Testing Continuity between Versions 5.3.9 and 6.3.1 of Plaque Simulator for Planning Eye Plaque Brachytherapy Cases

The purpose of this study is to examine the challenges of accepting and commissioning a new treatment planning system for eye plaque brachytherapy. Currently Oregon Health and Science University (OHSU) utilizes v5.3.9 of the Plaque Simulator software to plan all of its eye plaque brachytherapy cases. However, v5.3.9 is no longer supported by its manufacturer, Eye Physics, LLC. OHSU is upgrading to a supported version of Plaque Simulator, v6.3.1. Prior to planning brachytherapy cases in v6.3.1 an investigation needs to be launched concerning the technical and dosimetric differences between v5.3.9 and v6.3.1. A study investigating the percent difference in doses to the prescription point, sclera, and tumor apex between v5.3.9 and v6.3.1 was created for 28 patients who had undergone eye plaque brachytherapy during 2015 and 2016 at OHSU. The sample size was distributed evenly across five out of seven of the Collaborative Ocular Melanoma Study (COMS) non– notched plaques (n=5 for each plaque size) with a smaller sample size for the notched COMS 20 plaque (n=3). Doses to the prescription point, sclera, and tumor apex were compared to treatment plans created in v5.3.9 and v6.3.1. Acceptance of v6.3.1 requires that the percent difference between its results and v5.3.9 are less than 5%. The prescription point percent differences between v5.3.9 and v6.3.1 were 0% for all (28 out of 28) cases. The sclera doses were between 2–4% lower in v6.3.1 than v5.3.9 for 93% (26 out of 28) cases; the remaining two cases (Trials 24 and 26) had percent differences of –5.21% and –6.22%, respectively. The tumor apex percent differences were less than 1% for 89% (25 out of 28) of cases and less than 1.5% for the remaining three cases. Dosimetric differences between v5.3.9 and v6.3.1 are attributed to the change in the carrier factor correction data set used to calculate the attenuation of radiation via the Silastic insert of the COMS plaque. The percent differences for carrier factor correction between the outer (r=2 mm) and inner (r=3 mm) sclera are –3.36% and – 1.82%, respectively. The carrier factor corrections in v6.3.1 are from Chiu Tsao et al. 1993 for I–125 seed model 6711. It is recommended that the data set from Chiu Tsao et al. 1993 be adopted until a more suitable data set is found. The effect of planning cases based on the true location of the tumor within the eye (3D planning) versus planning to the apex of the tumor (1D planning) were examined in v6.3.1. The same patient data was used as in the comparison between v5.3.9 and v6.3.1, but the tumors locations were moved. A best guess was made as to the location of the tumor based on physician notes and fundus images. The purpose of this study was to establish proof of concept. The doses to the prescription point remained unchanged for 1D versus 3D planning. Doses to the sclera were unchanged for 75% (21 out of 28) of cases. Of the cases where dose changed between 1D and 3D planning, the percent difference was no greater than 0.06% to the sclera. Doses to the tumor apex remained unchanged for 93% (26 out of 28) cases. The cases that saw a change in tumor apex only saw a percent difference of 0.1% and 0.01%, respectively. Doses to the prescription point, sclera, and tumor apex are negligible and do not affect the quality of care. Although 3D planning requires an additional time commitment from the physicist or dosimetrist, proof of concept has been established and is recommended for estimating normal tissue doses

The Relationship of Demographic Variables and the Utilization of Personnel Resources and Services By Fifth Grade Public School Students.

Public school children's steadily increasing need for special supportive help is indicated by federal and state statutes (P. L. 198, Michigan and P. L. 94-142, Federal). This study of 253 fifth grade students analyzed the demographic variables of sex, family structure, race, and socio-economic status and their relationship to the types and proportions of personnel services used as well as their relationship to academic achievement. A survey form was designed for this purpose to indicate for each child: (1) sex, (2) family structure, (3) race, (4) socio-economic status, (5) type of personnel services used, (6) reading achievement, and (7) mathematics achievement. This form was filled out by participating classroom teachers. The data were analyzed using Chi-Square and Mann-Whitney and Kruskal-Wallis tests at the Statistical Research Laboratory at The University of Michigan. The two demographic variables which were shown to significantly affect personnel resource utilization as well as academic performance in the sample population were low socio-economic status and single-parent family structure. No statistically significant differences, in proportions of personnel resources and services used or in academic performance, were demonstrated in this sample population on the basis of the sex or the race of the children involved. It was concluded that children from single-parent homes and those who come from lower socio-economic level homes perform significantly lower academically and use considerably more personnel resources and services. The recommendation was that further research obtained with the use of larger, more metropolitan population samples using the same procedures, could serve as an important basis to educators in the planning and delivery of personnel services and resources, based on more knowledge of the needs of the particular school populations involved.Ph.D.EducationUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/157808/1/8017340.pd

Understanding the biology of HER3 receptor as a therapeutic target in human cancer

HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors. Studies on the underlying mechanism implicate HER3 expression as a major cause of treatment failure in cancer therapy. Activation of HER3 signaling has also been shown to promote cancer metastasis. These data strongly support the notion that therapeutic inactivation of HER3 and/or its downstream signaling is required to overcome treatment resistance and improve the outcomes of cancer patients. Key words: HER3, Dimerization, Cell signaling, Therapeutic resistance, Tumor metastasis, Targeted therap

Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo. Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL