The playback of CDs and DVDs is also possible with these players. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol, IJHPCA, 2022 The Coronavirus in a Tiny Drop, VMD visualizations of aerosolized SARS-CoV-2, NYT, 2021 NIH Director's blog highlights neuroscience adaptation of VMDĪI-driven multiscale simulations illuminate mechanisms of SARS-CoV-2 spike dynamics, IJHPCA, 2021 Intelligent Resolution: Integrating Cryo-EM with AI-Driven Multi-Resolution Simulations to Observe the SARS-CoV-2 Replication-Transcription Machinery in Action, IJHPCA, 2022 At CeBIT in March 2006, NME demonstrated a prototype VMD player and announced that they were expecting to launch the format in the third quarter of 2006. #Hd vmd player 1080pThis first generation HD VMD Player offers True High Definition in 1080p in addition, it is backwards-compatible and capable of playing existing DVD formats. Multiscale modeling and cinematic visualization of photosynthetic energy conversion processes from electronic to cell scales, J. NAMD and VMD part of the team winning the ACM COVID-19 Gordon Bell Prize for 2020 NME HD VMD Multilayer Player ML622s High definition playback delivers 1080i/p resolution at up to 40mbps transfer rate, 6xhigher than DVD or even HDTV, with 24-25 frames per second, delivering an ultra crisp, realistic picture. Scalable molecular dynamics on CPU and GPU architectures with NAMD, JCP, 2020 The Coronavirus Unveiled, VMD visualizations of SARS-CoV-2, NYT, 2020 A VMD file is a multimedia file used by various CD-ROM video games developed by Sierra Entertainment, most notably Phantasmagoria. Low Cost New Medium Enterprises (NME) brings about the latest competitor format in the high-definition market in the form of the ML622S HD VMD player. VMD test builds for MacOS X 10.15 "Catalina" (April 24, 2020) Past announcements GalleryĪn Accessible Visual Narrative for the Primary Energy Source of Life from the Fulldome Show Birth of Planet Earth, 1st Place Winner, SC'19 Viz. It contains video and audio data in the Sierra Video and Music Data (VMD) format. HD DVD-RW, HD DVD-RAM High-Definition Versatile Multilayer Disc (HD VMD). VMD files are typically used for title and logo animations and in-game cutscenes. DVD authoring is the process of creating a DVD video capable of playing on a. ShowcaseĬhromatophore VR demo (VMD + Unreal Game Engine) shown in NVIDIA booth at SC'16Ĭhemical Visualization of Human Pathogens: the Retroviral Capsids, Finalist, SC'15 Viz. Visualization of Energy Conversion Processes in a Light Harvesting Organelle at Atomic Detail, 1st Place Winner, SC'14 Viz.
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On the other hand, tracks such as "Hold On" and "Bitter Apple" are more serene, sensuous and well crafted. They are also the most reminiscent of Depeche Mode - sprawling and decadent.Yet it seems that minus Gore's melodramatic input, these songs become strangely optimistic and hopeful. "Dirty Sticky Floors" and "Bottle Living" both clearly reflect the hedonist that Gahan's image tends to conjure up (in the lead up to this album, he has revealed an alter-ego "Evil Dave" as the influence behind these tracks). Paper Monsters is produced by Ken Thomas (Sigur Ros) and co-writing credits go to Knox Chandler (ex-Psychedelic Furs guitarist and musical all-rounder).Despite this collaboration, the album is deeply autobiographical throughout. #PAPER MONSTERS RELEASE SERIES#Comprising a series of sincere and polished narratives and drawing on many musical influences, you shouldn't expect a Depeche Mode album. So given his reticence in the past, it is a pleasant surprise to find that Paper Monsters is such an assured debut. If you want to see a particular app featured, drop us a line or suggest it in the comments.As the iconic frontman of Depeche Mode, Dave Gahan has lived the archetypal rock 'n' roll lifestyle and has somehow lived to tell the tale, although for 6 minutes in 1996, he was clinically dead.Luckily, he survived this tormented period of his life, but while colleague Martin Gore has extensively explored solo territory (including current release, Counterfeit 2), it seemed slightly odd that Gahan had never seen the appeal of relaying his exceptional story on his own terms. #PAPER MONSTERS RELEASE WINDOWS#It may all sound a bit familiar, but while Crescent Moon's platformer may not be a treasure trove of new ideas, the concepts it cribs are neatly arranged and wonderfully executed.Īpp of the Day highlights interesting games we're playing on the Android, iPad, iPhone and Windows Phone 7 mobile platforms, including post-release updates. Here you must time your jumps perfectly to guide a tiny dragon across an automatically scrolling landscape.