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.

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.

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.

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.

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

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!"

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/

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/

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

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

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

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

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.

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

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

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

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”

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

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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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..

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'..

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

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

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

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

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

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.

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.

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.

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

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

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

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

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

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.

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

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.

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.

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

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.

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

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

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".

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.

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

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

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