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Samsung ST150F Review
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I have misplaced my operations manual that came with the ST150F Camera.
Is it possible to get this manual on line or to order it?
Please advise and thanks.
Marvin Holt, here is user manual pdf:
http://org.downloadcenter.samsung.com/downloadfile/ContentsFile.aspx?CDSite=UNI_RU&CttFileID=5352409&CDCttType=UM&ModelType=N&ModelName=SAMSUNG ST150F&VPath=UM/201302/20130219172806795/ST150F_ST72_English.pdf
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hd video, hd, 3 inch LCD, compact, 720p, test, hdmi, wi-fi, wireless, 5x zoom, wifi, compact camera, 25mm, 5x, 16.2 megapixel, Samsung, Samsung ST150F Review, ST150F, samsung st150f


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Crock-Pot Beef Fajitas
I love how much easier the Crock-Pot can make meals. I think it is one of the most important things about the crock. The fact I can throw … Read More »
SpringIntoSavings Pinterest Contest: Win a Kitchen-Aid Stand Mixer!
We are SO ready for winter to be over and for the warm days to be here. So let's bring on spring and… #SpringIntoSavings We have joined together… Read More »
Crock-Pot Cinnamon Sweet Roll Casserole
This was a crowd pleaser! Print Crock-Pot Cinnamon Sweet Roll Casserole Ingredients 2 8ct Packages Refrigerated Sweet Rolls 5 Eggs 2 Teaspoons Vanilla Extract 2 Teaspoons Ground Cinnamon… Read More »
Crock-Pot Pecan Pie Bread Pudding
This turned out light and tasty. Do not use waxed paper to line your crock-pot. The waxed paper actually sticks to the bottom of this. Using spray oil… Read More »
FREE Kindle Book ~ Slow Cooker Comfort Foods 150 Recipes
A great FREE Kindle Book to download today. Slow Cooker Comfort Foods 150 Recipes. I am not sure how long this will be FREE to download so double… Read More »
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Naples House Rental Photos and Description
Pool, garden, 3 bedrooms, 2 bathrooms, double garage, close to the beach, newly
Discover a oasis of rest and relaxation in our beautiful home at Queens Blvd, at Kings Lake.New renovated and re-furnished.
You can find our 150 squaremeter big house on a big garden-plot with screened and beheated pool.The community of Kings Lake is therefore awarded by its beautiful position in East-Naples. Naples is one of the most beautiful, richest and safest cities in the United States.
The long beach and the famous shopping and dining place on the 5th Avenue.The Supermarket 'Publix' is virtualy around the corner , only 0.7 mile is lying between you and Publix. Our house has got 3 Bedrooms and 2 Bathrooms equipped with a shower and a Bathtub. Our well-planed house has a lot of retreats , because the masterbedroom with its own Bathroom and its own door to the pool is divorced of the other Bedrooms by the livingroom and the kitchen, so that you could easily live there with friends and other families. Our livingroom is equipped with a relaxing couch witch have 3 electric-adjustable armchairs in addition to a big 36 zoll TV. We have 2 folding beds for up to 2 persons and you can stay them in every room, how you like.
We also offer you a 32' TV in every Bedroom and Free-WiFi connection in the house and also free calls to the local landline and a printer/fax.The Kitchen is equipped with everything you'll need.The Kitchen is directly connected to the Livingroom and the terrace with pool , so that you can easily serve food. Our Patio-set contains a big-table and chairs for up to 6 -8 People and a BBQ-Grill.
We are also offering chances for sunbathing next to the pool. The Economyroom contains a washer and a dryer.
Beach-accesoires like an umbrella , 4 chairs and some cooling-boxes are also aviable. We offer enough towels for both beach and pool.
Bedding and Dishes are also stored in the cupboards and shelfes.
The garage is big enough for your car and there stay 4 brand-new bikes for you, that you can use for free.
If you have any Questions you can call our german property manager in Naples.
- Suitability:
- Events Allowed
- Long-term Renters Welcome
- children welcome
- non smoking only
- pets not allowed
About Sylvia & Reinhard Bauch
For over 15 years we are on vacation in the U.S., initially without children on the Harley Davidson. Later, with our now almost adult children. Whether California or
Route 66, we have seen of this beautiful country quite a bit. Now, our heart is stuck here in Naples.
Sylvia & Reinhard Bauch purchased this house in 2013
Why Sylvia & Reinhard Bauch chose Naples
Our house in Queens Blvd reflects exactly what we like: complete privacy, centrally located, real America feel.
What makes this house unique
The wonderful green garden cosi pool, quiet roads and paths for walking and invite the walken. Ruck Zuck on the beach or while shopping in world-class restaurants.


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FlorenceAdd to Wishlist
Florence Photo Album Professional Series, Bound Portfolio with 12 Permanent Non Reflective Page Protectors & Inserts, 11x14", Color: Black
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Swimmer nabs monster lobster off California coastDecember 12, 2013 @ 1:51 pm
HUNTINGTON BEACH, Calif. (AP) - Joseph Ali says onlookers thought he was drunk when he dove into the nighttime waters around a Southern California pier. But he came away with a monster of a lobster and the catch of a lifetime.
Ali tells the Orange County Register ( http://bit.ly/IQe4r3) he was closing his father's business, Zack's Pier Plaza in Huntington Beach, on Monday when he saw the ocean was calm and decided to dive for dinner.
He was down about 15 feet going after a smaller lobster when he saw the giant. He says it was too big to grab properly, but it latched onto him, and he wrestled it to shore.
The lobster weighed nearly 18 pounds _ even a 5-pounder is considered trophy-sized _ and was likely at least 30 years old.
Information from: The Orange County Register, http://www.ocregister.com
(Copyright 2013 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.)
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Cassis and mint on the nose. Penetrating currant and shoe polish flavors are still quite tightly wrapped; minerally hint of lead pencil. A ripe, dense wine but still a bit hard. Finishes with firm tannins and good but not outstanding length. This is quite densely packed; the Coach Insignia, though lighter, will offer easier early drinkability.Author: Stephen Tanzer
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Keith Patrick (SHADOW KINGDOM RECORDS RECORDING ARTIST/FORMER SINISTER REALM) was blessed with a guitar at the age of 13, A year and a half he studied music theory and by the age of 16 he was playing in clubs in the mid 80's with a top 40 band by the name of "BLACK SMOKE". With a close friend that played bass and the drummer of Black Smoke, he started doing covers of Ozzy w/Randy Rhoads, Led Zeppelin, Van Halen etc. in the Lehigh Valley area. Then to later write with classical guitar studies and his influences of these great idols of his. He started an original band "MOULIN ROUGE" which have recorded professional demos (being scouted by ELEKTRA RECORDS in 1990 with the hit song "NITE TIME LOVER") and played shows in the Lehigh Valley area. After the demise of the band, he won the guitar hero contest sponsored by M.A.P.P. magazine and then soon after started the band "FUZLAND PILGRIMZ" (WWW.MYSPACE.COM/FUZLANDPILGRIMZ ) which played for three years in the early 90's in the Lehigh Valley music scene and New York City showcases. After the demise of that band, he then did two solo cds " PRAY JUDAS" and "INTEGRITY" and now his recent solo cd "KICKIN AGAINST THE GOADS"(WWW.REVERBNATION.COM/KEITHPATRICK or WWW.MYSPACE.COM/KEITHPATRICK ) which on these cds he programmed (at his studio WWW.MYSPACE.COM/KPBSTUDIOS ) a drum machine, played bass, keyboards and played all guitar parts with speed and accuracy. After that he started writing serious hard and melodic tunes. After numerous musicians, he finally found the right singer and the right drummer to form this modern day Led Zeppelin, which is now "HAPLESS CHILD" with 3 cds ( WWW.REVERBNATION.COM/HAPLESSCHILD OR WWW.MYSPACE.COM/HAPLESSCHILDMUSIC ). Then in 2009 joined "SINISTER REALM" for their 1st cd (WWW.MYSPACE.COM/ENTERTHESINISTERREALM) which is signed to shadow kingdom records and was in many european magazines such as decibel, karrang and terrorizer. Be sure to hit us up on facebook at www.facebook.com/haplesschildband OR www.facebook.com/haplesschildmusic . Thanks to all our loyal fans for listening and for all your support !!!! We are currently hard at work on our new and upcoming cd "VISIONS OF MURDER". We will keep you posted !!!!


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Flyclothing.com was started 12 years ago when the internet was just a baby! Google was only about 4 years old and retail--even with the largest stores--wasnt yet realized.
If you you like what we do here, check out our beautiful brand of fun and colorful interchangeable watches at www.fly-watches.com. We also carry all kinds of sports products at www.sloppysaz.com
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Vintage SF Forty Niners T-Shirt
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Check out this cool vintage NFL t-shirt from Junkfood Clothing. This vintage red NFL t-shirt features a retro SF Forty Niners design on a soft Poly-Cotton t-shirt. T-Shirt is 50/50 Polyester Cotton and is machine washable. Officially Licensed by the NFL.
