Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

Keratin 6A (KRT6A) promotes radioresistance, invasion, and metastasis in lung cancer via p53 signaling pathway.

BACKGROUND: It is reported that the incidence rate and mortality of lung cancer are very high. Therefore, early diagnosis and identification of specific biomarkers are crucial for the clinical treatment of lung cancer. This study aims to comprehensively investigate the prognostic significance of KRT6A in human lung cancer. METHODS: The GEO2R online tool was utilized to analyze the differential expression of mRNA between lung carcinoma tissues and radioresistant tissues in the GSE73095 and GSE197236 datasets. DAVID database was used to perform GO and KEGG enrichment analyses on target genes. The Kaplan-Meier plotter tool was used to analyze the impact of key messenger ribonucleic acid on the survival status of lung cancer. In addition, quantitative real-time polymerase chain reaction (qPCR) was used to investigate the impact of key genes on the phenotype of lung cancer cells. After the knockout, we conducted cell migration and CCK-8 experiments to detect their effects on cell proliferation and invasion. RESULTS: 40 differentially expressed genes (DEGs) were chosen from GSE73095 and 118 DEGs were chosen from GSE197236. Kaplan-Meier map analysis showed that the overall cancer survival rate of the high-expression KRT6A group was higher than that of the low-expression group (P < 0.05). Besides, cell experiments have shown that when the KRT6A gene is downregulated, the proliferation and invasion ability of lung cancer cells is weakened. CONCLUSIONS: Our research concluded that KRT6A may take part in the radioresistance and progression of lung cancer and can be a potential biomarker for lung cancer patients.

Total flavonoids of Broussonetia papyrifera alleviate non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signaling pathways.

BACKGROUNDS: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. The leaves of Broussonetia papyrifera contain a large number of flavonoids, which have a variety of biological functions. METHODS: In vitro experiments, free fatty acids were used to stimulate HepG2 cells. NAFLD model was established in vivo in mice fed with high fat diet (HFD) or intraperitoneally injected with Tyloxapol (Ty). At the same time, Total flavonoids of Broussonetia papyrifera (TFBP) was used to interfere with HepG2 cells or mice. RESULTS: The results showed that TFBP significantly decreased the lipid accumulation induced by oil acid (OA) with palmitic acid (PA) in HepG2 cells. TFBP decreased the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDLC) in serum. TFBP could also effectively inhibit the generation of reactive oxygen species (ROS) and restrained the level of myeloperoxidase (MPO), and enhance the activity of superoxide dismutase (SOD) to alleviate the injury from oxidative stress in the liver. Additionally, TFBP activated nuclear factor erythroid-2-related factor 2 (Nrf2) pathway to increasing the phosphorylation of AMP-activated protein kinase (AMPK). Meanwhile, protein levels of mTORC signaling pathway were evidently restrained with the treatment of TFBP. CONCLUSION: Our experiments proved that TFBP has the therapeutic effect in NAFLD, and the activation of Nrf2 and AMPK signaling pathways should make sense.

A carboxy-terminal ubiquitylation site regulates androgen receptor activity.

Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition, but this is associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiquitylases. We then identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methylation sites and previously identified phosphorylation sites. Mutagenesis of K911 increases AR stability, chromatin binding, and transcriptional activity. We further found that K313, a previously reported ubiquitylation site, could also be methylated and acetylated. Mutagenesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications at K313 differentially regulate AR activity. Together these studies expand the spectrum of AR posttranslational modifications, and indicate that the K911 site may regulate AR turnover on chromatin.

Peri-zygomatic complications on zygomatic implants with or without penetrating the external surface of zygoma: A 2-year retrospective study.

