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31 episodes with HCK
7 episodes with HCK
Ready to make real progress in your fitness and health? In this episode, Jason Khalipa, Gabe Yanez, Dennis Marshall and Matt DellaValle share expert-approved tips on training smarter, balancing intensity, and staying motivated. From workout strategies and equipment hacks to mastering recovery and nutrition, this episode has everything you need to level up your routine. Whether you're into Jiu-Jitsu, CrossFit, or just getting stronger every day, these proven methods will help you hit your goals faster! Never let momentum get to zero. Listen to the Jason Khalipa Podcast every Monday and Thursday on Apple Podcasts, Spotify, or YouTube. Follow Jason: https://instagram.com/jasonkhalipa?igshid=MzRlODBiNWFlZA== Follow TRAIN HARD: https://www.instagram.com/trainhard.fit/?hl=en Never Zero Newsletter: https://www.th.fit/ NCFIT Programming For Gym Owners: https://www.nc.fit/programming Philanthropy: https://avaskitchen.org/ Chapters: 0:00 Introduction to stair workouts and gear enthusiasm 0:04 Talking about stair workouts and love for fitness equipment 1:57 How to use interval training for better cardio 6:10 Balancing hard work and rest for great fitness results 8:23 Why choosing the right intensity matters for your health 12:23 Jiu-Jitsu: Balancing effort and learning for real progress 14:37 Why staying consistent is better than going too hard 18:30 Taking it slow when returning to Jiu-Jitsu after surgery 20:18 Getting back into fitness after a break is easier than you think 23:54 Adding sprinting to your workouts for better fitness and skills 25:37 Creative training tips for long-distance running success 29:22 How cool new shoes can improve your workout experience 31:12 Modern running shoes: Comfort, recovery, and accessibility 34:55 Cyclists: Don't forget training matters more than gear 36:48 Fitness gear is fun but not always needed for progress 40:32 How structure helps athletes stay focused and committed 42:08 HCK race format sticking around for global consistency 45:42 Why personal fitness goals beat competition 47:37 Set clear goals to stay focused and improve your workouts 50:56 Commitment and personal targets drive motivation 52:35 Tailor fitness goals without forcing competition 55:49 Everyone's fitness journey is unique—don't compare 57:30 Planning and consistent training help reach your goals 1:00:54 Healthy eating: Balance and quality over extreme diets 1:02:38 How balanced eating can boost performance and health 1:06:23 Funny moments with porta potties and running stories 1:08:16 Extreme challenges show why staying committed matters
C'est l'histoire d'ouvriers qui viennent de se faire virer et qui, de rage, décident d'aller voir dans l'usine ce que cachent leurs patrons. Ces ouvriers ne s'attendaient pas du tout à ce qu'ils ont trouvé en ouvrant la porte du hangar… Le 10 juillet 1982 le musée de l'automobile ouvre à Mulhouse (68), après bien des péripéties : les 500 voitures des frères Schlumpf étaient planquées dans le plus grand secrets dans la filature HCK !Valérie-Anne raconte l'histoire des frères Schlumpf et de la collection du musée de l'auto.Les liens qui vont bien https://www.musee-automobile.fr/decouvrir-le-musee/histoire-schlumpf/https://www.largus.fr/actualite-automobile/cite-de-lautomobile-lhistoire-incroyable-du-musee-schlumpf-10262392.htmlhttps://www.lemonde.fr/m-le-mag/article/2024/10/17/la-jeune-heritiere-la-belle-mere-et-les-millions-dilapides_6354541_4500055.htmlhttps://www.jds.fr/magazine/actu-magazine/de-la-filature-hkd-au-musee-de-l-auto-370627_Ahttps://grandest.cfdt.fr/portail/actualites-syndicales-cfdt-de-la-region-grand-est-alsace-champagne-ardenne-lorraine/salle-de-presse-regionale/1977-1979-c-etait-le-musee-des-travailleurs-partie-2-l-alsace-/-dimanche-21-juillet-2024-srv2_1369483Le générique du podcast c'est toujours David Nilsson. Plus d'infos sur notre label Podcut et notre patreon : podcut.studio Merci pour vos contributions !Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.
Odd one this episode as I had a piece of audio disappear so I had to make a quick repair. The music is ace though with HCK 9 ft Linadre - Go Down Together, Kosher and Sleepytime Ghost ft Nioke - Gunshot, Emma Hunter - Guilty, PMad - Sword.
A new research perspective was published in Oncotarget's Volume 14 on May 19, 2023, entitled, “Targeting the Src N-terminal regulatory element in cancer.” The signaling pathways displayed by cancer cells are often composed of the same components as the physiological ones, yet the overall result is a pathological deregulation. In this new paper, researchers Betlem Mezquita, Marjorie Reyes-Farias and Miquel Pons from the Universitat de Barcelona and Universitat Internacional de Catalunya discuss the non-receptor protein tyrosine kinase Src as a good example. “Src, the first discovered oncogene, is the leading member of the Src family of kinases (SFK) that includes Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck, and Lyn.” Src is the first described proto-oncogene and a demonstrated player in cancer progression, as it affects proliferation, invasion, survival, cancer stemness, and drug resistance. Src activation is linked to poor prognosis in many cancer types, yet mutations in this protein are rarely observed. In addition, being a demonstrated cancer target, unspecific inhibition of the kinase activity has proven inefficient in clinics since the inhibition of Src in non-cancerous cells results in unacceptable toxicity. Thus, there is a need for new target regions in Src that could inhibit Src activity only in certain cell types, e.g., cancer cells, while maintaining the normal physiological activity in healthy cells. The Src N-terminal regulatory element (SNRE) includes the poorly studied intrinsically disordered region with unique sequences for each of the members of the Src family. In this perspective, the researchers discuss the non-canonical regulatory mechanisms involving the SNRE and their potential use as oncotargets. “Our group has designed a screening system to search chemical libraries for binders of the Src SNRE [88] and we are currently following up a promising lead.” DOI: https://doi.org/10.18632/oncotarget.28434 Correspondence to: Miquel Pons - mpons@ub.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28444 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords: Src family kinases, intrinsically disordered proteins, SNRE, cell-type selective drugs, drug resistance About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
An HCK reunion! Our friend, Zach Krantz, joins the show live at Twin Peaks to fill us in on his new project: Krantz's Korner.
