Leveraging pharmacokinetic parameters as covariate in Bayesian logistic regression model to optimize dose selection in early phase oncology trial.

Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.

Advances in the Causes and Treatment of Floating Toes after the Weil Osteotomy: A Scoping Review.

The floating toe deformity is classified as a forefoot deformity wherein the distal portion of the toe does not establish touch with the ground, resulting in a suspended or elevated position while the finger is in a relaxed state. At first, it garnered considerable interest as a complication It is worth noting that this condition is particularly common in children under the age of 8, which usually disappears as the individual reaches maturity. Studies have shown that with the aggravation of floating toe deformity, its adverse effects on patients' gait and overall quality of life also increase. Despite the prevalence of floating toe deformity in clinical settings, there is a lack of comprehensive literature investigating its underlying causes and potential preventive strategies. This scope review follows the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) statement guidelines for scope reviews. The literature was obtained from various full-text databases, including China National Knowledge Infrastructure Database (CNKI), Wanfang Database, PubMed, and Web of Science Database. Our search focused on published literature related to floating toes, Weil osteotomy, and distal metatarsal osteotomy, up until March 1, 2023. The literature search and data analysis are conducted by two independent reviewers. If there are any disagreements, a third researcher will participate in the discussion and negotiate a decision. Furthermore, two experienced foot and ankle surgeons conducted a thorough literature analysis for this review. Sixty-two articles were included. Through the clinical analysis of the structural changes of the forefoot before and after operation, the classification of floating toe was described, the causes of pathological floating toe were summarized, and the possible intervention measures for the disease were put forward under the advice of foot and ankle surgery experts. We comprehensively summarize the current knowledge system about the etiology of floating toe and put forward the corresponding intervention strategy. We recommend that future studies will focus on the improvement of surgical procedures, such as the combination of Weil osteotomy, proximal interphalangeal (PIP) arthrodesis and flexor tendon arthrodesis.

Interactive Multi-Stage Robotic Positioner for Intra-Operative MRI-Guided Stereotactic Neurosurgery.

Magnetic resonance imaging (MRI) demonstrates clear advantages over other imaging modalities in neurosurgery with its ability to delineate critical neurovascular structures and cancerous tissue in high-resolution 3D anatomical roadmaps. However, its application has been limited to interventions performed based on static pre/post-operative imaging, where errors accrue from stereotactic frame setup, image registration, and brain shift. To leverage the powerful intra-operative functions of MRI, e.g., instrument tracking, monitoring of physiological changes and tissue temperature in MRI-guided bilateral stereotactic neurosurgery, a multi-stage robotic positioner is proposed. The system positions cannula/needle instruments using a lightweight (203 g) and compact (Ø97 × 81 mm) skull-mounted structure that fits within most standard imaging head coils. With optimized design in soft robotics, the system operates in two stages: i) manual coarse adjustment performed interactively by the surgeon (workspace of ±30°), ii) automatic fine adjustment with precise (<0.2° orientation error), responsive (1.4 Hz bandwidth), and high-resolution (0.058°) soft robotic positioning. Orientation locking provides sufficient transmission stiffness (4.07 N/mm) for instrument advancement. The system's clinical workflow and accuracy is validated with lab-based (<0.8 mm) and MRI-based testing on skull phantoms (<1.7 mm) and a cadaver subject (<2.2 mm). Custom-made wireless omni-directional tracking markers facilitated robot registration under MRI.

An overview on CV2/CRMP5 antibody-associated paraneoplastic neurological syndromes.

