New FTY720-docetaxel nanoparticle therapy overcomes FTY720-induced lymphopenia and inhibits metastatic breast tumour growth

Purpose: Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity. Methods: Docetaxel, FTY and glucosamine were covalently conjugated to poly(lactic-co-glycolic acid) (PLGA). NPs were characterised by dynamic light scattering and electron microscopy. The cellular uptake, cytotoxicity and in vivo antitumor efficacy of CNPs were evaluated. Results: We show for the first time that in triple negative breast cancer cells FTY provides chemosensitisation to DTX, allowing a four-fold reduction in the effective dose. We have encapsulated both drugs in PLGA complex NPs (CNPs), with narrow size distribution of ~ 100 nm and excellent cancer cell uptake providing sequential, sustained release of FTY and DTX. In triple negative breast cancer cells and mouse breast cancer models, CNPs had similar efficacy to systemic free therapies, but allowed an effective drug dose reduction. Application of CNPs has significantly reversed chemotherapy side effects such as weight loss, liver toxicity and, most notably, lymphopenia. Conclusions: We show for the first time the DTX chemosensitising effects of FTY in triple negative breast cancer. We further demonstrate that encapsulation of free drugs in CNPs can improve targeting, provide low off-target toxicity and most importantly reduce FTY-induced lymphopenia, offering potential therapeutic use of FTY in clinical cancer treatment

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

Optimal placement of colocated and non-colocated LWA nodes in dense deployments

Heterogeneous networks mitigate the co-tier interference which arises due to densification of homogeneous small cells deployment. LTE-Wi-Fi Aggregation (LWA) is one such realization of Hetnet which enables a tighter interworking between LTE small cells and Wi-Fi Access Points (AP) at radio level. LWA node deployment can be realized in colocated and non-colocated fashion. In this work, we have addressed the problems pertaining to dense deployment of LWA nodes. The placement of LWA nodes is done with the following objectives (i) Minimizing the number of LWA nodes without coverage hole (ii) Maximizing the Signal-to-Interference-plus-Noise Ratio (SINR) in every subregion of a building (iii) Minimizing the power spent at the User Equipment (UE) and at the LWA node. We have formulated the problems as Mixed Integer Non-Linear Programming (MINLP) problems. The performance of the proposed optimal LWA placement has been compared with Minimum Interference Region (MIR) placement. We could observe that the proposed optimization problem has improved dual coverage region by 43% and improved SINR by 8 dB compared to MIR. Also, the proposed optimization has lead to 10% energy saving at LWA node and 36% energy saving at UE

Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy

Abstract Purpose/Objectives Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. Materials/Methods Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine‐based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan–Meier method and compared between groups via the log‐rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. Results 121 patients were included with a median age of 62 years (37–86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving 60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19‐9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19‐9 (p = 0.03). In those patients that normalized their CA 19‐9, median overall survival was 16 months. Conclusions In this exploratory analysis normalization of CA‐19‐9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non‐metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor‐directed interventions