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Abstract Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.

Background: High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD). Consumption of dark chocolate, which is high in flavonoids that may reduce CVD risk, is an attractive intervention to reduce to BP. Additionally, the use of mobile health (mHealth) technologies (eg, telehealth, smartphones, and wearable devices) can improve outcomes in patients with CVD. Objective: The purpose of this study was to investigate the impact of dark chocolate intake on BP, subject use of mHealth, and integration of mHealth into a clinical trial. Methods: The COCOA-BP (ChOcolate COnsumption And Blood Pressure) study was a prospective, single-center, pre-/postintervention study that enrolled 62 healthy volunteers. The study consisted of 3 phases: smartwatch/smart BP monitor familiarization and washout from chocolate (week 1); control (week 2); and intervention (weeks 3 and 4). During the intervention phase, subjects consumed 50 g of dark chocolate per day. The primary endpoint was change in resting systolic BP between the intervention and control phases. Additional endpoints included device accuracy and correlation with physical activity. Results: Mean resting systolic BP was 116.4 mm Hg before chocolate intake among 62 participants (mean age 37 years; 61% female). After chocolate intake, mean resting systolic BP was 116.0 mm Hg (difference –0.4; P = .69). These findings suggest that 2 weeks of dark chocolate intake did not reduce resting systolic BP. There was poor agreement between mHealth device and standard (nurse-performed) measurements. Conclusion: In this study, short-term dark chocolate intake did not seem to reduce BP. mHealth technology shows great potential for use in clinical studies, but challenges related to device accuracy and compliance need to be addressed.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. The presence of a dense desmoplastic stroma rich in fibroblasts, extracellular matrix, and immune cells plays a critical role in disease progression, therapy response and is a distinguishing feature of PDAC. PDAC is currently treated with a combination of surgery, chemotherapy and radiation therapy in selected cases which results in long-term survival only in a small percentage of patients. Cancer therapies that incorporate immunotherapy-based techniques have become increasingly common in recent years. While such a strategy has been shown to be effective for immunogenic, “hot” tumors like melanoma and lung cancer, thus far PDAC patients display poor responses to this therapeutic approach. Various factors, such as low tumor mutational burden, increased infiltration of immunosuppressive cells, like MDSCs and Treg cells promote tolerance and immune deviation, further aggravating adaptive immunity in PDAC. In this review we will elaborate on the ability of PDAC tumors to evade immune detection. We will also discuss various 3D model system that can be used as a platform in preclinical research to investigate rational combinations of immunotherapy with chemotherapy or targeted therapy, to prime the immune microenvironment to enhance antitumor activity.

Major depressive disorder (MDD) is a chronic mental illness which affects people's well-being and is often detected at a later stage of depression with a likelihood of suicidal ideation. Early detection of MDD is thus necessary to reduce the impact, however, it requires monitoring vitals in daily living conditions. EEG is generally multi-channel and due to difficulty in signal acquisition, it is unsuitable for home-based monitoring, whereas, wearable sensors can collect single-channel ECG. Classical machine-learning based MDD detection studies commonly use various heart rate variability features. Feature generation, which requires domain knowledge, is often challenging, and requires computation power, often unsuitable for real time processing, MDDBranchNet is a proposed parallel-branch deep learning model for MDD binary classification from a single channel ECG which uses additional ECG-derived signals such as R-R signal and degree distribution time series of horizontal visibility graph. The use of derived branches was able to increase the model's accuracy by around 7%. An optimal 20-second overlapped segmentation of ECG recording was found to be beneficial with a 70% prediction threshold for maximum MDD detection with a minimum false positive rate. The proposed model evaluated MDD prediction from signal excerpts, irrespective of location (first, middle or last one-third of the recording), instead of considering the entire ECG signal with minimal performance variation stressing the idea that MDD phenomena are likely to manifest uniformly throughout the recording.