Īt a time when the App Stores are swamped with copycat games, Paper Monsters is much more than that. This little extra is, by itself, better than a lot of other 69p fare available on the App Store. #PAPER MONSTERS RELEASE FOR FREE#It opens up for free once you've finished the main game's first world. Players can also unlock an infinity-running mode, Drag 'n Dash. Originally, Paper Monsters only lasted 16 stages and several of those were quick boss fights, but developer Crescent Moon has just added a Valentine's themed present in the shape of six additional levels. No box quotes to speak of, he's a silent protagonist. More of these can bought through in-app purchases and swapped for extra outfits and hats for your corrugated cardboard friend to wear, but all of this is entirely optional. There are other collectibles, and special gold coins are awarded here and there. He's limited to three hearts' worth of life, which can be swiftly taken from him by passing enemies, falling icicles and other aggressors.Įlsewhere, Mario-style coins are replaced with buttons, and every stage features a number of hard-to-reach golden paper clips to acquire. There are warp pipes that send your cardboard hero scuttling into the background of a level, or aquatic stages where you turn into a curiously waterproof paper submarine equipped with miniature torpedoes.Ĭardboard-box-man's health is a constant worry, however. While Paper Monsters' visuals draw the eye, its levels carefully trace the outlines of many a platformer before it. The art style looks good enough that you'll want to reach in through the screen and start pulling things apart along their Sellotape seams just to see how it all works. #PAPER MONSTERS RELEASE FULL#The game's origami landscapes and wafer-thin scenery are a delicious collage for the eyes, full of papier-mâché toadstools and flowers that bloom as you pass. #PAPER MONSTERS RELEASE HOW TO#He also attended the Nintendo school of how to defeat enemies, so cheerfully hopping on the heads of your folded paper foes sends them crumpling into ticker tape. Your angular paper pal can bound over obstacles and perform an acrobatic pirouette that double-jumps him to higher platforms. You command his movements via a virtual control stick for your left thumb and a jump button for your right, which are wisely kept hidden by default to avoid mussing up the graphics. He's a friendly little guy would probably rip off an arm if you needed somewhere to write down a shopping list. The jovial star of Paper Monsters is a nameless but constantly smiling cardboard box who merrily trundles along on tiny cut-out legs. If Art Attack's Neil Buchanan ever made a platform game, it might look something like Paper Monsters: a simple side-scrolling affair set in a bright, homemade world. Puzzles and environmental interactions form a large part of Memoranda. Navigational points can be double-tapped for instant transition even if you’re on the opposite side of the screen, and are indicated by a green icon when using the highlighter so it’s hard to get lost. Both touch and button controls feel nice and fluid, with very short transition times and some helpful little QoL features such as an objective highlighter. Memoranda is a very well-executed point-and-click game. Gameplay Please say I’m not the only one who thinks that’s creepy! The game is best described as short and bittersweet, as while charming it generated a sense of unease that left me with a furrowed brow by the time I was done. The overall tone of Memoranda is definitely melancholic, and a little dark, with references to topics such as suicide and depression sprinkled liberally throughout the various stories. This leads to the most unusual and illogical sequence of events I’ve ever seen in a game, from helping a wheelchair-bound man escape his restrictive mother to helping the florist worm out of a holiday she doesn’t want to go on. One day, out of the blue, she starts having trouble remembering her name. One occupant of this bizarre place is Mizuki, a young woman with a rather nasty case of insomnia thanks to the persistent dogging of a peculiar and primarily invisible old sailor. It’s a town where the normal rules of logic don’t apply, where it’s completely normal to meet humanimals – people who are transitioning between a human and an animal, or vice versa – and people who are utterly obsessed with the most mundane of things, such as making spaghetti. Memoranda takes place in a quaint seaside town with no name, occupied by a whole host of quirky individuals. MEMORANDA SURVIVAL GAME CODEReview code used, with many thanks to CarbonFire Studio! Story and Characters I really appreciate you smoking in my apartment when I just want to