Tumor biomarkers for diagnosis, prognosis and targeted therapy.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo[3,4-b]pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors.

Targeting mitochondrial complex I (CI) is emerging as an attractive anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against oxidative phosphorylation (OXPHOS)-dependent cancer, which merits further study.

Connecting curve: A new tool for locating hidden attractors.

Attractors in nonlinear dynamical systems can be categorized as self-excited attractors and hidden attractors. In contrast to self-excited attractors, which can be located by the standard numerical computational method, hidden attractors are hard to detect due to the fact that its basin of attraction is away from the proximity to equilibrium. In multistable systems, many attractors, including self-excited and hidden ones, co-exist, which makes locating each different oscillation more difficult. Hidden attractors are frequently connected to rare or abnormal oscillations in the system and often lead to unpredicted behaviors in many engineering applications, and, thus, the research in locating such attractors is considerably significant. Previous work has proposed several methods for locating hidden attractors but these methods all have their limitations. For example, one of the methods suggests that perpetual points are useful in locating hidden and co-existing attractors, while an in-depth examination suggests that they are insufficient in finding hidden attractors. In this study, we propose that the method of connecting curves, which is a collection of points of analytical inflection including both perpetual points and fixed points, is more reliable to search for hidden attractors. We analyze several dynamical systems using the connecting curve, and the results demonstrate that it can be used to locate hidden and co-existing oscillations.