Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

Significance:

We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.

See related commentary by van Galen, p. 646.

This article is highlighted in the In This Issue feature, p. 627

Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28) outperforms that in tisagenlecleucel (CD19-4-1BB) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BB CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BB-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence.

Significance:

Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28-CARs outperform 4-1BB-CARs when antigen density is low. However, 4-1BB-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.

This article is highlighted in the In This Issue feature, p. 627

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.

Significance:

T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.

Significance:

T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627

Rhabdomyosarcoma (RMS) is the most common childhood soft-tissue sarcoma. The largest subtype of RMS is embryonal rhabdomyosarcoma (ERMS) and accounts for 53% of all RMS. ERMS typically occurs in the head and neck region, bladder, or reproductive organs and portends a promising prognosis when localized; however, when metastatic the 5-yr overall survival rate is ~43%. The genomic landscape of ERMS demonstrates a range of putative driver mutations, and thus the recognition of the pathological mechanisms driving tumor maintenance should be critical for identifying effective targeted treatments at the level of the individual patients. Here, we report genomic, phenotypic, and bioinformatic analyses for a case of a 3-yr-old male who presented with bladder ERMS. Additionally, we use an unsupervised agglomerative clustering analysis of RNA and whole-exome sequencing data across ERMS and undifferentiated pleomorphic sarcoma (UPS) tumor samples to determine several major endotypes inferring potential targeted treatments for a spectrum of pediatric ERMS patient cases.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc. (ACP), and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative of the Cleveland Clinic’s internal medicine residents to improve diabetes care and outcomes within an underserved patient population at an East Cleveland, OH, health center.

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.

Methods:

SMI, VAT, and SAT were assessed from abdominal CT images for 1,998 patients with stage I–III colorectal cancer diagnosed between 2006 and 2015. Restricted cubic splines (RCS) were used to investigate associations of SMI, VAT, and SAT with overall mortality.

Results:

Average age of the participants was 67.9 ± 10.6 years and 58% were men. During a median follow-up of 4.3 years, 546 (27%) patients died. Among men, the association of SMI and mortality was statistically significant in a nonlinear way in the RCS analyses, with lower SMI levels associated with higher mortality. SMI was not associated with mortality among women. SAT was associated with mortality in a nonlinear way for men and for women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality in men or women.

Conclusion:

Associations of abdominal skeletal muscle mass with mortality among patients with colorectal cancer were not the same for men and for women.

Impact:

This study stresses the importance for more attention on sex-related differences in body composition and cancer outcomes.

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.

For years, clinical and basic researchers have been aware of the presence of PTEN in the nucleus in cell culture, animal models, and both healthy and diseased human tissues. Despite the early recognition of nuclear PTEN, the understanding of the mechanisms of its nuclear localization, function in the nucleus, and importance in biology and human disease has been lacking. Over the last decade, emerging concepts for the complex involvement of nuclear PTEN in a variety of processes, including genome maintenance and DNA repair, cell-cycle control, gene expression, and DNA replication, are illuminating what could prove to be the key path toward a full understanding of PTEN function in health and disease. Dysregulation of nuclear PTEN is now considered an important aspect of the etiology of many pathologic conditions, prompting reconsideration of the therapeutic approaches aimed at countering the consequences of PTEN deficiency. This new knowledge is fueling the development of innovative therapeutic modalities for a broad spectrum of human conditions, from cancer and metabolic diseases, to neurological disorders and autism.

BACKGROUND AND PURPOSE:

NeuroQuant is an FDA-approved software that performs automated MR imaging quantitative volumetric analysis. This study aimed to compare the accuracy of NeuroQuant analysis with visual MR imaging analysis by neuroradiologists with expertise in epilepsy in identifying hippocampal sclerosis.

MATERIALS AND METHODS:

We reviewed 144 adult patients who underwent presurgical evaluation for temporal lobe epilepsy. The reference standard for hippocampal sclerosis was defined by having hippocampal sclerosis on pathology (n = 61) or not having hippocampal sclerosis on pathology (n = 83). Sensitivities, specificities, positive predictive values, and negative predictive values were compared between NeuroQuant analysis and visual MR imaging analysis by using a McNemar paired test of proportions and the Bayes theorem.

