Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor–specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Mice expressing the human extracellular regions of CD3 and PSMA were generated to examine antitumor efficacy in the presence of an intact immune system and PSMA expression in normal tissues. PSMAxCD3 accumulated in PSMA-expressing tissues and tumors as detected by immuno-PET imaging. Although PSMAxCD3 induced T-cell activation and showed antitumor efficacy in mice with low tumor burden, PSMAxCD3 lost efficacy against larger solid tumors, mirroring the difficulty of treating solid tumors in the clinic. Costimulatory receptors can enhance T-cell responses. We show here that costimulation can enhance the antitumor efficacy of PSMAxCD3. In particular, 4-1BB stimulation in combination with PSMAxCD3 enhanced T-cell activation and proliferation, boosted efficacy against larger tumors, and induced T-cell memory, leading to durable antitumor responses. The combination of CD3 bispecific antibodies and anti-4-1BB costimulation represents a therapeutic approach for the treatment of solid tumors.

The N-acetylglucosaminidase LytB of Streptococcus pneumoniae is involved in nasopharyngeal colonization and is responsible for cell separation at the end of cell division; thus, lytB mutants form long chains of cells. This paper reports the construction and properties of a defective pneumococcal mutant producing an inactive LytB protein (LytB_E585A). It is shown that an enzymatically active LytB is required for in vitro biofilm formation, as lytB mutants (either lytB or producing the inactive LytB_E585A) are incapable of forming substantial biofilms, despite that extracellular DNA is present in the biofilm matrix. Adding small amounts (0.5 to 2.0 μg/ml) of exogenous LytB or some LytB constructs restored the biofilm-forming capacity of lytB mutants to wild-type levels. The LytB_E585A mutant formed biofilm more rapidly than lytB mutants in the presence of LytB. This suggests that the mutant protein acted in a structural role, likely through the formation of complexes with extracellular DNA. The chain-dispersing capacity of LytB allowed the separation of daughter cells, presumably facilitating the formation of microcolonies and, finally, of biofilms. A role for the possible involvement of LytB in the synthesis of the extracellular polysaccharide component of the biofilm matrix is also discussed.

IMPORTANCE It has been previously accepted that biofilm formation in S. pneumoniae must be a multigenic trait because the mutation of a single gene has led to only to partial inhibition of biofilm production. In the present study, however, evidence that the N-acetylglucosaminidase LytB is crucial in biofilm formation is provided. Despite the presence of extracellular DNA, strains either deficient in LytB or producing a defective LytB enzyme formed only shallow biofilms.

Biological nitrogen fixation can be an important source of nitrogen in tropical forests that serve as a major CO₂ sink. Extensive deforestation of the Amazon is known to influence microbial communities and the biogeochemical cycles they mediate. However, it is unknown how diazotrophs (nitrogen-fixing microorganisms) respond to deforestation and subsequent ecosystem conversion to agriculture, as well as whether they can recover in secondary forests that are established after agriculture is abandoned. To address these knowledge gaps, we combined a spatially explicit sampling approach with high-throughput sequencing of nifH genes. The main objectives were to assess the functional distance decay relationship of the diazotrophic bacterial community in a tropical forest ecosystem and to quantify the roles of various factors that drive the observed changes in the diazotrophic community structure. We observed an increase in local diazotrophic diversity (α-diversity) with a decrease in community turnover (β-diversity), associated with a shift in diazotrophic community structure as a result of the forest-to-pasture conversion. Both diazotrophic community turnover and structure showed signs of recovery in secondary forests. Changes in the diazotrophic community were primarily driven by the change in land use rather than differences in geochemical characteristics or geographic distances. The diazotroph communities in secondary forests resembled those in primary forests, suggesting that at least partial recovery of diazotrophs is possible following agricultural abandonment.

IMPORTANCE The Amazon region is a major tropical forest region that is being deforested at an alarming rate to create space for cattle ranching and agriculture. Diazotrophs (nitrogen-fixing microorganisms) play an important role in supplying soil N for plant growth in tropical forests. It is unknown how diazotrophs respond to deforestation and whether they can recover in secondary forests that establish after agriculture is abandoned. Using high-throughput sequencing of nifH genes, we characterized the response of diazotrophs’ β-diversity and identified major drivers of changes in diazotrophs from forest-to-pasture and pasture-to-secondary-forest conversions. Studying the impact of land use change on diazotrophs is important for a better understanding of the impact of deforestation on tropical forest ecosystem functioning, and our results on the potential recovery of diazotrophs in secondary forests imply the possible restoration of ecosystem functions in secondary forests.

