This study was an analysis of a national sample of U.S. medical office visits from 2014 to 2016, a period when evidence of effectiveness was emerging for a variety of beneficial type 2 diabetes agents with regard to potential reduction in diabetes comorbidities. Ideal therapy was defined as an American Diabetes Association–identified beneficial agent plus metformin. The associations between atherosclerotic cardiovascular disease or obesity and use of these agents were explored.

Background:

Energy balance–related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear.

Background:

The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I–III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I–III colorectal cancer.

Background:

Limited treatment options are available for oral mucositis, a common, debilitating complication of cancer therapy. We examined the association between daily delivery time of radiotherapy and the severity of oral mucositis in patients with head and neck cancer.

Background:

The Center to Reduce Cancer Health Disparities (CRCHD), NCI, implemented Screen to Save, NCI's Colorectal Cancer Outreach and Screening Initiative to promote awareness and knowledge of colorectal cancer in racial/ethnic and rural populations.

Adeno-associated virus (AAV) recombinants are currently the vector of choice for many gene therapy applications. As experimental therapies progress to clinical trials, the need to characterize recombinant adeno-associated viruses (rAAVs) accurately and reproducibly increases. Accurate determination of rAAV infectious titer is important for determining the activity of each vector lot and for ensuring lot-to-lot consistency. The following protocol developed in our laboratory uses a 96-well TCID₅₀ format and quantitative polymerase chain reaction (qPCR) detection for the determination of rAAV infectious titer.

This protocol is used to determine the concentration of DNase-resistant vector genomes (i.e., packaged in the capsid) in purified recombinant adeno-associated virus (rAAV) preparations. The protocol begins with treatment of the vector stock with DNase I to eliminate unencapsidated AAV DNA or contaminating plasmid DNA. This is followed by a heat treatment to heat-inactivate DNase I, to disrupt the viral capsid, and to release the packaged vector genomes for quantification by real-time polymerase chain reaction (PCR) using a set of standards (linearized plasmid used for vector production) containing known copy numbers. To accomplish high-throughput titration, the primer and probe sets used in real-time PCR are usually designed to target common elements present in most rAAV genomes, such as promoters and poly(A) signals. This strategy significantly reduces the number of PCRs, controls, and turnaround time. Several important controls should be included in the assay as follows: The first two controls should have a known copy number of the rAAV genome plasmid treated or not treated with DNase I. This control tests the effectiveness of DNase treatment. To control for potential cross-contamination between samples during the preparation process, a blank control containing nuclease-free water only should be processed and tested in parallel. A validation vector sample with a known titer should be included in every assay to monitor interassay variability. Finally, for the PCR run, a no-template control (NTC) is included to indicate cross-contamination during PCR setup.

This protocol describes a simple single-step column purification (SSCP) of rAAV2 by gravity flow based on its affinity to heparin, without ultracentrifugation.

It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in people of African ancestry, but between 1% and 11% in all other populations. Research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions that impacted selection of its haplotypes are synthesized to provide evidence for TRPV6 as a germline susceptibility locus in cancer. Recently elucidated mechanisms of TRPV6 channel deactivation are discussed in relation to the location of the allele favored in selection, suggesting a reduced capacity to inactivate the channel in those who have the ancestral haplotype. This could result in an excessively high cellular Ca²⁺, which has been implicated in cancer, for those in settings where calcium intake is far higher than in their ancestral environment. A recent report associating increasing calcium intake with a pattern of increase in aggressive prostate cancer in African-American but not European-American men may be related. If TRPV6 is found to be associated with cancer, further research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African ancestry.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07–1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer.Significance:The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer.Significance:This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.Significance:NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799

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:

Endovascular treatment of petrous dural AVFs may carry a risk of iatrogenic facial nerve palsy if the facial nerve arterial arcade, an anastomotic arterial arch that supplies the geniculate ganglion, is not respected or recognized. Our purpose was to demonstrate that the use of a treatment strategy algorithm incorporating detailed angiographic anatomic assessment allows identification of the facial nerve arterial arcade and therefore safe endovascular treatment.

BACKGROUND AND PURPOSE:

It is currently not completely clear how well radiologists perform in evaluating large-vessel occlusion on CTA in acute ischemic stroke. The purpose of this study was to investigate potential factors associated with diagnostic error.