OBJECTIVES: The main purpose of this retrospective study was to assess the difference in the incidence of peri-zygomatic complications (PZCs) when zygomatic implants (ZIs) penetrate or do not penetrate the external surface of zygoma. MATERIALS AND METHODS: This study included 32 patients with edentulous maxillae or potentially edentulous maxillae undergo zygomatic implantation. The patients were divided into the penetration group (P-group) and the non-penetration group (N-group) according to whether the apex of implants penetrated the external surface of zygoma in postoperative CBCT. The extension length, the penetration section of the implants, and the skin thickness at the corresponding position were simultaneously measured. Clinical follow-up was conducted regularly until 2 years after surgery. The occurrence of PZCs (including peri-zygomatic infection, skin numbness, non-infectious pain, and foreign body sensation) was recorded. A mixed effect logistic model was used to compare the difference of complication rate between the P-group and the N-group, and odds ratio (OR) was calculated. Then identify the impact of the extension length, penetration section and skin thickness in P-group with the same model. RESULTS: A total of 71 ZIs were implanted in 32 patients, including 37 implants in the P-group and 34 implants in the N-group. During the 2-year follow-up, a total of 13 implants occurred PZCs, with an overall complication rate of 18.3%. Thereinto, the incidence rate was 29.7% in the P-group, and 5.9% in the N-group (OR = 6.77). In P-group, there was a significant difference in complication rate of different extension lengths, while the penetration section and skin thickness had no statistical significance on the complication rate. CONCLUSION: Under the limitation of this study, to minimize the risk of PZCs, ZI should be placed in a manner that avoids the apex penetrating the external surface of the zygoma.

Molecular mechanism of Xiaohuoluo wan for rheumatoid arthritis by integrating in vitro and in vivo chemomics and network pharmacology.

The cause of rheumatoid arthritis (RA) is unclear. Xiaohuoluo wan (XHLW) is a classical Chinese medicine that is particularly effective in the treatment of RA. Given the chemical composition of XHLW at the overall level has been little studied and the molecular mechanism for the treatment of RA is not clear, we searched for the potential active compounds of XHLW and explored their anti-inflammatory mechanism in the treatment of RA by flexibly integrating the high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based in vitro and in vivo chemomics, network pharmacology, and other means. The results of the study identified that the active compounds of XHLW, such as alkaloids, nucleosides, and fatty acids, may play an anti-inflammatory role by regulating key targets such as IL-2, STAT1, JAK3, and MAPK8, inducing immune response through IL-17 signaling pathway, T-cell receptor, FoxO, tumor necrosis factor (TNF), and so forth, inhibiting the release of inflammatory factors and resisting oxidative stress and other pathways to treat RA. The results of this study provide referable data for the screening of active compounds and the exploration of molecular mechanisms of XHLW in the treatment of RA.

Segmental disturbance of white matter microstructure in predicting mild cognitive impairment in idiopathic Parkinson's disease: An individualized study based on automated fiber quantification tractography.

PURPOSE: The neurobiological mechanisms and an early identification of MCI in idiopathic Parkinson's disease (IPD) remain unclear. To investigate the abnormalities of types of white matter (WM) fiber tracts segmentally and establish reliable indicator in IPD-MCI. METHODS: Forty IPD with normal cognition (IPD-NCI), thirty IPD-MCI, and thirty healthy controls were included. Automated fiber quantification was applied to extract the fractional anisotropy (FA) and mean diffusivity (MD) values at 100 locations along the major fibers. Partial correlation was performed between diffusion values and cognitive performance. Furthermore, machine learning analyses were conducted to determine the imaging biomarker of MCI. Permutation tests were performed to evaluate the pointwise differences under the FWE correction. RESULTS: IPD-MCI had similar but more severe and widespread WM degeneration in the association, projection, and commissural fibers compared with IPD-NCI. Meanwhile, IPD-MCI showed distinct degeneration pattern in the association fibers. The FA of the anterior segment of right inferior fronto-occipital fasciculus (IFOF) was positively correlated with MoCA (P < 0.05) and executive function (P < 0.05). The MD of the middle and posterior segment of left superior longitudinal fasciculus (SLF) was negatively correlated with MoCA P < 0.05), executive (P < 0.05), visuospatial function (P < 0.05). Furthermore, the AUC of support vector machine model was 0.80 in the validation dataset. The FA of anterior segment of right IFOF contribute the most. CONCLUSION: This study demonstrated that regional tract-specific microstructural degeneration, especially the association fibers, can be used to predict MCI in IPD. Especially, the right IFOF may be a significant imaging biomarker in predicting IPD with MCI.