Bacteria accumulate small, organic compounds called compatible solutes via uptake from the environment or biosynthesis from available precursors to maintain the turgor pressure of the cell in response to osmotic stress. The halophile Vibrio parahaemolyticus has biosynthesis pathways for the compatible solutes ectoine (encoded by ectABC-asp_ect) and glycine betaine (encoded by betIBA-proXWV), four betaine-carnitine-choline transporters (encoded by bccT1 to bccT4), and a second ProU transporter (encoded by proVWX). All of these systems are osmotically inducible with the exception of bccT2. Previously, it was shown that CosR, a MarR-type regulator, was a direct repressor of ectABC-asp_ect in Vibrio species. In this study, we investigated whether CosR has a broader role in the osmotic stress response. Expression analyses demonstrated that betIBA-proXWV, bccT1, bccT3, bccT4, and proVWX are repressed in low salinity. Examination of an in-frame cosR deletion mutant showed that expression of these systems is derepressed in the mutant at low salinity compared with the wild type. DNA binding assays demonstrated that purified CosR binds directly to the regulatory region of both biosynthesis systems and four transporters. In Escherichia coli green fluorescent protein (GFP) reporter assays, we demonstrated that CosR directly represses transcription of betIBA-proXWV, bccT3, and proVWX. Similar to Vibrio harveyi, we showed betIBA-proXWV was directly activated by the quorum-sensing LuxR homolog OpaR, suggesting a conserved mechanism of regulation among Vibrio species. Phylogenetic analysis demonstrated that CosR is ancestral to the Vibrionaceae family, and bioinformatics analysis showed widespread distribution among Gammaproteobacteria in general. Incidentally, in Aliivibrio fischeri, Aliivibrio finisterrensis, Aliivibrio sifiae, and Aliivibrio wodanis, an unrelated MarR-type regulator gene named ectR was clustered with ectABC-asp, which suggests the presence of another novel ectoine biosynthesis regulator. Overall, these data show that CosR is a global regulator of osmotic stress response that is widespread among bacteria.

IMPORTANCE Vibrio parahaemolyticus can accumulate compatible solutes via biosynthesis and transport, which allow the cell to survive in high salinity conditions. There is little need for compatible solutes under low salinity conditions, and biosynthesis and transporter systems need to be repressed. However, the mechanism(s) of this repression is not known. In this study, we showed that CosR played a major role in the regulation of multiple compatible solute systems. Phylogenetic analysis showed that CosR is present in all members of the Vibrionaceae family as well as numerous Gammaproteobacteria. Collectively, these data establish CosR as a global regulator of the osmotic stress response that is widespread in bacteria, controlling many more systems than previously demonstrated.

Background:

Drugs are the fastest growing cost in the Canadian health care system, owing to the increasing number of high-cost drugs. The objective of this study was to examine the characteristics of high–drug-cost beneficiaries of public drug plans across Canada relative to other beneficiaries.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

A chemotherapy-induced shift to ICOSL⁺ B cells in breast tumors correlated with better survival.

Adolescents with type 1 diabetes face self-management challenges that make it difficult for them to achieve good glycemic control. In our population of adolescents with poorly controlled type 1 diabetes, the use of continuous glucose monitoring (CGM) improved patients’ glycemic time in range (TIR) and identified hypoglycemia more frequently than with intermittent self-monitoring of blood glucose throughout a 4-week interval. However, the adolescents were unable to synthesize this information to problem-solve or reduce the frequency of hypoglycemic events. Setting SMART (specific, measurable, achievable, relevant, and time-bound) diabetes management goals and providing intensive diabetes education and support could increase adolescents’ TIR and prevent hypoglycemia.

Real-time continuous glucose monitoring (CGM) use may lead to behavioral modifications in food selection and physical activity, but there are limited data on the utility of CGM in facilitating lifestyle changes. This article describes an 18-item survey developed to explore whether patients currently using CGM believe the technology has caused them to change their behavior.

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.

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.

For almost first-time home buyers, owning a home can be a very rewarding experience. With a little caution and some attention to detail, you can avoid costly mistakes.

With the acquisition of a start-up specialising in encrypted messaging and cloud services, Zoom will finally be able to make good on its claims of offering end-to-end encryption.

The Milky Way ate another galaxy called Gaia-Enceladus, and the waves passing through a star have shown us that it happened at most 11.6 billion years ago

Proxima Centauri b, a planet orbiting our nearest stellar neighbour, is being blasted with cosmic rays and solar flares – which could make it warm enough to host life

The ‘haunted doll’ look of Donald Trump’s son-in-law has attracted a lot of attention. When people comment on famous women and surgery there is often a backlash, but should the same apply here?