In hour two, we have another Duncan Robinson debate after he gets a few minutes in garbage time last night. Then, it's an HCK reunion - Zach Krantz joins the show live from Twin Peaks.
Luke Rogers COO of Aterian #ATN discusses how they have identified 22 zones of potentially mineralised pegmatite which confirm the presence of a swarm of rare-metal hosting targets for future exploration and evaluation. Highlights · 22 zones of potentially mineralised pegmatite have been identified over the southern projects, confirming the presence of a swarm of rare-metal hosting targets for future exploration and evaluation. o Fieldwork over the HCK-1 zone indicates a strike length of c 2,500 m with widths up to 100 m, in places. o Multi-method geophysical survey currently underway in preparation for the preliminary scout drilling programme to commence in Q2 2023. o Prospective HCK-1 targets include tantalum, niobium, tin, tungsten, and lithium. · Mr. Godfrey Kamanzi has joined as head of Aterian's Rwandan metal trading business. Mr Kamanzi has extensive experience in the Rwandan minerals sector where he previously worked with RCS, the RMB, and multiple mining companies managing tagging and traceability programmes. · Partnership discussions have begun with several artisanal mining parties to improve artisanal mining productivity through mechanisation, and to provide material to the Company's metal trading business. · 1Villager.com, an online stakeholder management tool, has been engaged to support Whistleblower management, social license reporting, and stakeholder engagement, as part of the ongoing obligation by the Company to ethical supply chain management as a member of the ITSCI Programme for Responsible Mineral Supply Chains compliance To read the full RNS click here
Mashallah. Heute nochmal kleines Update zur Wüsten-WM. Justus hat ein Hck gefunden um gleichzeitig zu boykottieren aber trotzdem alle Games zu sehen. Nico klingt wie Weltraumschrott wegen Billo-Ersatzmikro von Saturn. Ilkan war Schweiz aber redet nicht darüber. Und ganz zum Schluss gibs EINEN TRICK DEN NIKLASSE HASSEN.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.19.512953v1?rss=1 Authors: Zhu, K., He, Q., Tsai, S.-F., Mudalige, D. M., Tang, A., Henrion, M. Y. R., Liu, Y., Vijayan, R., Zaidi, S. S. A., Branden, L., Cadiz, M. P., Hodos-Nkhereanye, R., Moein, S., Alamprese, M. L., Bennett, D. A., De Jager, P., Kuo, Y.-M., Ronaldson, P. T., Chang, R. Abstract: Microglia, the innate immune cells of the brain, are essential determinants of late-onset Alzheimer Disease (LOAD) neuropathology. Here, we developed an integrative computational systems biology approach to construct causal network models of genetic regulatory programs for microglia in Alzheimer Disease (AD). This model enabled us to identify novel key driver (KDs) genes for microglial functions that can be targeted for AD pharmacotherapy. We prioritized FCER1G, HCK, LAPTM5, ITGB2, SLC1A2, PAPLN, GSAP, NTRK2, and CIRBP as KDs of microglial phagocytosis promoting neuroprotection and/or neural repair. In vitro, shRNA knockdown of each KD significantly reduced microglial phagocytosis. We repurposed riluzole, an FDA-approved ALS drug that upregulates SLC1A2 activity, and discovered that it stimulated phagocytosis of A{beta}1-42 in human primary microglia and decreased hippocampal amyloid plaque burden/phosphorylated tau levels in the brain of aged 3xTg-AD mice. Taken together, these data emphasize the utlility of our integrative approach for repurposing drugs for AD therapy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Welcome Back to the Show. As the Squad continues our takeover of Hot Chkn Ktchn in Woodbridge, VA. As We complete the Medic Challenge, we talk about HCK and their UNITY Through FOOD ideals and what is in store for them. Check out the final episode of this takeover. Find us on all Major Social media platforms @AMPPEDUPSQUAD or email us: amppedupsquad@gmail.com Drop a question and be featured on the show.