sleep, honest… You can find out more, or just check out a couple of screenshots, by heading over to Steam.Developer|Publisher: Bit Byterz | CarbonFire Studio If this sounds like a game you might be interested in, you'll be glad to hear that Memoranda is coming in only a couple of weeks, on January 24th to be exact. Whether that something relates to their sanity or just a roll of toilet paper, I have no idea, but its certainly a compelling mystery. A man might appear as a giant elephant in one scene and a giant frog in the other, but the one thing that links these seemingly random elements together is the simple fact that they are all losing something. But don't be fooled by their appearance as things aren't always exactly as they seem. MEMORANDA SURVIVAL GAME FREEAnd if you're worried about story and puzzle spoilers, I've checked it over twice and I haven't seen anything that would ruin the game for you, so feel free to have a look:Īfter watching the trailer you're probably well aware that Memoranda has a rather. Since this is something that is incredibly hard to explain through words alone, allow me to instead show you the bizarrely charming trailer. Since this was my first time hearing about him I decided to do a bit of research into his work, and apparently most of his stories have a surreal atmosphere about them - words I would use to describe Memoranda as well given that its a story of a young lady who slowly realizes that she is forgetting her own name! Memoranda is a hand-drawn point & click adventure game inspired by Haruki Muramaki's short stories. You have 4000 rounds of machine gun ammo and it is honestly tricky to use all of it up.Withstanding bullet after bullet, and an occasional missile or two. It may seem lightweight, but it can take some heavy damage.In overall durability, strength, and versatility, the Coyote is unmatched. However, you’ll be pleasantly surprised when you find its hidden arsenal of naval mines inside. It is a lightweight helicopter with 2 mounted machine guns in the chaotic world of Just Cause 4, that isn’t a whole lot to work with. This is a perfect example of how first impressions can be deceiving. It is very common to find on the Black Hand and Army of Chaos bases and is regularly used by both forces throughout the map.ġ. A5 Coyote Assault Helicopter (Best for Durability)įor Rico, this is a good way to start the day.Ĭlick the link to check out what the A5 Coyote can do!.Completing the mission Training: Communication Skills to unlock for supply drops.Which you can easily take down with your missiles. In a worst-case scenario, you can use it to flee the only thing fast enough to catch you is another Spectre. They are found almost everywhere, which makes them the perfect in a pinch aerial friend. If the need arises then it also makes for a great getaway vehicle So, grapple on to it, high jack it, and raise some hell. If you are in a pinch, this is commonly used by the Black Hand.On top of being the fastest helicopter, it also holds a total of 100 missiles that are strong enough to destroy even heavy armored vehicles with a few hits.They are often used by the Black Hand and the Army of Chaos, so they are easy to find, with the added perk of being the fastest helicopter in the game reaching speeds just over 300 km/h. #720P JUST CAUSE 4 FULL#Picture this, you’ve gotten into a little scuffle with some Black Hand soldiers when they call for backup and suddenly you’re set upon by the full forces of an army? They’re coming at you from all sides and you're running out of ammo! Don’t panic, instead use one of these to turn the tides. Want to see the Spectre in action? Check out this video! The sleek and speedy Spectre in all its glory. Or you can sometimes steal them from the Black Hand or the Army of Chaos.Ģ. Spectre Attack Helicopter (Best for Speed).The Bloodhound Heli is one of those items, taking over the Hatun Ukucha region unlocks it for supply drops. Since you are liberating a nation you must advance the frontline of your army to take over different regions of the map. By completing multiple missions in one region, you weaken it for your army to take over. Conquering regions allows you to advance in the storyline, as well as, unlocks different weapons and vehicles for supply drops.They are occasionally used by the Black Hand and Army of Chaos, so you can sometimes be found at base sites.You only need a few of them to take down even your toughest foes. And for when you're dealing with a bulkier opponent that is totting around some heavy armor, you have 100 explosive missiles.You get a maximum of 1,000 machinegun rounds, that easily take down other vehicles and helicopters with a few consecutive hits.Eliminate any enemy in a matter of moments when you’re behind the wheel of these flying behemoths. It may not be the fastest or most durable, but in terms of strength, it takes the cake. This bulky aerial beast comes equipped with high-powered machine guns and explosive missiles. If you’re looking to optimize destruction, then this is the helicopter for you. You’ll learn all about their different strengths and practical applications you can use in your own gameplay experiences.