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We're sorry but you can't collect Welcome Rewards® nights at this hotel
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The Mont Clare Boutique Apts is located in Perth City Centre, East Perth, Western Australia, Australia
The high ceilings and character features of the historic Chamber of Commerce building have been incorporated into the brand new and distinctive Mont Clare Boutique Apartments. Ultra modern in design there is a variety of spacious 1 2 and 3 bedroom apartments with a choice of 1 1.5 or 2 bathrooms available. All apartments offer well-equipped kitchens that overlook an open-plan living and dining area. The bathrooms also include a good-sized laundry. All apartments feature individually controlled reverse-cycle air-conditioning free cable television Foxtel remote control colour television direct dial ISD/STD telephone with data port and hairdryer. Mont Clare also offers a fifteen metre heated outdoor swimming pool and a professionally-equipped gymnasium. Situated underneath the recreation area is an eighty eight bay secure car park and individual lock-up storage areas for each apartment. Mont Clare represents exceptional value for money in a desirable and central apartment.
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At 1844 Restaurant, we strive to obtain the freshest grown and harvested ingredients for our menu offerings
Serving dinner Thursday, Friday and Saturday 5-10pm
New Beer And Wine List
We have just introduced our newest choices when it comes to libations. Stop in and enjoy a delicious glass of wine or refreshing pint of craft beer.
Hand picked by local Sommelier Bradley Ladik and our resident Beer Expert Liam Earl.
Historic Country Setting
Step back in time for a relaxing and delicious meal on the grounds of our 19th century farmhouse. We are currently accepting reservations for groups of any size, or just the intimate enjoyment of couples.
Call 724-845-1844 to save a table today.


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To piss pound or intensely slam into; to gyrate rapidly back and forth into another orphus.
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Local pairs team skates to fourth-place finish
Date: November 13, 2009
by: Jen Blanco | Associate Editor
The 2009 US Figure Skating National Championship Silver Medalist pairs team of Caydee Denney and Jeremy Barrett finished fourth at the 2009 NHK Trophy Nov. 5-8 in Tokyo, Japan.
The pair, who trains at the Ellenton Ice and Sports Complex, had a strong showing for the United States in one of the first competitions of the season. The NHK is part of the ISU Grand Prix of Figure Skating.
Denney and Barrett are currently on pace to be one of two pairs teams representing the United States in the upcoming 2010 Winter Olympics in Vancouver, Canada. The pair, who has only been skating together for 15 months, trains under Lyndon Johnston, a two-time Olympian, Jim Peterson, the Professional Skating Association Developmental Coach of the Year and Allison Smith.
Denney and Barrett will return to the ice in Skate Canada Nov. 19-22 in Kitchener, Ontario.
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Stuff the bus
A bus isn't just for transporting people anymore.
Freedom ringers
As Freedom Elementary celebrated Veterans Day with its annual "Let Freedom Ring" courtyard ceremony Nov. 12, there was a special treat in the crowd: original Parent-Teacher Organization member Sharri Cagle and two of her three children, Lindsey and Logan.
Help for homes
Habitat for Humanity is known for building homes for families.


text: The 10 best Google Android applications Find out which applications scored the top prizes in Google's open source development project Brad Reed (Network World) 0 - - - - print email prev next Loading... Compare Everywhere This application is very similar to GoCart, in that it uses Android's built-in camera to scan barcodes and compare prices for products at different retail outlets. It also lets customers rate products to see how quality and long-lasting they are, and to create shopping lists a la Amazon.com. This application was created by Jeffrey Sharkey. Prev Next 2/12 Comments on this image There are currently no comments for this image. Post new comment Comment Name Email (This will be kept private) Users posting comments agree to the PC World comments policy. Login or register to link comments to your user profile, or you may also post a comment without being logged in. Close The 10 best Google Android applications 12 images


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Connective tissue growth factor (CTGF) is widely thought to promote the development of fibrosis in collaboration with transforming growth factor (TGF)-β; however, most of the evidence for its involvement comes from correlative and culture-based studies. In this study, the importance of CTGF in tissue fibrosis was directly examined in three murine models of fibrotic disease: a novel model of multiorgan fibrosis induced by repeated intraperitoneal injections of CTGF and TGF-β2; the unilateral ureteral obstruction (UUO) renal fibrosis model; and an intratracheal bleomycin instillation model of pulmonary fibrosis.
Intraperitoneal coadministration of CTGF and TGF-β2 elicited a profound fibrotic response that was inhibited by the human anti-CTGF antibody FG-3019, as indicated by the ability of FG-3019 to ameliorate the histologic signs of fibrosis and reduce the otherwise increased hydroxyproline:proline (Hyp:Pro) ratios by 25% in kidney (P < 0.05), 30% in liver (P < 0.01) and 63% in lung (P < 0.05). Moreover, administration of either cytokine alone failed to elicit a fibrotic response, thus demonstrating that CTGF is both necessary and sufficient to initiate fibrosis in the presence of TGF-β and vice versa. In keeping with this requirement for CTGF function in fibrosis, FG-3019 also reduced the renal Hyp:Pro response up to 20% after UUO (P < 0.05). In bleomycin-injured animals, a similar trend towards a FG-3019 treatment effect was observed (38% reduction in total lung Hyp, P = 0.056). Thus, FG-3019 antibody treatment consistently reduced excessive collagen deposition and the pathologic severity of fibrosis in all models.
Cooperative interactions between CTGF and TGF-β signaling are required to elicit overt tissue fibrosis. This interdependence and the observed anti-fibrotic effects of FG-3019 indicate that anti-CTGF therapy may provide therapeutic benefit in different forms of fibroproliferative disease.
Fibroproliferative diseases, including chronic pulmonary, hepatic, renal and vascular fibrosis, contribute to nearly half of all deaths in the USA[1,2]. These disorders frequently affect multiple organ systems, complicating the elucidation of their underlying pathogenesis and hindering the development of effective treatments. Nevertheless, two secreted factors, transforming growth factor (TGF-β and connective tissue growth factor (CTGF), are widely regarded as universal mediators of fibrogenesis, although the precise mechanisms that underlie their concerted effects remain unclear [3-8]. Because TGF-β is a potent inducer of CTGF, most models postulate that CTGF acts as a downstream mediator of TGF-β activity, whereas other studies support an interdependent rather than merely sequential relationship between TGF-β and CTGF and their respective profibrotic activities [9-11].
CTGF is a multifunctional heparin-binding glycoprotein that is normally expressed at low levels but dramatically enriched in virtually all fibrotic conditions [8]. Cell-based studies have shown that CTGF regulates multiple processes that contribute to fibrogenesis, including cell proliferation, migration, adhesion, survival and extracellular matrix production; that it does so as both a downstream and cooperative mediator of TGF-β signaling; and that it affects a variety of cell types that participate in the fibrogenic process, regardless of tissue origin, including mesenchymal stem cells, hepatic stellate cells, renal podocytes, mesangial cells, parietal and tubular epithelial cells, pulmonary type II alveolar cells, mesothelial cells, vascular smooth muscle cells, endothelial cells, cardiomyocytes, pericytes and fibroblasts [4]. Moreover, correlative studies in diseased human tissues indicate important links between CTGF and TGF-β in a number of fibrotic disease states, including diabetic nephropathy, idiopathic and non-idiopathic pulmonary fibrosis, liver fibrosis, skin fibrosis (including keloids and systemic sclerosis), atherosclerosis, congestive heart failure, pancreatitis and various forms of malignant disease [3,8].
Data from animal models of human disease also support the importance of CTGF and its interactions with TGF-β in fibrosis. The small interfering (si)RNA-mediated knockdown of CTGF, for example, has been shown to suppress fibrotic responses in three models of liver fibrosis [5,12,13] and in a chronic allograft nephropathy model [14]. Similarly, antisense-mediated knockdown of CTGF has been shown to suppress fibrosis or its indicators in models of type 1 and type 2 diabetic nephropathy [15], unilateral ureteral obstruction (UUO) and subtotal (5/6) nephrectomy-induced kidney fibrosis [16,17], chemically induced liver fibrosis [18], hypertrophic scarring after dermal wound repair [19], and capsular scarring and contracture surrounding breast implants [20]. Notably, TGF-β induction was also reduced after siRNA- and antisense-mediated CTGF knockdown in five of six models in which it was examined [5,12,13,15,16,18], thus indicating that CTGF activity directly or indirectly enhances the expression of its own inducer in a positive feedback manner. In addition, the expression of known TGF-β targets was inhibited by antisense CTGF knockdown in the 5/6 nephrectomy model despite concurrent overexpression of a TGF-β transgene, suggesting that CTGF also promotes TGF-β activity in a fibrotic setting [17]. Thus, CTGF may influence both the level and function of TGF-β and like CTGF, the targeted inhibition of TGF-β itself attenuates fibrogenesis in these and other disease models. However, the myriad crucial functions of TFG-β make it unattractive as a direct target for antifibrotic therapy [3].