Accuracy assessment of implant placement with versus without a CAD/CAM surgical guide by novices versus specialists via the digital registration method: an in vitro randomized crossover study.

BACKGROUND: Many studies demonstrated that surgical guides might reduce discrepancies compared with freehand implant placement. This randomized crossover study aimed to assess the effects of approaches, practitioners' experience and learning sequences on the accuracy of single tooth implantation via digital registration method. No similar study was found. METHODS: This in vitro randomized crossover study enrolled 60 novice students (Group S) and 10 experienced instructors (Group I). Sixty students were randomly and evenly assigned to two groups (Group SA and SB). In Group SA, 30 students first performed single molar implant on a simulation model freehand (Group SAFH), and then with a CAD/CAM surgical guide (Group SASG). In Group SB, another 30 students first performed guided (Group SBSG) and then freehand (Group SBFH). Ten instructors were also divided into Group IAFH/IASG (n = 5) and IBSG/IBFH (n = 5) following the same rules. The accuracy of implant placement was assessed by the coronal and apical distance (mm) and angular (°) deviations using the digital registration method. T tests and nonparametric tests were used to compare the results among different groups of approaches, experience and sequences. RESULTS: For students, the coronal and apical distance and the angular deviations were significantly lower in surgical guide group than freehand group in total and in learning freehand first subgroup, but for learning surgical guide first subgroup the apical distance deviation showed no significant difference between two approaches. For students, the angular deviation of freehand group was significantly lower in learning surgical guide first group than learning freehand first group. For instructors, the coronal and apical distance and angular deviations showed no significant difference between two approaches and two sequences. For freehand approach, the coronal and apical distance and the angular deviations were significantly higher in student group than instructor group, while not significantly different between two groups for surgical guide approach. CONCLUSIONS: For novices, using a surgical guide for the first implant placement may reduce the potential deviations compared with freehand surgery, and may reach a comparable accuracy with that of specialists. For simple single molar implantation, the surgical guide may not be significantly helpful for experienced specialists.

Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease.

Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.

The expression profiles of circular RNAs and competing endogenous RNA networks in intrahepatic cholangiocarcinoma.

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse etiologies, morphologies, and clinical outcomes, but our knowledge of its epidemiology and carcinogenesis is very limited. Materials and methods: The expression patterns of circRNAs were explored in iCCA tissues and corresponding adjacent normal ones, denoted by (iCCA) and (iCCAP), respectively, using high-throughput sequencing. Results: A total of 117 differential expressed (DE) circRNAs were identified. Based on the parental transcripts of circRNAs, these DE circRNAs were related to several important GO terms and were enriched in important pathways. Two circRNA-mediated ceRNA networks were constructed and many important metabolic pathways related to mRNAs were regulated by DE circRNAs via miRNAs. Conclusion: Our study revealed the DE circRNAs in the iCCA tissues compared with iCCAP ones, suggesting that circRNAs may play crucial roles in the pathogenesis of iCCA.

A triple-classification for differentiating renal oncocytoma from renal cell carcinoma subtypes and CK7 expression evaluation: a radiomics analysis.

