Effectiveness, safety and pharmacokinetics of Polo-like kinase 1 inhibitors in tumor therapy: A systematic review and meta-analysis.

Objective: To provide a systematic review of existing meta-analysis on the efficacy, safety and pharmacokinetics of the novel Polo-like kinase-1 (Plk1) inhibitors in various tumor treatments, and assess the methodological quality and the strength of evidence of the included meta-analysis. Methods: The Medline, PubMed, Embase, etc. were searched and updated on 30 June 2022. 22 eligible clinical trials involving a total of 1256 patients were included for analyses. Randomised controlled trials (RCTs) compared the efficacy or safety, or both of any Plk1 inhibitors with placebo (active or inert) in participants. To be included, studies had to be RCTs, quasi-RCTs, and nonrandomized comparative studies. Results: A meta-analysis of two trials reported progression-free survival (PFS) of the overall population (effect size (ES), 1.01; 95% confidence intervals (CIs), 0.73-1.30, I2 =0.0%, P<0.001) and overall survival (OS) of the overall population (ES, 0.91; 95% CIs, 0.31-1.50, I2 =77.6%, P=0.003). 18 adverse events (AEs) reflected that the possibility of occurrence of AEs in the Plk1 inhibitors group was 1.28 times higher than in the control group (odds ratios (ORs), 1.28; 95% CIs,1.02-1.61). The results of meta-analysis showed that the incidence of AEs in the nervous system was the highest (ES, 0.202; 95% CIs, 0.161-0.244), followed by blood system (ES, 0.190; 95% CIs, 0.178-0.201) and digestive system (ES, 0.181; 95% CIs, 0.150-0.213). Rigosertib (ON 01910.Na) was associated with a decreased risk of AEs in digestive system (ES, 0.103; 95% CIs, 0.059-0.147), but BI 2536 and Volasertib (BI 6727) increased risk of AEs in blood system (ES, 0.399; 95% CIs, 0.294-0.504). Five eligible studies reported the pharmacokinetic parameters of the low dosage (100 mg) cohort and the high dosage (200 mg) cohort, and there was no statistical difference in the total plasma clearance, terminal half-life and apparent volume of distribution at steady state. Conclusions: Plk1 inhibitors work better in improving OS and they are well tolerated, effective and safe in reducing the severity of illness while improving the quality of life, especially in patients with non-specific tumors, respiratory system tumors, musculoskeletal system tumors, and urinary system tumors. However, they fail to prolong the PFS. From the vertical whole level analysis, compared to other systems in the body, Plk1 inhibitors should be avoided as far as possible for the treatment of tumors related to the blood circulatory system, digestive system and nervous system, which were attributed to the intervention of Plk1 inhibitors associated with an increased risk of AEs in these systems. The toxicity caused by immunotherapy should be carefully considered. Conversely, a horizontal comparison of three different types of Plk1 inhibitors suggested that Rigosertib (ON 01910.Na) might be relatively suitable for the treatment of tumors associated with the digestive system, while Volasertib (BI 6727) might be even less suitable for the treatment of tumors associated with the blood circulation system. Additionally, in the dose selection of Plk1 inhibitors, the low dose of 100 mg should be preferred, and meanwhile, it can also ensure the pharmacokinetic efficacy that is indistinguishable from the high dose of 200 mg. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022343507.

Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor.

Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.

Global dynamics of an SIRS epidemic model with saturation incidence.

In this paper, the dynamical behavior of an SIRS epidemic model with birth pulse, pulse vaccination, and saturation incidence is studied. By using a discrete map, the existence and stability of the infection-free periodic solution and the endemic periodic solution are investigated. The conditions required for the existence of supercritical bifurcation are derived. A threshold for a disease to be extinct or endemic is established. The Poincaré map and center manifold theorem are used to discuss flip bifurcation of the endemic periodic solution. Moreover, numerical simulations for bifurcation diagrams, phase portraits and periodic solutions, which are illustrated with an example, are in good agreement with the theoretical analysis.

Periodic solutions and bifurcation in an S I S epidemic model with birth pulses.

