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The goals of the present study were to define the effects of simultaneous cisplatin/tecemotide therapy on tumor development in a human mucin 1 (MUC1) transgenic lung cancer mouse model and to examine the effects of radiotherapy (RTX) on splenocytes, serum cytokines, and immune response to tecemotide. Two hundred twenty-six human MUC1 transgenic C57BL/6 mice were used in five studies designed to assess (i) serum cytokine and immune responses following four weekly 10-μg doses of tecemotide; (ii) the effects of simultaneous administration of cisplatin (2.5 mg/kg × 2 doses/cycle × 4 cycles) and tecemotide (2 cycles × 8 weekly 10-μg doses/cycle) therapy on tumor development, serum cytokines, and immune response; (iii) the dose–response effects of RTX on lymphocyte counts 16 hours following doses of 2 to 8 Gy; (iv) the time course of lymphocyte recovery from 16 hours to 20 days following 8-Gy RTX; and (v) the effects of simultaneous administration of RTX (8 Gy) and tecemotide on the immune response to tecemotide (four weekly 10-μg doses). Serum cytokines were analyzed by multiplex immunoassay, IFNγ immune responses by enzyme-linked immunosorbent spot (ELISpot), and lung tumor foci by lung whole mounts. Simultaneous cisplatin/tecemotide therapy resulted in significant and additive reduction in lung tumor foci compared with control mice, with significantly elevated serum IFNγ levels and specific IFNγ immune responses observed in both tecemotide and tecemotide + cisplatin–treated mice. Finally, neither cisplatin nor radiation interfered with the immune response to tecemotide. Cancer Immunol Res; 2(6); 581–9. ©2014 AACR.
Lung cancer is the leading cause of cancer-related fatalities worldwide in men and women, with 1.38 million deaths annually (1). Non–small-cell lung cancer (NSCLC) accounts for 80% to 85% of lung cancers, with a poor prognosis for patients with stage III/IV or recurrent disease (2, 3). The standard first-line therapy for patients with unresectable stage III NSCLC is platinum-based doublet chemotherapy and radiotherapy (RTX) with curative intent. However, improvements in survival with the standard therapy are modest, and the 5-year survival rate is only 15% (4). The limited efficacy of chemo-radiotherapy (CRT) for NSCLC has raised interest in the development of immunotherapy as an additional treatment modality to prolong survival. The identification of tumor-associated antigens (TAA) in patients with lung cancer has made immunotherapy an attractive alternative to traditional chemotherapy (5, 6).
Tecemotide [formerly L-BLP25 or Stimuvax (Merck KGaA)] is an antigen-specific cancer immunotherapy designed to target the TAA mucin 1 (MUC1) glycoprotein that is aberrantly overexpressed and often under- or unglycosylated in various epithelial cancers, including those of the lung, breast, and prostate (7, 8). Results from several studies have suggested that epithelial carcinogenesis may be facilitated by MUC1 (9–14). Tecemotide elicits a cellular immune response by using T-cell epitopes from the variable number of tandem repeat region (VNTR) of the MUC1 antigen associated with HLA class I molecules, resulting in the induction of IFNγ secretion into the serum and of MUC1-specific CTL (15–18).
A randomized phase II clinical trial demonstrated a survival benefit of tecemotide and low toxicity in patients with stage IIIB/IV NSCLC who had undergone primary CRT (19, 20). In clinical trials of tecemotide, a single low i.v. dose (300 mg/m2 to a maximum of 600 mg) of cyclophosphamide is administered 3 days before immunotherapy. It is thought that cyclophosphamide enhances delayed-type hypersensitivity humoral and cellular immune responses by reducing T-suppressor function. Recently, results of the global phase III START trial of tecemotide in stage III NSCLC showed that the primary objective of overall survival (OS) prolongation was not met, while predefined subgroup analyses revealed a clinically meaningful prolongation of OS in patients previously treated with concomitant CRT (21).
Previously, we developed a chemically induced lung tumor model in human MUC1 transgenic (hMUC1.Tg) C57BL/6 mice by administering 10 weekly doses of the chemical carcinogen urethane (18). During the carcinogenesis phase, serum proinflammatory cytokines were distinctive and associated with tumor development and progression. Administering two cycles (eight weekly doses/cycle) of tecemotide separated by 11 weeks induced secretion of the Th1 cytokines interleukin (IL)-12, IL-2, and IFNγ into the blood, and resulted in a reduction of lung tumor foci in urethane-induced hMUC1.Tg mice. Thus, this preclinical lung tumor model may be useful in determining the effectiveness and tailoring the treatment regimens of tecemotide and CRT or other combination therapies.
