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"Blyth, Gavin"
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Velo city : architecture for bikes
\"The world's major cities are making room for cyclists, helping them to ride, store, share, and buy their bicycles more easily than ever before. As a result, bike-related design has become one of the hottest fields in architecture. From racetracks to commuter paths and from bike sharing to bridges, this comprehensive survey details every aspect of this brave new cycling world. Drawing on the latest trends in bike design and fashion it places each project in context to provide an eclectic visual record of the world built around cycling. With an introductory essay that considers the history and future of cycling and packed with numerous color illustrations, this book is perfect for design enthusiasts and cyclists alike\"--Provided by publisher.
Book
Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
Journal Article
Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma
Despite recent advances in the treatment of medulloblastoma, patients in high-risk categories still face very poor outcomes. Evidence indicates that a subpopulation of cancer stem cells contributes to therapy resistance and tumour relapse in these patients. To prevent resistance and relapse, the development of treatment strategies tailored to target subgroup specific signalling circuits in high-risk medulloblastomas might be similarly important as targeting the cancer stem cell population. We have previously demonstrated potent antineoplastic effects for the PI3Kα selective inhibitor alpelisib in medulloblastoma. Here, we performed studies aimed to enhance the anti-medulloblastoma effects of alpelisib by simultaneous catalytic targeting of the mTOR kinase. Pharmacological mTOR inhibition potently enhanced the suppressive effects of alpelisib on cancer cell proliferation, colony formation and apoptosis and additionally blocked sphere-forming ability of medulloblastoma stem-like cancer cells
in vitro
. We identified the HH effector GLI1 as a target for dual PI3Kα and mTOR inhibition in SHH-type medulloblastoma and confirmed these results in HH-driven Ewing sarcoma cells. Importantly, pharmacologic mTOR inhibition greatly enhanced the inhibitory effects of alpelisib on medulloblastoma tumour growth
in vivo
. In summary, these findings highlight a key role for PI3K/mTOR signalling in GLI1 regulation in HH-driven cancers and suggest that combined PI3Kα/mTOR inhibition may be particularly interesting for the development of effective treatment strategies in high-risk medulloblastomas.
Journal Article
Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma
We provide evidence that a member of the human Schlafen (SLFN) family of proteins, SLFN5, is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Targeted deletion of
SLFN5
results in decreased PDAC cell proliferation and suppresses PDAC tumorigenesis in in vivo PDAC models. Importantly, high expression levels of SLFN5 correlate with worse outcomes in PDAC patients, implicating SLFN5 in the pathophysiology of PDAC that leads to poor outcomes. Our studies establish novel regulatory effects of SLFN5 on cell cycle progression through binding/blocking of the transcriptional repressor E2F7, promoting transcription of key genes that stimulate S phase progression. Together, our studies suggest an essential role for SLFN5 in PDAC and support the potential for developing new therapeutic approaches for the treatment of pancreatic cancer through SLFN5 targeting.
Journal Article
Schlafen 5 is an intracellular immune checkpoint and controls IFN responses in pancreatic ductal adenocarcinoma
We provide evidence that human and murine Schlafen 5 (SLFN5) proteins are modulators of type I IFN responses and the immune response in pancreatic ductal adenocarcinoma (PDAC). Blocking expression of Slfn5 in PDAC enhanced IFN responses, suppressed tumor growth, and prolonged survival in immunocompetent mice. Notably, immunophenotypic analysis revealed a reduction in tumor-associated macrophages alongside an increase in tumor-infiltrating effector cells in tumors over time. These findings suggest SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of therapies for PDAC and possibly other malignancies.
Journal Article
Schlafen 5 is an intracellular immune checkpoint and controls interferon responses in pancreatic ductal adenocarcinoma
We provide evidence that human and murine SLFN5 proteins are modulators of Type I IFN responses and the immune response in pancreatic cancer. Blocking expression of Slfn5 in PDAC enhances IFN-responses, suppresses tumor growth, and prolongs survival in immunocompetent mice. Notably, immunophenotypic analysis reveals a reduction in tumor-associated macrophages (TAMs) alongside an increase in tumor infiltrating effector cells in tumors over time. These findings implicate SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of therapies for PDAC and possibly other malignancies.We provide evidence that human and murine SLFN5 proteins are modulators of Type I IFN responses and the immune response in pancreatic cancer. Blocking expression of Slfn5 in PDAC enhances IFN-responses, suppresses tumor growth, and prolongs survival in immunocompetent mice. Notably, immunophenotypic analysis reveals a reduction in tumor-associated macrophages (TAMs) alongside an increase in tumor infiltrating effector cells in tumors over time. These findings implicate SLFN5 acts as an intracellular immune checkpoint and identify it as a unique therapeutic target for the development of therapies for PDAC and possibly other malignancies.