The dynamical behavior of an S I S epidemic model with birth pulses and a varying population is discussed analytically and numerically. This paper investigates the existence and stability of the infection-free periodic solution and the endemic periodic solution. By using discrete maps, the center manifold theorem, and the bifurcation theorem, the conditions of existence for bifurcation of the positive periodic solution are derived. Moreover, numerical results for phase portraits, periodic solutions, and bifurcation diagrams, which are illustrated with an example, are in good agreement with the theoretical analysis.

Algorithm-based qualitative and semiquantitative identification of prevalent vertebral fracture: agreement between different readers, imaging modalities, and diagnostic approaches.

UNLABELLED: We compared SQ and ABQ diagnosis of VF imaged by radiography and X-ray absorptiometry. Mild ABQ VF had stronger associations with osteoporosis than mild SQ VF. Interobserver agreement (radiographic diagnosis) was better for ABQ. INTRODUCTION: Vertebral fracture (VF) assessment from images acquired by X-ray absorptiometry (VFA) is often based on a semiquantitative approach (SQ); prevalent VF is identified if vertebral height appears reduced by >20%. Algorithm-based qualitative definition of osteoporotic VF (ABQ) requires evidence of endplate depression, and there is no threshold for reduction in vertebral height. The aims of this study were to (1) compare the prevalence of VFs; (2) compare the characteristics of women with and without VFs; (3) compare interobserver agreement; and (4) compare agreement between methods and imaging modalities for ABQ and SQ definitions of VFs. MATERIALS AND METHODS: Spine radiographs and absorptiometry images for 203 elderly women were assessed using ABQ (readers ABQ-1 and ABQ-2). These readings were compared with SQ assessments (readers SQ-1 and SQ-2) of the same images performed in a previous study. Agreement between readers and methods was assessed by kappa (kappa) statistics. RESULTS: The prevalence of VF was 15-18% (radiography) and 12-24% (VFA) for ABQ and SQ, respectively. Women with ABQ or SQ fractures were older and had lower BMD than those without fracture (p < 0.01). Mild ABQ (but not SQ) VF was associated with low BMD. Kappa scores for interobserver agreement for radiography and VFA, respectively, were as follows: ABQ, kappa = 0.74 (95% CI, 0.60, 0.87) and 0.65 (95% CI, 0.48, 0.81); SQ, kappa = 0.53 (95% CI, 0.46, 0.60) and 0.51 (95% CI, 0.44, 0.58). For agreement between ABQ-1 and SQ-1, kappa = 0.55 (95% CI, 0.39, 0.72) for radiography and 0.41 (95% CI, 0.25, 0.58 for VFA. CONCLUSIONS: The prevalence of radiographic VF identified by ABQ and SQ was similar, but on VFA was 50% higher for SQ. Mild ABQ VF was associated with low BMD. Interobserver agreement for radiographic diagnosis was significantly better for ABQ than for SQ. Agreement between ABQ and SQ was moderate.

Comparison of densitometric and radiographic vertebral fracture assessment using the algorithm-based qualitative (ABQ) method in postmenopausal women at low and high risk of fracture.