RESULTS:

NeuroQuant analysis had a similar specificity to neuroradiologist visual MR imaging analysis (90.4% versus 91.6%; P = .99) but a lower sensitivity (69.0% versus 93.0%, P < .001). The positive predictive value of NeuroQuant analysis was comparable with visual MR imaging analysis (84.0% versus 89.1%), whereas the negative predictive value was not comparable (79.8% versus 95.0%).

CONCLUSIONS:

Visual MR imaging analysis by a neuroradiologist with expertise in epilepsy had a higher sensitivity than did NeuroQuant analysis, likely due to the inability of NeuroQuant to evaluate changes in hippocampal T2 signal or architecture. Given that there was no significant difference in specificity between NeuroQuant analysis and visual MR imaging analysis, NeuroQuant can be a valuable tool when the results are positive, particularly in centers that lack neuroradiologists with expertise in epilepsy, to help identify and refer candidates for temporal lobe epilepsy resection. In contrast, a negative test could justify a case referral for further evaluation to ensure that false-negatives are detected.

SUMMARY:

The cerebral ventricles have been studied since the fourth century BC and were originally thought to harbor the soul and higher executive functions. During the infancy of neuroradiology, alterations to the ventricular shape and position on pneumoencephalography and ventriculography were signs of mass effect or volume loss. However, in the current era of high-resolution cross-sectional imaging, variation in ventricular anatomy is more easily detectable and its clinical significance is still being investigated. Interpreting radiologists must be aware of anatomic variations of the ventricular system to prevent mistaking normal variants for pathology. We will review of the anatomy and development of the lateral ventricles and discuss several ventricular variations.

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We have to capture carbon dioxide to slow climate change, but instead of simply burying it we could first use it to extract useful metals from old electrical equipment

Within months researchers will attempt to create a ball of plasma hotter than the sun inside the Joint European Torus, a doughnut-shaped machine in south-east England

Ironbark is one of 2020’s anticipated movies. Benedict Cumberbatch plays the MI6 handler of a Russian spy who may have helped prevent nuclear war

A self-powered device that generates electricity from the wind can also absorb and break down harmful nitric oxide and nitrogen dioxide from the air

Kate Darling researches human-robot interaction. She explains why we are prone to forming emotional connections with robots and what we can learn from our relationships with pets and other animals

Businesses, individuals with land, and local governments are competing to host an underground nuclear waste facility in the UK, and receive a yearly £2.5 million incentive

Robots made of 3D-printed muscle and rat spines could help us understand conditions like motor neurone disease and the technique may eventually be used to build prosthetic devices

The road to haircut hell is paved with good questions. Questions like: Is the coronavirus pandemic the Flowbee’s time to shine?

Because we don't have enough on our plates as it is, now we've got 'murder hornets' flying around the United States. Murder hornets (actually Asian Giant Hornets, but that name didn't strike enough fear into the masses) have a sting powerful enough that China recommends medical treatment if stunk more than ten times, and emergency treatment if stung more than 30. *pours out a little liquor for Macaulay Culkin in My Girl*. And where is his glasses?! He can't see without his glasses! Put his glasses on! Here's a video of Coyote Peterson getting stung by one (the Japanese Giant Hornet was previously believed to be a subspecies of the Asian Giant Hornet, but has since been recategorized as a color morph). This is a video of a praying mantis eating a Giant Asian hornet until it's just a pile of limbs. So yeah, praying mantises -- start breeding them. And make sure to selectively breed them too so we can produce them bigger and bigger until they're preying on us because the way things are going how is that not how this ends? Keep going for the video while I surround my Animal Crossings town with preying mantises to protect my villagers and keep my five-star rating (okay, three).

Safety fears derail plan to import reactors.

Skimming system tripled previous best effort at oil collection.

Cheap, printable photovoltaics might finally live up to their early promise.

