In 2016, the proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to azithromycin rose to 3.6%. A phylogenetic analysis of 334 N. gonorrhoeae isolates collected in 2016 revealed a single, geographically diverse lineage of isolates with MICs of 2 to 16 μg/ml that carried a mosaic-like mtr locus, whereas the majority of isolates with MICs of ≥16 μg/ml appeared sporadically and carried 23S rRNA mutations. Continued molecular surveillance of N. gonorrhoeae isolates will identify new resistance mechanisms.

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla_KPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla_KPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, bla_KPC has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of bla_KPC has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 bla_KPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of bla_KPC (predominantly bla_KPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), bla_KPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-bla_KPC and bla_KPC plasmids and the common presence of multiple replicons within bla_KPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control.

BRAF^V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAF^V600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort "basket" study of the BRAF inhibitor vemurafenib in non-melanoma BRAF^V600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.

Summary:

In this issue of Cancer Discovery, Li and colleagues provide a blueprint for the identification and functional validation of cancer-associated mutations in noncoding regions of the genome. Integration of whole-genome sequencing and high-throughput epigenome editing screens is starting to reveal the extent to which noncoding genetic lesions contribute to cancer.

See related article by Li et al., p. 724.

Unlike replicative senescence, oncogene-induced senescence caused heterochromatin-body formation.

Pemigatinib was effective in patients with cholangiocarcinomas with FGFR2 fusions or rearrangements.

The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.

Chlorotoxin, a small peptide component of scorpion venom, may help pinpoint glioblastoma cells for destruction when engineered into a chimeric antigen receptor T-cell therapy. The concept has shown efficacy in mice, without off-target toxicity, and will soon be assessed in patients.

Background:

Sex steroid hormones and sex hormone–binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear.

High-throughput sequencing methods have created exciting opportunities to explore the regulatory landscape of the entire genome. Here we introduce methods to characterize the genomic locations of bound proteins, open chromatin, and sites of DNA–DNA contact in Xenopus embryos. These methods include chromatin immunoprecipitation followed by sequencing (ChIP-seq), a combination of DNase I digestion and sequencing (DNase-seq), the assay for transposase-accessible chromatin and sequencing (ATAC-seq), and the use of proximity-based DNA ligation followed by sequencing (Hi-C).

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.

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.

Consistently, the field of genetic counseling has advocated that parents be advised to defer elective genetic testing of minors until adulthood to prevent a range of potential harms, including stigma, discrimination, and the loss of the child's ability to decide for him- or herself as an adult. However, consensus around the policy of "defer-when-possible" obscures the extent to which this norm is currently under siege. Increasingly, routine use of full or partial genome sequencing challenges our ability to control what is discovered in childhood or, when applied in a prenatal context, even before birth. The expansion of consumer-initiated genetic testing services challenges our ability to restrict what is available to minors. As the barriers to access crumble, medical professionals should proceed with caution, bearing in mind potential risks and continuing to assess the impact of genetic testing on this vulnerable population.

BACKGROUND AND PURPOSE:

It is not known how radiomics using ultrasound images contribute to the detection of BRAF mutation. This study aimed to evaluate whether a radiomics study of gray-scale ultrasound can predict the presence or absence of B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation in papillary thyroid cancer.

Competition ushers in new era to recognise the country’s standout real estate projects and senior leaders.

Prof. Jason Pomeroy talks about the rise of the digital economy and its impact on the workplace.

Perhaps astronomers need help from something that thinks a bit less like a human.

THE CORONAVIRUS lockdown is now causing serious damage to the UK's economy, Tory MP Steve Baker has warned - stressing he was now "gravely concerned" at the situation

APRIL saw 20.5 million job losses in the United States, the biggest rise in the jobless rate since the Great Depression.

Huge constellations of satellites like SpaceX’s Starlink could make ground-based astronomy impossible, and we’re running out of time to deal with the problem

The International Astronomical Union has concluded a review of satellite mega constellations such as SpaceX's Starlink satellites and found they will have a major impact on large telescopes, but not naked eye astronomy

A huge black hole in a distant galaxy caused the largest explosion we have ever seen, with the energy of 10 billion suns – and it isn't clear why it was so big

An explosion 4.6 billion light years away has released 10 times more energy than the sun will put out in its lifetime, making it the most extreme supernova ever found

The coronavirus pandemic is making life feel slower than ever, but observing timescales across the universe can bring us some comfort, writes Chanda Prescod-Weinstein

The country faces the same problem today it did two months ago: There are not enough tests to contain the virus.

Your weekly selection of awesome robot videos

For the first time, NASA's Astrobee robot has demonstrated autonomous free flight in space

This cozy little box provides a remote home for Skydio's fully autonomous obstacle-avoiding drone

Experts representing a diversity of views on autonomous weapons systems collaborate on a realistic policy roadmap

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

The first clinical uses of whole-genome sequencing show just how challenging it can be.

Astronomers using the Fiber-fed Extended Range Optical Spectrograph (FEROS) on the MPG/ESO 2.2-m telescope at ESO’s La Silla Observatory have found a stellar-mass black hole in HR 6819 (also known as HD 167128), a naked-eye stellar system located 1,119 light-years away in the constellation of Telescopium. The system is made up of an inner binary [...]

Astronomers using the MeerKAT telescope at the South African Radio Astronomy Observatory in Cape Town, South Africa, have solved a longstanding mystery of X-shaped radio galaxies. Many galaxies far more active than the Milky Way have enormous twin jets of radio waves extending far into intergalactic space. Normally these go in opposite directions, coming from [...]

Following China’s switch to a two-child policy, there has been a slight rise in congenital anomalies, perhaps because parents are older on average at conception

Some of this year's Oscar nominees, including Andrew Garfield and Michael Shannon, react to news of their nomination.

The U.S. Senate on Wednesday approved William Evanina, President Donald Trump's nominee for a top counterintelligence position, after he was blocked for almost two years over a Republican request for documents related to the investigation of Russia and Trump's 2016 election campaign.

George Engelmann, a perennial swing voter in swing-state Wisconsin, says President Donald Trump has won his vote for November's election thanks to his response to the coronavirus pandemic.

President Donald Trump said on Thursday his administration was considering further economic measures, possibly via executive orders, to provide help against the economic fallout from the novel coronavirus pandemic.

Lucianne Walkowicz says the American Girl doll 'Luciana Vega' stole her name and likeness

Experts theorize there are between 100 million to 1 billion black holes in the Milky Way

Mercury-nominated UK rapper, Ty, has died aged only 47 after contracting coronavirus.

Joseph R. Biden said Friday President Trump's ham-handed response to the coronavirus has helped to steer the nation into a Great Depression-like economic tailspin.

Mr. Biden said Mr. Trump "utterly failed" to prepare for COVID-19 and said the virus has "laid bare" the damage Mr. Trump has done by pursuing ...

President Trump said the U.S. must start its economy "all over again" Friday as the unemployment rate from the coronavirus crisis rose to the highest level since the Great Depression.

"It's going to be a transition to greatness," the president said during a discussion at the White House with 19 ...

Provisions for credit losses were $30.2 million, an increase of 397.9 per cent from a year earlier

Trying to make sense of calamities that have already caused more destruction to people’s livelihoods than the Great Recession

America can take its next steps toward reopening by placing an emphasis on emerging health data and closely examining how early states are performing, Housing and Urban Development Secretary Dr. Ben Carson asserted Saturday.

The newfound 'invisible' object is only 1,000 light years from home

New modeling of coronavirus behavior suggests that an intervention strategy based on shield immunity could reduce the risk of allowing the higher levels of human interaction needed to support expanded economic activity.