Paraneoplastic neurological syndrome refers to certain malignant tumors that have affected the distant nervous system and caused corresponding dysfunction in the absence of tumor metastasis. Patients with this syndrome produce multiple antibodies, each targeting a different antigen and causing different symptoms and signs. The CV2/collapsin response mediator protein 5 (CRMP5) antibody is a major antibody of this type. It damages the nervous system, which often manifests as limbic encephalitis, chorea, ocular manifestation, cerebellar ataxia, myelopathy, and peripheral neuropathy. Detecting CV2/CRMP5 antibody is crucial for the clinical diagnosis of paraneoplastic neurological syndrome, and anti-tumor and immunological therapies can help to alleviate symptoms and improve prognosis. However, because of the low incidence of this disease, few reports and no reviews have been published about it so far. This article intends to review the research on CV2/CRMP5 antibody-associated paraneoplastic neurological syndrome and summarize its clinical features to help clinicians comprehensively understand the disease. Additionally, this review discusses the current challenges that this disease poses, and the application prospects of new detection and diagnostic techniques in the field of paraneoplastic neurological syndrome, including CV2/CRMP5-associated paraneoplastic neurological syndrome, in recent years.

Lack of evolutionary convergence in multiple primary lung cancer suggests insufficient specificity of personalized therapy.

Multiple primary lung cancer (MPLC) is an increasingly prevalent subtype of lung cancer. According to recent genomic studies, the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence. We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found. Using our own and other relevant public data, evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk, indicating evolutionary contingency rather than adaptive convergence. Additionally, tumors from the same MPLC patient are as genetically diverse as those from different patients, while within-tumor genetic heterogeneity is significantly lower. Furthermore, the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor, but not with samples from other tumors or other patients. Overall, there is no evidence of adaptive convergence during the evolution of MPLC. Most importantly, the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient. To fully exploit the strategic value of precision medicine, targeted therapies should be designed and delivered on a per-lesion basis.

Effect of flushing temperature on preparation ability of rotary nickel-titanium files.

PURPOSE: The effect of flushing at different temperatures on the preparation ability of rotary nickel-titanium files was investigated to provide guideline for clinical application. METHODS: Sixty ProTaper Universal F1 rotary nickel-titanium files were randomly divided into three groups treated by flushing at 6°C, 23°C, and 40°C. Root canal preparation was conducted by step-by-step method on standardized nickel-titanium instrument fracture models. During preparation, the thrust force was set as 10 N, and water was continuously flushed. The motor speed was 350 rpm (rounds per minute), and the torque was 3.0 N cm. When the set torque was reached, the motor automatically rotated in the reverse direction and was pulled out. RESULTS: Root canal preparation was performed using ProTaper Universal F1 rotary nickel-titanium files treated by flushing. The numbers of rotations before the device was fracture were 429.33 ± 214.68, 821.92 ± 410.43, and 1304.92 ± 297.81, respectively. When each root canal was completed, the numbers of instrument rotations were 272.15 ± 88.30, 188.85 ± 34.36, and 163.41 ± 16.18, respectively. Rank sum test and analysis of variance were performed by IBM SPSS Statistics v21.0 software, and both of them were p < 0.01, indicating that the number of cycles to failure (NCF) and the number of instrument rotations for each root tube were statistically different at the three temperatures. CONCLUSIONS: The self-made resin-simulated curved root canal can replace the real root canal to complete the root canal preparation experiment. The group of nickel-titanium files treated by flushing at 23°C can prepare more root canals and prolong the life of nickel-titanium files than at 6°C. When flushing was done at 40°C, the number of root canals prepared by nickel-titanium files was the highest, and it was not easy to damage the instrument, but lateral perforation occurred easily during root canal preparation.

Comparative study of the oxidation of cold-pressed and commercial refined camellia oil during storage with 1H and 31P NMR spectroscopy.

The oxidation of cold-pressed and commercial refined camellia oil stored at room temperature for one year was comparatively studied by 1H and 31P NMR spectroscopy. The oxidation of extra virgin olive oil (EVOO) under the same conditions was further compared. The 1H NMR showed that no aldehydes were formed in the studied period. Coupled with the changes of unsaturated acyl groups, the oxidation degrees of the three oils could be obtained follow the order: commercial refined camellia oil > cold-pressed camellia oil > EVOO. The 31P NMR showed that the evolution of diacylglycerols (DGs) and ratio D in commercial refined camellia oil was fairly different from other two oils. Besides, the kinetics curves of unsaturated acyl groups and ratio D both fit to an exponential equation with high coefficients which indicated that the oxidation of the studied oils progressed in an exponential way with storage time at room temperature.