The world of video games holds many mysteries. Whether it be monks fighting on a hand, screenshots that make games look like other games, or...

BEIJING (Reuters) - Chinese regulators have approved Novartis' Mayzent to treat relapsing multiple sclerosis in adults, the Swiss drug maker said in a statement on Saturday. Other drugs approved by China's National Medical Products Administration to treat MS include Novartis' Gilenya, Bayer's Betaferon and Sanofi's Aubagio. China has an estimated 30,000 patients with MS. (Reporting by Roxanne Liu and Kevin Yao in Beijing; Editing by Edwina Gibbs

The notoriously independent-minded federal judge who once said he was disgusted by the conduct of Michael Flynn could block the administration's bid to drop criminal charges against the former adviser to President Donald Trump, legal experts said.

"Right now it is a concern, but they're taking measures ... we'll be up and running again shortly."

Graham Ford hailed Ben Stokes as a "great entertainer" after the England all-rounder's recent recognition by Wisden.

There are all sorts of ways the home cook can help conserve precious energy, this recipe for vegan coconutty ‘cheesecake’ being a case in point

Reducing waste in the kitchen isn’t just about saving food: the time and energy it takes to cook food are also important resources that are easily squandered.

The best way to save energy, besides loving your leftovers, is by cooking less: swap out a cooked element of your meal for a nutritious vegetable salad or raw dish (such as today’s coconut and lemon “cheesecake”); or make one-pot wonders that don’t use multiple cooker rings. And when you do need to cook more, make extra portions for the freezer.

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Investment mandate of the Clean Energy Financing Corporation will be changed, but no guarantee hydrogen will be produced from renewables

The Morrison government will change the investment mandate of the Clean Energy Finance Corporation, directing it to make up to $300m available for a new Advancing Hydrogen Fund as part of the national hydrogen strategy.

The Coalition’s move to create a dedicated hydrogen financing fund will be confirmed on Monday, and comes ahead of other changes the government intends to make to the CEFC’s investment program, including requiring it to support new investments in grid reliability.

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Workers at ‘most toxic place in America’ are terrified to return to a site where there has been very little protection from the outbreak

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For more than a month, coronavirus has brought cleanup of a 586-square-mile decommissioned nuclear production complex in south-eastern Washington state to a near standstill.

Most of the more than 11,000 employees at the Hanford site were sent home in late March, with only essential workers remaining to make sure the “most toxic place in America” stays safe and secure.

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Nuclear Regulatory Commission keen to allow material to be disposed of by ‘land burial’ – with potentially damaging effects

The federal agency providing oversight of the commercial nuclear sector is attempting to push through a rule change critics say could allow dangerous amounts of radioactive material to be disposed of in places like municipal landfills, with potentially serious consequences to human health and the environment.

Related: Coca-Cola and Pepsi falling short on pledges over plastic – report

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What kind of an effect do trees have on aerosol particle concentrations in cities? Modelling carried out at the University of Helsinki revealed that the air was cleanest on the street level with three rows of trees of variable height situated along boulevard-type city street canyons.

A recent study has described new states that can be found in super-cold atom experiments, which could have applications for quantum technology.

Tesla Inc "must not reopen" its vehicle factory in the San Francisco Bay area as local lockdown measures to curb the spread of the coronavirus remain in effect, the local county health department said on Friday.

Tesla Inc "must not reopen" its vehicle factory in the San Francisco Bay area as local lockdown measures to curb the spread of the coronavirus remain in effect, the local county health department said on Friday.

Forest fires are raging in the contaminated area near the Chernobyl nuclear power plant, but officials insist there is no radiation threat.

Three new wildfires have broken out in the radiation-contaminated evacuation zone around the wrecked Chernobyl nuclear power plant in Ukraine.

2019 was the hottest year on record for Europe as global warming trends continue, major analysis has shown.

Some NHS medics are being re-tested for Covid-19 after being wrongly cleared of carrying the virus.

Imam and priest tell of comfort given to grieving families and compassion of staff

The number of vehicles on roads during the coronavirus pandemic has hit its highest level since the lockdown began.