RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17–1.36; P = 2.57 × 10–9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer–promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology.Significance:This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer–promoter interaction loops.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.

While immuno-oncology has made significant advances in activating local tumor immune responses, leading to improved outcomes, the role of systemic immunity in cancer incidence remains poorly understood. Le Cornet and colleagues prospectively studied circulating immune cells quantified by DNA methylation markers in relation to incidence of breast, colorectal, lung, and prostate cancer among initially healthy individuals. A positive association with cancer risk was observed for higher FOXP3+ T-cell–mediated immune tolerance and lower CD8+ T-cell–mediated cytotoxicity. Further studies of systemic immunity in cancer development are crucial to identify novel prediction markers and interventional targets for cancer immunoprevention.See related article by Le Cornet et al., p. 1885

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5–10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.

BACKGROUND AND PURPOSE:

Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma.

BACKGROUND AND PURPOSE:

Endolymphatic hydrops in patients with Menière disease relies on delayed postcontrast 3D-FLAIR sequences. The purpose of this study was to compare the degree of perilymphatic enhancement and the detection rate of endolymphatic hydrops using constant and variable flip angles sequences.

BACKGROUND AND PURPOSE:

Embolization is widely performed to treat brain arteriovenous malformations, but little has been reported on factors contributing to complications. We retrospectively reviewed a nationwide surveillance to identify risk factors contributing to complications and short-term clinical outcomes in the endovascular treatment of brain arteriovenous malformations.

BACKGROUND AND PURPOSE:

Accurate differentiation between glioblastoma and solitary brain metastasis is of vital importance clinically. This study aimed to investigate the potential value of the inflow-based vascular-space-occupancy MR imaging technique, which has no need for an exogenous contrast agent, in differentiating glioblastoma and solitary brain metastasis and to compare it with DSC MR imaging.

As home sellers commonly propose to state a lower price in the sale contract than the actual transaction value, home buyers have to bear additional risks from such real estate transactions.

Paris Games Week 2020 organizer SELL announced it has cancelled this years event due to concerns over the ongoing coronavirus (COVID-19) pandemic. The event was set to run from October 23 to 27. 

Read the message from SELL below:

Dear players,

It is with great emotion that we have made the difficult decision to cancel Paris Games Week, initially scheduled from 23rd to 27th October and which would have marked our 10th anniversary.

The current context and the necessary anticipation of both the technical and logistical complexities of an event such as Paris Games Week have led us to cancel this edition.

This year should have been special, with a line-up full of new releases, and an anniversary edition which we were thrilled to celebrate with you.

We are going to work with all the industry players to enable us all to live our passion. We are already preparing next year’s edition and are looking forward to seeing you again.

Our Very Best Regards,

The Paris Games Week Team

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/443416/paris-games-week-2020-cancelled-due-to-coronavirus-pandemic/

A gameplay trailer for a Prince of Persia reboot, called Prince of Persia: Redemption, was posted on YouTube in March 2012 and was discovered this week. 

The LinkedIn profile for the former Ubisoft employee Christophe Prelot revealed he worked on a cancelled Prince of Persia title from April 2010 to 2011 as a 3D level artist. The game was in development for the PlayStation 3, Xbox 360 and Windows PC. 

Ubisoft assistant technical director Marc-Andre Belleau in 2018 left a comment on the video asking, "Where did you get that?!"

View the video below:

Thanks ResetEra.

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/443408/footage-of-cancelled-prince-of-persia-redemption-from-2012-discovered/

Ancestors is the latest attempt to gamify millions of years of evolution but doesn't have the excitement gene, says Jacob Aron

QR codes, tracking apps and drones at toll booths are just some of the tech tools China is deploying to monitor the spread of the new coronavirus

Sony has managed to best its top-of-the-line noise cancelling earbuds with a new, improved, and best of all, cheaper model.

Big Tech is coming for your transaction data.

This week, new claims about the accuracy of the Garden of Eden story emerged online and in tabloid magazines. Professor Tom Meyer, a scripture expert known as the Bible Memory Man, argues that there are two artifacts—a 4,000-year-old seal and roughly 3,600-year-old stone—that provide evidence both for the location of the Garden of Eden and the Adam and Eve story. But do his claims add up? (Spoiler alert: No)

In a story, reported this week in the Daily Express, Meyer, who teaches at his alma mater Shasta Bible College and University, refers first to a Sumerian king list, an inscribed Middle Bronze aged stone prism currently housed at the Ashmolean Museum in Oxford. The prism dates to between 2100 B.C. and 1650 B.C. and was discovered in 1922 by Herbert Weld-Blundell during his excavations in Kish, the ancient capital of Sumer, in Mesopotamia. It was purchased by the Ashmolean shortly thereafter.

Meyer said, “In addition to enumerating the long reigns of pre-flood rulers, this prism lists Eridu—an ancient site in southern Iraq—as the first city ever built.” This is significant, he says, because “The ancient site of the Garden of Eden… is thought by some to be located at Eridu under a cluster of tels” (Tels are artificial hills).

Read more at The Daily Beast.

STATE PENSIONS are calculated by National Insurance contributions - but can you top up any missed years?

Rafael Nadal revealed this week he was doubtful there will be further tennis in 2020.

Out of 28,000 suggestions, NASA selected the name Perseverance for its Mars 2020 rover, which will search for signs of life on the Red Planet

Mars could have had an ancient ocean in its northern hemisphere, and a large raft of volcanic rock may have floated across it to settle into mounds we can see today

SpaceX’s first crewed launch is planned for 27 May and will be run from a mission control with desks set six feet apart to comply with social distancing protocols

We’ve found a 200-metre cliff in Mars's Hellas basin, the first evidence of a river that flowed on the planet for more than 100,000 years

Your weekly selection of awesome robot videos

A new two-way teleoperation system sends your motions to the robot and the robot's motions to you

New York City study shows that drones could deliver life-saving medical supplies several minutes before an ambulance arrives

She’s also learning to iron.

