Blockade of STAT3 Signaling Contributes to Anticancer Effect of 5-Acetyloxy-6,7,8,4'-Tetra-Methoxyflavone, a Tangeretin Derivative, on Human Glioblastoma Multiforme Cells.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4'-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment.

Development and verification of a novel bone collector with automatic size separating function for orthopedics surgery.

BACKGROUND: Autologous bone dust can be filled in bone defects to promote effective bone healing but typically it is lost when using suction during surgery. The aim of this study was to develop a novel bone collector that can be used to collect bone chips/dust of varying sizes without changing current surgical procedures. RESEARCH DESIGN AND METHODS: This collector was designed to connect to a surgical continuous suction system and comprised a plate filter with a 3 mm hole and featured a taper filter with a mesh size of 0.27 mm for the separation and collection of both coarse and fine bone chips/dust. The bone collector was manufactured using nylon 3D printing and plastic injection with biocompatible materials. RESULTS: The bone collector functional test revealed high bone chip collection efficiency (93%) with automatic size separation function. Low (3.42%) filtration errors showed that most of the water can be drained smoothly from the bone collector. In clinical usability testing, bone collectors can provide functions demonstrated in in vivo spinal fusion and femoral fracture surgeries with different bone grafting size requirements. CONCLUSIONS: The novel bone collector has been validated as a viable and effective surgical device, offering surgeons an additional option to enhance patient outcomes.

Selective modulation of MHC class II chaperons by a novel IFN-γ-inducible class II transactivator variant in lung adenocarcinoma A549 cells.

Class II transactivator (CIITA) plays a critical role in controlling major histocompatibility complex (MHC) class II gene expression. In this study, two novel alternatively spliced variants of human interferon (IFN)-γ-inducible CIITA, one missing exon 7 (CIITAΔE7), the other with TAG inserted at exon 4/5 junction (CIITA-TAG), were identified and characterized. Both variants are naturally occurring since they are present in primary cells. Unlike CIITA-TAG, CIITAΔE7 is expressed more abundantly in lung adenocarcinoma A549 cells than in the non-transformed counterpart BEAS-2B cells following IFN-γ stimulation. Transfection experiments showed that CIITAΔE7 induced a markedly lower level of surface HLA-DR, -DP, -DQ expression than CIITA-TAG in A549 cells but not in BEAS-2B cells, although both variants elicited similar amounts of total DR, DP, and DQ proteins. This differential effect was correlated with, in A549 cells, decreased expression of Ii and HLA-DM genes, along with increased expression of HLA-DO genes. Ii and HLA-DM are chaperons assisting in HLA class II assembly, while HLA-DO functions to inhibit endosomal peptide loading and HLA class II membrane transport. These findings raise the possibility that CIITAΔE7 interacts with unknown cancer-associated factors to selectively modulate genes involved in the assembly and transport of HLA class II molecules.

Cytokeratin 8-MHC class I interactions: a potential novel immune escape phenotype by a lymph node metastatic carcinoma cell line.

Defective human leukocyte antigen (HLA) class I expression in malignant cells facilitates their escape from destruction by CD8(+) cytotoxic T lymphocytes. In this study, a post-translational mechanism of HLA class I abnormality that does not involve defects in the HLA subunits and antigen processing machinery components was identified and characterized. The marked HLA class I downregulation phenotype of a metastatic carcinoma cell line can be readily reversed by trypsin, suggesting a masking effect by serine protease-sensitive HLA class I-interacting factors. Co-immunoprecipitation, combined with LC-tandem mass spectrometry and immunoblotting identified these factors as cytokeratin (CK) 8 and its heterodimeric partners CK18 and CK19. Ectopic CK8/18 or CK8/19 expression in HEK293 cells resulted in surface CK8 expression with an HLA class I downregulation phenotype, while redirecting CK8/18 and CK8/19 to the endoplasmic reticulum (ER) had no such effect. This observation and the failure to constrain CK8/18 and CK8/19 membrane trafficking by an ER-Golgi transport inhibitor suggested an ER-independent route for CK8 access to HLA class I molecules. Monoclonal antibody mapping revealed a potential CK8 blockade of HLA class I-CD8 and -TCR contacts. These findings, along with the emerging role of cell surface CK8 in cancer metastasis, may imply a dual strategy for tumor cell survival in the host.

