STING agonist inflames the cervical cancer immune microenvironment and overcomes anti-PD-1 therapy resistance.

Background: Cervical cancer poses a significant global threat to women's health. However, current therapeutic interventions, such as radiotherapy, chemotherapy, surgical resection, and immune checkpoint inhibitors, face limitations in the advanced stages of the disease. Given the immunosuppressive microenvironment in cervical cancer, it is imperative to explore novel perspectives. In this regard, STING agonists have emerged as promising candidates. Methods: The expression profiles and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Prognostic analysis of STING downstream genes (CCL5, CXCL9, CXCL10) and immune infiltration analysis were conducted using Kaplan-Meier Plotter, ESTIMATE, and deconvo_CIBERSOR. Single-cell RNA-seq (scRNA-seq) analysis was conducted to evaluate the potential of MSA-2 in cervical cancer treatment employing SingleR, chi-squared test, and Gene Set Enrichment Analysis (GSEA). Cellular interaction analysis utilized the CellChat package to assess the potentiation of cellular interaction following MSA-2 administration. Murine tumor models involving U14 and TC-1, were conducted, and the IF of tissue was subsequently conducted to assess the tumor microenvironment status after treatment. Results: Prognosis in cervical cancer correlated with elevated expression of STING downstream genes, indicating prolonged survival and reduced recurrence. These genes positively correlated with immune infiltration, influencing stromal scores, immune scores, and estimate scores. Specific immune cell populations, including CD8+ T cells, M1-type macrophages, NK cells, and T follicular helper cells, were associated with STING downstream genes. scRNA-seq in a classic immune-excluded model revealed that MSA-2 exerts priming and activating functions on vital components within TME, and intensifies their intercellular communications. The in vivo assay ultimately demonstrated that MSA-2, either as a standalone treatment or in combination with anti-PD-1, effectively suppressed the growth of subcutaneous cervical tumors. Moreover, the combination strategy significantly augmented efficacy compared to anti-PD-1 monotherapy by eliciting a robust antitumor immune response. Conclusion: This study highlights the pivotal role of the STING pathway and the potential of MSA-2 in reshaping the immune microenvironment in cervical cancer. Combining MSA-2 with immune checkpoint inhibitors presents a transformative approach, holding promise for improved prognosis. Further investigations are warranted to explore the broader immune landscape and potential long-term effects of MSA-2 in cervical cancer treatment.

CAR-NK cells for cancer immunotherapy: recent advances and future directions.

Natural Killer (NK) cells, intrinsic to the innate immune system, are pivotal in combating cancer due to their independent cytotoxic capabilities in antitumor immune response. Unlike predominant treatments that target T cell immunity, the limited success of T cell immunotherapy emphasizes the urgency for innovative approaches, with a spotlight on harnessing the potential of NK cells. Despite tumors adapting mechanisms to evade NK cell-induced cytotoxicity, there is optimism surrounding Chimeric Antigen Receptor (CAR) NK cells. This comprehensive review delves into the foundational features and recent breakthroughs in comprehending the dynamics of NK cells within the tumor microenvironment. It critically evaluates the potential applications and challenges associated with emerging CAR-NK cell therapeutic strategies, positioning them as promising tools in the evolving landscape of precision medicine. As research progresses, the unique attributes of CAR-NK cells offer a new avenue for therapeutic interventions, paving the way for a more effective and precise approach to cancer treatment.

Eres-UNet++: Liver CT image segmentation based on high-efficiency channel attention and Res-UNet+.

Computerized tomography (CT) is of great significance for the localization and diagnosis of liver cancer. Many scholars have recently applied deep learning methods to segment CT images of liver and liver tumors. Unlike natural images, medical image segmentation is usually more challenging due to its nature. Aiming at the problem of blurry boundaries and complex gradients of liver tumor images, a deep supervision network based on the combination of high-efficiency channel attention and Res-UNet++ (ECA residual UNet++) is proposed for liver CT image segmentation, enabling fully automated end-to-end segmentation of the network. In this paper, the UNet++ structure is selected as the baseline. The residual block feature encoder based on context awareness enhances the feature extraction ability and solves the problem of deep network degradation. The introduction of an efficient attention module combines the depth of the feature map with spatial information to alleviate the uneven sample distribution impact; Use DiceLoss to replace the cross-entropy loss function to optimize network parameters. The liver and liver tumor segmentation accuracy on the LITS dataset was 95.8% and 89.3%, respectively. The results show that compared with other algorithms, the method proposed in this paper achieves a good segmentation performance, which has specific reference significance for computer-assisted diagnosis and treatment to attain fine segmentation of liver and liver tumors.