In the work described here, a novel CTGF and TGF-β synergy model was developed based on the prior observation that simultaneous or serial subcutaneous coadministration of TGF-β3 and CTGF elicited the formation of persistent fibrotic lesions in neonatal mice, whereas administration of either cytokine alone failed to produce any persistent effect [21]. In this study, we extended these findings to a model in which intraperitoneal co-injections of TGF-β2 and recombinant human CTGF produced profound peritoneal fibrosis, abdominal adhesions, and disseminated fibrosis in vital organs, including lung, heart, kidney and liver. As had been shown in the earlier subcutaneous fibrosis model, fibrosis in the intraperitoneal administration model also required the coadministration of both TGF-β and CTGF, thus demonstrating a robust cooperative interaction between these two factors in the genesis and maintenance of a fibrotic response. Furthermore, FG-3019, a fully human recombinant monoclonal antibody against human CTGF, blocked fibrosis in this model and in two additional clinically relevant rodent fibrosis models, the UUO model of kidney fibrosis and the bleomycin model of lung fibrosis, both of which also respond to TGF-β/Smad-targeted interventions [22-24]. Thus, treatment with a CTGF-blocking antibody reduced the severity of fibrosis in all three models, thereby indicating that anti-CTGF therapy may be clinically beneficial in diverse fibroproliferative diseases.
Production and characterization of FG-3019 monoclonal antibody
FG-3019, a fully human recombinant DNA-derived CTGF-reactive monoclonal IgG1/κ antibody, was isolated and cloned from genetically engineered mice expressing human immunoglobulin transgenes (Medarex, Princeton, NJ, USA) [25], which had been immunized with recombinant human CTGF. Using engineered CTGF fusion proteins and CTGF proteolysis fragments, FG-3019 binding activity was mapped to the cysteine-rich von Willebrand Factor type C (VWC) domain of CTGF (Figure 1A). Synthetic peptides derived from the VWC domain sequences of CTGF efficiently displaced FG-3019 in competitive CTGF ELISAs, including a peptide corresponding to CTGF amino acids 135-157, suggesting that these sequences participate in the recognition and binding of CTGF by FG-3019. This segment of the CTGF primary sequence is poorly conserved between related CCN family proteins, including NOV and CYR61 but well conserved within CTGF proteins encoded by diverse mammalian species [26]. Indeed, FG-3019 binds CTGF from a variety of mammalian species, including rodents, and radioimmunoassays indicate that it binds human and rat CTGF with Kd values of approximately 0.1 and 0.3 nmol/l, respectively (data not shown). To confirm the specificity of FG-3019 towards CTGF, as opposed to the structurally related CCN proteins CYR61 or NOV, binding of FG-3019 to recombinant proteins was compared by immunoblot analysis; FG-3019 was indeed avidly associated with CTGF, but not with CYR61 or NOV (Figure 1B). This result was also confirmed by ELISA (data not shown).
Figure 1. The FG-3019 binding epitope overlaps with the VWC domain of connective tissue growth factor (CTGF). (A) The region of the FG-3019 binding epitope (CTGF amino acids 142 to 157, indicated in yellow) is superimposed on the structure of the collagen IIa VWC domain [50]. By sequence homology, the general structural features of this domain are predicted to be conserved in CTGF and other CCN (connective tissue growth factor) proteins [51]. The predicted FG-3019 binding site lies outside of a fibronectin-1-like module within the VWC domain of CTGF. A physical interaction between the VWC domain of Xenopus CTGF and TGF-β family members TGF-β1 and bone morphogenetic protein (BMP)-4 was reported [9]. The location of the VWC domain relative to the insulin-like growth factor binding protein (IGF-BP), thrombospondin-1 (TSP1) and C-terminal cysteine knot (CT) homology domains of CCN family members is also indicated. (B) Recombinant human CTGF, CYR61 and NOV proteins (visualized by Coomassie blue in the upper panel) were analyzed by western blot using FG-3019, anti-CYR61 and anti-NOV antibodies. FG-3019 specifically bound CTGF without crossreacting with CYR61 or NOV.
Profibrotic effects of TGFβ2 and CTGF coadministration in neonatal mice
A novel model of multiorgan fibrosis was developed, involving the repeated intraperitoneal injection of newborn mice with a combination of TGF-β2 and CTGF. Whereas the gross anatomy of control mice treated with vehicle, TGF-β2 or CTGF alone appeared normal, animals treated with both cytokines together exhibited a profound thickening of the abdominal wall and peritoneal membrane (Figure 2A, B). In severe cases, a thickened fibrous membrane covered the surface of almost all the abdominal organs, and fibrous adhesions were readily apparent between adjacent organs or between otherwise free tissues and the abdominal wall. Organ fibrosis was quantitatively scored by comparing the Hyp:Pro ratios within tissues, which is a standard measure of collagen content relative to total organ protein. Hyp:Pro ratios in the kidney, liver, lung and heart were substantially increased after coadministration of TGF-β2 and CTGF, whereas treatment with either cytokine alone did not increase Hyp:Pro ratios relative to vehicle controls (Table 1), thus demonstrating a clear interaction between CTGF and TGF-β in this model. By these measures, Hyp:Pro changes after coadministration of TGF-β2 and CTGF were most dramatic in kidney and liver (increases of 65% and 160%, respectively, over control,), with more moderate but significant increases of 34% and 11% being seen in heart and lung, respectively (P < 0.001 in kidney, liver and heart, P < 0.01 in lung). Because the latter tissues lie outside the peritoneal cavity, this significant increase in their relative Hyp:Pro content indicates that the intraperitoneal coadministration of TGF-β2 and CTGF elicited a systemic rather than purely local fibrotic response. The coadministration of CTGF and TGF-β2 was also associated with a 28% reduction in final body weight (mean ± SE 7.62 ± 0.10 g) compared with healthy controls (10.59 ± 0.24 g), which was significant (P < 0.001). In addition, the severe intra-abdominal fibrosis in these animals appeared to be associated with compromised bowel motility, as indicated by increased accumulation of fecal material in their intestines (data not shown).
Table 1. Hydroxyproline:proline ratio by treatment group and organ in the TGF-β/CTGF synergy model
Figure 2. Gross anatomy in the transforming growth factor-β/connective tissue growth factor (TGF-β/CTGF) synergy model. Peritoneal cavities of (A) healthy control animals, (B) animals coadministered CTGF and TGF-β2, and (C) animals coadministered CTGF and TGF-β2 and treated with anti-CTGF antibody FG-3019. Extensive fibrotic membranes surrounded most organs in the abdominal cavity in vehicle-treated mice that received both TGF-β2 and CTGF. A substantial reduction in gross fibrotic pathology was observed in mice that received TGF-β2 and CTGF plus FG-3019.
In animals that received both TGF-β2 and CTGF, simultaneous treatment with FG-3019 resulted in substantial visible suppression of the peritoneal membrane and abdominal cavity fibrotic responses (Figure 2C). Overt intra-abdominal adhesions were not noted in these animals. This qualitative reduction in gross fibrotic effect was accompanied by a 22% improvement in the mean final (day 21) body weight in the FG-3019-treated cohort (9.32 ± 0.32 g) compared with animals that received TGF-β2 and CTGF without FG-3019 treatment (P < 0.001), although the FG-3019 treated animals were still 12% lighter than healthy controls (P < 0.001). FG-3019 treatment also substantially reduced Hyp:Pro ratios in all organs examined. Specifically, the increase in relative Hyp:Pro content (that is, the fibrotic response) elicited by coadministration of TGF-β and CTGF was reduced by 63% in lung (P < 0.05), 25% in kidney (P < 0.05), 30% in liver (P < 0.01) and 15% in heart after FG-3019 treatment (Table 1).
The observation that frank fibrosis only occurred after coadministration of both TGF-β and CTGF, as opposed to either cytokine alone, and that it was attenuated by FG-3019 antibody treatment, was also confirmed by an independent histologic analysis (Comparative Biosciences, Inc., Sunnyvale, CA, USA). Microscopic analysis of stained liver sections revealed multifocal fibrosis of the hepatic capsule in eight of eight animals that received both cytokines (Figure 3A, Table 2). In addition, multiple foci of trace or mild parenchymal fibrosis, primarily in periportal liver regions, were present in three animals that received both cytokines. Thus, the response to TGF-β/CTGF coadministration was primarily one of capsular fibrosis with occasional parenchymal involvement. By contrast, histologic evidence of capsular or parenchymal liver fibrosis was entirely absent in all animals that received either CTGF or TGF-β alone, and focal evidence of trace capsular fibrosis without parenchymal fibrosis was seen in only two of eight animals that received FG-3019 (Figure 3B). Thus, the incidence of any degree of fibrosis after dual-cytokine treatment was significantly reduced by CTGF-targeted FG-3019 treatment (Fisher's exact test, P = 0.007) and analysis of variance by ranks showed that the histologic liver fibrosis severity scores (0 = no fibrosis, 1 = minimal, 2 = minimal to mild, 3 = mild and 4 = moderate fibrosis) for animals that received both TGF-β2 and CTGF (median 1.5, range 1 to 4) were significantly higher than for animals that received vehicle, TGF-β2 or CTGF alone (all scores = 0; Dunn's test, P < 0.001) and that they were significantly reduced by FG-3019 treatment (median 0, range 0 to 1, P < 0.01). Likewise, mild to moderate renal capsular fibrosis was observed in three of eight animals that received both cytokines without FG-3019 treatment (Figure 3C), whereas no evidence of fibrosis was seen in any other animal from any other group, including the FG-3019 treatment group (Figure 3D). Fibrosis of the renal parenchyma was not seen in any animal in this study, nor was inflammation noted in any tissue.