A panel of Transcription factors identified by data mining can predict the prognosis of head and neck squamous cell carcinoma.

BACKGROUND: Transcription factors (TFs) are responsible for the regulation of various activities related to cancer like cell proliferation, invasion, and migration. It is thought that, the measurement of TFs levels could assist in developing strategies for diagnosis and prognosis of cancer detection. However, due to lack of effective genome-wide tests, this cannot be carried out in clinical settings. METHODS: A complete assessment of RNA-seq data in samples of a head and neck squamous cell carcinoma (HNSCC) cohort in The Cancer Genome Atlas (TCGA) database was carried out. From the expression data of six TFs, a risk score model was developed and further validated in the GSE41613 and GSE65858 series. Potential functional roles were identified for the six TFs via gene set enrichment analysis. RESULTS: Based on our multi-TF signature, patients are stratified into high- and low-risk groups with significant variations in overall survival (OS) (median survival 2.416 vs. 5.934 years, log-rank test P < 0.001). The sensitivity and specificity evaluation of our multi-TF for 3-year OS in TCGA, GSE41613 and GSE65858 was 0.707, 0.679 and 0.605, respectively, demonstrating good reproducibility and robustness for predicting overall survival of HNSCC patients. Through multivariate Cox regression analyses (MCRA) and stratified analyses, we confirmed that the predictive capability of this risk score (RS) was not dependent on any of other factors like clinicopathological parameters. CONCLUSIONS: With the help of a RS obtained from a panel of TFs expression signatures, effective OS prediction and stratification of HNSCC patients can be carried out.

Anti-inflammatory and antitumour activity of various extracts and compounds from the fruits of Piper longum L.

OBJECTIVES: To explore effective extraction method and to find active constituents, we investigated the biological activity of three extracts and isolated active compounds from the fruits of Piper longum L. METHODS: Three extracts from the fruits were obtained by reflux, ultrasonic and supercritical fluid extraction, respectively. Active compounds were isolated by the bioassay-guided method. The anti-inflammatory activity, antiproliferation activity and cytotoxicity were evaluated. The apoptosis was detected by Hoechst 33258 staining assay. The relevant proteins were investigated by Western blot assay. KEY FINDINGS: The anti-inflammatory activity and cytotoxicity of supercritical fluid extract (SE) were stronger than those of the other two extracts. Among all isolated compounds, the anti-inflammatory activity of eight compounds was stronger than that of indomethacin, and compounds 8, 9, 11, 14 and 15 were found to possess anti-inflammatory effect for the first time. Compounds 1, 2, 3 and 14 exhibited significant cytotoxicity against cancer cells. SE and piperine were found to reduce colony formation, inhibit cell migration and promote apoptosis through increasing cleaved PARP and the ratio of Bax/Bcl-2. CONCLUSIONS: The anti-inflammatory and antitumour effects of SE were better than those of the other two extracts. The compounds responsible for the activity were elucidated. SE and piperine inhibit cell growth through apoptosis.

Chronic hepatitis B virus infection and total and cause-specific mortality: a prospective cohort study of 0.5 million people.

OBJECTIVES: Chronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality. DESIGN: Population-based prospective cohort study. SETTING: China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008. PARTICIPANTS: 475 801 participants 30-79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline. PRIMARY AND SECONDARY OUTCOME MEASURES: Total and cause-specific mortality. RESULTS: A total of 35 822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95% CI: 2.01 to 2.31) than in women (HR=1.74, 95% CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95% CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95% CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95% CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95% CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95% CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants. CONCLUSIONS: Among Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.

Prediction of head and neck squamous cell carcinoma survival based on the expression of 15 lncRNAs.