Subscribe to PTW, AIPT's official wrestling podcast:Subscribe on Apple PodcastsSubscribe on Google PlaySubscribe on SpotifySubscribe via RSSDouble turns are one of the most difficult stories to pull off in all of professional wrestling, but on this week's PTW Wrestling Podcast, we bear witness to one for the ages as HCK loses his smile and "Heel" Dana Fowler actually had a really great time. This week, we discuss the Arcade Anarchy main event from Dynamite, as well as a WrestleMania card that has just about fully taken shape.You can find PTW on Apple Podcasts, Spotify, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends!If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Heute im Podcast bei Mitarbeiter oder Fans. - Hans-Christoph Kaiser (HCK) - Ohne Fans keine Digitalisierung! Das ist die Aussage von HCK. Er beschreibt, in meinem Interview, wie er in seiner Karriere bereits einige Höhen und Tiefen mitgenommen hat. Er stand mal auf der Gewinnerseite, aber auch mal auf der Verliererseite. Und jetzt, so behauptet HCK, wird es einige Gewinner geben, die jetzt reagieren und die Verlierer die eben nicht reagieren. Was er genau damit meint, hört ihr in meinem Podcast.... Viel Spaß beim zuhören und zuschauen Euer Christian www.christian-brink.de www.hans-christoph-kaiser.com #christianbrink #hanschristopkaiser #vortrag #buch #mitarbeitermotivation #positivereinstellung #zumnachdenken #redner #speakers #speaker #gesundeunternehmen #businesscoach #buchautor #gesundheitsmanagement #unternehmensberatung #followtofollow #liketolike #positivevibes #positivehaltung #positivität #businessman #unternehmermindset #unternehmertum #unternehmerwissen #unternehmermentalität #mitarbeiterzufans
Kids can be resilient, capable, confident and healthy. Mike Haley with Highly Capable Kids highlights the 40 assets they need, how to use HCK in public or private schools and the life-changing outcomes!
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS Mike "The Wolverine" Pursell is on vacation this week, so friend of the show Dana Fowler joins JVD and HCK to talk about the week in wrestling shows and news. This week's Raw was one of the best in recent memory, featuring great action, violent beatdowns, and genuinely funny moments. SmackDown, on the other hand, was...a show that happened. This week we talk about what each show did to build toward SummerSlam and also talk about news surrounding AEW's first television episode. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS WWE presented Raw Reunion this week, which was a fun show that also unfortunately exemplified a lot of problems today's product has. On this week's episode of Poor Taste Wrestling, we break down why "The Gratitude Era" is bad for WWE, talk a great, if promo-heavy, episode of SmackDown LIVE, AEW's weekly series being made official, and a lot more. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS AEW's Fight For the Fallen and WWE's Extreme Rules are both in the books, and a new Universal Champion was crowned in the process. On this week's Poor Taste Wrestling podcast, we break down both shows and discuss what it means for the future of both companies. Also: More talk about why 205 Live is the best show you're not watching, and Bray Wyatt finally re-debuts. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS WWE and AEW both have big shows this weekend in Extreme Rules and Fight For the Fallen, respectively, so we're taking a look at both shows and giving our predictions. Oh yeah, Evolve is running its first-ever WWE Network special at the same time as Fight For the Fallen, but I'm sure that's a total coincidence. Also: Enzo Amore and Joey Janela have a sad fight in New Jersey, and Kevin Owens' cuts a pipebomb-lite. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS WWE has been making big moves to try to get themselves out of the rut they're in, including the shocking decision to bring Eric Bischoff and Paul Heyman in as Executive Directors of SmackDown and Raw respectively, reportedly to operate in a manner similarly to how Triple H presides over NXT. The Paul Heyman era began this week and it showed. While Bischoff's reign supposedly won't begin until after Extreme Rules, it does seem like WWE is taking steps to right the ship. Why is WWE so worried? Oh yeah, a company called AEW ran their second major show, Fyter Fest, this weekend. While it was needlessly violent at times, it was another great show from the nascent promotion, and can only be seen as a good omen for things to come. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS The wrestling world seemed to tense up this week, as there were Twitter beefs aplenty, especially involving The Tweetslayer himself, Seth Rollins. Rollins had thoughts of everyone from Jon Moxley to Will Ospreay this week, and Kenny Omega had some rare fightin' words to fling at WWE as well. We're also coming off a surprisingly very entertaining WWE Stomping Grounds, and just a day away from AEW's next event, Fyter Fest, so we break down both of those on this week's episode. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS WWE's next pay-per-view event, Stomping Grounds, goes down this Sunday, so we are joined this week by friend of the show Dana Fowler to break down the card and talk about why the show most likely won't matter in the grand scheme of things, because lately in WWE, nothing matters. We're also talking NJPW's G1 Climax tournament, as the A and B block have been announced, and AEW's next major milestone of selling out All Out in just fifteen minutes. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS Super ShowDown was just as bad as you probably imagined it'd be, if not worse thanks to a downright frightening main event. But NJPW put on yet another classic show with Dominion, so this week a lot of our discussion is dedicated to that. And it's not all bad under the WWE umbrella. This week, Pat makes an impassioned plea for disenfranchised WWE fans to give 205 Live a chance. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS While pretty much the entire wrestling world has been unhappy with WWE for the past number of months, this past Saturday's NXT TakeOver XXV helped remind us that there is still plenty to get excited about under the WWE umbrella, and the future could still be bright. This week on PTW, we break down NXT's show, touch upon Jon Moxley's explosive interview with Chris Jericho, and Mike explains why he cancelled his WWE Network subscription. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts Subscribe on Google Play Subscribe on Spotify Subscribe via RSS Despite a few production hiccups, Double or Nothing turned out to be the best introductory PPV wrestling fans could ask for. Not only did it feature fantastic wrestling from top to bottom, but Cody and Dustin put on the best match of their careers, The Young Bucks and Lucha Bros showed why tag team wrestling is better than ever, and Kenny Omega and Chris Jericho gave us a match for the ages. Oh, and who can forget the pop when Jon Moxley made his way through the crowd to show Jericho and Omega who the new player in town is. Unfortunately, WWE didn't come out of this week on such a high note. Raw was downright terrible aside from a few memorable moments, and SmackDown, while good, couldn't outshine the buzz around its new competitor. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Subscribe on Apple Podcasts: https://podcasts.apple.com/us/podcast/poor-taste-wrestling/id1390416194 Subscribe on Google Play: https://www.google.com/podcasts?feed=aHR0cHM6Ly9mZWVkcy5zaW1wbGVjYXN0LmNvbS81ckQ5QjRtQg%3D%3D Subscribe on Spotify: https://open.spotify.com/show/4DMUt9hDZYBPPeLKMc1NW3 Subscribe via RSS: https://feeds.simplecast.com/5rD9B4mB One of the most exciting weekends in recent pro wrestling history is upon us, as AEW's inaugural show Double or Nothing goes down this Saturday! This week on Poor Taste Wrestling, we're joined by friend of the show Dana Fowler to go over the card and talk about what this could mean for the future of American wrestling. Not to be outdone, WWE had one of its more fun shows of the year last weekend in Money in the Bank, so we also talk fallout from that show, including Brock Lesnar winning the Money in the Bank briefcase. Some Raw and SmackDown talk go down as well, especially around the newly announced 24/7 Championship. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
It's PTW's one year anniversary! And to celebrate we have a packed show full of lots of news. AEW officially announced that they will air on TNT once a week starting this fall, and that Double or Nothing will be available via the B/R Live app in addition to traditional pay-per-view. In WWE news, morale has reportedly never been lower backstage. And of course, there's a pay-per-view this Sunday, so we take a look at the Money in the Bank card and give our predictions for the event. Who do you think will become Mr. and Miss Money in the Bank this year? Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Confidence in WWE programming may actually be at an all-time low, but don't worry, Vince McMahon's got the solution: more Roman Reigns, dammit! The "wild card rule" was announced this week, diluting the brand split even more and making us wonder if Vince has finally truly lost his mind. Luckily, a compilation of insane Vince stories made the rounds this week as well, so we talk about those as well on this week's episode of Poor Taste Wrestling. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Welcome to the 50th episode of Poor Taste Wrestling! It's too bad WWE didn't get the memo about this momentous week and put on another horrible episode of Raw in the face of still-declining ratings. Thankfully, AEW came to the rescue this week, as we spend most of the episode talking about Double or Nothing, Tony Khan's vision for All Elite Wrestling, Dean Ambrose's departure from WWE and the subsequent return of Jon Moxley, and a lot more. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Besides Bray Wyatt's absurd and amazing Firefly Fun House video package, WWE has sort of been the pits lately. Thankfully, there's a lot of non-WWE stuff to catch up on, such as Dustin Rhodes officially joining AEW for next month's Double or Nothing, nZo (fka Enzo Amore) hyping up his new career in Ring of Honor, and Ryback fumbling his way through a reddit AMA. We're talking all that and more this week in an unconventional episode of Poor Taste Wrestling. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
While WrestleMania may have fostered some excitement and good will amongst wrestling fans, this week's nonsensical Superstar Shake-up took it all away. This week on Poor Taste Wrestling, we're trying to make sense of what we witnessed over the two day event, and take stock of the state of Raw and SmackDown LIVE's new rosters. Welcome to the Podcast Experience. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Just like that, WrestleMania week has come and gone. It was a wild weekend, full of amazing matches, big surprises, jerks getting the trash beaten out of them, and one memorable (if incredibly long) WrestleMania. This week on Poor Taste Wrestling we try to cover as much as we can about the weekend in just over an hour, including TakeOver (one of the best WWE PPVs in history), WrestleMania, the Hall of Fame ceremony, NJPW and ROH G1 Supercard, Raw and SmackDown. Phew! That's a lot of wrestling. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
WrestleMania is finally here! All the wrestling you can possibly consume is going down in the New York/New Jersey area this weekend, and Poor Taste Wrestling will be there live! But before that, we sat down with friend of the show Dana Fowler to break down the mammoth WrestleMania 35 card and give our predictions on the Showcase of the Immortals. If you're going to be in the New York/New Jersey area this weekend and want to get your hands on free PTW stickers, let us know on Twitter, Instagram or via email and we'll get you one! Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
With all the WrestleMania talk, it's easy to lose track of what's sure to be the best show of the weekend: NXT TakeOver: New York. On this week's episode of Poor Taste Wrestling, we break down the card and give our predictions for the biggest show in NXT's year. There's still of course plenty to talk about on the main roster, including Charlotte's shock SmackDown Women's Championship win and Kofi Kingston officially punching his ticket to WrestleMania. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
In honor of WrestleMania being just two weeks away, this week on the Poor Taste Wrestling podcast, we're doing things a little bit differently. While we do touch upon some of the events of the week (namely Kofi Kingston and Baron Corbin...Baron f*cking Corbin?!), this week is all about the best WrestleMania matches of all time. While there have been plenty of memorable matches throughout WrestleMania history, each of us picked three of our favorites, followed by what all three hosts agree to be the greatest moment in WrestleMania history. Get ready for the Showcase of the Immortals by taking a walk down memory lane with this week's PTW. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Fastlane is in the rear view mirror, and now it's all about one show: WrestleMania! The Showcase of the Immortals is just three weeks away, and we're starting to get a clearer picture of the event's card, thanks to an excellent episode of SmackDown Live and a solid episode of Raw. We're talking about all of this on this week's episode of the Poor Taste Wrestling podcast, plus a lot more Ahmed Johnson and Snooki talk than you were probably expecting. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. Have a question you want answered on air? Or just some feedback for the show? Email us at ptw@aiptcomics.com. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