Table 2. Incidence of histologic liver fibrosis by severity score
Figure 3. Hepatic and renal fibrosis in mice receiving transforming growth factor (TGF)-β and connective tissue growth factor (CTGF) is ameliorated by FG-3019 treatment. (A, B) Liver and (C, D) kidney of 21-day-old animals coadministered TGF-β2 and CTGF; animals were treated with either (A, C) vehicle or (B, D) FG-3019. All agents were administered daily for 20 days beginning one day after birth. Arrows indicate regions of robust capsular fibrosis inhibited by FG-3019 treatment. Representative images are shown (all haematoxylin and eosin, original magnification × 200).
Effect of CTGF inhibition in a UUO-induced kidney fibrosis model
Previous studies have demonstrated a direct correlation between CTGF levels and renal pathology in the UUO-induced kidney fibrosis model [16,27]. In the current study, ligated kidneys of vehicle-treated animals were compared with non-ligated control kidneys of the same animals to determine the fibrotic effect of UUO using the standard tissue Hyp:Pro ratio to assess the fibrotic response. In addition, to determine whether disruption of CTGF signaling inhibits the UUO-induced fibrotic response, ligated kidneys of animals treated for 2 weeks with either vehicle or FG-3019 were compared.
In vehicle-treated control animals, UUO induced a clear fibrotic effect, as indicated by a fourfold increase in the mean Hyp:Pro ratio in ligated kidneys compared with non-ligated control kidneys (0.175 ± 0.011 vs. 0.045 ± 0.0005; P < 0.001). The kidneys of animals treated with 10 and 30 mg/kg FG-3019 were significantly protected from UUO-induced fibrosis, as indicated by reduction of 20% and 15%, respectively, in their induced Hyp:Pro ratios compared with untreated UUO control mice (P < 0.05) (Figure 4), respectively. Histologic analysis using trichrome staining revealed interstitial fibrosis, fibroblast proliferation and increased collagen accumulation in all obstructed kidneys regardless of treatment, with a slight but subjective decrease in the amount of fibrosis seen in the 10 mg/kg FG-3019 treatment group (not shown). Increased trichrome staining was associated with the fibroblast proliferation, and was noted in the interstitium of the cortex, the surrounding glomeruli and the medullary regions of all obstructed kidneys. Marked hydronephrosis, characterized by tubular dilation and tubular epithelial loss, was also seen throughout the cortex in all obstructed kidneys regardless of treatment. In addition, multifocal lymphocytic infiltrates were commonly observed in the interstitium of obstructed kidneys, particularly in perivascular regions; however, this was also unaffected by treatment.
Figure 4. FG-3019 inhibits renal collagen deposition after unilateral ureteral obstruction (UUO). Hydroxyproline:proline (Hyp:Pro) ratios in renal tissues from UUO mice are expressed as the mean change above the mean Hyp:Pro ratio of unligated control kidneys (0.0446 ± 0.0005, n = 35). Mean renal Hyp:Pro ratio increases for the 10 and 30 mg/kg FG-3019 treatment groups (gray bars) were 20% and 15% lower than for the UUO kidneys of vehicle-treated controls (white bar), respectively. *P < 0.05 compared with UUO + vehicle (analysis of variance, Fisher's least significant difference).
Effect of FG-3019 in a bleomycin-induced pulmonary fibrosis model
To confirm that CTGF actively contributes to the pathogenesis of pulmonary fibrosis, and that CTGF inhibition may alleviate the pulmonary fibrotic response, the effect of FG-3019 treatment was examined in a bleomycin-induced lung fibrosis model [24,28]. Bleomycin-treated animals were compared with healthy controls to determine the fibrotic effect of pulmonary bleomycin instillation. Bleomycin-treated animals treated for 2 weeks with either vehicle or FG-3019 were further compared, to investigate the importance of CTGF signaling in pulmonary fibrogenesis. Fibrosis in this model was scored by the standard measure of total lung Hyp, which takes into account the variable Pro content in lung, which is often unrelated to changes in total lung collagen content.
In control mice, bleomycin treatment increased mean ± SEM Hyp content to 452 ± 18 μg per lung (n = 6) compared with non-fibrotic saline-treated controls (285 ± 8 μg per lung; n = 10); a significant 59% increase of 167 μg per lung (P < 0.001). Compared with vehicle-treated bleomycin controls, FG-3019 anti-CTGF antibody treatment resulted in a consistent reduction in mean induced lung Hyp content; a 38% reduction in induced fibrosis in the 10 mg/kg FG-3019 treatment group exhibited a trend towards a treatment effect (P = 0.056) (Figure 5).
Figure 5. FG-3019 inhibits collagen deposition in lungs of bleomycin-treated mice. Pulmonary hydroxyproline (Hyp) content (μg/lung) of bleomycin-treated mice is expressed as the mean change from Hyp content of healthy control lungs (285 ± 8 μg/lung, mean ± SEM, n = 10). Mean Hyp content (μg/lung) increases for the 3, 10 and 30 mg/kg FG-3019 treatment groups (gray bars) were 27, 38 and 13% lower than for the bleomycin mice treated with vehicle (white bar), respectively. *P = 0.056 vs. bleomycin + vehicle (ANOVA, Fisher's LSD).
FG-3019 Plasma Concentration
Circulating FG-3019 antibody levels were measured by ELISA to confirm FG-3019 exposure after intraperitoneal injection in the studies described above. In the bleomycin and UUO studies, mean ± SD FG-3019 plasma concentrations measured 48 hours after the final FG-3019 dose of 10 mg/kg were 184 ± 45.6 and 216 ± 71.8 μg/mL, respectively. Consistent with the lower daily and cumulative dose delivered in the neonatal TGF-β/CTGF synergy study, the FG-3019 plasma concentration 24 hours after the final 1.84 mg/kg dose was 21.8 ± 11.5 μg/mL.
Fibrosis, the excessive and persistent formation of scar tissue, is responsible for the morbidity and mortality associated with organ failure in a variety of chronic diseases affecting the lung, kidneys, eyes, heart, liver and skin. CTGF is strongly overexpressed in fibrotic tissue and is directly linked to the chronic fibrotic effects of TGF-β, VEGF, insulin-like growth factor, angiotensin II and other factors. CTGF acts as a cofactor with TGF-β to induce fibroblasts to become myofibroblasts that deposit collagen, ultimately resulting in organ scarring and dysfunction, and in the most severe forms, organ failure and death. Indeed, CTGF levels in tissue, blood or vitreal fluid have been shown to correlate with the degree and severity of fibrosis in many diseases [29]. Examples include diabetic nephropathy, glomerulosclerosis and IgA nephropathy (kidney), diabetic retinopathy and advanced macular degeneration (vitreal fluid), cirrhosis, biliary atresia and nonalcoholic steatohepatitis (serum, liver), congestive heart failure (myocardium), and various forms of pulmonary and skin fibrosis (serum, tissue) [5,29-32].
In the studies described here, the anti-CTGF antibody FG-3019 consistently diminished fibrotic responses in a novel model of CTGF and TGF-β synergy, and in previously described acute inflammatory models of lung and kidney fibrosis. Thus, the anti-fibrotic activity of FG-3019 in each of these models supports a key role for CTGF in mediating fibrogenesis. Indeed, FG-3019 alleviated the fibrosis associated with acute bleomycin and UUO injury even though the relatively severe nature of these acute injury models may limit the observable treatment benefit. It was not possible to determine from these models the specific nature of the anti-fibrotic effects of FG-3019, and additional studies will be needed to determine whether the FG-3019 action is exerted directly through effects on initiation, progression or resolution of fibrosis, or indirectly via effects on initial injury and/or early inflammatory response to injury [33]. Nevertheless, the UUO and bleomycin models were chosen because they have been extensively investigated, and because TGF-β and CTGF have each been implicated in their development and progression [16,22-24,28]. Thus, in the lung and kidney fibrosis models, endogenous TGF-β and CTGF were induced [28], and in the CTGF and TGF-β synergy model, recombinant exogenous TGF-β and CTGF were coadministered directly, with the latter approach resulting in profound encapsulating peritoneal sclerosis and systemic multiorgan fibrosis. Thus, each model provides a useful scenario for investigating CTGF/TGF-β cooperativity and the potential clinical utility of antifibrotic agents.
Previous findings indicated that coadministration of CTGF and TGF-β is required for the establishment of a persistent fibrotic effect in skin after subcutaneous administration [21,34-36]. In the current cooperative interaction model, intraperitoneal coadministration of TGF-β2 and CTGF resulted in the development of profound abdominal fibrosis and disseminated fibrosis in extraperitoneal organs, thus indicating induction of a systemic fibrotic response. Notably, induction of fibrosis in this model required concomitant exposure to both TGF-β and CTGF in a manner indicating functional synergy between these two cytokines in the fibrogenic response. These results indicate that CTGF is both necessary and sufficient to initiate fibrosis in the presence of increased TGF-β signaling, and that TGF-β is both necessary and sufficient to elicit fibrosis in the presence of increased CTGF. Because TGF-β is a potent inducer of endogenous CTGF, it is important to consider why the addition of further exogenous CTGF is required for TGF-β to elicit an overt fibrotic response. One possible explanation is that in the presence of pathologic fibrosis, TGF-β is indeed required, but fails to elicit enough endogenous CTGF on its own. This implies that independent pathways of CTGF regulation are also necessary. Moreover, it suggests that a CTGF threshold must be met to initiate or maintain fibrogenesis, and if so, then even partial inhibition of its activity to levels below a crucial threshold should provide anti-fibrotic benefit. Indeed, in the cooperative interaction model, FG-3019 anti-CTGF treatment reduced the overall level of fibrosis observed after CTGF and TGF-β coadministration in liver, kidney and lung. The magnitude of Hyp:Pro changes is influenced by pre-existing collagen content, the presence of less affected sample areas, and potential accumulation of non-collagenous proteins during fibrosis, whereas the histologic fibrosis scores measure the overall microscopic appearance of a tissue, including tissue areas that may be differentially affected, such as capsular or parenchymal regions. Thus, both measures support the qualitative conclusion that CTGF and TGF-β cooperate to promote tissue fibrosis, and that CTGF inhibition can suppress fibrogenesis.
