AIMS:Choice of first-in-human dose has critical implications for the safety of Phase I participants as well as the likelihood of reaching the therapeutic dose range during escalation. In this analysis, we present a population concentration-response modelling approach for selecting the Phase I starting dose for a novel stimulator of interferon response cGAMP interactor 1 (STING) agonist, SNX281. METHODS:Given the immune agonist mechanism of SNX281, we opted to select the starting dose according to the minimum anticipated biological effect level (MABEL). To determine the MABEL concentration, we fitted a population concentration-response model to cytokine induction data from an ex vivo whole blood assay. We selected a whole blood assay to obviate the need for free fraction scaling for this highly protein-bound drug. We used the population concentration-response model to estimate the lower 10th percentile for the 10% maximal interferon-β response concentration of SNX281, which was chosen as the MABEL concentration. We translated the ex vivo MABEL concentration to a human MABEL dose using a human pharmacokinetic projection based on allometric scaling from preclinical species. RESULTS:The human dose-peak concentration relationship projection fell within 2-fold of the clinical result. After the application of a safety factor, the MABEL dose was applied in the clinic and did not demonstrate dose-limiting toxicities. CONCLUSIONS:Our novel population modelling-based MABEL strategy for first-in-human dose selection resulted in successful clinical translation of a small molecule STING agonist.

Supplementary Figure 1. miR-21 mimic suppresses expression of ANKRD46, DDAH1 and RECK. SKHep1 cells were transfected with miR-21 or negative mimic. RNA was isolated and expression of ANKRD46, DDAH1 and RECK was assessed by qPCR. (Mean, {plus minus} SD, n=3).

Supplementary Data 1. Excel sheet with fold change in gene expression following anti-miR-21 treatment.

Supplementary Table 1. Hits from the dalotuzumab enhancer screen. Supplementary Table 2. Patient and disease characteristics. Supplementary Table 3. Summary of dose-limiting toxicities. Supplementary Table 4. Summary of clinical efficacy in breast cancer patients.

RAS mutation/signature does not predict response to mTOR/Wee1 combination.

Supplementary Figure 4. Pathway analysis of gene expression changes following anti-miR-21 treatment. SKHep1 cells treated with anti-miR-21 were subjected to microarray gene expression analysis. Changes in cellular processes (top) and pathways (bottom) upon anti-miR-21 treatment are shown.

Supplementary Figure 4. Responder biomarker hypothesis for ridaforolimus and dalotuzumab?based therapy

Supplementary Figure 3. Change in Ki67 levels with ridaforolimus and dalotuzumab combination therapy

Supplementary figure, table and data legend

Hierarchical clustering was performed on the response data across the cell line panel to the single agent treatments. Drugs with similar mechanisms of action clustered together.

We ran 8 titration point curves (shown in gray) and then picked 4 concentration points that cover best the response curve for all cell lines (shown in red). The first point is the top plateau, the last is the bottom plateau and the other 2 are in between.

Supplementary Figure 2. Anti-miR-21 treatment causes limited caspase 3/7 activation in non-transformed cell lines. Caspase 3/7 activation after treatment of SKHep1, IMR-90, and WI-38 cells with MM control or anti-miR-21 for 72 hours. (Mean, {plus minus} SEM, n=3).

Supplementary Figure 1, Table 1 from De novo Discovery of a γ-Secretase Inhibitor Response Signature Using a Novel In vivo Breast Tumor Model

Supplementary Figures 1-5, Tables 1-2 from Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells

Supplementary Methods and Figure Legends

Subclinical pulmonary tuberculosis (PTB) is defined as "…a state of disease due to viable Mycobacterium tuberculosis that does not cause TB-related symptoms but does cause other abnormalities that can be detected using existing radiologic and mycobacteriologic assays." In high-income countries, subclinical PTB is usually diagnosed during active case finding, is acid-fast bacilli smear negative, and associated with minimal or no lung parenchymal abnormality on chest radiograph. In the absence of symptoms, the epidemiologic risk of TB and chest radiograph are critical to making the diagnosis. In a cohort of 327 patients with subclinical PTB, we address the question-how well field radiologists perform at identifying features important to the diagnosis of PTB, the presence or absence of which have been established by a panel of expert radiologists? Although not performing badly compared with this "gold standard," field readers were nevertheless susceptible to overread or underread films and miss key diagnostic features, such as the presence of a lung parenchymal abnormality, typical pattern, or cavitation. In the context of active case finding during which most patients with subclinical PTB are discovered, limitations of the chest radiograph need to be recognized, and sputum, ideally induced, should be submitted regardless of the radiographic findings.

Supplementary Figure 1. Treatment and pharmacodynamic assessment schedules.

Supplementary Figure 2. Combination therapy with ridaforolimus and dalotuzumab potentiates PI3K pathway inhibition and blocks cancer cell proliferation

Supplementary Tables 1 and 2. Supplementary Table 1: Fold de-repression of miR-21 target genes after anti-miR-21 treatment. Supplementary Table 2: Taqman Primer and Probes

ObjectivesRelatively little is known about the prevalence, risk factors, and public health consequences of peripheral lymph node (PLN)–associated pulmonary tuberculosis (PTB).MethodsWe developed a 10-year (2010-2019) population-based cohort of PLNTB patients in Canada. We used systematically collected primary source data and expert reader chest radiograph interpretations in a multivariable logistic regression to determine associations between sputum culture positivity and demographic, clinical, and radiographic features. Public health risks were estimated among contacts of PLNTB patients.ResultsThere were 306 patients with PLNTB, among whom 283 (92.5%) were 15-64 years of age, 159 (52.0%) were female, and 293 (95.8%) were foreign-born. Respiratory symptoms were present in 21.6%, and abnormal chest radiograph in 23.2%. Sputum culture positivity ranged from 12.9% in patients with no symptoms and normal lung parenchyma to 66.7% in patients with both. Respiratory symptoms, abnormal lung parenchyma, and HIV-coinfection (borderline) were independent predictors of sputum culture positivity (odds ratio [OR] 2.24 [95% confidence interval [CI] 1.15-4.39], P = 0.01, OR 4.78 [95% CI 2.41-9.48], P < 0.001, and OR 2.54 [95% CI 0.99-6.52], P = 0.05), respectively. Among contacts of sputum culture-positive PLNTB patients, one secondary case and 16 new infections were identified.ConclusionIsochronous PTB is common in PLNTB patients. Routine screening of PLNTB patients for PTB is strongly recommended.