In this retrospective study, whole-genome sequencing (WGS) data generated on an Ion Torrent platform was used to predict phenotypic drug resistance profiles for first- and second-line drugs among Swedish clinical Mycobacterium tuberculosis isolates from 2016 to 2018. The accuracy was ~99% for all first-line drugs and 100% for four second-line drugs. Our analysis supports the introduction of WGS into routine diagnostics, which might, at least in Sweden, replace phenotypic drug susceptibility testing in the future.

Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 μg/ml; the mean NTZ maximum concentration (C_max) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis. Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.)

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.)

Summary:

Over the last two decades HER2 aberrations have been thoroughly investigated as potential therapeutic targets in advanced non–small cell lung cancer, with relatively modest results. Two articles published in this issue of Cancer Discovery further expand the knowledge on therapeutic exploitation of HER2 in lung cancer, addressing a large unmet medical need.

See related article by Li et al., p. 674.

See related article by Tsurutani et al., p. 688.

Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that 1) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and 2) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs.

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

We're bringing you something new: SpeakerChat. This event is both a way to revisit some great eLearning Guild content from a recorded session while also […]

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Royal Enfield (रॉयल एनफील्ड) मोटरसाइकिल बाइकर्स की पसंद होने के साथ साथ बाइक मॉडिफाई करने वालों में भी लोकप्रिय है। देशभर में ऐसी कई स्टार्ट-अप कंपनियां खुल गई हैं जिन्हें एनफील्ड को कस्टमाइज करने में महारथ हासिल हैं।

Yell at yer friends in 1-4 player co-op while working under time pressure to serve up meals to an unforgiving god in Overc—er sorry, Cannibal Cuisine. It’s certainly got a familiar vibe to it, so if you liked the frantic food prep of that other friendship-ender perhaps you’ll like doing it with a new secret […]

As US-Iran tensions rise following the assassination of an Iranian general and missile attacks on US troops, UN diplomat Neil Walsh warns cyberattacks can be just as impactful

Pollen has a natural tendency to adsorb mercury and forms the basis of a new class of tiny robots that speed through toxic water to purify it

The hacker in question hasn't even graduated high school yet.

FRENCHIC, the British paint brand with eco-friendly formulas for breathing new life into furniture, homes and garden decor, has seen sales surge 500 percent recently as lockdown sends DIYers into overdrive.

Mercury is mostly iron, which may be because a series of close encounters with a young Venus billions of years ago stripped away its rocky outer layers

Mercury is much denser than the other rocky planets in the solar system, and that may be because a collision vaporised its surface and the debris was blown away by the sun

Argonne will use the CS-1 to help discover cancer therapies and understand colliding blackholes

After finding common ground, Jen and Judy split up to spend time with new friends who could end up being something more.

First Minister Nicola Sturgeon has said the Scottish Government is looking into expanding the current guidance about exercise during the lockdown.

Platform sandals meet 40-denier tights as rock’n’roll goes bourgeois at Paris fashion week

At his Celine catwalk show on Friday night, the designer Hedi Slimane distilled what looks to be the most compelling trend of this season of fashion shows. Working title: rock’n’roll bourgeois.

Slim knee-length dresses were worn with slinky chain belts; towering platform sandals with sensible 40-denier semi-sheer tights; slim bootcut velvet trousers worn with Princess-line above-the-knee coats. This was a masterclass in Parisian allure: take one part Avenue Montaigne privilege, and mix with one part backstage pass. Shaken, not stirred.

Never has one man in inexpensive rumpled suits been so loved by the style set - but Sanders’ clothes signal an authenticity other politicians can only dream of

Of all the things we’ll miss about Bernie Sanders, now that he has dropped out of the Democratic race, his style should be the least of it. Not only because his politics are so right on – this is the man who believes in free education and Medicare for all and who has had many Americans, who until recently felt disenfranchised by mainstream politics, feeling activated by it. But also because his clothes are so seemingly unremarkable.

He wears crumpled suits that look borrowed from a slightly larger man and creased shirts with straight-lace striped ties. The inconspicuousness of his geography teacher shoes are matched only by his inoffensive navy round-neck jumpers.

From yoga apps to an intelligent jumprope

Around 250 Indian students and tourists were seen queuing with their luggage at the airport as they prepared for the journey home.

Following a healthy diet or exercising could impact how your brain ages, but the effects on cognitive skills later in life depend on specific gene variants that not everyone has

Taking deep breaths and forcing a cough can help clear mucus, but these techniques are unlikely to prevent or treat coronavirus infections – here’s why

Fans shouldn't expect Disney's planned live-action remake of its animated hit Hercules to be "a literal translation," according to the film's producer Anthony Russo.

That's actually better than usual.

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

High-temperature superconductors have the potential to revolutionize today's technologies. 'Higgs spectroscopy' could bring about a watershed as it reveals the dynamics of paired electrons in superconductors. Remarkably, the dynamics also reveal typical precursors of superconductivity even above the critical temperature at which the materials investigated attain superconductivity.

The "High Quality Camera" unlocks a world of photography options for the Pi.

Follow our live coronavirus updates here Coronavirus: the symptoms

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Britain is set to enjoy yet more sunshine as the mercury soars to highs of 23C in some areas later this week.

Follow our live coronavirus updates HERE Coronavirus: The symptoms

Follow our live coronavirus updates HERE Coronavirus: the symptoms

Read our live coronavirus updates HERE Coronavirus: The symptoms

Follow our live coronavirus updates HERE Coronavirus: The symptoms

Eight people were rescued from a rockfall while out taking their daily exercise on the Isle of Wight.

Temperatures will soar this week with the UK set to be hotter than Ibiza amid the coronavirus lockdown.

A Banksy mural in Bristol has been given a face mask in a coronavirus-themed makeover.

Former Olympic rower Kenny Dwan has recalled the emotional moment he left hospital after a three-week battle with coronavirus.

Commercial space trips are a step closer to becoming reality after Virgin Galactic's spaceship took a glide and landed safely in the New Mexico desert.

Joggers, cyclists and surfers across Spain have emerged from their homes as adults were allowed out for exercise for the first time in seven weeks.

Italians were today enjoying the chance to exercise in parks for the first time in eight weeks as their country took its first significant steps out of its coronavirus lockdown.

Stars have paid tribute to Mercury Prize-nominated rapper Ty who has died aged 47 after contracting coronavirus.

Wales has taken the first step to easing lockdown by relaxing exercise rules and reopening some libraries, tips and garden centres.