Although the TGF-β/CTGF cooperative interaction model has properties suggestive of broad relevance to fibrotic disease, it may be specifically relevant to the formation of abdominal adhesions after surgery and to peritoneal fibrosis associated with dialysis procedures. Fibrosis in the TGF-β/CTGF cooperative interaction model was associated with profound peritoneal adhesions and signs of intestinal obstruction, a common presentation in patients diagnosed with postoperative peritoneal adhesions [37]. Moreover, CTGF mRNA is significantly increased in postoperative adhesions after peritoneal wounding in animal models [38] and in patients undergoing peritoneal dialysis [39]. Thus, it is likely that CTGF and TGF-β contribute to the formation of intra-abdominal adhesions in a cooperative and potentially targetable manner.
Together, these data provide both gain- and loss-of-function evidence that CTGF plays a crucial role in fibrotic tissue injury, because exogenous CTGF was required to initiate a fibrotic response in the presence of increased TGF-β levels, and because treatment with a CTGF-blocking antibody attenuated the fibrotic response in three independent models of pathologic fibrosis. Moreover, with regard to clinical utility, these data support the conclusion that the anti-CTGF monoclonal antibody, FG-3019, may be useful in controlling the progression of renal, pulmonary and hepatic fibrosis in patients with diseases such as diabetic nephropathy, systemi sclerosis or idiopathic pulmonary fibrosis. These results were obtained in studies of relatively limited treatment duration (14-20 days), as required by use of a human antibody in rodents, so that the added benefit of longer duration treatment regimens could not be assessed. In these studies, the optimum dose and regimen for FG-3019 administration was not fully established, and may differ by disease. However, the antifibrotic effects of FG-3019 have been reproduced in other studies, including comparisons where non-immune IgG groups were used [40].
CTGF exhibits a broad spectrum of biological activities, including effects on bone and cartilage development [41], cell adhesion and chemotaxis [42], and angiogenesis [43], none of which were addressed in these experiments. Moreover, fibrotic tissue remodeling also influences other clinically relevant processes, including cancer progression and organ-graft rejection. In addition to its antifibrotic effects, the FG-3019 anti-CTGF antibody used here has also been shown to attenuate tumor growth, metastasis and angiogenesis in mouse models of pancreatic cancer and to attenuate the anchorage-independent growth of CTGF-overexpressing pancreatic cancer cells [44-46]. Thus, taken together, these studies indicate that CTGF is a clinically relevant target in fibrosis and other disease states.
Animal selection and handling
Mice (Charles River Laboratories, Inc., Wilmington, MA, USA) were handled according to standards provided in the National Institutes of Health Guide and the Animal Welfare Act and to protocols approved by the Institutional Animal Care and Use Committee.
UUO kidney fibrosis study
In total, 40 male Swiss Webster mice (32-35 g) were assigned to one of four groups (10 mice/group). On the first day of dosing, mice received an intraperitoneal dose of vehicle or FG-3019 (10 or 30 mg/kg), and 4 hours later, mice were anesthetized with isoflurane and UUO was performed on the left kidney [22]. The right (unoperated) kidney served as control. Thereafter, mice received vehicle or FG-3019 every other day to give a total of seven doses. Fourteen days after UUO, the surviving mice were anesthetized with isoflurane, blood was collected via the abdominal vein for plasma FG-3019 concentration by ELISA, and both the left and right kidneys were harvested. Mice that survived to the scheduled termination date were examined for successful ureteral ligation. Five mice with unsuccessful ligations (one from the UUO and vehicle group and four from the UUO and 10 mg/kg FG-3019 group) were excluded from analysis. Half of each kidney was processed for histopathologic analysis. The remaining half of each kidney was processed for determination of Hyp and Pro levels.
Bleomycin-induced lung fibrosis study
In total, 40 male C57BL/6 mice (23-26 g) were assigned to one of four bleomycin-treated fibrosis groups (10 mice/group) and treated with FG-3019 (3, 10 or 30 mg/kg) or vehicle (control group). On the first dosing day, mice received an intraperitoneal dose of either vehicle or FG-3019, and 2 hours later received an intratracheal instillation of bleomycin (Bristol-Myers Squibb, Princeton, NJ, USA) at a dose of 0.08 U/50 μL/mouse under isoflurane anesthesia [24,47]. An additional non-fibrosis control group of 10 mice received an intratracheal instillation of saline, and was treated with vehicle. Thereafter, mice received vehicle or FG-3019 every other day to give a total of seven doses. During the dosing period, mice were observed daily, and weights were measured approximately three times per week. Animal weights in all bleomycin treatment groups were somewhat reduced versus saline non-bleomycin control, but final weights did not differ significantly between treatment groups. Similarly, bleomycin-associated mortality was similar between groups exposed to this agent. Fourteen days after the bleomycin instillation, the surviving mice were anesthetized with isoflurane. Blood was collected from the abdominal vein and placed in lithium-heparin tubes and spun at 4°C, then the plasma was frozen at -70°C for subsequent determination of FG-3019 concentration. All dissected lung lobes were quickly freed of non-parenchymal tissue, perfused with ice-cold saline, and hydrolyzed in 6 mol/l HCl at 105°C for 22 hours for subsequent whole-lung Hyp determination by high-performance liquid chromatography (HPLC) amino acid analysis. The standard measure of total lung Hyp in this model controls for the occasional inconsistent distribution of bleomycin injury associated with intratracheal instillation. Owing to the non-uniform nature of local bleomycin injury, histology samples were not collected.
TGF-β/CTGF synergy study
Ten pregnant female Balb/c mice were used, with two dams assigned to each of five experimental groups to provide seven to 10 neonates per group. In each group, neonates were treated with up to two cytokines and with vehicle or FG-3019, as follows: no cytokine vehicle treatment control (healthy control; n = 10 neonates); TGF-β2 and vehicle (n = 7 neonates); CTGF and vehicle (n = 7 neonates); TGF-β2 and CTGF and vehicle (n = 10 neonates); and TGF-β2 and CTGF and FG-3019 (n = 8 neonates).
Mice aged 1 day old received their first intraperitoneal dose of FG-3019 (1.84 mg/kg) or vehicle (both in a volume of 0.05 mL), followed 1 hour later by intraperitoneal administration of recombinant human TGF-β2 (300 μg/kg) and/or CTGF (300 μg/kg) in a volume of 0.05 mL. This dosing regimen continued once daily for 20 consecutive days. Two mice died: one in the CTGF group (on day 10) and one in the group coadministered TGF-β2 and CTGF (on day 21, before scheduled termination). One day after the final FG-3019 dose, surviving mice were weighed and killed after blood collection for determination of plasma FG-3019 concentration. Organs were harvested for histopathologic analysis (kidney and liver) and determination of total Hyp and Pro (kidney, lung, liver and heart).
Hyp and Pro determination
Hydroxyproline and proline were determined by the method of Palmerini et al. [48], except that L-azetidine 2-carboxylic acid (Sigma-Aldrich, St Louis, MO, USA) was substituted for 3,4-dehydroproline as an internal standard. Tissues were hydrolyzed in 6M HCl for 22 hours at 105°C. Samples underwent pre-column derivitization with o-phthalaldehyde and then 4-chloro-7-nitrobenzofuran (Sigma-Aldrich) to form fluorescent adducts of proline and hydroxyproline. The fluorescent adducts were separated and determined by reverse-phase HPLC followed by fluorometric detection.
Histologic analysis
Tissue sections were independently examined in an unblinded manner by a licensed pathologist (Comparative Biosciences, Inc.). In the dual-cytokine synergy study, tissue sections were stained with hematoxylin and eosin and with trichrome, and a subjective but relative fibrosis severity score from 0 to 4 was assigned for each examined organ as given in Results, with small focal areas of trace fibrosis constituting 'minimal' fibrosis, and larger multifocal (that is,, non-diffuse) areas of fibroblasts and extracellular matrix accumulation constituting 'moderate' fibrosis.
Test articles
FG-3019 was cloned, expressed and purified from a recombinant CHO cell line derived for this purpose. For bleomycin and UUO studies, FG-3019 was prepared in a vehicle solution consisting of 25 mmol/l L-histidine and 137 mmol/l sodium chloride, pH 6.0. For the TGF-β and CTGF synergy study, FG-3019 was prepared in phosphate-buffered saline (PBS; Cellgro™, Mediatech, Herndon, VA, USA). E. coli-derived TGF-β2 and baculovirus-derived recombinant human CTGF [49] were also prepared in PBS vehicle.