The final pit stop on the Road to WrestleMania 35 is this Sunday, when WWE Fastlane emanates from the Quicken Loans Arena in Cleveland, Ohio. An uncharacteristically plot-heavy episode of Raw set several story threads into motion for this show, including a last-minute reformation of The Shield and Becky's last chance to get into the Raw Women's Championship match at WrestleMania. This week on Poor Taste Wrestling we're breaking down both those and every other match on the Fastlane card with special guest Dana Fowler. We also have a discussion about kayfabe, and how much WWE is flirting with completely dismantling it as of late. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
It was a week of returns in WWE. Most importantly, Roman Reigns kicked off Raw to announce that after just four months, he Superman Punched leukemia back into remission, and the Big Dog is back! Meanwhile, closing Monday's show was the shocking return of Batista, who attacked Ric Flair before his birthday celebration and called out Triple H. And over on the blue brand, Kevin Owens was introduced as the new #1 contender for Daniel Bryan's WWE Championship, leapfrogging Kofi Kingston. We're talking all that on this week's edition of Poor Taste Wrestling, and we also have special guest and AiPT! Movies Editor Nathaniel Muir on to talk about the new movie about Paige's life, Fighting With My Family, which is miraculously getting great reviews across the board. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
It's an NXT invasion! Much like this week's episodes of Raw and SmackDown, this week's Poor Taste Wrestling podcast focuses on the surprise additions of Tommaso Ciampa, Johnny Gargano, Ricochet and Aleister Black to WWE's main roster. We talk about why it happened, what it means for the future of both the main roster and NXT, and where we go from here. In addition, we talk about the Elimination Chamber pay-per-view, which ended up being a solid show with a fantastic main event. But will Kofi Kingston be able to win the big one? Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
One of the Road to WrestleMania's two pit stops, Elimination Chamber, happens this Sunday and it should be a pretty good one: the WWE Championship will be decided inside the Chamber, as will the first-ever (well, kind of) WWE Women's Tag Team Champions. We've got special guest and friend of the show Dana Fowler on to give our predictions on the show, talk about that ending to Raw that saw Becky Lynch removed from the main event against Ronda Rousey and Charlotte Flair inserted into it, and also talk about what truly matters: late '90s/early 2000s WCW midcard wrestlers. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
We may be on the Road to WrestleMania, but this was a pretty slow week in WWE television. The wrestling news world never slows down though, as there have been even more rumblings of rumors that All Elite Wrestling is looking to poach top WWE talent, and that WWE talent is listening. On this week's episode of Poor Taste Wrestling, we discuss the rumor of a "current, big time WWE Superstar" being offered an "outstanding" deal by the fledgling competitor, and try to figure out who it could be. We're also hot about WWE continuing to chop parts off of people's names, and Jeff Jarrett getting a push in 2019, so we air our grievances. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
Another five day "weekend" of WWE wrestling is in the books, and while Royal Rumble was largely very predictable (yours truly correctly predicted every match except one), that's a very good thing. This week on Poor Taste Wrestling we're breaking down the entire card -- all six hours of it -- and what it means for WrestleMania. We couldn't forget about NXT TakeOver: Phoenix either, since as usual, NXT upstaged the main roster with another excellent supercard. Johnny Gargano and Tommaso Ciampa hold both singles titles in NXT -- now what? Lastly, unfortunately, we talk about the news that Dean Ambrose is leaving WWE in April after his contract is up, and Hideo Itami has been granted his release. The presence of AEW seems to already be affecting the landscape of WWE in ways not seen since the heyday of WCW. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
The Road to WrestleMania starts this weekend! The Royal Rumble is traditionally one of the most fun wrestling events of the year, and this year's show has a particularly stacked card. Friend of the show and special guest Dana Fowler joins us on this week's episode to break down the card and give our predictions on every match, including both the men's and women's Royal Rumble match, two world title matches, two women's title matches, and everything else going down this Sunday in Phoenix, Arizona. If you want to read our predictions from other members of the AiPT! staff, be sure to check out our Royal Rumble predictions article, as well as our predictions for *NXT TakeOver: Phoenix*. In addition to predictions, there is of course plenty of wrestling news to cover, including rumors of several talents hoping for their release from WWE so they can jump ship to All Elite Wrestling. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
On this week's episode of Poor Taste Wrestling, we're breaking down the excellent NXT UK TakeOver: Blackpool event, which featured some solid matches, the crowning of two new champions, and some genuine surprises in the form of Finn Balor and the debut of the Ring General, WALTER. NXT UK has sort of struggled to find its footing amongst the five brands of wrestling WWE pumps out on a weekly basis, but this event was worthy of the name TakeOver and should help put the nascent brand on the map. On the main roster side of things, the biggest news this week was that Braun Strowman has been pulled from the Universal Championship match against Brock Lesnar at the Royal Rumble, and we ultimately found out later that night that Finn Balor will take his place. The WWE Women's Tag Team Championships were also finally officially unveiled, and we learned they will be decided next month at Elimination Chamber. However, the segment they were announced in was a little...weird. Rounding out this week's wrestling discussion is more AEW talk, as Chris Jericho went into great detail on his podcast about the process of signing with AEW, and why he chose them over WWE. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can find Poor Taste Wrestling on iTunes, Google Play, or wherever you get your podcasts. As always, if you enjoy the podcast, be sure to leave us a positive rating, subscribe to the show, and tell your friends! If you'd like more wrestling news, opinions and hot takes, follow us on Twitter and Instagram for up-to-the-minute news and opinions.
