![]() The climactic fight in a church with a yakuza sword and a Gatling gun is easily the film’s biggest highlight that’s worth every buck.Ĭast: Nagarjuna, Sonal Chauhan, Anikha Surendran, and Gul Panag. Ghost 1990 PG-13 2 h 7 m IMDb RATING 7.1 /10 217K YOUR RATING Rate POPULARITY 1,272 51 Play trailer 2:21 4 Videos 99+ Photos Drama Fantasy Romance After a young man is murdered, his spirit stays behind to warn his lover of impending danger, with the help of a reluctant psychic. The film works to a large extent because it presents action like never seen before in Telugu cinema. Sonal Chauhan gets a meaty part and has quite a few scenes where she gets to flaunt her action skills. He uses his charisma effortlessly to make every frame look stylish on screen. Nagarjuna is cool as a cucumber in the role of a former agent turned mean killing machine. Lately, horror movies look awesome, and the ring scared me seriously even though the premise was quite stupid. The film does take inspiration from Hollywood blockbusters like Taken and John Wick but never tries to mimic what these films achieved in terms of action. The film takes its own time to take-off, quite literally, but the pay-off is worth the wait. Sattaru takes a very predictable plot and shifts all his focus on delivering solid action stretches. The attempt to make an ultraviolent action film without dumbing down its impact for the masses deserves special praise. The Ghost delivers what the promos promised, which is slick action with a lot of bloodshed. What happened five years ago in Dubai when Vikram swore to clean up the underworld and why he’s called The Ghost forms the crux of the story. As Vikram takes charge of protecting the family, he crosses paths with some men from his past in Dubai. Anu informs Vikram about the life threats she’s been receiving and she doesn’t want anything to happen to her daughter. The call takes him to Ooty where the siblings put their bitter past behind them. The story quickly cuts to five years later and we are introduced to Vikram’s sister Anu ( Gul Panag), who reaches out to him after 20 years. When his recklessness ends up costing the life of a young boy on a rescue mission in Dubai, the guilt eats him up and he decides to fix it by taking on the underworld. Nagarjuna plays Vikram, a former Interpol agent with anger issues. Also read: GodFather movie review: Chiranjeevi's charisma makes this thriller enjoyable If not for anything, you could just watch the film to see how handsome Nagarjuna looks while wielding the Yakuza sword. With his latest outing, The Ghost, Sattaru pushes the boundaries to present a slick action-thriller that’s largely engaging, despite a very predictable plot. The film gave a new lease of life to yesteryear star Rajasekhar, who turned out to be a revelation in a project that truly felt international in spite of its limited budget. Filmmaker Praveen Sattaru truly established himself as a filmmaker with great action sensibilities when he made PSV Garuda Vega a few years ago. ![]()
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![]() ![]() And it is Audubon who in 1833 identified the passenger pigeon, Ectopistes migratorius, as the most numerous bird on the continent, highlighting the point by describing a mile-wide flock of migrating pigeons that passed over his head and blocked the sun for three straight days. As part of what he called his “frenzy” for avians, the French-American naturalist attempted to survey and document in drawings all the native bird species of North America. Devere Burt.John James Audubon knew birds. One of the most interesting persons I have met in my life.Ĭlick on his name in the scroll down, or click on "our members" and he is top row, middle. He is an artist in his retirement, and has works in major galleries around the country. If you go to the link below, you can click on his name on the left side, and see him and some of his wildlife artwork. He and an associate had to scale a snow covered mountain and grab handfulls of nests, take them back to their laboratory and photograph every stage of the fleas life. He actually discovered a previously unknown Antartic Flea that lives their entire life in the nest of certain birds there. One of my favorites is when he was sent to the Antartic to look for fleas.Yes, fleas. To listen to his stories and exploits is truly awe inspiring. The individual I am speaking of is Devere Burt. ![]() But it happens dozens of times a year, I understand.