, C21H18N2O2S, adopt an anti disposition with respect to the central C—N bond. The diphenyl­amine rings are twisted relative to each other by a dihedral angle of 82.55 (10)°. The 3-meth­oxy­benzoyl fragment is twisted relative to one of the diphenyl­amine rings, forming a dihedral angle of 74.04 (9)°. In the crystal, pairs of inter­molecular N—H⋯S hydrogen bonds link the mol­ecules into centrosymmetric dimers, forming columns parallel to the a axis.
doi:10.1107/S1600536811025785
PMCID: PMC3212333  PMID: 22090990
15.  1,1-Dibenzyl-3-(4-fluoro­benzo­yl)thio­urea 
In the title compound, C22H19FN2OS, the 2-fluoro­benzoyl group adopts a trans conformation with respect to the thiono S atom across the N—C bond. In the crystal, inter­molecular N—H⋯S, C—H⋯S and C—H⋯O hydrogen bonds link the mol­ecules, forming a two-dimensional network parallel to (101).
doi:10.1107/S1600536811026687
PMCID: PMC3213443  PMID: 22091022
16.  Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice 
Oncogene  2009;28(23):2289-2298.
BRAF, a cellular oncogene and effector of RAS-mediated signaling, is activated by mutation in ~60% of melano-mas. Most of these mutations consist of a V600E substitution resulting in constitutive kinase activation. Mutant BRAF thus represents an important therapeutic target in melanoma. In an effort to produce a pre-clinical model of mutant BRAF function in melanoma, we have generated a mouse expressing BRAF V600E targeted to melanocytes. We show that in these transgenic mice, widespread benign melanocytic hyperplasia with histolo-gical features of nevi occurs, with biochemical evidence of senescence. Melanocytic hyperplasia progresses to overt melanoma with an incidence dependent on BRAF expression levels. Melanomas show CDKN2A loss, and genetic disruption of the CDKN2A locus greatly enhances melanoma formation, consistent with collaboration between BRAF activation and CDKN2A loss suggested from studies of human melanoma. The development of melanoma also involves activation of the Mapk and Akt signaling pathways and loss of senescence, findings that faithfully recapitulate those seen in human melanomas. This murine model of mutant BRAF-induced melanoma formation thus provides an important tool for identifying further genetic alterations that cooperates with BRAF and that may be useful in enhancing susceptibility to BRAF-targeted therapeutics in melanoma.
doi:10.1038/onc.2009.95
PMCID: PMC3125533  PMID: 19398955
BRAF; p53; CDKN2A; AKT; melanoma; senescence
17.  1,1-Dibenzyl-3-(3-chloro­benzo­yl)thio­urea 
In the title compound, C22H19ClN2OS, the thiono and carbonyl groups are trans positioned with respect to a partially double C—N bond. The amide group is twisted relative to the thio­urea fragment, forming a dihedral angle of 46.75 (11)°. In the crystal, inter­molecular N—H⋯S and C—H⋯O hydrogen bonds link the mol­ecules into a one-dimensional polymeric structure parallel to the c axis.
doi:10.1107/S1600536811023191
PMCID: PMC3151829  PMID: 21837130
18.  2-Bromo-N-(dibenzyl­carbamothioyl)benzamide 
The 2-bromo­benzoyl group in the title compound, C22H19BrN2OS, adopts an E conformation with respect to the thiono S atom across the N—C bond. In the crystal structure, the mol­ecule is stablized by N—H⋯O inter­molecular hydrogen bonds, forming a one-dimensional chain along the b axis.
doi:10.1107/S1600536811014711
PMCID: PMC3089282  PMID: 21754516
19.  Methyl 3-(3-benzoyl­thio­ureido)propano­ate 
In the title compound, C12H14N2O3S, the propyl acetate group and the benzoyl group adopt a cis–trans conformation, respectively, with respect to the thiono S atom across the C—N bonds. The phenyl ring is twisted relative to the the thio­urea mean plane, forming a dihedral angle of 24.16 (9)°. An intra­molecular N—H⋯O hydrogen bond occurs. The crystal packing is stabilized by inter­molecular N—H⋯O and C—H⋯O hydrogen bonds, forming a chain along the a axis.
doi:10.1107/S160053681100568X
PMCID: PMC3100062  PMID: 21754071
20.  Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer 
British Journal of Cancer  2010;102(5):827-832.