Evaluation of 5-aminolevulinic acid-mediated photodynamic therapy on cervical low-grade squamous intraepithelial lesions with high-risk HPV infection.

BACKGROUND: The treatment options for low-grade squamous intraepithelial neoplasia (LSIL) of the cervix with high-risk HPV infection have not been standardized. Studies show that photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA-PDT) might be effective. In this retrospective study, the clinical efficacy and safety of ALA-PDT in the treatment of LSIL were evaluated. METHODS: ALA-PDT was performed in 55 LSIL patients aged 21-45 years who also showed high-risk HPV infection and cervical ectropion. HPV test, cytology, colposcopy and pathology were examined before and after treatment. Meanwhile, PDT-related symptoms and adverse reactions were also reviewed. RESULTS: At 6-month follow-up after PDT, except for 5 patients who showed the persistence of LSIL lesions, the pathological regression ratio of 90.1% (50/55) was achieved. No HPV-DNA was detected in exfoliated cervical cells in 81.8% (45/55) patients. Among them, the HPV clearance ratio of I Degree cervical ectropion was 96.2%, significantly higher than that of II Degree (70.8%) and III Degree (60%). Significant shrunk of cervical ectropion and reduction of vaginal secretions after PDT were seen in 78.0% patients. CONCLUSION: ALA-PDT is a safe and effective therapeutic option for patients of reproductive age who suffer from LSIL with high-risk HPV infection and cervical ectropion.

Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Malignancies.

This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for Cmax , AUCinf , and AUClast of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.

Absolute Bioavailability of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.

Sinomenine Attenuates Traumatic Spinal Cord Injury by Suppressing Oxidative Stress and Inflammation via Nrf2 Pathway.

Traumatic spinal cord injury (SCI) is a devastating condition with few efficacious drugs. Sinomenine, a bioactive alkaloid extracted from medicinal herb, has been used as a treatment of rheumatoid diseases. This present study explored the therapeutic effects of sinomenine on locomotor dysfunction and neuropathology in SCI. Our findings revealed that sinomenine mitigated neurological deficits and enhanced neuronal preservation, paralleled with a reduction of apoptosis. Also, sinomenine significantly reduced inflammatory cytokines and oxidative stress factors. We further examined erythroid-2-related factor 2 (Nrf2) nuclear translocation, which mainly controls the coordinated expression of important antioxidant and detoxification genes. An increase in Nrf2 translocation from cytoplasm to nucleus and Nrf2-mediated transactivation was observed after sinomenine administration. Knocking down Nrf2 by siRNA could counteract sinomenine-mediated anti-oxidant stress and anti-inflammation following H2O2-stimulated and LPS-stimulated PC12 cells. Together, our findings indicated that sinomenine has the potential to be an effective therapeutic agent for SCI by inhibiting inflammation and oxidative stress via Nrf2 activation.

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

Vemurafenib prolongs survival in patients with BRAFV600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAFV600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers.

Arthroscopic-assisted balloon tibioplasty versus open reduction internal fixation (ORIF) for treatment of Schatzker II-IV tibial plateau fractures: study protocol of a randomised controlled trial.