The biggest news of the week in the world of pro wrestling is of course the official announcement of All Elite Wrestling, a new promotion spearheaded by Cody Rhodes and the Young Bucks, and financially backed by the Khan family, billionaires who own the NFL's Jacksonville Jaguars and the Premier Leagu's Fulham FC soccer team. The announcement came with the surprise appearances by PAC (f/k/a Neville) and Chris Jericho, who have signed to the promotion as well. From there we go over results from NJPW's Wrestle Kingdom 13, a show that largely lived up to our lofty expectations, featuring probably the final NJPW matches for the Young Bucks, Cody and Kenny Omega in light of the AEW news. After that, it's back to our regularly scheduled WWE talk, including our thoughts on the first true week of the company's "fresh start" (spoiler: SmackDown was great, Raw not so much...so, nothing's really changed), and we look forward to a Royal Rumble card that is really shaping up to be something special. Poor Taste Wrestling is hosted by JJ "Job Van Dam" Travers, Mike "The Wolverine" Pursell, and "HCK" Patrick Ross. You can follow PTW's parent site at aiptcomics.com, and follow us on Instagram and Twitter @AiPTwrestling.
The start of the HCK show didnt go quite as planned.
Friday on the HCK show, they were joined by Ira Winderman to talk about the NBA playoffs.
HCK talks about the saftey in the NFL and if they think players are worried about their future.
HCK debates UF vs UM with a Joe Zagacki appearance.
Souvent associée au début des années 1990 et au courant de l'anti-mode ou de la déconstruction (Kawakubo, Yamamoto, Margiela...), la mode d'avant-garde semble en 2015 une chose du passé. Faut-il forcément y voir le signal de la mutation du secteur de la mode, désormais peu engagé à s'opposer à un présent qu'il a pris le parti de célébrer ? N'est-ce pas plutôt l'avant-garde qui est intrinsèquement démodée ? La projection d'une réalité utopique, qui était le programme des avant-gardes artistiques, littéraires et de mode, peut-elle encore s'inscrire de façon pertinente à l'agenda d'une culture ? Qui sont les créateurs qui perpétuent malgré tout la « tradition de l'avant-garde », au cœur de l'industrie de la mode et à ses marges ? Benjamin Simmenauer, ancien élève de l'ENS et agrégé de philosophie, est enseignant associé à l'IFM, et co-fondateur du cabinet d'études HCK, basé à Paris.
For our second Episode of the TIGI Podcast, our new co-host YodaPow3r (http://www.youtube.com/user/YodaPow3r) joins as we talk to our first ever guest HCK aka Charlie (http://hckblog.com/) and (http://www.youtube.com/user/HCKStudios), an American Gamer living in Japan.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 03/06
The pleiotropic cytokine interleukin-6 (IL-6) is one of the major growth factors for multiple myeloma cells. It was previously shown that IL-6 induces the activation of Src family kinases Hck, Lyn and Fyn and that Hck is associated with the IL-6-receptor beta chain (gp130) via an acidic domain in gp130. In the first part of this thesis the acidic domain is narrowed down from 41 to 18 amino acids by a peptide-based functional screening assay. A derivative of the acidic domain, an 18mer lipopeptide, peptide 18AD, is characterised on the cellular and molecular level. IL-6-dependent growth of human and murine myeloma cells is inhibited with an IC50 of 25-30 µM by the addition of peptide 18AD to the growth medium. These cells remain unaffected by treatment with a control peptide with scrambled sequence (18sc). Furthermore, growth of IL-6-independent myeloma cells is not inhibited by peptide 18AD. In IL-6-dependent cells, peptide 18AD causes the same degree of apoptosis induction as IL-6 deprivation. On the molecular level it is shown by peptide competition assays that the association of Hck and gp130 is inhibited by peptide 18AD in a concentration dependent way. Peptide 18AD blocked the IL-6-induced activity of the Src family kinases Hck, Lyn and Fyn. Results from different factor-dependent cell lines demonstrate a common mechanism of the molecular peptide effects on Src family kinase activity, but the involved pathways downstream of the kinases appear to differ among species and cell lines tested. Treatment of human IL-6-dependent myeloma cells with peptide 18AD reduced the activating tyrosine phosphorylation of the signal transducer and activator of transcription 3 (STAT3), while STAT3 activation remains unaffected in murine cells. The Co-immunoprecipitations from different overexpressed receptor-deletionmutants and Hck confirms that the association is mainly due to the interaction between the kinase and a 9 amino acids spanning region within the acidic domain which carries the highest accumulation of acidic residues. Apparently, a sequence of 8-9 amino acids within gp130 with the prevalence of acidic side chains resembles a potential pseudosubstrate domain of tyrosine kinases and is responsible for localisation and activation of Src family kinases in response to receptor stimulation. The identification of sequence motives similar to the acidic domain of gp130 in other cytokine receptors, receptor tyrosine kinases and adapter proteins by an in silicio motive scan might suggest a general role of such motives. This could be the efficient recruitment of cytoplasmic kinases to signalling complexes at the time of ligand