Strategies to reduce nonurgent emergency department use: experience of a Northern Virginia Employer Group.

BACKGROUND: This administrative claims analysis evaluated the impact of a health plan-sponsored Emergency Room Utilization Management Initiative (ERUMI), which combined increased patient copays for ED visits with educational outreach to reduce inappropriate ED use and encourage use of retail health clinics (RHCs) and other alternative treatment sites among a commercially insured population. METHODS: Emergency department (ED) utilization rates for select acute but nonurgent conditions that could be treated appropriately in an RHC were compared for members of an employer group with (intervention group) and without (comparators) ERUMI. Utilization was compared for baseline period (January-June 2009) and ERUMI implementation period (January-June 2010). RESULTS: A total of 56,896 members (14,224 intervention, 42,672 matched comparators) were included. ED utilization for conditions that could be treated appropriately by RHCs decreased by 10.39 visits/1000 members in the intervention group versus 6.29 visits in comparators. RHC visits rose for both the groups, with a greater increase in the intervention group (22.61 visits/1000 members, P<0.001) versus comparison (1.64/1000, P=0.064). After ERUMI implementation, intervention group members were nearly 5 times more likely than comparators to choose RHCs over ED for nonurgent care. CONCLUSIONS: The health plan-sponsored ERUMI program, consisting of both financial and educational components, decreased nonurgent ED utilization while increasing the use of alternative treatment sites.

Design of a patient-specific mandible reconstruction implant with dental prosthesis for metal 3D printing using integrated weighted topology optimization and finite element analysis.

The aim of this study was used a weighted topology optimization method to design a patient-specific mandibular implant for reconstruction and restoration of appearance in patients with severe mandibular defects. A finite element (FE) model was constructed and the defect region was defined from the unilateral first premolar to the second molar. The reconstruction implant included main body, fixation wing and dental prosthesis. Standard topology optimization was performed using stress constraint to identify optimal fixation wing structure (denoted as WOS) with solid core main body. Two independent optimal main body with internal beam supporting structures defined as WOSA and WOSO optimized from the WOS model under axial and oblique conditions were then obtained, respectively. Final optimal model (WBOS) was generated using a weighted topology optimization that considered 60% and 40% contributions of WOSA and WOSO models, respectively. The WBOS model was fabricated using metal 3D printing and fixed on the resting acrylonitrile butadiene styrene (ABS) bone to perform fracture testing. Stress concentration were found in the upper area connected to the main body of the mesial wing and corresponding maximum values under axial/oblique loads were reduced from 778/925 MPa of the WOS model to 764/720 MPa of the WBOS model. The reduction in percentage variations of weight between original (91.1 g) and final optimal (24.5 g) models was 73.14% for fabricated 3D printing models. The WBOS model also exhibited a higher resistant force (2163 N) when compared with the original model (1678 N). This study developed a design strategy with weighted topology optimization and fabrication for producing patient-specific implants using metal 3D printing. The obtained reconstruction implant can provide good biomechanical performance and recovery of appearance for oral rehabilitation.

Price and quality transparency: how effective for health care reform?

Many in Minnesota and the United States are promoting price and quality transparency as a means for reforming health care. The assumption is that with such information, consumers and providers would be motivated to change their behavior and this would lead to lower costs and higher-quality care.This article attempts to determine the extent to which publicizing information about the cost and quality of medical care does, in fact, improve quality and lower costs, and thus should be included in any reform strategy. The authors reviewed a number of studies and concluded that there is a general lack of empirical evidence on the effect of price transparency on health care costs and that the evidence on the effectiveness of quality transparency is mixed.

Medicare's Physician Quality Reporting System (PQRS): quality measurement and beneficiary attribution.