Recent evidence suggests that long noncoding RNAs (lncRNAs) are essential regulators of many cancer-related processes, including cancer cell proliferation, invasion, and migration. There is thus a reason to believe that the detection of lncRNAs may be useful as a diagnostic and prognostic strategy for cancer detection, however, at present no effective genome-wide tests are available for clinical use, constraining the use of such a strategy. In this study, we performed a comprehensive assessment of lncRNAs expressed in samples in the head and neck squamous cell carcinoma (HNSCC) cohort available in The Cancer Genome Atlas database. A risk score (RS) model was constructed based on the expression data of these 15 lncRNAs in the validation data set of HNSCC patients and was subsequently validated in validation data set and the entire data set. We were able to stratify patients into high- and low-risk categories, using our lncRNA expression panel to determine an RS, with significant differences in overall survival (OS) between these two groups in our test set (median survival, 1.863 vs. 5.484 years; log-rank test, p < 0.001). We were able to confirm the predictive value of our 15-lncRNA signature using both a validation data set and a full data set, finding our signature to be reproducible and effective as a means of predicting HNSCC patient OS. Through the multivariate Cox regression and stratified analyses, we were further able to confirm that the predictive value of this RS was independent of other predictive factors such as clinicopathological parameters. The Gene set enrichment analysis revealed potential functional roles for these 15 lncRNAs in tumor progression. Our findings indicate that an RS established based on a panel of lncRNA expression signatures can effectively predict OS and facilitate patient stratification in HNSCC.

Scutellarin synergistically enhances cisplatin effect against ovarian cancer cells through enhancing the ability of cisplatin binding to DNA.

Platinum resistance is a major limitation in the treatment of ovarian cancer. Combination of natural compounds with platinum-based agents is a new strategy for cancer chemotherapy. Recently, we found that scutellarin sensitized the anticancer effect of cisplatin to ovarian cancer cells. How scutellarin interacts with cisplatin and sensitizes its effect is unclear. Here, we found that the combination treatment of scutellarin and cisplatin enhanced apoptosis in ovarian cancer cells via increasing the extent of platinum-DNA adducts and the ratio of Bax/Bcl-2. The changes in UV-visible spectra indicated that scutellarin could form complex with cisplatin. Moreover, combination treatment prevented BamH1 digestion on pBR322 plasmid DNA more effectively suggesting that their interaction might cause a greater conformational change in the DNA, which finally induced the DNA strand breaks and enhanced apoptotic signaling pathway response. Our study supports that scutellarin acts as a potential sensitizer to cisplatin treatment and the combination of scutellarin and cisplatin may be a novel therapeutic strategy to overcome platinum resistance of ovarian cancer.

Protocatechuic acid inhibits the growth of ovarian cancer cells by inducing apoptosis and autophagy.

Protocatechuic acid (PCA), present in many fruits and vegetables, exhibited various biological activities. Here, we provided evidence that it could be developed as a potential chemotherapeutic agent against human ovarian cancer. We found that PCA treatment significantly reduced the cell viability and colony formation of OVCAR-3, SKOV-3, and A2780 cells. OVCAR-3 cells were selected as a test model system for investigating molecular mechanism. PCA treatment induced cell cycle arrest in G2 /M phase, the activation of poly (ADP-ribose) polymerase (PARP) and caspase-3, the upregulation of Bax and downregulation of Bcl-2 in OVCAR-3 cells. We also observed that PCA treatment significantly caused upregulation of autophagy-related protein LC3-II and induced GFP-LC3 puncta formation. Furthermore, cotreatment with PCA and autophagy inhibitor attenuated the cytotoxicity induced by PCA in OVCAR-3 cells. Moreover, our results showed that PCA increased the intracellular levels of glutathione and decreased intracellular reactive oxygen species that might be related to the inhibition effect of PCA on OVCAR-3 cells. Our data revealed that PCA could modulate apoptosis and autophagy, suggesting the potential of PCA for chemoprevention and chemotherapy of ovarian cancer.

Techniques for Stereotactic Neurosurgery: Beyond the Frame, Toward the Intraoperative Magnetic Resonance Imaging-Guided and Robot-Assisted Approaches.