BACKGROUND: To investigate the value of computed tomography (CT)-based radiomics model analysis in differentiating renal oncocytoma (RO) from renal cell carcinoma subtypes (chromophobe renal cell carcinoma, clear cell carcinoma) and predicting the expression of Cytokeratin 7 (CK7). METHODS: In this retrospective study, radiomics was applied for patients with RO, chRCC and ccRCC who underwent surgery between January 2013 and December 2019 comprised the training cohort, and the testing cohort was collected between January and October 2020. The corticomedullary (CMP) and nephrographic phases (NP) were manually segmented, and radiomics texture parameters were extracted. Support vector machine was generated from CMP and NP after feature selection. Shapley additive explanations were applied to interpret the radiomics features. A radiomics signature was built using the selected features from the two phases, and the radiomics nomogram was constructed by incorporating the radiomics features and clinical factors. Receiver operating characteristic curve was calculated to evaluate the above models in the two sets. Furthermore, Rad-score was used for correlation analysis with CK7. RESULTS: A total of 123 patients with RO, chRCC and ccRCC were analyzed in the training cohort and 57 patients in the testing cohort. Subsequently, 396 radiomics features were selected from each phase. The radiomics features combining two phases yielded the highest area under the curve values of 0.941 and 0.935 in the training and testing sets, respectively. The Pearson's correlation coefficient was statistically significant between Rad-score and CK7. CONCLUSION: We proposed a non-invasive and individualized CT-based radiomics nomogram to differentiation among RO, chRCC and ccRCC preoperatively and predict the immunohistochemical protein expression for accurate clinical diagnosis and treatment decision.

Multimodal striatal neuromarkers in distinguishing parkinsonian variant of multiple system atrophy from idiopathic Parkinson's disease.

AIMS: To develop an automatic method of classification for parkinsonian variant of multiple system atrophy (MSA-P) and Idiopathic Parkinson's disease (IPD) in early to moderately advanced stages based on multimodal striatal alterations and identify the striatal neuromarkers for distinction. METHODS: 77 IPD and 75 MSA-P patients underwent 3.0 T multimodal MRI comprising susceptibility-weighted imaging, resting-state functional magnetic resonance imaging, T1-weighted imaging, and diffusion tensor imaging. Iron-radiomic features, volumes, functional and diffusion scalars of bilateral 10 striatal subregions were calculated and provided to the support vector machine for classification RESULTS: A combination of iron-radiomic features, function, diffusion, and volumetric measures optimally distinguished IPD and MSA-P in the testing dataset (accuracy 0.911 and area under the receiver operating characteristic curves [AUC] 0.927). The diagnostic performance further improved when incorporating clinical variables into the multimodal model (accuracy 0.934 and AUC 0.953). The most crucial factor for classification was the functional activity of the left dorsolateral putamen. CONCLUSION: The machine learning algorithm applied to multimodal striatal dysfunction depicted dorsal striatum and supervening prefrontal lobe and cerebellar dysfunction through the frontostriatal and cerebello-striatal connections and facilitated accurate classification between IPD and MSA-P. The dorsolateral putamen was the most valuable neuromarker for the classification.

A triple-classification for the evaluation of lung nodules manifesting as pure ground-glass sign: a CT-based radiomic analysis.

OBJECTIVES: To construct a noninvasive radiomics model for evaluating the pathological degree and an individualized treatment strategy for patients with the manifestation of ground glass nodules (GGNs) on CT images. METHODS: The retrospective primary cohort investigation included patients with GGNs on CT images who underwent resection between June 2015 and June 2020. The intratumoral regions of interest were segmented semiautomatically, and radiomics features were extracted from the intratumoral and peritumoral regions. After feature selection by ANOVA, Max-Relevance and Min-Redundancy (mRMR) and Least Absolute Shrinkage and Selection Operator (Lasso) regression, a random forest (RF) model was generated. Receiver operating characteristic (ROC) analysis was calculated to evaluate each classification. Shapley additive explanations (SHAP) was applied to interpret the radiomics features. RESULTS: In this study, 241 patients including atypical adenomatous hyperplasia (AAH) or adenocarcinoma in situ (AIS) (n = 72), minimally invasive adenocarcinoma (MIA) (n = 83) and invasive adenocarcinoma (IAC) (n = 86) were selected for radiomics analysis. Three intratumoral radiomics features and one peritumoral feature were finally identified by the triple RF classifier with an average area under the curve (AUC) of 0.960 (0.963 for AAH/AIS, 0.940 for MIA, 0.978 for IAC) in the training set and 0.944 (0.955 for AAH/AIS, 0.952 for MIA, 0.926 for IAC) in the testing set for evaluation of the GGNs. CONCLUSION: The triple classification based on intra- and peritumoral radiomics features derived from the noncontrast CT images had satisfactory performance and may be used as a noninvasive tool for preoperative evaluation of the pure ground-glass nodules and developing of individualized treatment strategies.