INTRODUCTION: Arthroscopic-assisted balloon tibioplasty is an emerging technology that has shown advantages in recovering depression of the articular surface. However, studies evaluating clinical outcomes between arthroscopic-assisted balloon tibioplasty and traditional open reduction internal fixation (ORIF) are sparse. This is the first randomised study to compare arthroscopic-assisted balloon tibioplasty with ORIF, and will provide guidance for treating patients with Schatzker types II, III and IV with depression of the medial tibial plateau only. METHODS AND ANALYSIS: A blinded randomised controlled trial will be conducted and a total of 80 participants will be randomly divided into either the arthroscopic-assisted balloon tibioplasty group or the ORIF group, at a ratio of 1:1. The primary clinical outcome measures are the knee functional scores, Rasmussen radiological evaluation scores and the quality of reduction based on postoperative CT scan. Secondary clinical outcome measures are intraoperative blood loss, surgical duration, visual analogue scale score after surgery, hospital duration after surgery, complications and 36-Item Short-Form Health Survey score. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the Institutional Review Board of the Second Affiliated Hospital of Wenzhou Medical University (batch: 2017-12). The results will be presented in peer-reviewed journals after completion of the study. TRIAL REGISTRATION NUMBER: NCT03327337, Pre-results.

Vemurafenib in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma: an open-label, multicenter phase I study.

BACKGROUND: Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAFV600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients. METHODS: This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26). RESULTS: After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0-67.1%). Median progression-free survival was 8.3 months (95% CI 5.7-10.9%); median overall survival was 13.5 months (95% CI 12.2%-not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%). CONCLUSION: Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT01910181 . Registered 29 July 2013, prospectively registered.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

The primary objective of this phase 1, open-label, multicenter, 3-period, fixed-sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P-glycoprotein (P-gp) substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Following a 28-day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8-28), and a single oral dose of digoxin 0.25 mg on day 29 and vemurafenib 960 mg twice a day for 7 days (days 29-35) in period C. Log-transformed area under the concentration-time curve and peak concentration values for digoxin were compared between periods A (digoxin alone) and C (digoxin + vemurafenib) using an analysis of variance model. Twenty-six patients were evaluated for the primary pharmacokinetic analysis. The geometric mean ratio (period C/period A) of area under the curve to the last measurable concentration for digoxin was 1.82 (90%CI 1.63 to 2.02), and the geometric mean ratio of peak concentrations was 1.47 (90%CI 1.30 to 1.65); the 90%CIs were outside of the equivalence limits of 0.82 to 1.22, indicating an effect of vemurafenib on digoxin. Multiple oral doses of vemurafenib were generally well tolerated, with an adverse event profile similar to that previously seen in phase 2 and 3 studies of vemurafenib monotherapy. This study confirmed vemurafenib as an inhibitor of P-gp in vivo with a statistically significant drug-drug interaction with digoxin. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates.

Cancer-associated fibroblasts induce epithelial-mesenchymal transition through secreted cytokines in endometrial cancer cells.

Endometrial cancer (EC) is the most common malignant gynecological disease. Cancer-associated fibroblasts (CAFs) serve an important role in the development and progression of EC through epithelial-mesenchymal transition (EMT). The aim of the present study was to examine the association between CAFs and EMT, and the possible mechanisms of action. Firstly, the CAFs and normal fibroblasts (NFs) were isolated and cultured, then an immunofluorescence assay was performed to analyze the purity and level of activation of CAFs and NFs, and then the conditional medium (CM) of CAFs and NFs was prepared. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting examined the expression levels of epithelial (E)-cadherin, neural (N)-cadherin and vimentin. A Matrigel® invasion assay and wound healing assay were used to analyze the effect of the CM on invasion and migration. An ELISA assay also measured the levels of various cytokines in the CM. In addition, EMT-associated proteins in metastatic lung tissues were detected by immunohistochemical assay. The results indicated that the CM of CAFs may decrease the level of E-cadherin, and increase the levels of N-cadherin and vimentin, while increasing the levels of invasion and metastasis in EC cells. The concentration of epidermal growth factor, transforming growth factor-ß, hepatic growth factor and fibroblast growth factor in the CM of CAFs increased significantly, in comparison with the NFs group (P<0.05). The exogenous growth factors induced migration and invasion of EC cells. CAFs induced lung metastasis and the EMT process in vivo. These data suggested that cancer-associated fibroblasts may induce EMT through the secreted cytokines in endometrial cancer cells.

LINC01088 inhibits tumorigenesis of ovarian epithelial cells by targeting miR-24-1-5p.

