Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the ...endogenous
-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (
), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.
The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of ...the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
ObjectivesTo evaluate the impact of government HIV strategies that aimed to increase HIV testing uptake and frequency among gay and bisexual men (GBM) in New South Wales (NSW), Australia.
Design We ...analysed HIV testing data from existing passive and sentinel surveillance systems between 2010 and 2018.
Methods
Six indicators were measured: (1) state‐wide total HIV laboratory tests; (2) number of GBM attending publicly‐funded clinics; (3) 12‐monthly testing uptake; (4) annual testing frequency; (5) HIV testing with a STI diagnosis; and (6) HIV positivity. Mathematical modelling was used to estimate (7) the proportion of men with undiagnosed HIV. Indicators were stratified by Australian vs. overseas‐born.
Results
Overall, 43,560 GBM attended participating clinics (22,662 Australian‐born, 20,834 overseas‐born) from 2010‐2018. Attendees increased from 5,186 in 2010 to 16,507 in 2018. There were increasing trends (p<0.001 for all) in testing uptake (83.9% to 95.1%); testing with a STI diagnosis (68.7% to 94.0%); annual HIV testing frequency (1.4 to 2.7); and a decreasing trend (p<0.01) in HIV positivity (1.7% to 0.9%).Increases in testing were similar in Australian‐born and overseas‐born GBM. However, there were decreasing trends in the estimated undiagnosed HIV proportion overall (9.5% to 7.7%) and in Australian‐born GBM (7.1% to 2.8%), but an increasing trend in overseas‐born GBM (15.3% to 16.9%) (p<0.001 for all).
We present an 8 s detection of cosmic magnification measured by the variation of quasar density due to gravitational lensing by foreground large-scale structure. To make this measurement we used 3800 ...deg super(2) of photometric observations from the Sloan Digital Sky Survey (SDSS) containing 6200,000 quasars and 13 million galaxies. Our measurement of the galaxy-quasar cross-correlation function exhibits the amplitude, angular dependence, and change in sign as a function of the slope of the observed quasar number counts that is expected from magnification bias due to weak gravitational lensing. We show that observational uncertainties (stellar contamination, Galactic dust extinction, seeing variations, and errors in the photometric redshifts) are well controlled and do not significantly affect the lensing signal. By weighting the quasars with the number count slope, we combine the cross-correlation of quasars for our full magnitude range and detect the lensing signal at >4 s in all five SDSS filters. Our measurements of cosmic magnification probe scales ranging from 60 h super(-1) kpc to 10 h super(-1) Mpc and are in good agreement with theoretical predictions based on the WMAP concordance cosmology. As with galaxy-galaxy lensing, future measurements of cosmic magnification will provide useful constraints on the galaxy-mass power spectrum.
While effective in preventing stroke in patients with atrial fibrillation (AF), warfarin is limited by a narrow therapeutic profile, a need for lifelong coagulation monitoring, and multiple drug and ...diet interactions.
To determine whether a local strategy of mechanical left atrial appendage (LAA) closure was noninferior to warfarin.
PROTECT AF was a multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 59 hospitals of 707 patients with nonvalvular AF and at least 1 additional stroke risk factor (CHADS2 score ≥1). Enrollment occurred between February 2005 and June 2008 and included 4-year follow-up through October 2012. Noninferiority required a posterior probability greater than 97.5% and superiority a probability of 95% or greater; the noninferiority margin was a rate ratio of 2.0 comparing event rates between treatment groups.
Left atrial appendage closure with the device (n = 463) or warfarin (n = 244; target international normalized ratio, 2-3).
A composite efficacy end point including stroke, systemic embolism, and cardiovascular/unexplained death, analyzed by intention-to-treat.
At a mean (SD) follow-up of 3.8 (1.7) years (2621 patient-years), there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient-years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient-years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41-1.05), meeting prespecified criteria for both noninferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%). Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient-years for the device group 17/463 patients, 3.7% vs 2.4 events per 100 patient-years with warfarin 22/244 patients, 9.0%; hazard ratio HR, 0.40; 95% CI, 0.21-0.75; P = .005) and all-cause mortality (3.2 events per 100 patient-years for the device group 57/466 patients, 12.3% vs 4.8 events per 100 patient-years with warfarin 44/244 patients, 18.0%; HR, 0.66; 95% CI, 0.45-0.98; P = .04).
After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality.
clinicaltrials.gov Identifier: NCT00129545.
Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks ...(CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.
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•AI-based prediction of biomarkers (MSI, BRAF, and KRAS) using transformers•MSI prediction reaches clinical-grade performance on biopsies of colorectal cancer•Transformer-based biomarker prediction generalizes better and is more data efficient•Large-scale multi-cohort evaluation on over 13,000 patients from 16 cohorts
Wagner et al. show that transformer-based prediction of biomarkers from histology substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. The method significantly outperforms existing approaches for microsatellite instability detection in surgical resections and reaches clinical-grade performance on biopsies of colorectal cancer, solving a long-standing diagnostic problem.
Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor ...outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.
Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.
Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.
Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.
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