UNLABELLED: Using ABQ diagnosis, the sensitivity to detect VF of densitometric versus radiographic assessment in 755 postmenopausal women was 71-81% and specificity was 97%. Misdiagnosis was influenced by image quality and was more common for mild deformities. INTRODUCTION: Using densitometric vertebral fracture assessment (VFA), prevalent fractures are identified when vertebral height appears reduced by >or=20%. However, this approach does not discriminate between osteoporotic vertebral fracture (VF) and nonosteoporotic deformity, which increases the false-positive rate. Algorithm-based qualitative diagnosis (ABQ) focuses on vertebral endplate fracture to exclude these deformities but has not been applied in VFA. We wished to determine whether densitometric image quality is adequate for ABQ assessment. Our aims were to (1) calculate agreement between VFA and radiography using ABQ to identify prevalent VF and (2) identify the primary reasons for any discordant diagnosis. METHODS: Radiographic and densitometric spine images for postmenopausal women at low risk (LR; n = 459) and high risk (HR; n = 298) of VF were assessed using ABQ. Agreement between imaging modalities for VF diagnosis was assessed by kappa statistics using ABQ radiographic readings as the gold standard. RESULTS: The prevalence of VF was 11-29% (radiography) and 9-26% (VFA) in the LR and HR groups, respectively. Agreement between imaging modalities was good or very good (kappa = 0.62-0.81 in the LR and HR populations). The sensitivity to detect women with VF by VFA was 71% and 84% in the LR and HR populations, respectively, and specificity was 97%. Fifty-two (77%) and 60 (61%) of vertebrae misclassified by VFA in the LR and HR populations were mild fractures and 37 (54%) and 62 (63%) were wedge fractures. One third of fractures missed by VFA were related to poor or unreadable image quality (n = 27 and 28 vertebrae in the LR and HR populations, respectively). CONCLUSIONS: There was good agreement between VFA and radiography using ABQ to identify prevalent VF in women at LR or HR of osteoporotic VF. Vertebrae misclassified by VFA were primarily mild fractures or deformities, and two thirds of all fractures missed by VFA were related to poor or unreadable image quality.

Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.

UNLABELLED: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip. INTRODUCTION: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures. MATERIALS AND METHODS: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis. RESULTS: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures. CONCLUSIONS: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

Identification of vertebral fracture and non-osteoporotic short vertebral height in men: the MrOS study.

UNLABELLED: Non-osteoporotic SVH may mimic VF but is excluded in ABQ. In men, this led to discordance between ABQ and other methods, but SVH was not linked to low bone density. Exclusion of SVH could reduce false positives. INTRODUCTION: Non-osteoporotic short vertebral height (SVH) may mimic vertebral fracture (VF). The aims were to (1) compare the prevalence of VF in elderly men using the algorithm-based qualitative (ABQ), semiquantitative (SQ), and triage-quantitative morphometric (triage-QM) methods; (2) identify reasons for discordance between methods; and (3) determine whether SVH identified by ABQ is linked to low BMD. MATERIALS AND METHODS: We studied a subset of 732 men ages > or =65 yr participating in the Osteoporotic Fractures in Men (MrOS) Study. Criteria for VF were (1) ABQ: endplate depression; (2) SQ: estimated vertebral height reduction > or =20%; (3) triage-QM: vertebral height ratio >3 SD below the reference mean, on radiographs showing evidence of VF. Criteria for SVH (ABQ) were apparent "reduction" in vertebral height > or = approximately 15%, without evidence of endplate depression. RESULTS: The prevalence of at least one VF was 10% (ABQ); 13% (SQ) and 11% (QM-triage) and of at least one SVH (ABQ) was >50%. Agreement between methods was moderate (kappa = 0.42-0.62). Discordance between methods related mainly to classification of mild thoracic wedging or possible traumatic VF by ABQ. Mean BMD was lower in men with VF (any diagnostic method) than in those without (two-sample t-test, p < 0.05). For ABQ, BMD was similar in men with SVH (no VF) and men with normal vertebrae (ANOVA, p > 0.05). Mean BMD was significantly lower than expected in 40 men with VF identified by all three methods and average or more than average in those identified by a single method. CONCLUSIONS: Among elderly men (1) the prevalence of VF ranges from 10% to 13%: (2) agreement between diagnostic methods is moderate: discordance relates mainly to differential classification of mild thoracic deformities or ABQ definition of VF as traumatic; and (3) SVH identified by ABQ is common and not linked to low BMD.

Impulsive ecological control of a stage-structured pest management system.

The dynamics of a stage-structured pest management system is studied by means of autonomous piecewise linear systems with impulses governed by state feedback control. The sufficient conditions of existence and stability of periodic solutions are obtained by means of the sequence convergence rule and the analogue of the Poincare criterion. The attractive region of periodic solutions is investigated theoretically by qualitative analysis. The bifurcation diagrams of periodic solutions are obtained by using the Poincare map, as well as the chaotic solution generated via a cascade of period-doubling bifurcations. The superiority of the state feedback control strategy is also discussed.