We spoke with industry experts to identify what’s preventing developers from fully going green – and it all boils down to lack of finances.

As they implement stricter measures and distribute millions worth of donations to communities in need.

A centenarian who tested positive for COVID-19 has become the oldest local resident to die from the virus. The woman in her 100s was a resident of a long-term care or retirement home. She died on Thursday, the Windsor-Essex County Health Unit reported during its end-of-week epidemic data summary on Friday. “I would like to […]

Orange-coloured gel has been made into artificial skin that can be 3D printed in any shape and detect human touch – one day it could help robots feel

Tech firms are making record profits but paying little tax. Now global leaders are discussing ways to make them pay their fair share

In winter, the veins of leaves don’t get completely covered in frost. Mimicking this effect could be the best way to create ice-resistant surfaces

Join Pearse Keane to find out why the NHS is collaborating with AI company DeepMind and how deep learning could transform ophthalmology

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

The Pulitzer Prize Board this week awarded its commentary award to The New York Times' Nikole Hannah-Jones for her essay launching the "1619 Project." This will accelerate a trend already underway: subjecting schoolchildren to a curriculum that blames slavery on capitalism and whose creator believes socialism offers the best path to racial equity.

The creators of Kiki believe they can build an emotionally engaging social home robot that is also "completely useless"

Blue Frog Robotics CEO Rodolphe Hasselvander on the future of Buddy

Michael Kratsios, the fourth U.S. Chief Technology Officer, explains administration policies at the Fall Conference of the Stanford Institute for Human-Centered Artificial Intelligence

Experts discuss technological inequality and the “reskilling” problem at an MIT conference

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

“Today, the world has lost one of the greats of magic, but I have lost my best friend,” Siegfried Fischbacher said in a statement.

This is a video of the result of Youtuber Lil'Alien [Agentalex9 Alt.] feeding Rick Astley's rickrolling classic 'Never Gonna Give You Up' into the Jukebox neural network developed by OpenAI to create more song lyrics for the song. The music video consists of AI upscaled gifs from the original video. If you're really interested in the technology utilized and just what the hell is going on, there are a bunch of links on the video's Youtube page HERE. I just managed to watch the whole video and I can attest that, uh, that was really something. "Something good?" Haha, now let's not get ahead of ourselves. Keep going for whatever this is.

Warden Chris has left the building, now the inmates are running the asylum. Hear want these irregulars have to say about the news of this...

It’s a special edition of the RPGCast this week. Jon, Alex, Anna Marie, and Chris appreciate loot, bank Pokémon, link between and transfer worlds in...

Chris and Alice lead the charge this week. Blizzard announces a new game, Square Enix announces a plushie, and…wait…Blizzard has a new game? You’re making...

Chris drowns in potions. Anna Marie hits one hundred. Alice shops with e’s. And Manny plays some 360 games now that he finally has an...

Anna Marie hosts this week’s Cat Fancy, as the cast tries to figure out if touching girls is OK (we discover it isn’t OK to...

A post-E3 slump won’t get this podcast down! The RPG Cast chats about Judgment, discusses what little news did trickle in during the week, and looks ahead to an exciting #JRPGJuly.

Waters lap perilously close to audience as grand capes and latex trench coats are modelled

How to make the fashion industry engage with the climate crisis? Flood the venue, and submerge the front row.

Arriving at the Balenciaga show in Paris on Sunday morning, the audience found themselves entering at the periphery of what looked like a sports stadium, with banks of flip-up plastic seats around a central oval. In pitch blackness, it was hard to tell exactly, but attendants were on hand with torches, and strict instructions not to proceed beyond the third row.

People who attended religious services at least once a week were significantly less likely to die from 'deaths of despair,' including deaths related to suicide, drug overdose, and alcohol poisoning, according to new research.

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.