What has happened to Jared Kushner’s face?
Richard, by email

People get a little antsy about the subject of cosmetic surgery: they don’t like to be asked if they have had it, and public speculation over whether someone else has had it is generally considered to be de trop. I don’t really get this. Maybe it’s because I am 100% the world’s worst liar, but pretending to not see that someone’s face has completely changed is a form of magical thinking that is just beyond my capabilities.

Excellent film-maker that he is, Watiti seems to fit the Marvel blueprint far more easily than he does Star Wars’ more venerable, old-school template

When entertainment reporters play Hollywood roulette, the practice of attaching directors and stars to forthcoming movies based on little more than rumour, their little white balls nearly always seem to land on Taika Waititi’s number. If you’ve been keeping a close eye on this column over the past year, you’ve probably spotted the white-hot Kiwi director being touted for a remake of Flash Gordon and the next Deadpool movie among other projects, neither of which have yet come to fruition.

Waititi’s next film, according to reports this week, will be a Star Wars episode. Will he end up making it to the first day of production on this one? The chances seem better, as Disney has officially confirmed the appointment via the space saga’s official website, with 1917 co-writer Krysty Wilson-Cairns helping deliver a script. But this is Star Wars we are talking about – Colin Trevorrow, Josh Trank, Phil Lord and Christopher Miller, David Benioff and DB Weiss are among the numerous film-makers who have cheerily signed up to try to bring back the glory days of the long-running series in recent times, only to ultimately fall foul of Lucasfilm president Kathleen Kennedy’s merciless Force choke.

Valve is calling it quits on macOS support for its virtual reality platform. A Valve employee posted an update to the company’s SteamVR forums, noting that “SteamVR has ended macOS support so our team can focus on Windows and Linux.” Apple introduced “Metal for VR” back in June 2017 and highlighted a partnership with Valve. […]

At BroadwayCon, the phrase “I’ve never seen ‘Cats’” draws gasps and painted green witches are as common as colonial gear and trios of Schuyler sisters from the hit musical “Hamilton.” BroadwayCon took over part of the Javits Center in New York this past weekend with fans belting word-perfect renditions of show tunes amid a rotating […]

Although 50 doesn't keep in touch with Marquise, he is close to his seven-year-old son Sire, whom he fathered with model Daphne Joy.

PIERS MORGAN launched another blistering attack on Boris Johnson, accusing the prime minister of encouraging the public to break the lockdown through "absurdly reckless" leaks to the media.

Siemens stock surged on Friday after the German engineering company said it was speeding up cost savings to tackle the coronavirus downturn and the flotation of its energy business remained on track.

A potentially deadly disease affecting olive trees in Europe could take a huge economic toll in the next five decades, researchers have said.

UK businesses have furloughed 3.8 million workers during the coronavirus lockdown, Downing Street has said.

Medical students from University College London who were fast-tracked onto the NHS coronavirus frontline donned "lockdown costumes" for an online graduation ceremony.

You can donate at virginmoneygiving.com/fund/FoodforLondonNOW

LauncherOne to cap eight years of development with upcoming flight.

Astronauts had to stay locked away on their own for longer than usual, with no visits from loved ones

Disease, spread by spittlebugs, capable of infecting over 300 plant species

Tomorrow marks 75 since the nation celebrated VE day - the end of fighting against Nazi Germany in Europe.

Shares of cigarette companies have rallied over the past one month, with ITC, Godfrey Philips and VST Industries hitting record highs.

BusinessWeek's 'The Infotech 100', has ranked Bharti Airtel at the 21st position followed by Reddington India (55th) and RCom (66th). Successful business formula

The falling rupee will severely affect the small companies, whereas the big ones will be impacted moderately. Get rid of Debt | Adopt correct investment strategies

The Guardian’s data journalists in the UK, US and Australia explain how they have shone a light on the statistical narrative behind the pandemic, and what they have helped to reveal

Protective gear from The Crown, The Young Pope and Vikings have also been sent to key workers

Cosby's representative claims that the sex offender qualifies for early release due to his vulnerability to the illness

All the titles to add to your streaming list

'I have just got to keep going, making sure other people are going to be alright,' said Tim Simpson

The actress has resurfaced as a TikTok star

The hit show has just been renewed for a fifth season

In my opinion, there is nothing that will ever beat a homemade taco filled with anything lightly battered.

West Ham's players have become the second Premier League squad to defer part of their wages while owners David Sullivan and David Gold have injected £30million into the club in order to combat the financial impact of coronavirus.

The current break due to coronavirus has seen the rumour mill in overdrive. With no football happening on the pitch, transfer talk is dominating the sports pages.