A Bayesian pharmacokinetics integrated phase I-II design to optimize dose-schedule regimes.

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. Conditional on the drug concentration in plasma, we jointly model toxicity and efficacy as a function of the concentration. We quantify the risk-benefit of regimes using utility-continuously updating the estimates of PK, toxicity, and efficacy based on interim data-and make adaptive decisions to assign new patients to appropriate dose-schedule regimes via adaptive randomization. The simulation study shows that the PKIDS design has desirable operating characteristics.

Modulating JAK2/STAT3 signaling by quercetin in Qiling Baitouweng Tang: a potential therapeutic approach for diffuse large B-cell lymphoma.

Qiling Baitouweng Tang (QLBTWT) is a traditional clinical formula for treating diffuse large B-cell lymphoma (DLBCL), but its molecular action is not fully understood. This research is utilized in silico analysis and liquid chromatography tandem mass spectrometry (LC‒MS/MS) to identify the active constituents of QLBTWT with anti-DLBCL properties and their targets. The study identified 14 compounds, including quercetin, naringenin, and astilbin, as potentially effective against DLBCL. Molecular modeling highlighted the favorable interaction of quercetin with the JAK2 protein. In vitro studies confirmed the ability of quercetin to inhibit DLBCL cell growth and migration while inducing apoptosis and causing G2/M phase cell cycle arrest. Molecular dynamics simulations revealed that quercetin binds to JAK2 as a type II inhibitor. In vivo studies in U2932 xenograft models demonstrated that QLBTWT inhibited tumor growth in a dose-dependent manner, which was associated with the JAK2/STAT3 signaling pathway. Overall, this study elucidates the therapeutic effect of QLBTWT on DLBCL through quercetin-mediated suppression of the JAK2/STAT3 pathway, offering novel therapeutic insights for DLBCL.

T3 + 3: 3 + 3 Design With Delayed Outcomes.

Delayed outcome is common in phase I oncology clinical trials. It causes logistic difficulty, wastes resources, and prolongs the trial duration. This article investigates this issue and proposes the time-to-event 3 + 3 (T3 + 3) design, which utilizes the actual follow-up time for at-risk patients with pending toxicity outcomes. The T3 + 3 design allows continuous accrual without unnecessary trial suspension and is costless and implementable with pretabulated dose decision rules. Besides, the T3 + 3 design uses the isotonic regression to estimate the toxicity rates across dose levels and therefore can accommodate for any targeted toxicity rate for maximum tolerated dose (MTD). It dramatically facilitates the trial preparation and conduct without intensive computation and statistical consultation. The extension to other algorithm-based phase I dose-finding designs (e.g., i3 + 3 design) is also studied. Comprehensive computer simulation studies are conducted to investigate the performance of the T3 + 3 design under various dose-toxicity scenarios. The results confirm that the T3 + 3 design substantially shortens the trial duration compared with the conventional 3 + 3 design and yields much higher accuracy in MTD identification than the rolling six design. In summary, the T3 + 3 design addresses the delayed outcome issue while keeping the desirable features of the 3 + 3 design, such as simplicity, transparency, and costless implementation. It has great potential to accelerate early-phase drug development.

Deep learning-based detection and semi-quantitative model for spread through air spaces (STAS) in lung adenocarcinoma.

Tumor spread through air spaces (STAS) is a distinctive metastatic pattern affecting prognosis in lung adenocarcinoma (LUAD) patients. Several challenges are associated with STAS detection, including misdetection, low interobserver agreement, and lack of quantitative analysis. In this research, a total of 489 digital whole slide images (WSIs) were collected. The deep learning-based STAS detection model, named STASNet, was constructed to calculate semi-quantitative parameters associated with STAS density and distance. STASNet demonstrated an accuracy of 0.93 for STAS detection at the tiles level and had an AUC of 0.72-0.78 for determining the STAS status at the WSI level. Among the semi-quantitative parameters, T10S, combined with the spatial location information, significantly stratified stage I LUAD patients on disease-free survival. Additionally, STASNet was deployed into a real-time pathological diagnostic environment, which boosted the STAS detection rate and led to the identification of three easily misidentified types of occult STAS.

Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations.

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

Spicy food consumption and risk of vascular disease: Evidence from a large-scale Chinese prospective cohort of 0.5 million people.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

The Role of Perioperative C-Reactive Protein in Predicting the Prognosis of Epithelial Ovarian Carcinoma.

Background: Increasing epidemiological evidence supported that chronic inflammatory factors might be involved in the carcinogenesis and progression of various cancers. The present study tried to investigate the prognostic value of perioperative C-reactive protein (CRP) in prognosis of patients with epithelial ovarian carcinoma (EOC) from a tertiary university teaching hospital. Methods: The cutoff value of CRP was calculated according to receiver operating characteristic (ROC) curve. Variables were compared using Chi-square test. Progress-free survival (PFS) and overall survival (OS) time were assessed by Kaplan-Meier (KM) survival analysis and Log rank test based on serum CRP level. Univariate and multivariate Cox regression analyses were applied for assessing the relationship between clinicopathological parameters and survival. Results: Higher perioperative CRP levels (preoperative ≥5.15 mg/L and postoperative ≥72.45 mg/L) were significantly associated with serous tumor, high-grade, advanced stage, elevated preoperative CA125, suboptimal surgery, chemotherapy resistance, recurrence and death in EOC (P < 0.01). KM analysis suggested patients with elevated preoperative, postoperative and perioperative CRP had shorter survival (P < 0.01). Elevated perioperative CRP was an independent risk factor for PFS (HR 1.510, 95% CI 1.124-2.028; P = 0.006) and OS (HR 1.580, 95% CI 1.109-2.251; P = 0.011). Similar results were obtained for elevated preoperative CRP. Subgroup analysis further suggested that elevated perioperative CRP was also an independent risk factor for prognosis in advanced stage and serous EOC. Conclusion: Elevated perioperative CRP was an independent risk factor for poorer prognosis of EOC, particularly in advanced stage and serous patients.

Why there are so many contradicted or exaggerated findings in highly-cited clinical research?

It is not uncommon that clinical studies of the same intervention contradicted with each other, e.g., one study produced positive results, while the other produced negative results. Ioanndis (2005a) found that among 49 highly-cited original clinical research studies, published in New England Journal of Medicine, Journal of the American Medical Association, Lancet or in a high-impact medical specialty journal, 32% of them were contradicted in subsequent large-scale studies, or were shown to have potentially overestimated the efficacy of the experimental intervention. This finding is disturbing and of serious concern given the widespread impact of these highly-cited studies and the rigorous standards used to design and conduct the studies. We perform Bayesian analysis of these highly-cited clinical studies based on Bayesian factor. We identified one cause of the issue: p values strongly overstated the experimental evidence. For the highly-cited studies, when the p value was 0.05, there was a 74.4% percentage chance that the null hypothesis was true. The use of a p value of 0.05 as the criterion for significance caused many researchers to mistakenly draw conclusions of positive findings, which were then contradicted by subsequent large-scale studies.