ģ. Bloodhound Siege Helicopter (Best for Strength)Ĭheck out its destructive capabilities here! In this article, we will be taking a closer look at some of the best equipment you have in your aerial arsenal, helicopters. When you are risking your life to liberate an entire country of people, it may be a good idea to get to know all the tools you’ll have at your disposal.Įven more important is understanding their strategic strengths. This would definitely be considered that main guitar solo in the song and it has just a little bit of everything in it including large bends, fast legato licks, rapid shifts, string crossing licks, slides and more. I will also show you how I am picking select sections in order to help you be able to get it up to speed easier. Just simply piece it together phrase by phrase like I teach it in the video. #Lynyrd skynyrd sweet home alabama how toIt actually isn't that difficult to understand how to play. In the third lesson video I will tackle the main solo note-for-note. There are some tasty licks in this one so don't overlook it! In fact, learning this solo may serve as a nice warm-up for the following video lessons. In it I while tackle the first short but sweet guitar solo. The second video begins the solo marathon. There are some really cool guitar licks thrown within that chord work so that video alone might keep you busy for a while. In the first video below I will demonstrate how to play all of the intro, chords and rhythm guitar parts that are so iconic for the entire song. It is probably one the of the top 5 most famous songs of all-time. Needless to say, "Sweet Home Alabama" needs no introduction. This is not gonna be your typical Sweet Home Alabama guitar lesson! In these video lessons I am gonna not only break every section of the song down note-for-note, but for any of you brave guitarists out there I am also gonna teach you how to play the piano solo on the guitar! □ Rather than imagine elaborate levels themed on scenes, this game feels far more like chugging through the scene chronologically, before being spat out the other end with little sense of narrative flow. The Lost World feels especially spare, and obviously Jurassic Park III gave them a lot less to work with. LEGO JURASSIC WORLD GAME FREEYou’ll plough through most of the movies’ stories within two or three hours each, before Free Play. Although bearing in mind that they’re usually dauntingly enormous, this may be an attractive element to some. It’s a rather shorter game than we’re used to from TT Games. You’ll also occasionally play as dinos in the levels themselves, usually in rather boring quick-time-event-laden fight scenes. Once a movie’s story is complete, the hub (as well as all the levels, as usual) becomes accessible in “Free Play”, meaning you can re-explore it with any of the hundred or so characters you’ve unlocked.Īnd this time out, those characters include dinosaurs! Hurrah! There is much fun to be hand stomping about levels as a raptor, or baby T-Rex, etc, completing tasks only big lizards can do. To move from level to level, you must complete a section of each movie’s hub. There’s no big twist here, other than the four hub worlds (islands) being much more like a large sprawling level of their own. LEGO JURASSIC WORLD GAME SERIESWhat’s perhaps most striking about LJW is that it’s the most vanilla the series has been for a long while. And, as with every game in the series, you play as either one or two player, controlling as many as five or six characters in any level, each with different skills and tools. So, everyone knows the score by now, right? This time it’s all four Jurassic Park movies, recreated in Lego and gently spoofed, each famous scene reimagined as an exploratory platform game. And this is pretty much the case with every game in the franchise.