Modeling multiple-criterion diagnoses by heterogeneous-instance logistic regression.

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) that causes a significant burden in caregiving and medical costs. Clinically, the diagnosis of MCI is determined by the impairment statuses of five cognitive domains. If one of these cognitive domains is impaired, the patient is diagnosed with MCI, and if two out of the five domains are impaired, the patient is diagnosed with AD.

Discovery of pyrrolo[2,3-d]pyrimidin-4-one derivative YCH3124 as a potent USP7 inhibitor for cancer therapy.

USP7 is one of the most studied deubiquitinating enzymes, which is involved in the regulation of multiple cell signaling pathways and has been shown to be associated with the occurrence and progression of a variety of cancers. Inhibitors targeting USP7 have been studied by several teams, but most of them lack selectivity and have low activities. Herein, we reported a serious of pyrrole[2,3-d]pyrimidin-4-one derivatives through scaffold hopping of recently reported 4-hydroxypiperidine compounds.

Horospherical Decision Boundaries for Large Margin Classification in Hyperbolic Space.

Hyperbolic spaces have been quite popular in the recent past for representing hierarchically organized data. Further, several classification algorithms for data in these spaces have been proposed in the literature. These algorithms mainly use either hyperplanes or geodesics for decision boundaries in a large margin classifiers setting leading to a non-convex optimization problem.

An Empirical Bayes Approach to Shrinkage Estimation on the Manifold of Symmetric Positive-Definite Matrices.

The James-Stein estimator is an estimator of the multivariate normal mean and dominates the maximum likelihood estimator (MLE) under squared error loss. The original work inspired great interest in developing shrinkage estimators for a variety of problems. Nonetheless, research on shrinkage estimation for manifold-valued data is scarce.

Geometric Deep Learning for Unsupervised Registration of Diffusion Magnetic Resonance Images.

Deep learning based models for registration predict a transformation directly from moving and fixed image appearances. These models have revolutionized the field of medical image registration, achieving accuracy on-par with classical registration methods at a fraction of the computation time. Unfortunately, most deep learning based registration methods have focused on scalar imaging modalities such as T1/T2 MRI and CT, with less attention given to more complex modalities such as diffusion MRI.

Detection and Mitigation of SYN Flooding Attacks through SYN/ACK Packets and Black/White Lists.

Software-defined networking (SDN) is a new network architecture that provides programmable networks, more efficient network management, and centralized control than traditional networks. The TCP SYN flooding attack is one of the most aggressive network attacks that can seriously degrade network performance. This paper proposes detection and mitigation modules against SYN flooding attacks in SDN.

Nested Hyperbolic Spaces for Dimensionality Reduction and Hyperbolic NN Design.

Hyperbolic neural networks have been popular in the recent past due to their ability to represent hierarchical data sets effectively and efficiently. The challenge in developing these networks lies in the nonlinearity of the embedding space namely, the Hyperbolic space. Hyperbolic space is a homogeneous Riemannian manifold of the Lorentz group which is a semi-Riemannian manifold, i.

Nested Grassmannians for Dimensionality Reduction with Applications.

In the recent past, nested structures in Riemannian manifolds has been studied in the context of dimensionality reduction as an alternative to the popular principal geodesic analysis (PGA) technique, for example, the principal nested spheres. In this paper, we propose a novel framework for constructing a nested sequence of homogeneous Riemannian manifolds. Common examples of homogeneous Riemannian manifolds include the -sphere, the Stiefel manifold, the Grassmann manifold and many others.

Absorption, distribution, metabolism, and excretion of [C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats.

Introduction: Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown.

Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR and EGFR).

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFR and EGFR are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib.

Repressing MYC by targeting BET synergizes with selective inhibition of PI3Kα against B cell lymphoma.

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma.

Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells.

Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33.

Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CCs of 340 and 106 nM respectively.

Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors.

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold).

Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo[2,1-f][1,2,4]triazine derivatives.

A series of 6-aminocarbonyl pyrrolo[2,1-f][1,2,4]triazine derivatives were designed by scaffold hopping strategy. The IC values of compound 14a against PI3Ks were measured, showing selective activity against p110α and p110δ with ICs of 122 nM and 119 nM respectively. All the synthesized compounds were evaluated for their antiproliferative activity against human cancer cells by SRB assay.

An Aptamer-Based Capacitive Sensing Platform for Specific Detection of Lung Carcinoma Cells in the Microfluidic Chip.

Improvement of methods for reliable and early diagnosis of the cellular diseases is necessary. A biological selectivity probe, such as an aptamer, is one of the candidate recognition layers that can be used to detect important biomolecules. Lung cancer is currently a typical cause of cancer-related deaths.

Decrease in phosphorylated ERK indicates the therapeutic efficacy of a clinical PI3Kα-selective inhibitor CYH33 in breast cancer.

PI3Ks are frequently hyper-activated in breast cancer and targeting PI3Kα has exhibited promising but variable response in preclinical and clinical settings. CYH33 is a novel PI3Kα-selective inhibitor in phase I clinical trial. We investigated the efficacy of CYH33 against breast cancer and explored potential predictive biomarkers.

Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.

The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity.

Dual targeting of microtubule and topoisomerase II by α-carboline derivative YCH337 for tumor proliferation and growth inhibition.

Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel α-carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance.

Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents.

Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazole-6,11-dione derivatives from natural rhein were designed, synthesized and evaluated for their antitumour activities against human cancer cell lines A549 and HeLa in vitro.

Design and synthesis of pyrido[3,2-α]carbazole derivatives and their analogues as potent antitumour agents.

A series of pyrido[3,2-α]carbazole derivatives and their analogues have been prepared and evaluated for their antitumour activity against human lung cancer A549 cells and colon cancer HT29 cells. The intermediates 4a-4k are successfully synthesized from 1a-1k and ethyl 2-(3-bromopyridin-2-yl)acetate by Knoevenagel condensation and intramolecular Heck-type reaction, and this is a novel and efficient synthetic approach to the core scaffold of the target compounds. These target compounds have shown an interesting antitumour profile towards the tested cell lines with IC50 values ranging from 0.