stimulation. Here, the importance of the acidic domain-kinase interaction for the IL-6-signaling pathway is shown by the growth-inhibiting effect of peptide 18AD on myeloma cells. In the second part, a novel sequence and celltype-specific anti-myeloma agent, peptide 1A, is characterised. It was initially designed as the negative control for a "reverse alanine scan" to define the role of the acidic residues within the sequence of peptide 18AD. Unexpectedly it turned out to be at least a 25-fold more potent growth inhibitor of myeloma cells than peptide 18AD. Similar molecular bases of the observed effects of peptide 18AD and peptide 1A are very unlikely, because in contrast to peptide 18AD, peptide 1A efficiently kills IL-6-independent myeloma cells as well. Moreover, an excess of IL-6 fails to rescue the cells from peptide 1A-induced cell death. Peptide 1A shows, as tested so far, no effects on cells derived from non-tumor tissue or tumor cells of various origins other than multiple myeloma. Peptide 1A specifically kills myeloma cells by the induction of apoptosis and severely disturbs cell cycle progression. Apoptotic cell death induction by peptide 1A is shown by peptide 1A-induced caspase-3 activation and the cleavage of PARP, a substrate of effector caspases. Peptide-induced cell death can partly be inhibited by co-treatment with the pan-caspase inhibitor ZVAD-fmk. Major survival pathways like the STAT3, PI3K/Akt and the MAPK pathway are inhibited in peptide 1A treated cells. If a biotinylated version of the peptide is added to the growth medium, it is incorporated into human myeloma cells and localised in defined regions of the cytoplasm of myeloma cells. Here some of the molecular mechanisms of peptide 1A-induced cell death are elucidated. However, the direct molecular target(s) are still unknown. Despite the potential difference in the molecular mechanisms, both peptides 18AD and 1A are expected to prove useful for developing derivatives with possible applications for the treatment of multiple myeloma.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 05/19
Kristallstrukuturuntersuchungen zur dreidimensionalen Struktur der Src-Kinase Hck im Komplex mit dem Tyrosinkinasen-Inhibitor PP1 haben gezeigt, dass die Zusammensetzung der Aminosäuren an verschiedenen Positionen kritisch für die Sensitivität von Kinasen gegenüber diesem Inhibitor sein können. In dieser Arbeit sollten die für die Bindung von PP1 und Hck relevanten Aminosäuren identifiziert werden und gezeigt werden, dass Hck direkt durch PP1 inhibiert wird. Es sollte ein System entwickelt werden, dass zur Selektion niedermolekularer Kinase-Inhibitoren dient. In dieser Arbeit wurden PP1-insensitive Punktmutanten von Hck hergestellt. Die untersuchten Aminosäure-Positionen innerhalb von Hck begrenzen zum einem den Eingang zu einer hydrophoben Tasche (Position 338 und 403), zum anderen liegen sie innerhalb dieser Tasche (Positionen 314, 323, 325 und 336). Diese Positionen wurden durch Aminosäuren mit längeren oder polaren Seitenketten ersetzt. Es konnte gezeigt werden, dass die mutierten Positionen innerhalb der hydrophoben Tasche nicht wesentlich an der Bindung zu PP1 beteiligt sind. So zeigt zwar die Mutation zu Phenylalanin an den Positionen L325 und I336 Wildtyp-Aktivität, allerdings ist bei keiner der Taschen-Mutanten Inhibitor-Resistenz gegenüber PP1 nachweisbar. Die meisten der untersuchten Eingangs-Mutanten (Position 338 und 403) zeigen eine dem Wildtyp Hck vergleichbare Aktivität. Allein die Position 388 konnte als einzige Spezifitätsdeterminante von Hck für den Inhibitor PP1 identifiziert werden, da die Mutation dieser Aminosäuren zu einer erheblichen Reduktion der Sensitivität der Kinasen gegenüber PP1 führte. Die Position 403 hingegen wird nicht als Spezifitätsdeterminante von PP1 anerkannt, da die Mutanten sensitiv gegenüber PP1 sind. Zusammengefasst zeigen die Daten, dass PP1 die Src-Kinase Hck direkt über die Bindung in die hydrophobe Tasche in Nachbarschaft zur ATP-Bindungsstelle inhibiert. Das etablierte System der Mutation einer Aminosäureposition, die entscheidend die Bindung eines Inhibitors beeinflusst, kann nützlich sein, um die biologische Potenz von Inhibitoren und deren Zielstruktur-Spezifität zu untersuchen. Es kann zudem für die Spezifizierung und Optimierung von Kinase-Inhibitoren herangezogen werden.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06
Flt3 is the most recently discovered member of the platelet-derived growth factor receptor (PDGFR) subfamily of receptor tyrosine kinases (RTKs). It is expressed on early hematopoietic progenitor cells and is involved in their growth. Activating mutations of Flt3, such as internal tandem duplications (ITD) in the juxtamembrane (JM) region of Flt3, are among the most common genetic alterations found in patients with acute myeloid leukemia (AML). For this reason Flt3 is an attractive target for specific tyrosine kinase inhibitors, and a number of such compounds are currently being tested in clinical trials. However, the mechanisms of Flt3-mediated signal transduction are poorly understood. Src family tyrosine kinases (SFKs) are involved in the signaling processes of various RTKs, including those of the PDGFR subfamily . Most SFKs are expressed predominantly or exclusively in hematopoietic cells, and at least Hck and Lyn were found to be activated in AML patients. These observations