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IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification

1q21 amplification is an important prognostic marker in multiple myeloma. In this study we identified that IL6R (the interleukin-6 membrane receptor) and ADAR1 (an RNA editing enzyme) are critical genes located within the minimally amplified 1q21 region. Loss of individual genes caused suppression to the oncogenic phenotypes, the magnitude of which was enhanced when both genes were concomitantly lost. Mechanistically, IL6R and ADAR1 collaborated to induce a hyper-activation of the oncogenic STAT3 pathway. High IL6R confers hypersensitivity to interleukin-6 binding, whereas, ADAR1 forms a constitutive feed-forward loop with STAT3 in a P150-isoform-predominant manner. In this respect, ADAR1-P150 acts as a direct transcriptional target for STAT3 and this STAT3-induced-P150 in turn directly interacts with and stabilizes the former protein, leading to a larger pool of proteins acting as oncogenic transcription factors for pro-survival genes. The importance of both IL6R and ADAR1-P150 in STAT3 signaling was further validated when concomitant knockdown of both genes impeded IL6-induced-STAT3 pathway activation. Clinical evaluation of various datasets of myeloma patients showed that low expression of either one or both genes was closely associated with a compromised STAT3 signature, confirming the involvement of IL6R and ADAR1 in the STAT3 pathway and underscoring their essential role in disease pathogenesis. In summary, our findings highlight the complexity of the STAT3 pathway in myeloma, in association with 1q21 amplification. This study therefore reveals a novel perspective on 1q21 abnormalities in myeloma and a potential therapeutic target for this cohort of high-risk patients.




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An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma

Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor and together they regulate transcription of actin cytoskeleton genes. MKL1 is associated with hematologic malignancies and immunodeficiency, but its role in B cells is unexplored. Here we examined B cells from monozygotic triplets with an intronic deletion in MKL1, two of whom had been previously treated for Hodgkin lymphoma (HL). To investigate MKL1 and B-cell responses in the pathogenesis of HL, we generated Epstein-Barr virus-transformed lymphoblastoid cell lines from the triplets and two controls. While cells from the patients with treated HL had a phenotype close to that of the healthy controls, cells from the undiagnosed triplet had increased MKL1 mRNA, increased MKL1 protein, and elevated expression of MKL1-dependent genes. This profile was associated with elevated actin content, increased cell spreading, decreased expression of CD11a integrin molecules, and delayed aggregation. Moreover, cells from the undiagnosed triplet proliferated faster, displayed a higher proportion of cells with hyperploidy, and formed large tumors in vivo. This phenotype was reversible by inhibiting MKL1 activity. Interestingly, cells from the triplet treated for HL in 1985 contained two subpopulations: one with high expression of CD11a that behaved like control cells and the other with low expression of CD11a that formed large tumors in vivo similar to cells from the undiagnosed triplet. This implies that pre-malignant cells had re-emerged a long time after treatment. Together, these data suggest that dysregulated MKL1 activity participates in B-cell transformation and the pathogenesis of HL.




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Impacts of Operational Failures on Primary Care Physicians Work: A Critical Interpretive Synthesis of the Literature [Systematic Review]

PURPOSE

Operational failures are system-level errors in the supply of information, equipment, and materials to health care personnel. We aimed to review and synthesize the research literature to determine how operational failures in primary care affect the work of primary care physicians.

METHODS

We conducted a critical interpretive synthesis. We searched 7 databases for papers published in English from database inception until October 2017 for primary research of any design that addressed problems interfering with primary care physicians’ work. All potentially eligible titles/abstracts were screened by 1 reviewer; 30% were subject to second screening. We conducted an iterative critique, analysis, and synthesis of included studies.

RESULTS

Our search retrieved 8,544 unique citations. Though no paper explicitly referred to "operational failures," we identified 95 papers that conformed to our general definition. The included studies show a gap between what physicians perceived they should be doing and what they were doing, which was strongly linked to operational failures—including those relating to technology, information, and coordination—over which physicians often had limited control. Operational failures actively configured physicians’ work by requiring significant compensatory labor to deliver the goals of care. This labor was typically unaccounted for in scheduling or reward systems and had adverse consequences for physician and patient experience.

CONCLUSIONS

Primary care physicians’ efforts to compensate for suboptimal work systems are often concealed, risking an incomplete picture of the work they do and problems they routinely face. Future research must identify which operational failures are highest impact and tractable to improvement.




