BACKGROUND. Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB.METHODS. Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection.RESULTS. We identified and validated elevated blood basic leucine zipper transcription factor 2 (BATF2) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1–negative individuals, and 0.85 in HIV-1–infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1.CONCLUSIONS. Elevated blood BATF2 transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever.FUNDING. MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.
Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.
2506 Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS and RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort and the initial results for the multiple myeloma (MM) cohort. Methods: Patients with KRAS, NRAS or BRAF-mutant tumours were treated with RO5127566 using a novel schedule:4mg twice weekly in 4-week cycles. For MM patients, it was given 3 weeks out of 4 and co-administration of weekly dexamethasone was authorised. Response assessment was completed using RECIST 1.1 criteria for solid tumours and the International Myeloma Working Group (IMWG) criteria were used for MM. Results: A total of 20 patients with solid tumours (10 NSCLC, 5 gynaecological cancers and 5 miscellaneous cancers) and 1 MM patients were evaluable. Among the 10 KRAS-mutant NSCLC patients, tumour regression was seen in 6/10 (60 %), of which 3/10 (30 %) were partial responses. Two of these patients had maintained response for over 1 year and one patient is still on study after 30 cycles. Of the gynaecological cancers, 3/5 patients (60%) achieved a partial response ( KRAS-mutant endometrial and ovarian cancer and BRAF-mutant ovarian). Of these patients, 1 of the KRAS mutants had received 2 previous lines of MEK inhibitors and the BRAF mutant had previously received a BRAF inhibitor. In the miscellaneous group, 4 patients with colorectal cancer (2 BRAF and 2 NRAS) and 1 patient with NRAS-mutant melanoma were treated and none responded. Two patients with MM have been treated so far (1 KRAS, 1 KRAS+NRAS). The one evaluable patient has had an IMWG partial response (PR) after 1 cycle (FLC-λ from 324 mg/L to 161mg/L, ratio 0.03 to 0.08) without concomittant dexamethasone. This patient was previously treated with an immunomodulatory drug, a proteasome inhibitor and two ASCTs. Conclusions: RO5126766 has shown exciting preliminary activity across a wide range of RAS- and RAF-mutated malignancies, with significant response rates in lung and gynaecological cancers. To our knowledge, the PR seen in our MM patient represents one of the first responses to a single-agent RAF/MEK inhibitor in multiple myeloma in a trial context. Clinical trial information: NCT02407509.
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