Īs a side note. ![]() Personally I hope that both the Passenger Pigeon and the IBW are still around. Here is a link to the youtube video of this possible amazing find, that I dispute. The lack of a lightining bolt pattern on the body, etc, etc. Press stop ont he video when you get a good head shot and compare it to the Pileated Woodpecker. Here are side by side photos Check them out for yourself. I also believe that the bird in the video is obviously a Pileated Woodpecker. In a telephone pole! They seem to be 90% certain, but not 100%. Unconvinced because it seems to be nesting in a telephone pole and surely if that is the case, naturalists could ascertain for certain its existence. There is video evidence from Arkansas that seems to show a very good image of an IBW, yet I am unconvinced. There is a naturalist who is also very knowledgeable on the subject, that claims he observed one in Arkansas. Some of them also "believe" they have heard the call of an IBW, but again. But no photo or other evidence has been gathered as of yet. Members of his team "believe" they have witnessed an IBW from afar, flying by. He goes twice a year to a certain part of Florida with a team, to locate and verify the existence of the IBW. He is the former (now retired) President and CEO of the Cincinnati Museum of Natural History. One of the worlds most knowledgeable experts on the Ivory Billed Woodpecker, just happens to be in my pigeon club. Heck, my best friend claims to have seen a ghost! There have been more sightings of Big Foot (should be called "Big Feet" I think), little grey aliens, and Elvis, than there have been of the IBW. ![]() ![]() Leonhard in Passeier - San Leonardo in Passiria. Hotel Jägerhof is one of the most popular 3-star hotels in the city of St. Hotel Jägerhof offers breakfast for a fee.Ĭheck-in at the hotel starts at 2:00 and check-out is before 10:00 AM. This hotel has 2 different types of rooms available to relax in after a long day of traveling and exploring. The distance from the hotel to Gilfenklamm is 6.3 miles (10.2 km). Leonhard in Passeier - San Leonardo in Passiria like Gilfenklamm, Zwölferturm, and Penser Joch. The location of your hotel means you'll have easy access to the best attractions in the city of St. Located 0. The 3-star hotel is located 2.8 miles (4.4 km) from the city center. Youre eligible for a Genius discount at Hotel Jägerhof To save at this property, all you have to do is sign in. Skigebiet Ratschings-Jaufen ist innerhalb von 10 Minuten Autofahrt erreichbar. This accommodation is ideal for exploring the most famous attractions in the city of St. Leonhard in Passeier liegt 65 km vom Flughafen Bozen entfernt und stellt den Gästen einen Wellnessbereich, ein Restaurant und die Restaurants zur Verfügung. The hotel is 15 minutes' drive from San Leonardo in Passiria centre, easily reached by a public bus that stops right outside. The hotel's restaurant is recommended by numerous guide books and uses only the best seasonal ingredients. Hotel Jägerhof is located in the neighborhood of Burggrafenamt - Burgraviato. Einmaliger Geschmack, Entspannung, Erholung und Freizeitaktivitten fr die ganze Familie, all das finden Sie im Hotel Stroblhof im Passeiertal. A buffet breakfast is served each morning. The distance from Hotel Jägerhof to Innsbruck Airport is 29.9 miles (48.1 km). This accommodation is ideal for exploring the most famous attractions in the city. This accommodation has an average rating of 4.6 out of 5 and has been reviewed by 119 guests. Hotel Jgerhof is located in the neighborhood of Burggrafenamt - Burgraviato. This hotel offers you everything you'll need for an enjoyable holiday, including free Wi-Fi, swimming pool, and much more. Prices for the rooms are from $358, and it's located at Via Passiria, 29.Enjoy your vacation at the 3-star hotel, Hotel Jägerhof in the city of St. This place has an outdoor pool, skiing, a pool bar, and room service. The guest rating of Stroblhof Active Family Spa Resort is 8.80 out of 10. Rooms here start at $94 before taxes and depending on the season. Garni Birkenau has a guest rating of 9.00 out of 10, and offers skiing, breakfast, outdoor tennis, and hiking. Its guest rating is 9.30 out of 10 from previous guests. With rooms from $500, Hotel Bad Fallenbach, at Jaufenstraße 23 provides an outdoor pool, skiing, room service, and a restaurant. Offering skiing, a restaurant, a bar, and breakfast, it also has a guest rating of 9.50 out of 10 from previous guests. ![]() ![]() It has a 9.70 rating out of 10 from previous guests.Ī great place to stay is Hotel Jagerhof which has rooms starting at $158. Explore by amentities, price, map, and rating and let us help you choose the best. It offers an outdoor pool, skiing, room service, and a restaurant. Search and compare St Leonhard in Passeier, Italy hotels and accomomodations using our interactive hotel finder. Located at Kellerlahne 3a, Golf & Spa Resort Andreus has rooms from $552 (before taxes). ![]() ![]() Questo hotel si trova a 29,1 km da Funivia Monte Cavallo-Rosskopf e 29,3 km da Funivia Hochmuth.Avrai a disposizione molti servizi ricreativi, tra cui una sauna, nonché una terrazza e un giardino da dove potrai ammirare il paesaggio. Here are a few of the top rated hotels in San Leonardo in Passiria according to guests, and they are all representative of the type of hotel you can find here. Jägerhof Geniesser & Wanderhotel di San Leonardo in Passiria si trova a 1 minuti di auto da Ortler Skiarena e 7 minuti da Golfclub Passiria.Merano. Is it expensive to stay in San Leonardo in Passiria? Not always. How much are the best hotels in San Leonardo in Passiria? View Highest Rated Hotels in San Leonardo in Passiria So, here are the price ranges of the top hotels in San Leonardo in Passiria for your next trip. The average price of the highest rated hotels in San Leonardo in Passiria is $239, and the median price is $157. Prices of the Highest Rated Hotels in San Leonardo in PassiriaĪre you looking for the best hotel in San Leonardo in Passiria? After we analyzed the 10 highest rated hotels in San Leonardo in Passiria (the top 25%), we found a variety of options at different price ranges. ![]() ![]() "We are thrilled to bring together entrepreneurs, investors, industry experts, and thought leaders to help companies that provide solutions to consumers, create jobs, and contribute to our economy," said Diana White, CEO of Chandler Innovations. "Startup Connection was successfully held virtually last year, but we are so delighted to be able to offer an in-person experience once again." Attendees will learn how to leverage technology to work smarter and create lasting ties with their customers, employees, and the community. This year's theme is " Harnessing Technology to Build Community." Presenters will explore the various ways technology has impacted how organizations conduct business and build relationships with all stakeholders. These workshops will be held at the ASU Chandler Innovation Center. The second day will include a series of interactive workshops and panel discussions featuring some of the best subject matter experts in the state. ![]() The reception is sponsored by Fennemore, one of Arizona's prestigious law firms and 2021 Top Listed Law Firm Rated by Best Lawyers in America ®. "As an East Valley native, I know how important it is to support local small businesses, especially ones looking to improve our community through technology and innovation," said Schwartz. The reception's master of ceremonies will be Ian Schwartz, an Arizona celebrity and renowned Morning Meteorologist at KPHO/KTVK Arizona's Family. Networking, food, drinks, and special recognition of Chandler Innovations Incubator's fastest-growing companies. The free two-day event starts with a reception on Friday night at the Crowne Plaza Hotel and Golf Resort in Downtown Chandler. Morning Meteorologist at KPHO/KTVK Arizona's Family ![]() ![]() ![]() The sesame seeds and green onions really add to the flavor and texture, so make sure to grab a container of them in the asian aisle of your grocery store. So, to make sure you have a nice crispy outside that temperature MUST be around 350. Fry the chicken in the oil until well browned on all sides, 5 6 minutes. Bread and Fry the Chicken: Working in batches, dip the chicken into the egg, and then dredge into the flour mixture, coating completely. In a small bowl, whisk cornstarch with 1 Tablespoon of water to form a paste. If it's too low then you'll be left with a soggy breading. Heat the Oil: Fill a large skillet about 1/2-inch deep with oil. In a medium pot, add honey, vinegar, brown sugar, soy sauce, ketchup, ginger, garlic, and red chili flakes. I want to note, that when you are cooking up your chicken its really important that the temperature of your oil is spot on. My kids are big fans of the honey chicken at PF Changs and let me tell you, this is WAY better than that! They really love this meal which makes mama happy. press on MANUAL or PRESSURE COOK (this depends on which Instant Pot do you have), and cook on high for 3 minutes. Cover the pot with the lid, and make sure that the valve is in sealing position. This honey sauce is so divine, its sweet and tangy and oh so yummy. Add the chicken to the Instant Pot, followed by soy sauce, garlic, ginger, ketchup, hot sauce or sriracha. The original recipe is from Rasa Malaysia and I've made changes to better suit our family, like decreasing the sugar and replacing it with honey. No MSG for starters and nothing but fresh ingredients and an abundance of veggies on the side. Once the sugar has fully dissolved and a low boil is reached, whisk in the water and cornstarch. Add the soy sauce, brown sugar, orange juice, hoisin sauce, ground ginger, and garlic to the saucepan on medium-high heat. Cook for 60 seconds, then add the rehydrated soy curls. While the chicken is cooking, in a small saucepan, begin to make the sauce. Sauté: add 1 tablespoon of sesame oil to a pan over medium-high heat once warm, add white portions of the green onions and the garlic. In the meantime, measure and prepare all remaining ingredients. Using a slotted spoon, continue to move the chicken around the pot and fry for around 3 minutes until lightly golden or crispy. I love knowing exactly what is going in my Chinese food. Press the soy curls thoroughly