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Impacts of Operational Failures on Primary Care Physicians Work: A Critical Interpretive Synthesis of the Literature [Departments]




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Perspectives of specialists and family physicians in interprofessional teams in caring for patients with multimorbidity: a qualitative study

Background:

Patients with multimorbidity often require services across different health care settings, yet team processes among settings are rarely implemented. We explored perceptions of specialists and family physicians collaborating in a telemedicine interprofessional consultation for patients with multimorbidity to better understand the value of bringing physicians together across the boundaries of health care settings.

Methods:

This was a descriptive qualitative, interview-based study. Physicians who had previously participated in the Telemedicine Interprofessional Model of Practice for Aging and Complex Treatments (Telemedicine IMPACT Plus [TIP] Program) were invited to participate and asked to describe their experience of being a member of the program. Interviews were conducted from March to May 2016. We conducted an iterative and interpretive process using both individual and team analysis to identify themes.

Results:

There were 15 participants, 9 specialists and 6 family physicians. Three themes emerged in the analysis: creating new perspectives on care for patients with multimorbidity by sharing knowledge, skills and attitudes; the shift from a consultant model to an interprofessional team model (allowing a window into the community, extending discussions beyond the medical model and focusing on the patient’s health in context); and opportunities for learners, including learning about interprofessional collaboration and gaining exposure to a real-world model for caring for people with multimorbidity in outpatient settings.

Interpretation:

Family physicians and specialists participating in a TIP Program believed the program improved their knowledge and skills, while also serving as an effective care delivery strategy. The findings also support that learners require more exposure to nontraditional consultant models in order to care for patients with multimorbidity effectively.




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4 signs that show a home is overpriced

There are some signs that can help you determine whether you are paying too much for the house you want to buy.




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Riverpark Premier apartment for rent

Riverpark Premier is the most luxurious complex. The entire project planning consumed 14.509sqm consists of 268 units which have coverall range from 112 ~ 231sqm, mostly 3 bedrooms and 13 shophouses 129 ~ 244sqm in size. Riverpark Premier is located in Hillview District. This is ...




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Cyberpunk 2077 News Coming June 11

The official Twitter account for Cyberpunk 2077 has teased new information on the game will be released on June 11 via "Night City Wire."

CD Projekt RED global community lead Marcin Momot in a followup tweet that "Stuff will be shown!"

GET READY!📺 pic.twitter.com/eqQ3hMCOmA

— Cyberpunk 2077 (@CyberpunkGame) May 5, 2020

Stuff will be shown! pic.twitter.com/XzgQLH0w9P

— Marcin Momot (@Marcin360) May 5, 2020

Here is an overview of the game:

In the most dangerous megacity of the future, the real you is not enough. Become V, a cyber-enhanced mercenary outlaw going after a one-of-a-kind implant — the key to immortality. Customize your cyberware and skillset, and explore a vast city of the future obsessed with power, glamour and body modification. The choices you make will determine the story and shape the world around you.

Cyberpunk 2077 will launch for the PlayStation 4, Xbox One and Windows PC on September 17.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443392/cyberpunk-2077-news-coming-june-11/




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The Ascent is a Cyberpunk Action RPG, Announced for Xbox Series X and Xbox One

The Ascent is a new solo and co-op action RPG set in a cyberpunk world from developer Neon Giant and publisher Curve Digital. It was announced today during Microsoft's Inside Xbox showcase for the Xbox Series X and Xbox One. It will feature Smart Delivery. The Ascent will launch in Holiday 2020.

View the reveal trailer below:

Here is an overview of the game:

The Ascent is a solo and co-op action RPG set in a cyberpunk world. The mega corporation that owns you and everyone, The Ascent Group, has just collapsed. Confusion and chaos ensue, security and order are in disarray, and without protection, everyone is left to fend for themselves. Stop gangs and hostile corporations from taking over and discover what really happened.

Explore the Ascent Group arcology

Make allies as well as enemies as you explore the brimming arcology and its wide range of districts, from the deep slums to the higher luxury spheres.

Shoot and Loot

Consider enemies' height and weaknesses into account when fighting, making the most out of every opportunity. Take down even the worst opponents to find the rarest loot.

Customization and Augmentations

Modify your body with cyberware and gear up with weapons and equipment that suit your playstyle. Take a slick and precise approach or arm yourself to the teeth and go full chrome.