A First-in-Human Phase 1 Study of a Novel Selective Androgen Receptor Modulator (SARM), RAD140, in ER+/HER2- Metastatic Breast Cancer.

INTRODUCTION/BACKGROUND: This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM). PATIENTS AND METHODS: This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement. RESULTS: Twenty-two (21 AR+) heavily pretreated mBC patients were enrolled. Dose levels included 50 mg (n = 6), 100 mg (n = 13), and 150 mg (n = 3) once daily (QD). Most frequent (> 10%) treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each). Grade 3/4 TEAEs occurred in 16 (72.7%) patients and included elevations in AST/ALT and hypophosphatemia (22.7% each). Treatment-related TEAEs occurred in 17 per 22 patients (77.3%); 7 (31.8%) were Grade 3; none were Grade 4. The half-life (t1/2) of 44.7 hours supported QD dosing. At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response. Overall, clinical benefit rate at 24 weeks was 18.2%, and median progression-free survival was 2.3 months. SHBG decreased in 18 per 18 patients, and PSA increased in 16 per 20 patients. Paired baseline and on-treatment tumor biopsies demonstrated AR engagement. CONCLUSION: RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

LncRNA NUTM2A-AS1 positively modulates TET1 and HIF-1A to enhance gastric cancer tumorigenesis and drug resistance by sponging miR-376a.

Long noncoding RNA NUTM2A-AS1 has been shown to be dysregulated in non-small cell lung carcinoma. To date, it is unclear whether NUTM2A-AS1 plays a role in gastric cancer progression. The purpose of this study is to elucidate the molecular mechanism of the role of NUTM2A-AS1 in gastric cancer. mRNA and protein levels were measured by RT-qPCR and western blot methods. Invasion ability was examined by transwell assay. Cell viability was determined by MTT assay. Dual-luciferase assay, RNA pull down, and RNA immunoprecipitation were used to confirm direct binding of between miR-376a and NUTM2A-AS1 or TET1. Xenografting tumor assay and TCGA analysis showed the contributory role of NUTM2A-AS1 in vivo and human clinical setting. Our results suggested that NUTM2A-AS1 promoted cell viability, invasion, and drug resistance of gastric cancer cells, which was largely rescued by miR-376a. More interestingly, TET1 and HIF-1A were negatively regulated by miR-376a. TET1 could interact with HIF-1A to modulate PD-L1. Finally, we revealed that PD-L1 was key to NUTM2A-AS1- and miR-376a-mediated tumorigenesis and drug resistance. In summary, our conclusions facilitate us understand the underlying mechanism and develop novel treatment strategy for gastric cancer.

Fabrication of ZnO/Carbon Quantum Dots Composite Sensor for Detecting NO Gas.

ZnO and carbon quantum dots (CQDs) were synthesized by a hydrothermal method, and CQDs were doped into ZnO by a grinding method to fabricate a ZnO/CQDs composite. The X-ray diffraction and the scanning electron microscope revealed that the as-prepared ZnO has a structure of wurtzite hexagonal ZnO and a morphology of a flower-like microsphere which can provide more surface areas to adsorbed gases. The ZnO/CQDs composite has a higher gas sensitivity response to NO gas than ZnO microspheres. A gas sensitivity test of the ZnO/CQDs composite showed that the sensor had a high NO response (238 for 100 ppm NO) and NO selectivity. The detection limit of the ZnO/CQDs composite to NO was 100 ppb and the response and recovery times were 34 and 36 s, respectively. The active functional group provided by CQDs has a significant effect on NO gas sensitivity, and the gas sensitivity mechanism of the ZnO/CQDs composite is discussed.

Comparison between ultrasound-guided TIVAD via the right innominate vein and the right internal jugular vein approach.