to remove excess water. If you are craving some Chinese food then give this a try. ![]() Skip the takeout, save your money and wow your family. boneless skinless chicken breasts, cut into thin strips 1/4 cup cornstarch 2 Tbsp. When you want something cozy, comforting and warm (no, not a blanket) it calls for some crispy sticky honey chicken. Winter is being replaced by spring quickly around here and I'm ready for some fun dinners. Are you in a winter soup funk? Our weather has been gorgeous, with a blip of rainy weather, low 70's and we've been enjoying time in the backyard, grilling and going on hikes. ![]() ![]() ![]() He told Interview in 2020, “When we had our first kiss scene in season two, they were asking us, ‘Are you ready?’ My heart was pounding, I was shaking. “I understand why some actors don’t interact with people they’re supposed to hate… I get that, but Mary and I became friends.”Īs for Buchanan, being real-life friends with his co-stars has actually made shooting certain scenes awkward. And I couldn’t act anymore,” List joked in a 2020 interview with Collider. “I started to like Mary, and it was horrible. Even though Sam and Tory are enemies, the two actors cannot be more different off screen. Young love… who knew it was so painful? Rest assured, the Love Quad leaves all the fighting for the cameras. Having been wronged by the same person, Tory befriends Robby.īut what’s the Love Quad really like in real life? He knows he can’t trust anyone in Miyagi-Do, especially Sam. Robby is out of jail and turns to Cobra Kai. One of the greatest prophets of our time once said, “You’re probably with that blond girl who always made me doubt.” And she was right. Sam and Miguel reconcile and acknowledge that they never really moved on from each other. He comes to terms with the dark side of Cobra Kai and no longer wants to be associated with it. Cobra Kai gangs up on Miyagi-Do at a carnival one night, and Sam watches in horror as Hawk breaks Demetri’s arm. Tory shows no mercy, however, and continues to terrorize her nemesis. While Miguel’s in a coma, Sam’s still traumatized by the school fight. The power couple is officially Miyagi-D o-ver. As if the drunken kiss wasn’t already salt in the wound, Robby feels even more betrayed by his ex. (Apparently, prison doesn’t care about your love problems.) From his cell, he watches a news interview with Sam, who’s helping with a fundraiser to pay for Miguel’s hospital bills. After Robby’s arrested and put in jail, he’s unable to return Sam’s emails. Robby’s on the run after the tragic school fight, and Sam is consumed with guilt, thinking it’s all her fault. Just a normal day at school, right? (Seriously though, that’s a lawsuit waiting to happen.) Hell breaks loose in the hallways, but the chaos ends when Robby kicks Miguel off a balcony and leaves him in a coma. Robby hears all of this for the first time. (You know some poor school secretary is about to lose her job.) During their face-off, Tory accuses Sam of kissing Miguel at the party. “I’m coming for you, bitch,” she says to Sam. ![]() One day at school, Tory hijacks the intercom. Where are the parents in this town? Sam drunkenly kisses Miguel as Tory witnesses from afar. Tory helps Miguel overcome his previous relationship, and he encourages her to let her walls down.Īs both couples bask in their honeymoon phases, there’s another high school party with alcohol involved. She’s a skilled fighter with a mysterious side to her - and he’s intrigued. Meanwhile, Miguel tries to move on from Sam and starts dating Cobra Kai newcomer Tory. Soon enough, the karate counterparts realize that they may be more than just fighting partners. Sam and Robby’s training at Miyagi-Do teaches them to be in sync with one another, and this brings the pair even closer. In a jealous and drunk rage, Miguel pushes Robby but accidentally hits Sam, causing her to break things off. One evening, Sam and Robby attend a beach party together as friends. He’s confident but aggressive, strong but violent. ![]() While learning karate at the LaRusso residence, Robby and Sam quickly strike up a friendship.Īs Miguel trains at Cobra Kai, Sam notices changes in her boyfriend. Unaware of this feud between two grown men who clearly have never gone to therapy, the teens begin dating.