PURPOSE: To explore two issues that are relevant to inclusion of PQRS reporting in a value-based payment system: (1) what are the characteristics of PQRS reports and the providers who file them; and (2) could PQRS provide active attribution information to supplement existing attribution algorithms? DESIGN AND METHODS: Using data from five states for the years 2008 (the first full year of the program) and 2009, we examined the number and type of providers who reported PQRS measures and the types of measures that were reported. We then compared the PQRS reporting provider to the provider who supplied the plurality of the beneficiary's non-hospital evaluation and management (NH-E&M) visits. RESULTS: Although PQRS-reporting providers provide only 17 percent of the beneficiary's NH-E&M visits on average in 2009, the provider who provided the plurality of visits supplied only 50 percent of such visits, on average. IMPLICATIONS: PQRS reporting alone cannot solve the attribution problem that is inherent in traditional fee-for-service Medicare, but as PQRS participation increases, it could help improve both attribution and information regarding the quality of health care services delivered to Medicare beneficiaries.

CT scan utilization patterns in pediatric patients with recurrent headache.

UNLABELLED: Although unnecessary for children with headache and normal history, computed tomography (CT) scans are widely used. This study sought to determine current practice patterns of neuroimaging to diagnose pediatric headache in a variety of treatment settings and to identify factors associated with increased use of neuroimaging. METHODS: This retrospective claims analysis included children (aged 3­17 years) with ≥2 medical claims for headache. The primary outcome was CT scan utilization on or after first presentation with headache in a physician's office or emergency department (ED). RESULTS: Of 15 836 patients, 26% (4034 patients; mean age: 11.8 years) had ≥1 CT scan, 74% within 1 month of index diagnosis. Patients with ED visits were 4 times more likely to undergo a CT scan versus those without ED visits (P < .001 [95% confidence interval: 3.9­4.8]). However, even outside the ED, use of CT scans remained widespread. Two-thirds of patients with CT scans had no ED use.Among patients with no ED utilization, >20% received a CT scan during the study period. Evaluation by a neurologist was strongly associated with a lower likelihood of CT scan compared with other provider specialties (odds ratio: 0.37; P < .01 [95% confidence interval: 0.30­0.46]). CONCLUSIONS: Use of CT scans to diagnose pediatric headache remains high despite existing guidelines, low diagnostic yield, and high potential risk. Implementing quality improvement initiatives to ensure that CT scans in children are performed only when truly indicated will reduce unnecessary exposure to ionizing radiation and associated cancer risks.

Impact of medical homes on quality, healthcare utilization, and costs.

OBJECTIVES: To assess baseline quality metrics, healthcare utilization, and costs of commercially insured patients treated at practices participating in a patient-centered medical home (PCMH) pilot. STUDY DESIGN: Observational cohort study utilizing claims data for patients treated at PCMH and non-PCMH practices. METHODS: Data from Empire Blue Cross and Blue Shield, 1 of 14 plans in the HealthCore Integrated Research Database, were queried for patients identified based on visits to PCMH and non-PCMH practices during 2007-2008; outcome metrics were formulated from the baseline calendar year, 2009. Differences in healthcare utilization were determined with x(2) and 2-sample t tests. Regression models were used to test differences in adjusted emergency department (ED) use, inpatient services, and costs. RESULTS: The study included 31,032 PCMH and 350,015 non-PCMH patients. Among PCMH-treated patients, diabetics had higher rates of glycated hemoglobin testing; cardiovascular disease patients had higher rates of testing and better low-density lipoprotein cholesterol control; imaging rates for low back pain were lower; among pediatric patients, inappropriate antibiotic use for nonspecific or viral respiratory infections was lower. PCMH-treated adults and children had 12% and 23% lower odds of hospitalization, and required 11% and 17% fewer ED services, respectively, than non-PCMH patients. Risk-adjusted total per member per month costs were 8.6% and 14.5% lower for PCMH-treated pediatric and adult patients, respectively (P <.01). CONCLUSIONS: PCMH practices in this pilot were associated with better preventive health, higher levels of disease management, and lower resource utilization and costs in 2009 compared with practices not pursuing PCMH status.