Immunologic methods
Immunoblotting was carried out according to standard western blotting methods. FG-3019 or polyclonal antisera directed against either CYR61 or NOV were each used to determine the relative affinity of antibody preparations towards baculovirus-derived recombinant human CTGF, CYR61 and NOV. Rabbit polyclonal anti-NOV and anti-CYR61 antisera were generous gifts from Drs Maryvonne Laurent (Hôpital St. Antoine; Paris, France) and Ruth Lupu (UC Berkeley; Berkeley, CA, USA), respectively. For determinations of relative FG-3019 exposure, plasma FG-3019 antibody concentrations were determined by a sandwich ELISA using an exon-3 (VWC homology domain) CTGF peptide for capture of FG-3019 followed by detection with goat anti-human IgG linked to alkaline phosphatase.
Statistical analysis
Statistical analyses were performed using the Sigma Stat program (SPSS Science, Chicago, IL, USA). Continuous data were analyzed by one-way analysis of variance with the Fisher's least significant difference test comparing all groups. Ordinal histologic fibrosis scores were analyzed by the non-parametric Kruskal-Wallis statistic with Dunn's multiple comparison post-hoc tests. The Fisher's exact test was used to analyze 2 × 2 contingency data for the presence or absence of histologic fibrosis. In the UUO study, Hyp:Pro ratios from uninjured contralateral control kidneys from all groups were pooled with the healthy control group. P < 0.05 was considered statistically significant, and unless otherwise indicated, within-group distributions are expressed as mean ± SEM.
Competing interests
All authors are current employees of FibroGen, or were FibroGen employees when the studies were performed.
Authors' contributions
Animal studies were designed and performed by QW, GG, BN and WZ, with input, materials and supporting analyses provided by WU, JG, MB, LX and TS. TS coordinated the preparation of the manuscript. NO, AL and DY supervised the studies. All authors read and approved the final manuscript.
We thank K. Lea Sewell and Saniya Fayzullina for their assistance in manuscript preparation, and Mark Sternlicht for key contributions to manuscript editing and supplemental statistical analyses.
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Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, et al.: Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo.
Aikawa T, Gunn J, Spong SM, Klaus SJ, Korc M: Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer.
Mol Cancer Ther 2006, 5:1108-1116. PubMed Abstract | Publisher Full Text
Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N, et al.: Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis.
Cancer Res 2006, 66:5816-5827. PubMed Abstract | Publisher Full Text
Bennewith KL, Huang X, Ham CM, Graves EE, Erler JT, Kambham N, et al.: The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.
Cancer Res 2009, 69:775-784. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Wang Q, Wang Y, Hyde DM, Gotwals PJ, Lobb RR, Ryan ST, et al.: Effect of antibody against integrin alpha4 on bleomycin-induced pulmonary fibrosis in mice.
Biochem Pharmacol 2000, 60:1949-1958. PubMed Abstract | Publisher Full Text
Palmerini CA, Fini C, Floridi A, Morelli H, Vedovelli A: High-performance liquid chromatographic analysis of free hydroxyproline and proline in blood plasma and of free and peptide-bound hydroxyproline in urine.
J Chromatogr 1985, 339:285-292. PubMed Abstract | Publisher Full Text
Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR III, Carmichael DF: The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor.
J Biol Chem 2001, 276:40659-40667. PubMed Abstract | Publisher Full Text
O'Leary JM, Hamilton JM, Deane CM, Valeyev NV, Sandell LJ, Downing AK: Solution structure and dynamics of a prototypical chordin-like cysteine-rich repeat (von Willebrand Factor type C module) from collagen IIA.
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Perbal B: NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues.
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text: ESPN Feed: chris price http://assets.espn.go.com/i/tvlistings/tv_espn_original.gif ESPN en-us 10 ESPN Inc. http://espn.go.com/ Copyright 2010 ESPN Inc. Introducing the 2013 Ohio State Buckeyes recruiting class, which finished third in the ESPN class rankings.]]> February 05, 2013 15:58:05 PST Breaking down the 2012 Ohio State defensive line depth chart, a position in which the Buckeyes should be among the best groups in the country.]]> July 30, 2012 15:52:31 PDT


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Passion for Running
Running and a Life in Balance
Running based on Science
Unique experiences for runners and professionals.
A simple and powerful way to become stronger and faster runner.
It is important that you allow yourself some well-deserved time off after the race.
Mental fatigue can set in way before physical fatigue. We explore some great ways to combat it
Dr. Williams is Head of Biomechanics and Physical Therapy for OOL RUN
Dr. Anderson is Head Coach and Running Science Expert for OOL RUN
Dr. Pierce is Co-founder of the Furman Institute of Running and Scientific Training.
This 3-day retreat is for runners who are looking to maximize their potential from a 10K to a Full Marathon.
Explore the topics of running and recovery, with marathon legend Dick Beardsley.
FUNCTIONAL ANALYSES AND INTERVENTIONS FOR THE RUNNING ATHLETE (2 Day Course)


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Over fifteen years ago Marvel Comics found itself in a quandary. Having just avoided bankruptcy and stinging from bad fan reaction from misguided experiments such as the Spider-Man Clone Saga, the comic company found itself on shaky ground both creatively and financially. Marvel needed to make a change. In desperation for something new and refreshing they handed over a corner of the Marvel Universe to Joe Quesada who, in turn, handed over the reigns of the book to fanboy filmmaker Kevin Smith. The result was a run on Daredevil that many consider to be one of the best in the character's history. In this episode of Part-Time Fanboy Kristian, Paul, and Ian sit down to discuss Guardian Devil…Kevin Smith and Joe Quesada's intricately crafted take on Daredevil.
Part-Time Fanboy. Full-Time obsession on a Part-Time schedule.]]>
Kristian's Picks
Drawing Beautiful Women: The Frank Cho Method
By: Frank Cho
Genre: Educational
Publisher: Flesk Publications
Let's face it…for many comic artists, presenting the female form can be a challenge. One of the things that's often heard from beginning artists is how hard it can be to draw women in a dynamic and interesting fashion. Luckily Frank Cho has released this volume to help anyone who has a problem rendering those members of the sex with a somewhat curvier anatomy. Whatever you feel about Cho's artistic style it cannot be denied that he has an ability to illustrate captivatingly sensual women. He's practically built his whole career on it. So much like the old E.F. Hutton ads…when Frank Cho talks about drawing gorgeous women…you should listen. This is probably a book that just about every aspiring comic book artist should have in their library…at least those who prefer to draw their female fantasy figures with some sort of realistic anatomy that will get male (and some female) tongues wagging.
The James Bond Omnibus Volume 6
By: Ian Fleming and Yaroslav Horak
Genre: Action-Adventure
Publisher: Titan Books
A couple of weeks ago I recommended the latest Titan Books collection of Modesty Blaise and now I'm seeing that Titan is set to release a new James Bond collection of newspaper strips. I have some of the early editions of these Bond collections and I have to say that, much like the Modesty Blaise collections, I love these things. For fans of old comic strip art and fans of Bond these books are a must have. Most of the strips collected in these volumes are direct adaptations of the novels and books that created Bond in the first place. So if you've watched many of the films and been aghast at how many liberties they've taken with the character you should be picking these books up. These comics tend to be a more faithful version of Bond and his missions than the movies ever were or have been. The art in these strips is also terrific. There's a consistent old school workmanship present on these pages that you don't really see in modern comics anymore. Some of the stuff is a bit dated but that doesn't make it any less entertaining. These books are just all around great reads. You can click here for a review that I did of a story in a previous volume. If that doesn't convince you to pick this up I don't know what will.
Princess Ugg TPB
By: Ted Naifeh
Genre: Fantasy
Publisher: Oni Press
Take a sword and sorcery aesthetic, put a bit of a Harry Potter twist on it, drop a sprig of Red Sonja into it, and mix in a dash of teenage princess angst and you've got Princess Ugh. Courney Crumrin's Ted Naifeh returned to comics with this adorable series about a barbarian princess sent off to finishing school. Much of my description is a bit too simplistic to encompass just how fun and charming this series is. I'm actually extremely excited that this book is finally being released in a trade paperback edition as it's the perfect book to sit down and read with my daughter. Princess Ugg is the perfect protagonist for those little girls that are either growing out of the princess phase of their development or who have never really warmed up to it at all. Plus the art is just absolutely gorgeous. It's powerful enough to suck in those of us who grew up worshipping at the altar of Frazetta and wistful enough to appeal to little girls everywhere. This is a trade paperback I can't wait to get my hands on.
Punk Mambo # 0
By: Peter Milligan and Robert Gill
Genre: Superhero
Publisher: Valiant Entertainment
Valiant has been spreading its wings lately and with their latest book, Punk Mambo, they seem to be ready to jump into early Vertigo Comics territory. And if you're going to jump into Vertigo Comics territory I can think of few writers better than Peter Milligan to go to to get you that feel. Punk Mambo is a comic that is poised to take the Vertigo universe into somewhat seedier and darker places than most of their books have been to before. Sure, they've had Shadowman and Doctor Mirage but Punk Mambo has the feel of a comic that wants to go into Hellblazer or Preacher mode…which is great because, as far as I'm concerned, you can never really have too much of that kind of comic. Mambo looks to be a book that's ready to step outside the established norms of the Valiant line and embrace the edgier side of comics. It's great to see Valiant taking a chance on comics like this but then Valiant's been a company that's always been able to impress me. Hopefully Punk Mambo is a book that will go in as crazy a direction as some of Milligan's other books. If it does, it could end up becoming one of Valiant's most interesting comics.