BACKGROUND: To compare the efficacy and safety of right internal jugular vein (IJV) approach and right innominate vein (INV) approach for US-guided totally implantable venous access devices (TIVADs), and to explore the advantages and disadvantages of the two approaches. METHODS: Six hundred and nineteen adult patients had long-term infusion and chemotherapy needs and inconvenience of peripheral venous infusion. Right INV approach was used to implant 339 cases of TIVADs, and right IJV approach was used to implant 280 cases of TIVADs. The success rate of one-time catheterization and the incidence of complications in the two groups were retrospectively analyzed. RESULTS: All patients were successfully implanted in TIVAD. The success rates of one-time puncture in INV group and IJV approach group were 98.53% (334/339) and 95.36% (267/280), respectively. There was significant difference between the two groups (P = 0.020). The incidence of perioperative complications and long-term complications in the right INV group were 1.18% (4/339) and 3.54% (12/339), respectively, while those in the right IJV group were 1.43% (4280) and 3.93% (11280). There was no significant difference in the incidence of perioperative or long-term complications between the two groups (P = 0.785, P = 0.799, respectively). CONCLUSIONS: US-guided TIVADs via the right INV approach and the right IJV approach are both safe and reliable. The right INV approach improves the one-time puncture success rate, as long as the technique is properly operated, serious complications rarely occur.

Efficacy and safety of ultrasound-guided totally implantable venous access ports via the right innominate vein in adult patients with cancer: Single-centre experience and protocol.

BACKGROUND: Totally implantable venous access ports (TIVAPs) are widely used and are an essential tool in the efficient delivery of chemotherapy. This study aimed to evaluate the feasibility and safety of implantation of ultrasound (US)-guided TIVAPs via the right innominate vein (INV) for adult patients with cancer. METHODS: This study retrospectively reviewed the medical records of 283 adult patients with cancer who underwent US-guided INV puncture for TIVAPs between September 2015 and September 2017. It also analysed the technical success rate, operation time, and short-term and long-term surgical complications. RESULTS: Technical success was achieved in all patients (100%). The mean operation time was 28.31 ± 7.31 min (range: 23-39 min), and the puncture success rate for the first attempt was 99.30% (281/283). Minor complications included artery puncture during the operation in one patient, but no pneumothorax was encountered. The mean TIVAP time was 304.16 ± 42.54 days (range: 38-502 days). The rate of postoperative complications was 2.83% (8/283), including poor healing of the incision in one patient, catheter-related infections in three patients, port thrombosis in one patient, and fibrin sheath formation in three patients; no catheter malposition, pinch-off syndrome, catheter fracture, or other serious complications were observed. CONCLUSIONS: TIVAPs are widely employed for chemotherapy. The present study found that the novel approach of using US-guided INV puncture to implant TIVAPs in adult patients with cancer is both short-termly feasible and safe for long-term central venous access.

Manipulation of film quality and magnetic properties of CrO2 (100) films on TiO2 substrates with carrier gas and growth temperature.

High-quality CrO2 films were synthesized on TiO2 (100) substrates at different temperatures using the chemical vapor deposition method in argon or nitrogen atmosphere. It was found that the lower limit for the growth temperature of CrO2 films can be reduced to 310 or 300 °C when using Ar or N2 as the carrier gas, respectively. The quality of CrO2 film on TiO2 substrate can thus be improved by optimizing growth temperature in a much larger range (310-400 °C in Ar and 300-430 °C in N2, in contrast with 390-410 °C in O2), which is significant for the practical application of CrO2 films. The best film quality was achieved at 320 °C in either Ar or N2 atmosphere, at which CrO2 film has its narrowest orientation distribution and lowest roughness. Compared to films grown in O2, films grown in Ar were found to have larger saturation magnetizations (M s) and magnetic anisotropies, possibly due to numerous O vacancies. Films grown in N2 are actually N-doped films, and have lower M s than those grown in O2. The Curie temperature (T c) was also tuned by the carrier gas and growth temperature. Films grown in Ar or N2 generally have a higher T c value than those grown in O2. Furthermore, the thermal stability of the films was found to be remarkably improved when using N2 as the carrier gas.

Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action.

Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer.Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models.Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1 It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608-20. ©2017 AACR.