The roles of long non-coding RNAs (lncRNAs), a class of long non-protein-coding RNAs, in the tumorigenesis of ovarian epithelial cells remain unknown. In this study, we discovered that the expression of long intergenic non-coding RNA 1088 (LINC01088) was clearly reduced in benign epithelial ovarian tumor tissues compared to matched normal ovarian tissues. This was shown by global cDNA gene chip scanning and real-time qPCR, and validated in 42 clinical specimens. Furthermore, we found that LINC01088 inhibited the growth of ovarian cancer xenografts in nude mice. Correlation analysis between LINC01088 and mircoRNAs (miRNAs) conducted using primary clinical samples and RNA co-precipitation experiments revealed that miR-24-1-5p was one of the targets of LINC01088. Overexpression of miR-24-1-5p facilitated cell proliferation both in vitro and in vivo, however, LINC01088 could partially reverse the cell proliferation induced by miR-24-1-5p. Finally, we demonstrated that p21 activated kinase 4 (PAK4) was one of the downstream key targets of miR-24-1-5p by luciferase reporter assay and Western blotting; and our results showed a remarkable decrease in cell proliferation after overexpression of PAK4. We conclude that LINC01088 might function as a tumor suppressor, inhibiting the tumorigenesis of ovarian epithelial cells through LINC01088/ miR-24-1-5p/ PAK4 axis.

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

MiR-126 reverses drug resistance to TRAIL through inhibiting the expression of c-FLIP in cervical cancer.

TNF-related apoptosis-inducing ligand (TRAIL) represents one potential and ideal anti-tumor drug, because it kills cancer cells specifically without targeting normal cells. However, acquired drug resistance to TRAIL usually impedes the clinical use of TRAIL on cancer patients. In the present study, we established in vitro TRAIL-resistant cervical cancer cell lines through long-term exposure to TRAIL. Interestingly, we observed significant upregulation of c-FLIP in TRAIL-resistant Hela and SiHa cells (Hela-TR and SiHa-TR) compared to their parental Hela and SiHa cells. Although Hela-TR and SiHa-TR cells exhibited low-sensitivity to TRAIL treatment, knockdown of c-FLIP significantly increased the cytotoxicity of TRAIL to them. In contrast to high protein level of c-FLIP, expression of miR-126 was significantly downregulated in Hela-TR and SiHa-TR cells. Results of western blot analysis, luciferase assays and bioinformatics proved that c-FLIP was the target of miR-126. Furthermore, as c-FLIP is the cellular antagonist to caspase-8, transfection with miR-126 promoted the activation of caspase-8 induced by TRAIL. As a result, miR-126 increased the TRAIL-induced apoptosis in Hela-TR and SiHa-TR cells. In addition, miR-126 was also able to increase the cytotoxicity of TNF-α and FasL (caspase-8 inducers) to Hela-TR and SiHa-TR. We demonstrate that miR-126 impairs drug resistance to TRAIL, TNF-α and FasL through inhibiting the expression of c-FLIP in cervical cancer.

Learning Curve and Clinical Outcomes of Performing Surgery with the InterTan Intramedullary Nail in Treating Femoral Intertrochanteric Fractures.

Purpose. The purpose of this study is to evaluate the learning curve of performing surgery with the InterTan intramedullary nail in treating femoral intertrochanteric fractures, to provide valuable information and experience for surgeons who decide to learn a new procedure. Methods. We retrospectively analyzed data from 53 patients who underwent surgery using an InterTan intramedullary nail at our hospital between July 2012 and September 2015. The negative exponential curve-fit regression analysis was used to evaluate the learning curve. According to 90% learning milestone, patients were divided into two group, and the outcomes were compared. Results. The mean operative time was 69.28 (95% CI 64.57 to 74.00) minutes; with the accumulation of surgical experience, the operation time was gradually decreased. 90% of the potential improvement was expected after 18 cases. In terms of operative time, intraoperative blood loss, hospital stay, and Harris hip score significant differences were found between two groups (p = 0.009, p = 0.000, p = 0.030, and p = 0.002, resp.). Partial weight bearing time, fracture union time, tip apex distance, and the number of blood transfusions and complications were similar between two groups (p > 0.5). Conclusion. This study demonstrated that the learning curve of performing surgery with the InterTan intramedullary nail is acceptable and 90% of the expert's proficiency level is achieved at around 18 cases.