If you want to take action after listening to this episode please donate to Nahleen's medical fund by clicking here or going directly to: https://www.crowdrise.com/NahleenandCleosMedicalBills
You can also take action by going to Twitter and tweeting @BlueShieldCA and demanding that they get Nahleen the medication she needs!]]>
Part-Time Fanboy. Full-Time obsession on a Part-Time schedule.]]>
Written by: Jeremy Whitley
Art by: Ted Brandt and Rosy Higgins
Published by: Action Lab Comics
If there's one perfect comic out in the comic book market perfectly tailored for young girls it's Princeless. From my initial discovery of this charming and fun comic book, I've loved it. Not because I'm a little girl myself, obviously, but because I have a little girl of my own who happens to have grown to love comic books almost as much as her father did at her age. But as many older comic nerds can attest to, it's not always easy for dads to find appropriate material for their little female comic collecting fanatics. Oh, things are getting better when it comes to finding comic books with female protagonists that aren't just pin-up material masquerading as inspirational super heroine tales…but it's still the type of thing that has to be sought out for. Unfortunately, finding comics with a central female character isn't as easy dropping by the corner comic book store and plopping down a couple of bucks…that is, unless you're just looking for some ladies clad in skin tight hugging spandex.
Fortunately, Action Lab Comics has emerged in the last couple of years with books like Shinobi, Molly Danger, and Princeless to fulfill a need for female centric comics that feature positive and inspiring role models whose adventures young girls can enjoy. While Action Lab's whole stable of books isn't quite appropriate for young ladies they are certainly a publisher that seems to be making specific strides in releasing books that are attempting to fulfill a void that has been ignored by most comic publishers for way too long. Comics for girls are here, people, and Action Lab is making some serious strides in making them for the little ladies who want them.
The perfect case in point is Princeless. Priceless features the adventures of a princess that doesn't need to be rescued; in fact she tends to be the one doing the rescuing herself. It's a comic that's always been a fun read and is brimming with charm. And it's not just this overly cynical fanboy who thinks so. With each collection of Princeless that's been released I've sat down and read them with my daughter and it's turned into one of her favorite reads. As a matter of fact, when I got the advanced digital copy of this issue for review I made sure to read it with her and by the end of the issue she was begging for more Princeless.
In this chapter of Princeless we are introduced to yet another princess, The Pirate Princess…otherwise known as The Black Arrow. Much like many of the other princesses in Princeless, The Black Arrow has found herself trapped in a tower being held against her own will. Unable to make her own escape, she waits impatiently for an opportunity to secure her freedom or for someone else to secure it for her. Of course, the main protagonist of the series, Princess Adrienne and her stalwart companion Bedilia are the ones to help The Pirate Princess out of her predicament and during the rescue attempt the erstwhile hi-jinks ensue.
Series writer and creator Jeremey Whitley continues to deliver a terrific tale with this chapter of Princeless. All of the fun and humor and charm that have made Princeless the adorable comic that it's always been are present in the first edition of this latest mini-series. Whitley gives us another terrific female character in The Black Arrow who has a personality that is very much her own and brings an added dimension to the book. While Adrienne and Bedilia have always been spunky, The Pirate Princess ratchets the spunk factor up a bit. She is feisty, adventurous, and, most importantly, funny in her own way. In Whitley's hands The Pirate Princess becomes a very welcome addition to the cast of Princeless.
The Pirate Princess isn't the only newest addition to the pages of Princeless, however. Artists Ted Brandt and Rosy Higgins join the team for this mini-series and I have to say I was more than pleasantly pleased with their work. The new art team on Princeless brings a new distinctive style to the book without departing from the visual flair that had been established by those before them. Princeless has always been one of the better looking indie books out there and the new artists are able to keep that tradition going. Princeless is in good hands with the new craftspeople behind the imagery of The Pirate Princess.
Action lab continues to impress with this new mini-series. As a father of a young girl I'm thrilled that comics like these are being published today. While Action Lab seems to have a growing roster of all different kinds of comics I'm glad that part of their focus has been to keep putting out entertaining comics that focus on young female protagonists that can serve as inspirational entertainment for all the little girls who are getting into comics these days. Thanks to Action Lab and Jeremy Whitley for giving me another comic that I can hand to my little one without any trepidation at all. Well done.]]>
Kristian's Picks
Modesty Blaise Volume 25: Grim Joker
By: Peter O'Donnel, Eric Bandia Romero
Genre: Action-Adventure
Published by: Titan Books
Many people may not know the name "Modesty Blaise" but to a certain segment of the population she is known quite simply as, "The female James Bond." Unfortunately Modesty never really achieved the sort of pop star status that Mr. Bond did but that doesn't mean that she wasn't as intriguing a character as the more popular 007. Ms. Blaise began her life as a popular comic strip in the 1960's and the popularity of her comic found her adventures being adapted into several successful novels and short stories and not-so successful film adaptations. The movies probably never caught on because of the fact that they could never capture the complexity of her character the way that the comic strip or novels did. In films, Modesty would be reduced to one-dimensional sexpots or parody. On the comic page she was cunning, intelligent and became the template for every leather clad female adventurer that came after her from Emma Peel to the modern day Catwoman.
Titan Books has been reproducing Peter O'Donnel's Modesty Blaise strips for a while and this week sees them publish the twenty fifth volume (!) of highly entertaining newspaper comics that have Blaise engaged in all kinds of amazing adventures. I have several of these collections and I have to say that each one of these that I've read has been a treat. While the style of the storytelling may be a bit different than what many modern comic fans might expect, the stories themselves are still timeless and engaging. The art is nothing to sneeze at either. There were probably two or three artists that rendered Modesty's adventures during the run of the comic but each one brought a clear, distinctive power to the page. If you like super spies or international intrigue these Modesty Blaise collections may be right up your alley.
Wallace and Gromit Newspaper Strips Hardcover Volume 2
By: Various, Mychailo Kazybrid
Genre: Humor
Published by: Titan Books
It looks to be a good week for Titan Books and a good week for comic strip collections as well. I had no idea that Wallace and Gromit were stars of their own newspaper strip in England. It makes complete sense for the two most lovable characters in claymation history to have their own comic strip. If there was ever a property that seemed perfectly suited to the comic book page it would have to be Wallace and Gromit. The charm of their adventures just seem naturally suited for a translation into the sequential art form. If these comics are half as entertaining as the films these characters were spawned in I can say without a doubt that this will be a winning collection indeed. The fact that this is something that you'll be able to share with the kids in your family makes this book even more worth having.
Paul's Picks
The Humans #1
By: Keenan Marshall Keller, Tom Neely
Genre: Science Fiction/ Exploitation
Publisher: Image Comics
The Humans is a 70's biker/exploitation story about a roving chopper gang out of Bakersfield, who happen to be a bunch of apes. Imagine The Wild One meets Planet of the Apes.
I'm a huge fan of the outlaw biker genre, and seeing it mashed up with anthropomorphic apes just makes my heart happy. This looks to be a ton of fun, mixing a Corman-esque story (complete with Vietnam flashback!) and angst with Sons of Anarchy style violence.
Keenan Marshall Keller seems well versed in 70's alt-comix, and exploitation movies. Tom Neely draws some sweet choppers. And did I mention the apes? They're awesome. So much personality on each face. There's a 3 page preview on the comics Facebook page. If it doesn't bring a huge smile to your face, I feel sorry for you.
John Carter: Warlord of Mars #1
By: Ron Marz, Abhishek Malsuni
Genre: Science Fiction
Publisher: Dynamite Entertainment
Edgar Rice Burroughs was the first author that I was a "fan" of. I started with the Tarzan series, and quickly moved on to the Mars books. Around this time, Marvel was publishing their versions of Burroughs' heroes written by Marv Wolfman and illustrated by Gil Kane. I grabbed as many of them as I could.
When the movie adaptation, John Carter, didn't live up to box office expectations, I was pretty disappointed. I'm on record as really liking the movie (you can listen to the podcasts if you don't believe me) and wanted more. It really reminded me of why I loved the books: the adventure, the romance, and the unlikely friendship of John Carter and the Martian Thark Chief Tars Tarkas.
Dynamite Entertainment is the latest company to take on John Carter's adventures. Ron Marz has a great track record with cosmic heroes (Green Lantern and Silver Surfer) and pulp adventure (The Phantom) so he seems well suited for the task. I wasn't too familiar with Abhishek Malsuni before this book, but I had seen his cover for Zenescope's Grimm Tales of Terror #2. He's fairly new to the sci-fi world, but what art I've seen looks gorgeous.
Since it doesn't seem like we're getting a John Carter sequel anytime soon, this may be the best way outside of Burroughs's original books to visit the world of Barsoom.
