In this investigation, a magnetised plasma consisting of inertial ions fluid, charged immobile dust grains in the background and superthermally distributed electrons is considered to study head-on ...collision between dust ion acoustic multi-solitons. The extended Poincaré–Lighthill–Kuo (PLK) method is employed for the derivation of two KdV equations. Further, in order to determine the multi-solitons solutions of the two KdV equations, the Hirota bilinear method is used. The phase shifts due to head-on collision of multi-solitons have also been determined. The combined influence of superthermality of electrons, density ratio, magnetic field strength etc. on the characteristics of dust ion acoustic solitons, time evolution and the corresponding phase shifts of multi-solitons has been studied numerically. The findings of this investigation might be of great importance to elucidate and provide a comprehensive framework for the understanding of various nonlinear structures in space and astrophysical environments especially in Saturn’s magnetosphere.
Display omitted
•Interaction of ion acoustic multi-solitons is studied with dust as impurity.•The extended PLK method is employed for the derivation of two KdV equations.•The phase shifts due to head-on collision of multi-solitons is also determined.•The various parameters alter the time evolution and phase shifts of multi-solitons.
Polo-like kinases (PLKs) play important roles in regulating multiple aspects of cell cycle and cell proliferation. In many cancer types, PLK family members are often dysregulated, which can lead to ...uncontrolled cell proliferation and aberrant cell division and has been shown to associate with poor prognosis of cancers. The key roles of PLK kinases in cancers lead to an enhanced interest in them as promising targets for anticancer drug development. In consideration of PLK inhibitors and some other anticancer agents, such as BRD4, EEF2K and Aurora inhibitors, exert synergy effects in cancer cells, dual-targeting of PLK and other cancer-related targets is regarded as an rational and potent strategy to enhance the effectiveness of single-targeting therapy for cancer treatment. This review introduces the PLK family members at first and then focuses on the recent advances of single-target PLK inhibitors and summarizes the corresponding SARs of them. Moreover, we discuss the synergisms between PLK and other anti-tumor targets, and sum up the current dual-target agents based on them.
Display omitted
•Dual-target inhibitors based on PLK, such as PLK1/BRD4 dual inhibitors, and single-target agents were summarized.•We made an insight into the structure-activity relationships of these agents.•We summarize the synergistic mechanisms and effects of PLK based dual-target inhibitors.
In this investigation, the head-on collision of dust-acoustic (DA) multi-solitons in a magnetized space dusty plasma consisting of negative dust, Maxwellian electrons and q-nonextensively distributed ...ions under the influence of polarization force is studied. The presence of the q-nonextensive ions yields eloquent alteration in the polarization force. An increase in the nonextensive parameter (via q) lead to escalate the polarization parameter. Two-sided KdV equations are obtained by adopting Poincaré-Lighthill-Kuo (PLK) method. Further, the direct Hirota method is employed to carry out multi-solitons solutions of KdV equations. The q-nonextensive polarization force has a great impact on the phase shifts after the interaction of single, double, and triple-(DA) solitons. The combined effects of various physical parameters such as polarization force parameter (via R), nonextensivity (via q) and magnetic field strength (via Ω) on the phase shifts of DA multi-solitons have also been illustrated. It is found that the magnetic field alters the polarization effect which leads to modify the phase shifts. The findings of our investigation may be helpful to explore the interaction of multi-solitons in a magnetized space dusty plasma such as planetary rings and comet tails where nonextensively distributed ions, negative dust and Maxwellian electrons are prevalent.
Abstract Background Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I ...dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters. Methods This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12–450 mg. Results Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from ‘dose-linear PK’ behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (∼111 h). Conclusion This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.
The head-on collision between two ion-acoustic solitons (IASs) is studied in pair ions plasmas with hybrid Cairns–Tsallis-distributed electrons. The chosen model is inspired from the experimental ...studies of Ichiki et al. Phys. Plasmas 8, 4275 (2001). The extended Poincaré–Lighthill–Kuo (PLK) method is employed to obtain the phase shift due to the IASs collision. Both analytical and numerical results reveal that the magnitude of the phase shift is significantly affected by the nonthermal and nonextensive parameters (
and
), the number density ratios (
and
) as well as the mass ratio
. For a given mass ratio
(Ar
,
), the magnitude of the phase shift
decreases slightly (increases) with the increase of
(
). The effect of
on
is more noticeable in the superextensive distribution case (
< 1). As
increases
(Xe
,
), the phase shift becomes wider. In other terms, the phase shift was found to be larger under the effect of higher densities of the negative ions. Our findings should be useful for understanding the dynamics of IA solitons’ head-on collision in space environments namely,
-regions (
,
) and F-regions (H
, H
) of the Earth’s ionosphere and in laboratory double pair plasmas namely, fullerene (C
, C
) and laboratory experiment (Ar
, F
).