Background:
HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model.
Method:
Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg−1. Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set.
Results:
A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion.
Conclusion:
A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody.
doi:10.1038/sj.bjc.6605560
PMCID: PMC2833251  PMID: 20160731
HuHMFG1; AS1402; population pharmacokinetic; antibody; linear two-compartment; breast cancer
21.  ABNORMAL SENSORIMOTOR PLASTICITY IN ORGANIC BUT NOT IN PSYCHOGENIC DYSTONIA 
Brain : a journal of neurology  2009;132(Pt 10):2871-2877.
Dystonia is characterised by two main pathophysiological abnormalities: reduced excitability of inhibitory systems at many levels of the sensorimotor system, and increased plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short interval intracortical inhibition, SICI) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation, PAS) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.
doi:10.1093/brain/awp213
PMCID: PMC2997979  PMID: 19690095
associative plasticity; organic dystonia; psychogenic dystonia; paired associative stimulation; transcranial magnetic stimulation
22.  Cinnamoyl­thio­urea 
In the title compound [systematic name: 1-(3-phenyl­prop-2-eno­yl)thio­urea], C10H10N2OS, the acetyl­thio­urea fragment and the phenyl ring adopt an E configuration. The roughly planar but-2-enoyl­thio­urea fragment [maximum deviation = 0.053 (3) Å] forms a dihedral of 10.54 (11)° with the phenyl ring. An intra­molecular N—H⋯O hydrogen bond generates an S(6) ring. In the crystal, mol­ecules are linked into sheets parallel to (100) by N—H⋯S hydrogen bonds.
doi:10.1107/S1600536810040018
PMCID: PMC3009376  PMID: 21588993
23.  (E)-Ethyl 2-(3-cinnamoyl­thio­ureido)acetate 
In the title compound, C14H16N2O3S, the phenyl ring and the ethyl 2-(3-formyl­thio­ureido)acetate fragment adopt an E configuration with respect to the C=C bond. An intra­molecular N—H⋯O hydrogen bond generating an S(6) ring motif is observed. In the crystal, mol­ecules are linked by N—H⋯S, C—H⋯S and C—H⋯O hydrogen bonds, forming sheets lying parallel to the ab plane.
doi:10.1107/S1600536810037918
PMCID: PMC3009106  PMID: 21588982
24.  (E)-Methyl 2-(3-cinnamoyl­thio­ureido)acetate 
In the title compound, C13H14N2O3S, the methyl 2-(3-formyl­thio­ureido)acetate fragment and the phenyl ring adopt an E configuration. The mol­ecule exhibits an intra­molecular N—H⋯O hydrogen bond, which completes a six-membered ring. The crystal packing is stabilized by inter­molecular N—H⋯S contacts, generating a two-dimensional hydrogen-bonding network.
doi:10.1107/S1600536810030084
PMCID: PMC3007976  PMID: 21588609
25.  1,1′-Diphenyl-3,3′-(p-phenyl­enedicarbon­yl)dithio­urea 
The mol­ecule of the title compound, C22H18N4O2S2, lies across a crystallographic inversion centre. The central benzene ring forms dihedral angles of 29.39 (9) and 79.11 (12)°, respectively, with the thio­urea unit and the terminal phenyl ring. Intra­molecular N—H⋯O hydrogen bonds generate two S(6) ring motifs. In the crystal, mol­ecules are linked into chains along [10] by inter­molecular N—H⋯S hydrogen bonds.
doi:10.1107/S1600536809055834
PMCID: PMC2979780  PMID: 21579744

Results 1-25 (53)