Īnd yet again, they’re doing this with a game we’ve enjoyed! While Lego Jurassic World is not one of the strongest entries in the franchise, it’s an entertaining, family friendly celebration of the dinosaur romps, and about five hundred million times more entertaining than the appalling Jurassic World movie. This is mirrored in the peculiar amount of effort dedicated to refusing to send us review code, then telling us it was in the post before later admitting it never was. The sheer utter lack of care that makes that a persistent problem across every Lego game they release, let alone the lack of a windowed mode, or the refusal to adapt menu screens to work with a mouse, shows a level of contempt that’s ever-more tiresome. LEGO JURASSIC WORLD GAME WINDOWSStill, in mid-2015, they’re putting out games that can’t cope with Windows 7’s colour scheme, causing it to flicker and switch down to Basic. Warner with their Lego series just don’t appear to care very much about PC. Covering all four Jurassic Park movies and featuring an awful lot of stompy dinos, how does Lego Jurassic World one fare in their ever-growing catalogue? Here's wot I think:īefore we begin, a quick tangential issue. The prolific TT Games have a new Lego game just in time for the new Jurassic World movie. Classical scholars are, however, a bit more sophisticated. Shady Nasser, The Second Canonization of the Qurn (324/936): Ibn Mujhid and the Founding of the Seven Readings, Brill 2020. In simplest terms, textual criticism is the correction of errors in texts. Shady Nasser, The Transmission of the Variant Readings of the Qurn: The Problem of Tawtur and the Emergence of Shawdhdh, Brill 2012. The book is recommended for those western laymen who want an accurate but easy-to-read and concise historical account of early Islam and for students of Islam and those who desire a deeper understanding of this historical period. Keith Small, Textual Criticism and Qur’an Manuscripts, Lexington Books 2011. Written in a concise manner, the book is intended to lay a solid foundation for further study of Islam in the more in-depth works published by the Religion Research Institute. Now, if 16.5 of the verses involve a textual problem that is given less than an A rating in UBS, that means that 1320 variants at most are significant. While Dawn of Islam is an introductory text on Islam, it provides comprehensive coverage of the main elements of the religion. The book also presents a critical analysis of the Quran and the history of its transmission. 1 The current printed texts of the Qur’n are based on medieval Islamic tradition instead of the collation and analysis of extant manuscripts. These teachings can be traced in the well-known mythology of the people of the middle and Far East. His thoughts reflect ancient teachings about the earth, the sun and the creation. In simplest terms, textual criticism is the correction of errors in texts. It is widely acknowledged that there has never been a critical text produced for the Qur’n based on extant manuscripts, as has been done with other sacred books and bodies of ancient literature. Thirty-three revised and updated essays on the textual criticism of the Hebrew Bible, Qumran and the Septuagint, originally published between 20 are presented in this volume, the third volume of the author’s collected writings. The Qur’an repeats the mythology in vogue at the time of Mohammed. So let it be said from the outset that textual criticism has nothing to do with the criticism of music, art or literature. Focusing on the early periods of Islam, the author investigates how Islam began, including its religious and historical background, main historical figures, initial beginning, and subsequent expansion. Anyone who writes on textual criticism should begin with definitions. Relevant topics might include general exegetical issues, ancient languages and translation, the study of the historical Jesus, textual criticism, reception history of early Jewish/Christian literature, etc. Small's work is certain to reignite a vigorous debate about. Employing processes of textual criticism rigorously developed in New Testament studies, this work provides a fresh view of a controversial topic that has rarely been broached before regarding the establishment of the written text of the Qur'an. Best Sellers: Books for The Emotional Lives 8-10 Years oldĪbout CEO: Alasad Online Quran Tutor Updates: Keep touch & Remain Active Alasad Online Quran Mualim All Categories (Islamic Books, The Holt Quran, Modern Science, Curriculum) etc.Dawn of Islam: An Introduction to Early Islam presents a critical historical and theological introduction to Islam. By situating the manuscript evidence alongside the information provided by Islamic tradition, Small brings new insights to the history of the development of a standardized text of the Qur'an.Best Sellers: Books for School-Age Children 7-9 Years old.Best Sellers: Books for Middle Childhood 6-8 Years old.Best Sellers: Books for Young Children 5-7 Years old.Best Sellers: Books for School Starters 4-6 Years Textual Criticism and Qur’an Manuscripts The book is divided into four parts.Best