ĭaniel takes Johnny’s estranged and troubled son, Robby, under his wing at LaRusso Auto Group and his Miyagi-Do dojo. The catch? Miguel’s Cobra Kai sensei, Johnny Lawrence (William Zabka), is a longtime rival of Sam’s dad, Daniel LaRusso (Ralph Macchio). Sam meets underdog Miguel, and it doesn’t take a scientist to know there’s chemistry. Two households both alike in dignity, in fair Los Angeles, where we lay our scene. ![]() ![]() ![]() Parents placing money into multiple meal accounts will only be assessed the $2.75 fee once per deposit transaction. The convenience fee is $2.75 per deposit transaction. In order to use the online prepayment service, a convenience fee for each transaction will be assessed to cover the bank fees. Deposit confirmations will be sent directly to parent e-mail accounts. Money deposited into a mySchoolBucks account will usually arrive by the next morning. Payments may be made with a major credit or debit card (VISA, MasterCard and Discover) or eCheck at any time. If you have more than one child in the district you can handle all online pre-payments from the same online account. You will receive a confirmation number (to help you locate this transaction at a later date) and a printable receipt will open in a new window (after printing this page, close the receipt window and click “Finish” to complete your order).Review your order and click “Place Order” when you are finished.You can use a major credit card or eCheck to make your payment. You will be directed to a secure webpage to enter your payment information and Security Code.If you need to adjust the amounts, click on “Continue Shopping.” If the information is correct, click on “Check Out Now.” DO NOT deposit money for your entire family into ONE child’s account. If you have more than one child, enter the amount you wish to deposit into the column next to each child’s name. Enter an amount in the Deposit column next to your child’s name.Click on the “My Household” link on the left-side of the navigation bar.Click on “Add Another Student” to repeat the process for additional children.If the system finds a match, please verify it is the correct student and select the “Add Student” button.Enter student information (name of school, first name, last name and date of birth) and click “Find Student”.Click on “Look Up Your Student” to add one or more students.Click on the “My Household” link on the left-side navigation bar.How Do I Add Students to My Family Account? Create your Parent User Credentials (Login ID, Password and Security Question), click on the Notice Disclaimer box and click “Register.”.Enter your Parent Information (name, address, phone number and e-mail address) and click “Continue.”.Select “West Genesee Central School District” and click “Continue.”.Select “New York State” and click “Continue.”.Click on the “register for a Free Account” button.Money will be deducted accordingly from their account. The Myschoolbucks system gives each student a debit “account” that allows the student to purchase lunch and a la carte items from their cafeteria. Pay for lunch and/or a la carte items with cash or check at the time of purchase.Prepay by cash or check made out to “West Genesee Food Service.” Money should be placed in an envelope labeled with your child’s name and “lunch money” written on it.West Genesee parents now have three ways to pay for their child(ren)’s lunch and a la carte items: Questions about LCTI’s student meal accounts? Call the Food Services Office at 61.Parent/Guardian Food Services Information MySchoolBucks Contact MySchoolBucks at 1-85 or for technical support. Be sure to have your student’s LCTI identification number handy and when prompted to select a district, choose Lehigh Career & Technical Institute. MySchoolBucks offers a free smartphone app - MSB Anywhere - that’s available for both Apple and Android devices, so parents can monitor their student meal accounts on the go. Parents can also check account balances, set up low-balance alerts, schedule automatic payments and review recent purchases with the click of a button. MySchoolBucks is an online payment service that lets parents or guardians add money to their student’s meal account with a credit or debit card, eliminating the need to send cash or checks to school. | Make prepaying for your student’s school lunch easier and sign up for MySchoolBucks. Sign up for MySchoolBucks to make managing your student’s meal account easier. ![]() ![]() ![]() To be fair, this isn’t just Guild Wars this is pretty much every MMO I can think of, GW’s offering is just a little more palatable. While I still like the way GW2 handles questing hubs a lot and the game still rewards my meandering (even more so in certain areas where there are huge jumping puzzles to waste hours on), the process of ‘find area, kill stuff, click on interactive item, gather and turn in other item, get XP’ gets repetitive. ![]() While treating myself like a prisoner being tortured by sleep-deprivation was FUN, the lack of subscription and dynamic instancing in GW2 doesn’t make me feel like I’m missing nearly so much when I’m not playing. I’m not playing Guild Wars 2 at the breakneck pace I have in other MMOs for World of Warcraft expansions I’ve been known to play for as long as possible, get two hours or less of sleep, go to work and come home to do the same thing until I’m level capped. As with most things, there will always be better builds than others, but there’s a wide variety of builds that won’t get elitist jerks glowering down their noses at you. You can put up to 30 points in each