The development of stereotaxy can be dated back 100 years. However, most stereotactic neurosurgery still relies on the workflow established about half a century ago. With the arrival of computer-assisted navigation, numerous studies to improve the neurosurgical technique have been reported, leading to frameless and magnetic resonance imaging (MRI)-guided/verified techniques. Frameless stereotaxy has been proved to be comparable to frame-based stereotaxy in accuracy, diagnostic yield, morbidity, and mortality. The incorporation of intraoperative MRI guidance in frameless techniques is considered an appealing method that could simplify workflow by reducing coregistration errors in different imaging modalities, conducting general anesthesia, and monitoring the surgical progress. In light of this situation, manually operated platforms have emerged for MRI-guided frameless procedures. However, these procedures could still be complicated and time-consuming because of the intensive manual operation required. To further simplify the procedure and enhance accuracy, robotics was introduced. Robots have superior capabilities over humans in certain tasks, especially those that are limited by space, accuracy demanding, intensive, and tedious. Clinical benefits have been shown in the recent surge of robot-assisted surgical interventions. We review the state-of-the-art intraoperative MRI-guided robotic platforms for stereotactic neurosurgery. To improve the surgical workflow and achieve greater clinical penetration, 3 key enabling techniques are proposed with emphasis on their current status, limitations, and future trends.

An efficient cardiac mapping strategy for radiofrequency catheter ablation with active learning.

OBJECTIVE: A major challenge in radiofrequency catheter ablation procedures is the voltage and activation mapping of the endocardium, given a limited mapping time. By learning from expert interventional electrophysiologists (operators), while also making use of an active-learning framework, guidance on performing cardiac voltage mapping can be provided to novice operators or even directly to catheter robots. METHODS: A learning from demonstration (LfD) framework, based upon previous cardiac mapping procedures performed by an expert operator, in conjunction with Gaussian process (GP) model-based active learning, was developed to efficiently perform voltage mapping over right ventricles (RV). The GP model was used to output the next best mapping point, while getting updated towards the underlying voltage data pattern as more mapping points are taken. A regularized particle filter was used to keep track of the kernel hyperparameter used by GP. The travel cost of the catheter tip was incorporated to produce time-efficient mapping sequences. RESULTS: The proposed strategy was validated on a simulated 2D grid mapping task, with leave-one-out experiments on 25 retrospective datasets, in an RV phantom using the Stereotaxis Niobe® remote magnetic navigation system, and on a tele-operated catheter robot. In comparison with an existing geometry-based method, regression error was reduced and was minimized at a faster rate over retrospective procedure data. CONCLUSION: A new method of catheter mapping guidance has been proposed based on LfD and active learning. The proposed method provides real-time guidance for the procedure, as well as a live evaluation of mapping sufficiency.

Phosphorus removal from aqueous solution in parent and aluminum-modified eggshells: thermodynamics and kinetics, adsorption mechanism, and diffusion process.

Parent and aluminum-modified eggshells were prepared and characterized with X-ray diffraction, specific surface area measurements, infrared spectroscopy, zeta potential, and scanning electron microscope, respectively. Besides, phosphorus adsorptions in these two eggshells at different temperatures and solution pH were carried out to study adsorption thermodynamics and kinetics as well as the mechanisms of phosphorus adsorption and diffusion. The results indicated that high temperature was favorable for phosphorus adsorption in parent and aluminum-modified eggshells. Alkaline solution prompted phosphorus adsorption in parent eggshell, while the maximum adsorption amount was achievable at pH 4 in aluminum-modified eggshell. Adsorption isotherms of phosphorus in these eggshells could be well described by Langmuir and Freundlich models. Phosphorus adsorption amounts in aluminum-modified eggshell were markedly higher compared to those in parent eggshell. Adsorption heat indicated that phosphorus adsorption in parent eggshell was a typically physical adsorption process, while chemical adsorption mechanism of ion exchange between phosphorus and hydroxyl groups on the surface of eggshells was dominated in aluminum-modified eggshell. The time-resolved uptake curves showed phosphorus adsorption in aluminum-modified eggshell was significantly faster than that in parent eggshell. Moreover, there existed two clear steps in time-resolved uptake curves of phosphorus in parent eggshell. Based on pseudo-second order kinetic model and intraparticle diffusion model, we inferred more than one process affected phosphorus adsorption. The first process was the diffusion of phosphorus through water to external surface and the opening of pore channel in the eggshells, and the second process was mainly related to intraparticle diffusion.