Sellers: Books for Pre School-3-5 Years old.Best Sellers: Books for Toddlers 2-3 Years old.Best Sellers: Books for Babies 1-3 Years old.Best Sellers : Books for Infants 0-2 Years old. The attacker crafts an HTTP request that contains the below headers: Many are concerned because the Shellshock vulnerability is very easy to exploit through web applications running on vulnerable servers as shown in the following example. Exploiting Shellshock Vulnerability Using HTTP Requests A similar bug with identical consequences was discovered by Tavis Ormandy and was assigned the CVE identifier CVE-2014-7169. The shellshock vulnerability, discovered by Stephane Chazelas was assigned the CVE identifier CVE-2014-6271. Since the environment variables are not sanitized properly by Bash before being executed, the attacker can send commands to the server through HTTP requests and get them executed by the web server operating system. Even though Bash is not an internet-facing service, many internet and network services such as web servers use environment variables to communicate with the server’s operating system. #Shellshock live paper codeIn other words if exploited the vulnerability allows the attacker to remotely issue commands on the server, also known as remote code execution. Shellshock is a security bug causing Bash to execute commands from environment variables unintentionally. What is the Shellshock Remote Code Execution Vulnerability? It gained so much popularity from the fact that the vulnerability is found in Unix Bash shell, which can be found on almost every Unix / Linux based web server, server and network device. Shellshock is the latest vulnerability that most probably will be as popular if not more than the Heartbleed vulnerability, hence it is already being widely exploited via a worm called wopbot. Des expériences uniques peuvent être offertes aux lecteurs grâce à différents outils et options de lecture, y compris la recherche de mots et plusieurs couleurs de surbrillance. For the preparation of the ebook, an easy-to-use software, Kotobee Author, was used to add interactive elements, such as games and videos, allowing export in ePub3 format. Le contenu est interactif, comprenant notamment de l'audio, des vidéos, des animations par clics d'images, des widgets de livres et des questions d'autoévaluation pour engager les lecteurs. Kotobee Author permet aux utilisateurs de personnaliser entièrement l'image de marque de leurs e-books avec différents thèmes de couleurs et logos. Les formats SCORM, Tin Can et LTI permettent également l'intégration à divers systèmes LMS. Plagiarism Checker Kitaboo Recordit eloomi Authoring Kotobee Author Testportal The full list. Android 4.4+ (Kitkat, API 19) Content Rating. Take an in-depth look at 15 popular Learning Management platforms to find out which one is right for your needs. KOTOBEE AUTHOR ALTERNATIVE APKLes e-books créés peuvent également être exportés dans plus de 12 formats pour être lus sur différentes liseuses électroniques ou dans diverses applications, notamment Kindle, Kobo, Nook, iBooks et l'application Kotobee Reader. There are many choicer alternatives to iSpring Quiz maker. Kotobee Reader Download APK 1.8.1 (6.9 MB) If the download doesnt start, Click here. Find the best Kotobee Author alternatives and competitors. Kotobee Author permet aux utilisateurs de créer entièrement des e-books à partir de zéro ou d'importer du contenu existant dans une variété de formats, notamment HTML, PDF, Word et EPUB. Il s'intègre à divers LMS (Learning Management System). Le logiciel est adapté à n'importe quel secteur d'activité, mais il s'adresse avant tout aux auteurs et aux éducateurs. KOTOBEE AUTHOR ALTERNATIVE PDFKotobee Reader is optimized for the epub 3.0 standard, which supports interactivity and multiple languages. Découvrez comment ces logiciels de Logiciels pour éditeurs de livres et gestion des abonnements se mesurent à Flip PDF en termes de fonctionnalités, de facilité dutilisation, de service et de service client et davis utilisateurs. Kotobee Author est une solution de création et d'édition d'eBooks qui peut être utilisée pour créer des e-books avec du contenu interactif et les exporter dans plusieurs formats pour les afficher dans différentes liseuses. Access Kotobees free shared library, to download ebooks distributed by other users, and read offline. Les alternatives à Kotobee Publisher SketchUp Make 2017 Concevez vos plans vous même Google SketchUp Concevez vos plans vous même Adobe After Effects Créez des effets spéciaux et des animations. In order to evaluate the influence of oxygen supply on drug efficacy, 6606PDA cells were cultured with the above drugs for 30 h under normoxic (19% oxygen) or hypoxic (1% oxygen) conditions in an Innova® CO-48-230 incubator (New Brunswick Scientific Co., Inc., Edison, NJ, USA).