Systemic flaws within Glynn county’s district attorney offices led to a lack of action against the men involved in this ‘modern lynching’In the days and weeks after Ahmaud Arbery was shot and killed, multiple Glynn county law enforcement officials failed to thoroughly investigate his death and, in one case, refused to allow police officers to make arrests, the Guardian has learned.Arbery, 25, was jogging through the neighborhood just outside Brunswick, Georgia, on 23 February when he was shot dead by two white men. Gregory McMichael, 64, and his son Travis, 34, were charged with murder and aggravated assault on Thursday evening, after graphic video footage of the killing was released publicly and sparked national outrage.Lawyers for Arbery’s family have called the killing a “modern lynching” and decried the lack of action in the case prior to the release of the video, pointing to racial inequalities in the criminal justice system.In the police report, Gregory McMichael claimed Arbery “violently attacked” his son, who shot Arbery in self defense.Jackie Johnson, the Glynn county district attorney, refused to allow police officers who responded to arrest the two men, Glynn county commissioner Peter Murphy told the Guardian in a phone call on Friday.The police department was put in touch with one of Johnson’s assistant district attorneys after the shooting, but Johnson made the decision not to charge the father and son, the former having worked in her office for more than 20 years, Murphy said.“The police at the scene went to her, saying they were ready to arrest both of them,” Allen Booker, the Glynn county district 5 commissioner, told the Atlanta Journal-Constitution on Friday. “These were the police at the scene who had done the investigation. She shut them down to protect her friend McMichael.”Days later, Johnson recused herself. Johnson did not immediately respond to a request for comment. By 27 February, George Barnhill, the Waycross judicial district attorney, and the second of three DAs on the case, took over. Less than 24 hours after seeing the video and evidence compiled by the police, Murphy said, Barnhill decided to not charge the McMichaels.“And so within 24 hours the Glynn county police had been told by two separate DA offices not to make any arrests,” Murphy said. “And obviously, they want to assume no responsibility for their actions.”On 2 April, Barnhill sent an email to law enforcement authorities saying the 25-year-old Arbery had an “apparent aggressive nature” and that his family were “not strangers to the local criminal justice system”.“Arbery’s mental health records & prior convictions help explain his apparent aggressive nature and his possible thought pattern to attack an armed man,” Barnhill said in the email, which was first reported by the New York Times.“What it appears is he was purposely trying to assault the character of the victim and there’s just no reason why,” said Chris Stewart, one of the lawyers representing Arbery’s family.The family have pointed to the McMichaels’ connection to local law enforcement both at the district attorney’s office and police department as evidence of systemic flaws and roadblocks in their search for justice. It was only after the video of Arbery’s death was released this week that the third DA’s office requested the Georgia Bureau of Investigations (GBI) get involved.On Friday, GBI director Vic Reynolds told reporters he could not “answer what another agency did or didn’t see” in the first two months of the investigation.“But I can tell you that based on our involvement in this case and considering the fact we hit the ground running Wednesday morning and within 36 hours we had secured warrants for two individuals for felony murder, I think that speaks volumes for itself.”In a 7 April email sent to the office of Georgia attorney general Chris Carr, Barnhill recused himself because his son worked on a case involving Arbery while working in Johnson’s office.Lee Merritt, one of the lawyers who represents Arbery’s family, said Wanda Cooper-Jones, Arbery’s mother, found the connection between Barnhill’s son and her own on Facebook and brought it to the attention of his office.“She followed the links. That’s exactly how it happened,” he said to the Guardian on Friday by phone.According to a police report filed 23 February, Gregory and Travis McMichael grabbed their weapons, a .357 Magnum revolver and a shotgun, jumped into a truck and followed Arbery as he ran.In the email to Carr from early April, Barnhill references a “decent cell phone video of the entire shooting incident”, an apparent reference to the one leaked this week.Reynolds said on Friday that the investigation into the shooting, the video and the person who filmed it, would continue.“Every stone will be uncovered,” Reynolds said.

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

Half of the legendary Las Vegas magic duo died on Friday following complications from COVID-19.

More than 20 million Americans lost their jobs in the last month, and unemployment among African-Americans has hit 16.7 percent.

Now that the COVID-19 pandemic has forced millions into isolation, video games are seeing a surge in usage as people seek entertainment and social interaction. When we surveyed gaming-focused VCs in October, Andreessen Horowitz partner Jonathan Lai predicted that “next-generation games will be bigger than anything we’ve seen yet,” eventually reaching “Facebook scale.” This month, […]

During these long, mundane physically-distant days, stretching on into an uncertain future like an ever-lengthening beigeish corridor, it’s impossible not to miss hanging out with friends. Especially the kind of hanging out where you’re not really doing anything in particular, not talking about any one thing—just kind of being. As we continue to stay physically […]