DJ D-Nice, Miley Cyrus, Ben Gibbard, and a lot of Diplo.

Scientists set out to investigate a potential role of the gut microbiota in the development of cardio-metabolic diseases. They ended up identifying the common cholesterol-lowering drug statins as a potential microbiota-modulating therapeutic.

Your house number could be the key to the safe relaxation of COVID-19-related restrictions if governments follow a new exit strategy, which proposes the use of an 'odds-and-evens' approach to allowing people to head back to work and enjoy other activities after weeks of lockdown.

Scientists have revealed a novel mechanism through which the immune system controls autoimmunity and cancer. In the special focus of the researchers were regulatory T cells -- a type of white blood cells that act as a brake on the immune system.

The anti-cancer medicine venetoclax could improve the current therapy for estrogen receptor-positive (ER+) breast cancer, according to preclinical studies. The promising preclinical results for this 'triple therapy' have underpinned a phase 1 clinical trial in Melbourne, Australia, that is combining venetoclax with hormone therapy and CDK4/6 inhibitors in patients with ER+ breast cancer.

French Resistance member Cecile Rol-Tanguy, who risked her life during World War II by working to liberate Paris from Nazi occupation, has died. Rol-Tanguy died on Friday at her home in Monteaux, in central France, as Europe commemorated the 75th anniversary of the surrender of Nazi Germany to Allied forces. The cause of her death was not disclosed by French officials.

Wagner Moura and Ana de Armas give strong performances in a mostly effective retelling of the life and tragic death of a celebrated Brazilian diplomat

There’s an old school charm to Sergio, documentarian Greg Barker’s narrative portrait of UN diplomat Sérgio Vieira de Mello, a dramatic retelling of a life he already brought to the screen in a 2009 documentary of the same name. Barker’s knowledge of Sérgio’s life and accomplishments is backgrounded by a clear respect for who he was and so while the film is factually detailed, as one would expect, it’s also rooted in a desire to showcase his humanity, both in and out of work, with Barker deciding to lean into full-tilt romantic tragedy, perhaps also as a way of differentiating his two Sergios.

Related: Love Wedding Repeat review – laboured Netflix romcom farce

This uncanny story of preppy drug dealers has a touch of Heathers and a bit of Bret Easton Ellis, and an intriguing take on what high school is really like

Tayarisha Poe, like her partial namesake, has a gift for the uncanny. She is the photographer and film-maker behind this feature debut, which began as an online multimedia project and was developed as a conventional movie through the Sundance screenwriters and directors labs. What has emerged is an intriguing, opaque, tonally elusive story that seems weirdly unfinished. It is set in a privileged high school – a world of ivy-covered stone buildings and shady quadrangles where rich kids are separated into malign and mutually hostile cliques. It has a touch of Donna Tartt and Bret Easton Ellis, a hint of Heathers and a bit of the elegant, disdainful satire of Dear White People.

Somehow, though, it is odder, more stylised and contrived, always holding out the possibility that it is set in the future, or in an alternative present on some other planet, or inside the head of one of its characters who is having a disturbing dream – the kind that ends just as it is about to give up its meaning. Right until the closing credits, I half-expected the face of each person on screen to flip upwards, revealing a Stepford-like set of dials.

This heartwarming documentary traces the lives of a baseball star and her partner, now in their 90s, who pretended to be ‘just good friends’ for decades

This documentary from Netflix is a real heart-soother. Directed with tremendous sensitivity and intimacy by Chris Bolan, it’s a love story about two women now in their 90s – Terry Donahue and Pat Henschel, who have been together since the 1940s.

For decades they kept up the pretence of being “just good friends” to their families before finally coming out a few years ago. Talking to outsiders, they still describe each other as “cousins”. The legacy of shame and fear among older people in the gay community is explored in the film, but the overwhelming mood here is love.

The Hollywood Reporter says numerous attendees returned from the late-January festival with coronavirus symptoms

A new report suggests that January’s Sundance film festival, the annual gathering of cinephiles in Park City, Utah, may have been a key early hub for coronavirus in the US. The article, in the Hollywood Reporter, cites numerous attendees who experienced Covid-19-like symptoms either during or immediately after the festival. None were believed to have been tested for the disease.

Sundance this year attracted about 120,000 people to the small mountain resort, to watch films and party in confined spaces. The snowy conditions that make Park City perfect for skiing mean that socialising indoors is common, as are some flu-like symptoms as a result of the low temperature and high altitude.

The director of King of New York, Bad Lieutenant and The Funeral recommends film and TV for a coronavirus age, in the hope that ‘the light becomes more evident in the darkness’

• Read the rest of our Lockdown watch series
• The best arts and entertainment during self-isolation

The Day the Earth Stood Still (1951)

Restaurants and drive-in movie theatres are allowed to reopen in Las Vegas today, with casinos hoping to reopen by Memorial Day.

A species of plant that grew about 400 million years ago (Early Devonian period) produced a spectrum of spore sizes, which is an essential innovation necessary for all advanced plant reproductive strategies, including seeds and flowers. The Devonian period is one of the most important time periods for the evolution of land plants. It witnessed [...]

Modern Games is a new studio working to create games that combine physical and digital play. The company was founded by husband-and-wife team Justin and Amanda Kifer — serial entrepreneurs who previously launched companies including Citizen Local (acquired by MyLife in 2011) and Fidgetly, a fidget spinner company that also created a motion controller for […]