Antibacterial property and biocompatibility of Chitosan/Poly(vinyl alcohol)/ZnO (CS/PVA/ZnO) beads as an efficient adsorbent for Cu(II) removal from aqueous solution.

The feasibility of using chitosan/Poly(vinyl alcohol)/ZnO beads (CS/PVA/ZnO) as an adsorbent for removal of Cu(II) ions from aqueous solutions was studied in a batch method. The developed adsorbent material was characterized by XRD, FTIR, SEM and TEM analysis. Pure ZnO shows the characteristic peaks at (100), (002), (101), (102), (110), (103), (200) and (112) that were in good agreement with wurtzite ore having hexagonal lattice structure. Antibacterial properties and biocompatibility of the CS/PVA/ZnO was tested. CS/PVA/ZnO showed strong antibacterial property as well as it was biocompatible. The antibacterial activity of CS/PVA/ZnO against Escherichia coli, and Staphylococcus aureus were evaluated with the zone of inhibition method. The effect of various process variables such as solution pH, adsorbent dose, contact time, initial metal ion concentration, and temperature was investigated. The adsorption kinetic data was fitted well with the pseudo-second-order model. Langmuir and Freundlich isotherm models were used to analyze the equilibrium data. Langmuir model showed better correlation to the experimental data compared to Freundlich model. Different thermodynamic parameters namely, Gibbs free energy, enthalpy and entropy changes were also evaluated from the temperature dependence, and the results suggested that the sorption of Cu(II) onto CS/PVA/ZnO is spontaneous and endothermic in nature. The maximum adsorption capacity of CS/PVA/ZnO was found to be 90.90 at pH 4.5 and indicated that developed material could be effectively utilized for the removal of Cu(II) ions from aqueous environment.

Antibacterial and wound healing properties of chitosan/poly(vinyl alcohol)/zinc oxide beads (CS/PVA/ZnO).

Treatment against bacterial infection is crucial for wound healing. Development of cost-effective antibacterial agent with wound healing properties is still in high demand. In this study we aimed to design chitosan/poly(vinyl alcohol)/zinc oxide (CS/PVA/ZnO) beads as novel antibacterial agent with wound healing properties. CS/PVA/ZnO beads were synthesized, and characterized by using XRD, FTIR, SEM, and TEM analysis. Pure chitosan exhibits two peaks at 2θ=10 and 20 and the CS/PVA polymer matrix exhibit the peaks at 2θ=19.7° and another of low intensity at 2θ=11.5°. Pure ZnO shows the characteristic peaks at (100), (002), (101), (102), (110), (103), (200), and (112) that were in good agreement with wurtzite ore having hexagonal lattice structure. The antibacterial activity of CS/PVA/ZnO against Escherichia coli, and Staphylococcus aureus were evaluated with the zone of inhibition method. Antibacterial activity of CS/PVA/ZnO was higher than that of chitosan (CS) and poly(vinyl alcohol (PVA). Hemocompatibility and biocompatibility of CS/PVA/ZnO were tested in in vitro. Wound healing properties of CS/PVA/ZnO were tested in mice skin wound. CS/PVA/ZnO showed strong antimicrobial, wound healing effect, hemocompatibility and biocompatibility. Hence the results strongly support the possibility of using this novel CS/PVA/ZnO material for the anti bacterial and wound healing application.

Clinical Pharmacokinetics of Vemurafenib.

Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF V600 mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant. Population pharmacokinetic analysis identified a vemurafenib half-life of ≈57 h and elimination appears to be predominantly via the hepatic route. Pharmacokinetic parameters are generally consistent regardless of age, sex or race. No dose adjustments are necessary for patients with mild or moderate hepatic or renal impairment, but the effects of severe hepatic or renal impairment on vemurafenib pharmacokinetics are uncertain. Vemurafenib appears to be a substrate and inducer of cytochrome P450 (CYP) 3A4, a moderate inhibitor of CYP1A2 and both a substrate and inhibitor of the drug efflux transporters P-glycoprotein and breast cancer resistance protein. The relationship between plasma vemurafenib concentrations and response remains to be clarified.