tree, leading to a great deal of possible variation. Each class (“profession”) has an unique fifth stat that improves class-specific powers, like a thief’s stealth or an engineer’s toolkit. Secondary attribute (Boon (buff) Duration, Condition (DoT) Damage, Condition Duration, Critical Damage and Healing Power) and give you important bonuses. The Black Citadel? I think you mean ‘The Death Star,’ dude. Each of the four prime stats (Power, Precision, Toughness, Vitality) have their own trees, points in which increase that stat, its corresponding With so much of your survival in your own hands and different ways to approach one’s class, planning a build is anything from cookie-cutter. One of the prevailing themes of Guild Wars 2 is “the trinity is dead,” referencing the lack of dedicated tank, healer and DPS roles. As an additional layer, you’re able and encouraged to swap weapons mid-combat, letting me easily go from range to melee or change melee styles from backstab to frontstab by swapping mainhands. ![]() These abilities can wildly or minutely determine your actual playstyle my thief can shoot stinky centaur at range with her dual pistols or backstab Communist dredge (they live in Molesk, Moleberia and Molengrad!) in melee with daggers. As I mentioned in my previous article, your actual play abilities are determined by which weapons you have equipped each class can equip specific weapons from available types. The above being said – I adore building characters in GW2. Guild Wars 2 is not an intuitive game expect to spend some time looking up information on everything from the way abilities work to gear sets. There’s a great wiki but I shouldn’t have to rely on a wiki to teach me important aspects of gameplay the game itself should be doing that. Your first level gives you a very basic tutorial in movement and dodging and then sends you off into the world without an explanation of why each ability slot has four abilities stacked on it or what the hell a combo is and how you pull them off – a feat I still haven’t figured out after over 100 hours of play. However, the game never actually teaches you how DO most of this. GW2 does a good job of adding more elements to break this tedium: active dodging, dynamic abilities, weapon swapping in combat, etc. I want some depth to my gameplay, I want my game style to be more than the age-old WoW rogue press 2, 2, 2, 3, 4 in sequence until the boss explodes in loot (none of which is ever for me). It’s not massively simplified as some MMOs I’ve played fall into being (WoW, DCUO, Rift) and I think that’s great. My biggest complaint with Guild Wars 2 is that the game is hard to learn and it doesn’t NEED to be. Instead of a boat that’s a house…a house made out of boats. ![]() ![]() ![]() How to join Adobe’s Creative Cloud for free.The 10 most common myths about Creative Cloud.Don’t need full Cloud? Get PS + LR for $9.99/month. ![]()
![]() ![]() The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). This study demonstrates the potential use of MRTF/SRF inhibitors to prevent drug-induced lung fibrosis in a clinically relevant model of drug-induced disease. Prednisolone led to marked increases in lung fibrosis. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Mice treated with 100 mg/kg CCG-257081 gained weight vs. Animals were given intraperitoneal bleomycin for four weeks, and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib), or clinical standard of care (prednisolone). The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of chemotherapy-induced lung fibrosis. ![]() In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50s of 4 and 15 μM, respectively. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. A number of drugs can cause fibrosis, many of which are used to treat cancer, including chemotherapy agents and immune checkpoint inhibitors. A recently developed analog, CCG-257081, which co-crystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis.ĭrug-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality. Finally, using both siRNA and a previously validated pirin inhibitor, we show a role for pirin in TGF-β induced gene expression in primary dermal fibroblasts. We also show with genetic approaches that pirin modulates MRTF-dependent SRE.L Luciferase activation. Using biophysical techniques including isothermal titration calorimetry and X-ray crystallography, we verify that pirin binds these compounds in vitro. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent co-transcription factor, as a target of this series of compounds. Although these compounds are efficacious, the molecular target is unknown. A series of compounds (including CCG-1423 and CCG-203971) discovered through an MRTF/SRF dependent luciferase screen has shown remarkable efficacy in a variety of in vitro and in vivo models, including melanoma metastasis and bleomycin-induced fibrosis. ![]() |
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