indicate that SFKs could also be involved in Flt3 signaling. In this work the role of SFKs in signal transduction of the Flt3 receptor was investigated. A panel of Hck and Flt3 mutants was used in biochemical and biological assays to deduce the contribution of kinase activity, SH2 and SH3 binding domains and tyrosine phosphorylation status to Flt3-SFK interaction. The work presented shows that SFKs interfere with the maturation of wild type and Flt3 ITD receptors in human embryonic kidney 293 (HEK- 293) cells in a kinase-dependent manner. The SFK-mediated effect on receptor maturation is reflected by accumulation of the immature, intracellular form of Flt3 at the expense of the mature, plasma membrane-inserted form of the receptor. This effect of SFK kinase activity on receptor maturation is not limited to Flt3, because analogous results were also obtained for the Kit receptor, another member of the PDGFR subfamily. The demonstration of the role of SFKs in regulation of receptor maturation is novel and the exact mechanism underlying this effect requires further investigation. Using the HEK-293 cells it was also shown that Hck is able to phosphorylate Flt3 on tyrosine residues and to associate with autophosphorylated Flt3 in an SH2 domain-dependent manner. Hck-mediated tyrosine phosphorylation occurs in the JM region of Flt3. Tyrosine residues 589 and 591 in the JM region, when phosphorylated, were also identified as the docking sites for Hck. Although Hck phosphorylation and binding sites on Flt3 overlap, Hck-mediated phosphorylation of Flt3 is not sufficient for Flt3-Hck association. In contrast to the situation in HEK-293 cells, Hck neither interferes with Flt3 maturation nor phosphorylates Flt3 on tyrosine residues, and does not detectably associate with the Flt3 receptor in the hematopoietic murine cell line 32D clone 3 (32D cl.3). However, the level of the ectopic expression of Hck in 32D cl.3 cells was lower than in HEK-293 cells. This difference in Hck expression level probably accounts for both the lack of the Hck-mediated phosphorylation of Flt3 and the interference with its maturation in 32D cl.3 cells. The lower Hck expression level, however, does not account for the lack of detectable association of Hck with Flt3 in 32D cl.3 cells. Using biological assays in which activation of Flt3 can partially overcome the requirement for cytokine stimulation in 32D cl.3 survival and proliferation, it was shown that Hck is not involved in Flt3 signal transduction leading to Flt3-mediated cell survival and Flt3 ITD-dependent cell growth. Therefore, biological relevance of SFKs in Flt3 signaling remains unclear. In summary, although the binding and phosphorylation of Flt3 by Hck can be shown, the biological relevance of Hck in Flt3 signaling remains to be formally demonstrated. This research led to the novel finding that, at least when over-expressed or hyperactivated, SFKs interfere with the maturation process of RTKs. Various studies have shown that the ligandindependent activation of RTKs as well as their premature phosphorylation can interfere with maturation of RTKs. This study reveals that, by virtue of their phosphorylating of Flt3, Kit and possibly other RTKs, SFKs can regulate maturation of these RTKs and consequently alter their transport to the plasma membrane. Further studies are required to investigate the biological relevance of this function of SFKs.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 01/06
IL-6 spielt eine entscheidende Rolle für die Entstehung vieler Krankheiten, ins-besondere des Plasmozytoms. Über die molekularen Mechanismen die daran be-teiligt sind, lagen allerdings bisher wenig Daten vor. Aufgrund eigener Vorarbei-ten war bekannt, dass IL-6 die Src-Kinasen Hck, Fyn und Lyn aktiviert. Ziel die-ser Arbeit war es, genauere Erkenntnisse über die genauen Mechanismen dieser Aktivierung zu gewinnen. Mittels Mutationsanalysen wurde eine „saure Domäne“ zwischen den Aminosäu-ren 771 und 811 von gp130 als Bindungsregion für die Src-Kinase Hck identifi-ziert. Dieses Bindungsmotiv wurde bisher noch nicht für gp130 beschrieben. Die Bindung von Hck an gp130 war unabhängig von den benachbarten Bindungsstel-len für Shp-2 (Y759) und STAT3 (Y767, Y814). In faktor-abhängig wachsenden Baf-B03 Zellen resultierte die Deletion der Hck-Bindungsdomäne (d 771-811) in einem deutlich reduzierten Wachstum nach Stimulation von gp130. Die Aktivität der Src-Kinase Hck war in d-771-811 Transfektanten im Vergleich zu wt gp130 exprimierenden Zellen (Eg) deutlich reduziert. In d 771-811 exprimierenden Zel-len war außerdem die Aktivierung von Erk sowie die Deaktivierung und Dephosphorylierung von Pyk2 unterbrochen. Daher scheint der Signalweg an dem Hck beteiligt ist einen wesentlichen Einfluss auf die Vermittlung von Wachstumssignalen, die über gp130 stimuliert werden, zu besitzen. Zur Zeit werden die weiteren Signale untersucht, die durch über den Hck/gp130-Komplex vermittelt werden. Da IL-6 der ein wesentlicher Wachstumsfaktor in der Entstehung des Plasmozy-toms und die Expansion von frühen hämatopoetischen Vorläuferzellen ist, sollen diese Untersuchungen zur Identifizierung krankheits-relevanter Signalproteine oder -domänen führen. Diese Signalproteine würden dann wichtige Ziele für eine molekular definierte Therapie des Plasmozytoms darstellen.
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