Įvaluation of lactate concentration, proliferation and cell death. The cells were treated with vehicle (DMSO), 5 μM, 20 μM, 80 μM and 320 μM of galloflavin or each dosage combined with 20 mM of metformin. #Pancrea tabs plus code#The media were supplemented with 10% fetal calf serum (FCS, code S0615, Biochrom GmbH), 100 units/ml penicillin and streptomycin (code A2212, Biochrom GmbH) and 8 μg/ml Tylosin (code: T3397, Sigma-Aldrich). Tuveson (University of Cambridge, UK), and the human pancreatic cancer cell line MIA PaCa-2, which was purchased from ATCC (Manassas, VA, USA), were cultured in Dulbecco's Modified Eagle's Medium (DMEM, code: FG0435, Biochrom GmbH, Berlin, Germany) containing 4,5 g/l glucose (high glucose) or in DMEM (Biochrom GmbH) supplemented with glucose to a concentration of 0.5 g/l (low glucose). The murine pancreatic adenocarcinoma cell line 6606PDA, a gift from Prof. Dimethyl sulfoxide (DMSO, code: D2438, Sigma-Aldrich, Darmstadt, Germany), phosphate buffered saline pH 7.4 (PBS, code: 10010-015, Thermo Fisher Scientific, Waltham, MA, USA), galloflavin (code: 4795, Tocris, Wiesbaden-Nordenstadt, Germany), metformin (code: D150959, Sigma-Aldrich), trypan blue (code: 15250, Thermo Fisher Scientific).Ĭell culture and treatments. #Pancrea tabs plus plus#We also tested the combination therapy, galloflavin plus a high dose of metformin, in order to gain a therapeutic benefit by impairing oxidative phosphorylation and glycolysis. Thus, we decided to use galloflavin, an inhibitor of LDH, to evaluate if it inhibits proliferation and can induce death in pancreatic cancer cells. Indeed, genetic disruption of lactate dehydrogenases ablates the Warburg effect and restricts tumor growth ( 14). Another promising option for an effective chemotherapy is the inhibition of lactate dehydrogenase A (LDH-A) ( 10), which is a key enzyme in cancer, because cancer cells often favor metabolism via glycolysis ( 11- 13). The anti-cancerous effect of metformin has been suggested to be mediated by its inhibition of oxidative phosphorylation ( 9), which is a key process to generate ATP. Thus, it is still controversially discussed, if this drug has an anti-cancerous effect and if metformin should be applied in combination with standard therapies or needs to be tested in combination with other experimental drugs. However, this publication also suggested that patients with high metformin concentration in the blood might survive longer ( 8, 9). demonstrated that therapy with a regularly low anti-diabetic dose of metformin, besides standard chemotherapy, does not improve the overall survival compared to standard chemotherapy alone ( 8). published a meta-analysis stating that mainly studies, which might be flawed by not considering the so-called immortal time bias, show an effect of metformin on pancreatic cancer ( 7). It was also suggested that metformin improves the survival of patients, who suffer from pancreatic cancer ( 4- 6). Recent studies state that long-term ingestion of metformin, an often used anti-diabetic drug, is likely to reduce the risk of diabetic patients for the development of pancreatic cancer ( 2, 3). This demonstrates that surgical intervention plus adjuvant chemotherapy still lacks the needed efficacy to treat most of these patients successfully. Hence, pancreatic cancer is the fourth leading cause of cancer-related death in both women and men in the USA. Pancreatic cancer patients have a very poor five-year relative survival of 9% for all stages ( 1). Conclusion: Galloflavin, especially in combination with metformin, has a strong anti-cancerous effect on pancreatic ductal adenocarcinoma cells. The inhibition of proliferation by this combination therapy can be detected under hypoxic and normoxic conditions, leading to the assumption that this therapy might impair insufficiently supplied solid tumors as well as small clusters of cancer cells, e.g. Moreover, the combination of both agents increased these effects on pancreatic ductal adenocarcinoma cells. Results: We observed that monotherapies of galloflavin and metformin both inhibit proliferation and induce cancer cell death. Materials and Methods: We explored the effect of galloflavin and metformin on proliferation and cell death of murine 6606PDA and human MIA PaCa-2 cells. Background/Aim: In this study, we evaluated the effect of galloflavin, an inhibitor of lactate dehydrogenase, in combination with metformin, an anti-diabetic drug and inhibitor of oxidative phosphorylation, on pancreatic ductal adenocarcinoma cells. |
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