Welcome to the first Part-Time Fanboy giveaway/contest! Lionsgate Films via Partnershub are giving certain websites the chance to offer their readers the opportunity to win a Vudu digital download of the somewhat classic horror film The Blair Witch Project!
But here's the thing…I hated The Blair Witch Project. When I saw it in the theater I actually demanded that the theater give me my money back after I was done watching the film! That's how much I disliked this movie!
But still, I get that there are a lot of you out there who may feel differently than I do. Heck, it's one of the largest grossing independent features of all time and may be one of the most profitable indie flicks ever…so the filmmakers must have done something right! I understand that many people out there may absolutely love The Blair Witch Project! It seems to have scared the crap out of a lot of people! So if you are in that number of people who have a burning desire to own a free digital copy of The Blair Witch Project then here's what you have to do:
Send us an e-mail at firstname.lastname@example.com telling us if you have ever either asked for your money back or walked out mid-way through a movie at the movie theater and why. The person with the best/craziest/funniest story wins!That's it! That's all you have to do!
Now, obviously, the judging of the entries is subjective so just know that I'll be the final judge when it comes to the winner. I'll be taking entries until Friday, November 7, 2014 at twelve midnight! Good luck! Oh, but before you try and remember your moment of movie going disgust here's a tiny bit of legalese to take in:
Each household is only eligible to win One (1) Digital Download code for The Blair Witch Project via blog reviews and giveaways. Only one entrant per mailing address per giveaway. If you have won the same prize on another blog, you will not be eligible to win it again. Winner is subject to eligibility verification.
While you're thinking about that horrible movie experience that made you walk out/demand your money back be sure to check out the #LionsgateHorror Blog app I posted below and share it with your friends! It seems like a relatively decent way to access some interesting horror flicks that are probably better than The Blair Witch Project!
In the meantime have a happy, scary, and safe Halloween!!!
Part-Time Fanboy. Full-Time obsession on a Part-Time schedule.]]>
Welcome to the Part-Time Fanboy picks of the week for October 29, 2014! Each week some of the crew at PTF will pick their most anticipated books for that Wednesday's releases based on their own individual tastes. Hopefully this list will help give you, the discerning comic book reader, some ideas on what to pick up at the comic shop during that particular week.
Kristian's Picks
Wonder Woman # 35
By: Brian Azzarello, Cliff Chiang
Genre: Superhero
Publisher: DC Comics
OK, so I don't give a rat's ass about the direction that DC has gone in since "The New 52" began. I do have to admit though that among all of the disastrous missteps that the company has made since the revision of their superhero universe this version of Wonder Woman, along with Scott Snyder's Batman books, was, and remained, the crown jewel of the line. While I've not been a fan of everything they've done on the book, Azzarello and Chiang's bold choices have made Wonder Woman a comic that has had people talking for the past several years…something that hasn't happened in regard to Wonder Woman for a long time. A particular standout for me has been Cliff Chiang's art. From the outset, Chiang's gorgeous take on Wonder Woman has made her book one of the most beautiful comics on the stands. It's too bad that the Azzarelo/Chiang era is coming to an end for what seems to be an editorially mandated direction that's going to pull WW in to more cohesively align with the rest of the DC Universe. This final issue of Azzarello and Chiang's reign on the book will hopefully be a distinctive end to what many consider to be one of the better, if not best, runs this comic has ever had.
Stray Bullets Volume One: The Innocence of Nihilism
By: David Lapham
Genre: Crime
Publisher: Image Comics
Just before the twentieth anniversary of its first issue, Image Comics is re-issuing the first trade collection of what I consider to be one of the best comic books series of all time, Stray Bullets. David Lapham's tale of crime and noir-like intrigue first captivated readers way back in 1995 with dark tales of humanity's criminal underbelly that featured a sprawling cast of characters. Stray Bullets went on a long hiatus as the realities of self-publishing independent comic became too much of a strain for Lapham and he was forced to pursue more lucrative freelance work or smaller creator owned projects. Luckily, it seems as if Image Comics has given Stray Bullets a bit of a shot in the arm by re-publishing the first forty one issues in the Stray Bullets: Uber Allies Edition as well as releasing a brand new series. Fans have literally been chomping at the bit for some new Stray Bullets material for years but for those who have never had the pleasure of reading the series when it was originally published, or for those who find the Uber Allies Edition a bit too intimidating, this trade is the perfect gateway for anyone who's been curious about this series. I use the term "gateway" because this trade will be the equivalent of a gateway drug for any comic fan. Lapham is a master storyteller who is brilliant at captivating his audience and moving his story along at a breakneck pace. Once you read this book you will craving the next edition of Stray Bullets as soon as you finish. It is that good. In all honesty, you should just be picking up the Uber Allies Edition but if you're on a limited budget or still don't believe that this series is as kickass as I'm saying it is…well do yourself a favor and make this trade the first thing you pick up off of the shelf at the comic shop this week.]]>
Written by: John Crowther
Pencils and Inks by: Dell Barras
Published by: AC Comics
Reviewed by: Paul Stephen Edwards
This 25 page debut comic appears as a flip book to Femforce #170, and it accomplishes a neat trick. It feels like a time-capsule from the mid 1980s. I can easily imagine myself reading this comic while eating a bowl of cereal while waiting for the next Saturday morning cartoon.
The book begins with a three-page "hero stops a robbery in process" bit that establishes the hero's strength, agility, and powers. At the end of the sequence, we see that the hero is a girl, Rochelle. We get a narrated origin story over the next five pages. Rochelle was born with powers because of a contaminated in-vitro fertilization. As such, she has human and cockroach DNA.
The story that follows that set-up is entitled "Get Ready for a Mind Crash," and features Fletcher Jakes, the evil CEO of Byrne Time Industries and Mind Crash, the story's supervillain. There are John Byrne references throughout the book, both overt and in style choices. Byrne Time's evil scheme revolves around the distribution of a Candy Crush-ish game.
As anyone who's ever played one of these games can attest, it's simply the cover for a fiendish scheme of world domination. In this case, the company isn't just satisfied with a legion of mindless slaves staring at their screens. Children are physically taken through the game by Mind Crash and held for ransom. I'm not sure whether this approach is more profitable than in-app purchases, but it's their plan and they're sticking to it.
Rochelle witnesses one of her friends being kidnapped through her computer monitor and follows. She engages in battle with Mind Crash and is defeated. Mind Crash then indulges in the time-honored tradition of monologuing which gives Rochelle time to unleash a new superpower and save the day.
This is a very traditional book in tone and execution. Crowther isn't out to break new ground in plot or storytelling. He's just out to tell Rochelle's story. He clearly has a great affection for her and the pressures that she endures. One of the story's best moments involves her winning a track meet, but none of her siblings or friends notice because they're too involved in playing Mind Crash.
In fact, a nostalgic tone permeates the book. The villain's monologue is a callback to a simpler time when people weren't immersed in social media and smart devices.
Death's Head artist Dell Barras draws in a cartoony, high contrast style. His layouts are simple and effective: 3 to 5 panels per page with mostly diagonal gutters and the occasional spash. His art matches the tone of the story perfectly. The villains have perpetually clenched fists and scowls, while the good characters are smiling and have looser stances.
Overall, Rochelle: The Teen Cockroach is a well executed homage to the Saturday cartoons of our youth. Except for a few stray "damn"s and "hell"s, you could imagine this fitting in nicely with an episode of Spider-Man and His Amazing Friends or Gargoyles.
I don't think that the book has completely established its own unique voice yet. That's mostly because at 24 pages of story, it contains a prologue, an origin, and a first adventure. That's a lot to accomplish, and there's very little time to slow down and let the characters breathe and establish themselves. Still, there's plenty of room to grow.]]>


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Revolving Door: A New Food Magazine, Changes at 'Bridal Guide,' and More
For those looking for another food outlet to pitch, news this morning is that famed pork chef David Chang, he of the delicious Momofuku restaurants, is launching a new quarterly magazine called Lucky Peach on June 22. Big names like Ruth Reichl and Anthony Bourdain will be involved with the debut issue. And the magazine will have an iPad app come July. McSweeney's will be publishing the magazine, so it should be an interesting read. [via FishbowlNY]
After the jump, more of this week's media highlights from mediabistro's Revolving Door Newsletter.
Kristen O'Gorman Klein has been named Web editor at Bridal Guide. She had been multimedia assistant at Good Housekeeping. (mb)
Julie Vadnal has been named associate editor at ELLE. She had been assistant editor there. (mb)
Michael Hogan has been named executive features editor at AOL Huffington Post Media Group and editor-in-chief of Moviefone and AOL TV. He had been executive digital editor at Vanity Fair. (FBLA)
Alison Caporimo has been named associate editor at Every Day with Rachael Ray. She had been editorial assistant at Allure. (The Daily)
Daniel Maurer has been named editor at The Local East Village. He had been co-founder of New York's Grub Street blog. (Poynter)
Click here to receive mediabistro.com's Revolving Door Newsletter via email.
- Big Changes in Tech Journalism: 'Fake Steve Jobs' Is Your New Valleywag
- Anna Wintour Basically Admits That Putting Kimye on the Cover of Vogue Was a PR Stunt
- Angry Tech Exec's Note to NYT Reporter Must Be Seen to Be Believed
- Now That Paper Broke The Internet, Where Does It Go From Here?