Journal Article
Maxine takes tee for two
So we took [Tracy Shaw] along to the plush Formby Hall Golf Club near Southport to get in some practice for her scenes. She said: \"I've always fancied taking up golf and this gave me the perfect excuse to take lessons.
Newspaper Article
How my 21st was a right Mickey Mouse affair: Interview; Paul Fox ; Coronation Street's Paul Fox turned 21 on a fantastic weekend break with his pals at Euro Disney
Certainly his career, rather like his favourite ride at Disneyland - Space Mountain - suddenly went into orbit. A spell with the hit children's programme The Ward was followed by two years as Will Cairns in Emmerdale. During his time with the Yorkshire soap, Paul won an army of adoring fans. And many of them have followed him across the Pennines to his new soap home in Coronation Street. His postbag regularly bulges with fanmail from well-wishers, though some of it contains decidedly steamy propositions. Nearly as scary, perhaps, as the exhilarating Disneyland rides that Paul and his pals braved on the first day of their holiday - the hair-raising Space Mountain (twice!) and Big Thunder Mountain - before retiring for the night. But if the rides gave the friends nightmares, what happened the next morning was the stuff of pure childhood fantasy. As Paul tucked into breakfast, he was serenaded by Mickey Mouse and Pluto who presented him with a surprise birthday cake. THRILL SEEKERS: Paul and pals enjoy the theme park's scary rides; HOT SHOT: Moseying into town; IT'S A WONDERFUL WORLD: Paul at the entrance to Euro Disney; GOOFING ABOUT: Joking with Goofy; LOVE RAT: As [Mark Redmond] in Corrie, who is having an affair with dad [Mike Baldwin]'s fiancee [Linda Sykes]; SPECIAL TREAT: Mickey Mouse presents Paul's birthday cake
Newspaper Article
I was a washed-up alcoholic soap star until the day I started singing..now I'm heading for No.1; THE STREET'S CURLY WATTS GETS A ROCK 'N' ROLL MAKEOVER
\"I realised that the song sounded OK - and the guy at the studio asked me if I fancied doing some more tracks.\" [Kevin Kennedy] and two friends came across a previously unrecorded song called Bulldog Nation. They formed a company called D2M (Doors to Manual) and touted the track around record companies. Kevin, wife [Claire] and RCA stylist Lisa Harvey spent seven hours shopping in London to achieve the Matrix-style image of tight- fitting black T-shirt, padded black trousers and black boots and black leather coat. BLACK TO THE FUTURE: Stylist Lisa, who also works with the boy band Five, helps Kevin get rid of his Curly Watts look with a full-length black leather coat helped by his wife Claire and (above left) tries him out in grey. Inset, Kevin has hair treatment to make him blonder, and out on the town with Claire Pictures: NICKY JOHNSTON and GAVIN BLYTH
Newspaper Article
Meet my new Street sister Debs - and here's my real-life sister Debs too...; TV DENISE ON A NEWCOMER WHO'S LIKE FAMILY
DENISE Welch - Coronation Street's scheming Natalie Barnes - did a double take when she met her new screen sister Debs. Not only does she look like her real-life sister with the same shade of blonde hair, but she shares her name too. The two Debs are both in their late 30s and Denise's sister worked on cruise liners - just like the fictional Debs. The Street newcomer, played by ex-Brooksider Gabrielle Glaister, makes her debut this week. Now GAVIN BLYTH talks to Denise, 41 and married to actor Tim Healy, real sister [Debs], 38 and married to policeman Peter Dedos, and TV Debs - Gabrielle, 39, who has a live-in boyfriend.Denise's story THE WAY SHE WAS: Gabrielle as [Patricia] in Brookside with Max; GIRLS TOGETHER: Gabrielle Glaister who plays Natalie's sister Debs in the Street with Denise Welch and her real-life sister Debs Picture: MIKE SEWELL
Newspaper Article