Solo or Co-op

Play the entire game alone or work together with up to three friends in local or online co-op.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443427/the-ascent-is-a-cyberpunk-action-rpg-announced-for-xbox-series-x-and-xbox-one/




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A fingerprint can show if someone has taken cocaine or just touched it

A person who has ingested cocaine will excrete a compound that can be detected from a single fingerprint, even if they have washed their hands




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People will sell access to their fingerprints for just $7.56 a month

We are increasingly aware that our personal data is a valuable commodity – but just how valuable? A survey has revealed how much people are willing to sell their data for




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Liverpool ready to make major Sadio Mane transfer decision as Real Madrid eye star



Liverpool are looking to make Sadio Mane an offer that would tarnish Real Madrid's hopes of signing him.




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Liverpool boss Jurgen Klopp reveals private meetings with Steven Gerrard during lockdown



Jurgen Klopp never got to manage Steven Gerrard at Liverpool but the pair still have a strong relationship given their connections to the club.




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Man Utd to rival Jose Mourinho for transfer, Werner to Liverpool, Newcastle instruction



The summer transfer window is nearly upon us as Manchester United, Chelsea, Liverpool, Arsenal and the rest of the Premier League look to strengthen for whenever the new season starts. Express Sport brings you the latest updates throughout the day.




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Common herpes virus causes signs of Alzheimer's disease in brain cells

A study of brain cells in a dish adds to growing evidence that Alzheimer’s disease can be caused by herpes viruses, but antiviral treatment may help stop it




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Haaland urged to make Liverpool move as former coach questions Man Utd & Real Madrid for missing out

Alf Ingve Berntsen, who worked with the teenage striker at Byrne FK, believes a heavyweight European outfit should already have signed the Norwegian





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‘Liverpool used to fall apart, now they’re made of strong stuff’ – Ince hails Klopp’s title hopefuls

The former Reds midfielder has saluted the efforts of a team that could have regressed again after missing out on the Premier League crown in 2019





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Van Dijk billed as best defender in the world as AC Milan legend Baresi salutes Liverpool’s ‘leader’

The Rossoneri icon has sought to talk up the importance of defenders in any ambitious side, with those at Anfield having found one of real “quality”





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Van Dijk sounds ominous warning to rivals as Liverpool star claims he can get even better

The Netherlands international has become a talismanic presence for club country, but the commanding centre-half believes there is more to come





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Henderson to Fulham & Bale to Nottingham Forest? Ex-Liverpool director of football makes transfer claims

Damien Comolli, who took the England international to Anfield, saw the Reds enter into transfer talks with the Cottagers during the summer of 2012





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Liverpool news: One OVERLOOKED player predicted to star against Man City

LIVERPOOL midfielder Georginio Wijnaldum will be pivotal for Jurgen Klopp at Manchester City..




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Henderson, Keita and Gomez fit for Fulham says Liverpool boss Klopp

Club captain Jordan Henderson, summer signing Naby Keita and centre back Joe Gomez were all absent for the shock midweek Champions League defeat to Red Star Belgrade..




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Liverpool attempted to trademark 'Allez Allez Allez' after famous fan chant

Liverpool already have one song synonymous with the club but they did attempt to officially do likewise with another. The Reds tried to trademark 'Allez Allez Allez'..




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Liverpool woman reunited with her lost pet parrot Chanel after video goes viral

The footage of Chanel's "mam" Sandra has been viewed nearly 600,000 times




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Fears over serious illness in children overplayed, top doctor says

Fears that children may be at risk of a serious inflammatory condition linked to coronavirus have been downplayed by a leading doctor.




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Marketplaces Are Changing the Way We Do Enterprise IT

In one of my latest reports (Key Criteria for Evaluating Unstructured Data Management), one of the key criteria was the availability of…




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Electricity usage suggests we're living every day like a perpetual weekend

As people retreat to their homes, a group of analysts have seen a significant decrease in fuel consumption in the UK's largest sectors as transport reduces and offices and businesses close




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Lowe: Five NBA things I like and don't like, including Michael Jordan's 63-point masterpiece

Let's spotlight a new appreciation for Jordan's greatness, the art of rebounding and the Trae Young-John Collins duo.




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Virtual parliamentary proceedings cause spike in injuries for interpreters: union

Coping with iffy audio quality, occasional feedback loops, new technology and MPs who speak too quickly has resulted in a steep increase in interpreters reporting workplace injuries, according to the union that represents some 70 accredited interpreters who translate English into French and vice versa.




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Liverpool youngster Neco Williams singles out Adam Lallana as key influence at Melwood

Neco Williams has revealed how Adam Lallana has played a major role in helping him adapt to the demands of training regularly with Liverpool's first team.




