A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents. 相似文献
Purpose: Non-ambulatory persons with cerebral palsy are prone to low bone mineral density. In ambulatory persons with cerebral palsy, bone mineral density deficits are expected to be small or absent, but a consensus conclusion is lacking. In this systematic review bone mineral density in ambulatory persons with cerebral palsy (Gross Motor Function Classification Scales I–III) was studied.
Materials and methods: Medline, Embase, and Web of Science were searched. According to international guidelines, low bone mineral density was defined as Z-score?≤??2.0. In addition, we focused on Z-score?≤??1.0 because this may indicate a tendency towards low bone mineral density.
Results: We included 16 studies, comprising 465 patients aged 1–65?years. Moderate and conflicting evidence for low bone mineral density (Z-score?≤??2.0) was found for several body parts (total proximal femur, total body, distal femur, lumbar spine) in children with Gross Motor Function Classification Scales II and III. We found no evidence for low bone mineral density in children with Gross Motor Function Classification Scale I or adults, although there was a tendency towards low bone mineral density (Z-score?≤??1.0) for several body parts.
Conclusions: Although more high-quality research is needed, results indicate that deficits in bone mineral density are not restricted to non-ambulatory people with cerebral palsy.
Implications for Rehabilitation
Although more high-quality research is needed, including adults and fracture risk assessment, the current study indicates that deficits in bone mineral density are not restricted to non-ambulatory people with CP.
Health care professionals should be aware that optimal nutrition, supplements on indication, and an active lifestyle, preferably with weight-bearing activities, are important in ambulatory people with CP, also from a bone quality point-of-view.
If indicated, medication and fall prevention training should be prescribed.
FGFR–TACC, found in different tumor types, is characterized by the fusion of a member of fibroblast grown factor receptor (FGFR) tyrosine kinase (TK) family to a member of the transforming acidic coiled-coil (TACC) proteins. Because chromosome numerical alterations, hallmarks of FGFR–TACC fusions are present in many hematological disorders and there are no data on the prevalence, we studied a series of patients with acute myeloid leukemia and myelodysplastic syndrome who presented numerical alterations using cytogenetic traditional analysis. None of the analyzed samples showed FGFR3–TACC3 gene fusion, so screening for this mutation at diagnosis is not recommended. 相似文献
The concept of dynamic stabilization (DS) of the lumbar spine for treatment of degenerative instability has been introduced almost two decades ago. Dynamic stabilization follows the principle of controlling movement in the coronal plane by providing load transfer of the spinal segment without fusion and, at the same time, reducing side effects such as adjacent segment disease (ASD). So far, only little is known about revision rates after DS due to ASD and screw loosening (SL).
Purpose
The present study aimed to evaluate the longitudinal revision rates following dynamic pedicle screw stabilization in the lumbar spine and to determine specific risk factors predictive for ASD, SL, and overall reoperation in a large cohort with considerable follow-up.
Design
We carried out a post hoc analysis of a prospectively collected database in a level I spine center.
Patients Example
The patient sample comprised 283 (151 female/132 male) consecutive patients suffering from painful degenerative lumbar segmental instability with or without spinal stenosis who underwent DS of the lumbar spine (Ulrich Cosmic, Ulrich Medical, Ulm, Germany) between January 2008 and December 2011.
Outcome Measures
Longitudinal reoperation rate and risk factors predictive for revision surgery were evaluated.
Methods
We analyzed the longitudinal reoperation rate due to ASD and SL and overall reoperation. Risk factors such as age, gender, body mass index, lumbar lordosis (LL), number of segments, and number of previous surgeries were taken into account. Regular and mixed model logistic regressions were performed to determine risk factors for revision surgery on a patient and on a screw level.
Results
The mean age was 65.7±10.2 years (range 31–88). One hundred thirty-two patients were stabilized in 1 segment, 134 in 2 segments, 15 in 3 segments, and 2 patients in 4 segments. Reoperation rate for ASD and SL after 1 year was 7.4 %, after 2 years was 15.0%, and after a mean follow-up of 51.4±15 months was 22.6%. Reasons for revision were SL in 19 cases (6.6%), ASD in 39 cases (13.7%), SL and ASD in 6 cases, hematoma in 2 cases (0.7%), cerebrospinal fluid fistulae in 3 cases (1.1%), infection in 6 cases (2.1%), and implant failure in 1 case (0.4%). The patients' age, the number of stabilized segments, and the number of previous surgeries and postoperative LL had a significant influence on the probability for revision surgery.
Conclusions
Reoperation rates after DS of the lumbar spine are comparable with rigid fixations. The younger the patient and the more segments are involved, the lower the LL and the more previous surgeries were found, the higher was the risk of revision. Risk of revision was almost twice as high in men compared with women. We therefore conclude that for clear clinical indication and careful evaluation of preoperative imaging data, DS using the Cosmic system seems to be a possible option. The presented data will help to further tailor indication and patient selection. 相似文献
Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field. 相似文献
??Objective To investigate the effect of tooth movement at different time after the repair of alveolar bone defects. Methods Defective alveolar bone model was established on one side in forty white rabbits??which were filled with bone meal and attached with Bio-Gide membrane as experiment sides. The other side was performed routine tooth extraction as control. Track the mandibular second molar in both sides respectively in 1 week??1 month??2 months and 3 months after operation. One month later??the distance between the mandibular second molar and third molar was measured with electronic vernier caliper in the experiment side and control side. The mandibular tissue was made paraffin section and hematoxylin eosin staining. Three views of the periodontal ligament in a third place of the mesial roots of the second molar was randomly chosen to count the total number of osteoclasts. Paired-t test analysis was made to evaluate the displacement of the mandibular second molar in experiment and control side??and to evaluate the number of osteoclasts in two side. Results In Group 1w and Group 1 m??the displacement of the mandibular second molar in experiment group was smaller than that in the control side??P??0.05??. There was no statistical significance in Group 2 m and Group 3 m. The number of osteoclasts in the experiment side was less than the control group in Group 1 w and Group1 m??P??0.05??. No statistical significance in Group 2 m and Group 3 m was found. Conclusion Orthodontic treatment can be performed two months after the repair of alveolar bone defects. 相似文献