Prostate smooth muscle contraction and prostate enlargement contribute to lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Recent evidence demonstrated that inhibitors for ...polo-like kinases (PLKs) inhibit smooth muscle contraction of human prostate tissues. However, their additive effects to α1-blockers, and effects on prostate growth are unknown. Here, we examined effects of a novel and highly selective PLK1 inhibitor, onvansertib on prostate smooth muscle contraction alone and in combination with α1-blockers, and on proliferation and viability of prostate stromal cells (WPMY-1). Prostate tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath. Proliferation and viability were assessed by plate colony, EdU, and CCK-8 assay. Electric field stimulation (EFS)-induced contractions of human prostate tissues were inhibited to 34% by 100 nM and 1 μM onvansertib at 32 Hz, and to 48% and 47% by the α1-blockers tamsulosin and silodosin. Combination of onvansertib with tamsulosin or silodosin further reduced EFS-induced contractions in comparison to α1-blockers alone (59% and 61% respectively), and to onvansertib alone (68% for both). Noradrenaline-, phenylephrine-, methoxamine-, endothelin-1-, and ATP-induced contractions were inhibited by onvansertib (100 nM) to similar extent. Viability and proliferation of WPMY-1 cells were reduced in a concentration- and time-dependent manner (24–72 h, 10–100 nM). Onvansertib inhibits neurogenic, adrenergic, and endothelin-1- and ATP-induced contractions of human prostate smooth muscle, and proliferation of stromal cells. Contractions are reduced not more than 50% by α1-blockers. Combination of α1-blockers with onvansertib provides additive inhibition of prostate contractions.
Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To
identify novel mitosis-specific agents with higher selectivity than ...approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis.
Experimental Design: The first compound in this series, suitable for i.v. administration, has entered clinical development. To fully explore the
potential of Polo-like kinase 1 inhibition in oncology, we have profiled additional compounds and now describe a novel clinical
candidate.
Results: BI 6727 is a highly potent (enzyme IC 50 = 0.87 nmol/L, EC 50 = 11-37 nmol/L on a panel of cancer cell lines) and selective dihydropteridinone with distinct properties. First, BI 6727
has a pharmacokinetic profile favoring sustained exposure of tumor tissues with a high volume of distribution and a long terminal
half-life in mice ( V ss = 7.6 L/kg, t 1/2 = 46 h) and rats ( V ss = 22 L/kg, t 1/2 = 54 h). Second, BI 6727 has physicochemical and pharmacokinetic properties that allow in vivo testing of i.v. as well as oral formulations, adding flexibility to dosing schedules. Finally, BI 6727 shows marked antitumor
activity in multiple cancer models, including a model of taxane-resistant colorectal cancer. With oral and i.v. routes of
administration, the total weekly dose of BI 6727 is most relevant for efficacy, supporting the use of a variety of well-tolerated
dosing schedules.
Conclusion: These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated.
Invasive breast carcinoma (BRCA) is associated with poor prognosis and high risk of mortality. Therefore, it is critical to identify novel biomarkers for the prognostic assessment of BRCA.
The ...expression data of polo-like kinase 1 (PLK1) in BRCA and the corresponding clinical information were extracted from TCGA and GEO databases. PLK1 expression was validated in diverse breast cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Single sample gene set enrichment analysis (ssGSEA) was performed to evaluate immune infiltration in the BRCA microenvironment, and the random forest (RF) and support vector machine (SVM) algorithms were used to screen for the hub infiltrating cells and calculate the immunophenoscore (IPS). The RF algorithm and COX regression model were applied to calculate survival risk scores based on the PLK1 expression and immune cell infiltration. Finally, a prognostic nomogram was constructed with the risk score and pathological stage, and its clinical potential was evaluated by plotting calibration charts and DCA curves. The application of the nomogram was further validated in an immunotherapy cohort.
PLK1 expression was significantly higher in the tumor samples in TCGA-BRCA cohort. Furthermore, PLK1 expression level, age and stage were identified as independent prognostic factors of BRCA. While the IPS was unaffected by PLK1 expression, the TMB and MATH scores were higher in the PLK1-high group, and the TIDE scores were higher for the PLK1-low patients. We also identified 6 immune cell types with high infiltration, along with 11 immune cell types with low infiltration in the PLK1-high tumors. A risk score was devised using PLK1 expression and hub immune cells, which predicted the prognosis of BRCA patients. In addition, a nomogram was constructed based on the risk score and pathological staging, and showed good predictive performance.
PLK1 expression and immune cell infiltration can predict post-immunotherapy prognosis of BRCA patients.
The present study discusses an analytical simulation of the head-on collision between a pair of hydroelastic solitary waves propagating in the opposite directions in the presence of a uniform ...current. An infinite thin elastic plate is floating on the surface of water. The mathematical modeling of the thin elastic plate is based on the Euler–Bernoulli beam model. The resulting kinematic and dynamic boundary conditions are highly nonlinear, which are solved analytically with the help of a singular perturbation method. The Poincaré–Lighthill–Kuo method is applied to obtain the solution of the nonlinear partial differential equations. The resulting solutions are presented separately for the left- and right-going waves. The behavior of all the emerging parameters are presented mathematically and discussed graphically for the phase shift, maximum run-up amplitude, distortion profile, wave speed, and solitary wave profile. It is found that the presence of a current strongly affects the wavelength and wave speed of both solitary waves. A graphical comparison with pure-gravity waves is also presented as a particular case of our study.
Polo‐like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80% of ...human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in human tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug development. PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spindle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are undergoing evaluations as potential cancer treatments. This review includes an overview of PLK inhibitors in early clinical development (i.e., BI 2536, BI 6727, GSK461364, ON 019190.Na, and HMN‐214) and in advanced preclinical development (i.e., ZK‐thiazolidinone, NMS‐1, CYC‐800, DAP‐81, and LC‐445). If proof of principle is confirmed in large studies, PLK inhibitors will offer a new targeted antitumor therapy for cancer patients.
This manuscript reviews the PLK inhibitors in preclinical and clinical development in the therapeutic area of oncology.
PDF