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RB Leipzig chief responds to Timo Werner to Liverpool transfer talk

RB Leipzig chief executive Oliver Mintzlaff insists he is calm over the future of Timo Werner amid speculation linking the forward with Liverpool and Chelsea.




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Liverpool legend Kenny Dalglish tests positive for coronavirus and remains in hospital showing no symptoms

Liverpool legend Sir Kenny Dalglish has tested positive for Covid-19 but does not currently have any symptoms of the virus.




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Liverpool winger Xherdan Shaqiri opens up on helping Takumi Minamino settle into life at Anfield

Xherdan Shaqiri has revealed that he is part of a group of German-speaking players helping Takumi Minamino settle into life at Liverpool.




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​Liverpool's Roberto Firmino not focused on scoring goals, says former Red Emile Heskey

Former Liverpool striker Emile Heskey believes Roberto Firmino doesn't focus on scoring goals, instead providing the 'gel' that glues his side together.




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Marko Grujic concedes he may need to leave Liverpool this summer to progress his career

Marko Grujic has conceded that he may need to move on from Liverpool this summer if he is to fulfil his potential.




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Liverpool missing out on Mario Gotze was a blessing in disguise - Jurgen Klopp won't be tempted again

Liverpool fans would have been justified in feeling a little nervous when the summer transfer window of 2016 opened up.




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Sir Kenny Dalglish's family thank fans for 'humbling' support after Liverpool hero tests positive for Covid-19

The family of Liverpool legend Sir Kenny Dalglish have thanked football fans around the world for their messages of support after the 69-year-old was diagnosed with coronavirus.




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Transfer news LIVE: Paul Pogba to Real Madrid, Man Utd Sancho move, Gotze latest, Liverpool, Chelsea rumours

Welcome to the Evening Standard's live blog covering the latest transfer news and rumours from the Premier League and beyond.




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Liverpool legend Kenny Dalglish released from hospital and hails NHS staff as they battle coronavirus

Liverpool legend Sir Kenny Dalglish has praised the efforts of NHS staff across the UK after being released from hospital following a positive coronavirus diagnosis.




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Liverpool kits 2020-21 season: Stunning concept designs for Nike deal

Liverpool are set to be the best-looking team in the Premier League and across Europe next season if these concept kit designs are anything to go by.




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What Liverpool will miss out on if Kylian Mbappe joins Real Madrid... predicted by Football Manager

Real Madrid may have missed out on signing Kylian Mbappe this summer due to the coronavirus.




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Liverpool legend Kenny Dalglish expresses 'immense gratitude' to NHS and urges people to stay home

Liverpool legend Sir Kenny Dalglish has reiterated his "immense gratitude" to the NHS following his release from hospital and urged people to stay at home during the coronavirus pandemic.




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Transfer news LIVE: Harry Kane 'open' to Man Utd transfer, Grealish latest; Chelsea, Arsenal, Liverpool gossip

Welcome to the Evening Standard's live blog covering the latest transfer news and rumours from the Premier League and beyond.




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Jurgen Klopp reveals Liverpool squad shock at Kenny Dalglish coronavirus diagnosis – 'One of us has it'

Liverpool manager Jurgen Klopp has revealed the impact that club legend Sir Kenny Dalglish being diagnosed with coronavirus had on him and his players.




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Liverpool urged to re-sign 'genius' Philippe Coutinho by legend Phil Thompson – 'I would in a heartbeat'

Liverpool legend Phil Thompson has urged Jurgen Klopp to bring Philippe Coutinho back to Anfield, saying he would re-sign the Brazilian "in a heartbeat".




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Jurgen Klopp opens up on Liverpool's virtual training, missing his players and fines for late arrivals on Zoom

Jurgen Klopp has shed some light on how his Liverpool players are coping with lockdown measures, revealing virtual meetings with the squad are helping improve his own morale.




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Transfer news LIVE: Liverpool eye Mbappe deal, Aubameyang update, Chelsea want Mertens; Man Utd, Arsenal gossip

Welcome to the Evening Standard's live blog covering the latest transfer news and rumours from the Premier League and beyond.




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Liverpool fan Sven-Goran Eriksson: Very hard to declare Premier League null and void




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Graeme Souness vs Paul Pogba: Who wins the medals row between Manchester United star and Liverpool legend?

Paul Pogba vs Graeme Souness is the feud that keeps on giving after the two exchanged barbs again on Tuesday.




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Liverpool's Trent Alexander-Arnold backed to surpass Manchester United's Gary Neville by Jamie Carragher

The 21-year-old has been tipped to become the greatest right-back in Premier League history