In the present study, we sought to determine the effectiveness of tecemotide combined with cisplatin chemotherapy in lung cancer and whether cisplatin treatment would affect the tecemotide-induced specific immune response. We also sought to determine the effects of increasing doses of ionizing radiation on lymphocytes in our lung cancer mouse model and whether combining radiation and tecemotide treatment has any effects on the immune response to tecemotide.
Materials and Methods
Urethane, cyclophosphamide, cisplatin (cis-diammineplatinum(II) dichloride), tertiary amyl alcohol, and 2,2,2-tribromoethanol were purchased from Sigma-Aldrich. Tecemotide, placebo, and enzyme-linked immunosorbent spot (ELISpot) peptides (BP25 and scrambled BP1–424) were provided by Merck Serono Research, Merck KGaA.
To establish our breeding colony, heterozygous C57BL/6 hMUC1.Tg founder mice were purchased from Mayo Clinic (Scottsdale, AZ). For these studies, a total of 226 mixed-sex MUC1.Tg mice were supplied by our breeding colony maintained by the UC Davis Mouse Biology Program and housed at the UC Davis Center for Laboratory Animal Science vivarium. For all studies, mice were housed in cages of four and maintained in a room with constant temperature and humidity on a 12-hour/12-hour light/dark schedule, with free access to food and water. All animal studies were conducted under a protocol approved by the UC Davis Institutional Animal Care and Use Committee. UC Davis (Davis, CA) is an Association for Assessment and Accreditation of Laboratory Animal Care accredited institution. For all mouse studies, the week number refers to the age of the mice.
Immediately before the radiation treatment, all mice were anesthetized using a 1.2% solution of Avertin (tribromoethanol) prepared by dissolving 2,2,2-tribromoethanol in tertiary amyl alcohol. Each animal was injected intraperitoneally (i.p.) with 600 μL of the solution using a 25-gauge needle. Once unconscious (∼5 minutes), mice were irradiated at the desired doses described in the studies below. Proper anesthesia was ensured by evaluating the righting and tail pinch reflexes. Before treatment, the anteroposterior:posteroanterior diameter of the mice was determined using calipers. RTX was prescribed to midplane and treatment dosing was calculated to cover the entire thoracic cavity with at least 90% of the prescribed dose. The entire RTX treatment protocol was developed by a board-certified medical physicist and a board-certified radiation oncologist. Anesthetized mice were placed in the prone position on 5-cm solid water at laser isocenter, and the treatment area was covered with 0.5-cm bolus to ensure adequate dose build-up. Local thoracic RTX was delivered using an Elekta linear accelerator (Elekta AB) delivering 9-MeV electrons and incorporating a 3 cm × 3 cm cerrobend electron cutout field to ensure that the entire thoracic cavity was encompassed in the radiation field but sparing as much of the cranial vault and abdominal cavity as possible. Following radiation treatments, all animals were monitored until they had sufficiently recovered from anesthesia.
Multiplex cytokine assays
The Mouse Cytokine 20-plex Panel (Invitrogen; cat. no. LMC0006) was used to analyze the cytokine levels (pg/mL) in serum samples from the study evaluating serum cytokine and immune responses to tecemotide. The assays were performed according to the manufacturer's instructions. The concentration of each cytokine was calculated relative to the respective standard curves. For 20-plex analyses, cytokine concentrations were acquired on a BioPlex System using BioPlex software version 5.0 (Bio-Rad). For serum cytokine analyses in all other studies, a custom 6-plex panel was used, which consisted of IL-6, IL-1β, IFNγ, monocyte chemoattractant protein-1 (MCP-1), TNF-α, and macrophage inflammatory protein-1α (MIP-1α). The 6-plex analyses were performed on a Luminex 100/200 system running xPonent software version 3.1 (Luminex Corporation).
To establish the in-house control for these assays, wild-type C57BL/6 mice were challenged with lipopolysaccharide (LPS). Mice were injected i.p. with 200 μg of LPS from Escherichia coli serotype O114:B4 (Sigma-Aldrich) dissolved in 1× PBS. At 4 to 5 hours after injection, mice were euthanized by CO2 asphyxiation. Whole blood was collected by cardiac puncture and placed in a clotting tube for isolation of serum by centrifugation. The serum was flash-frozen in liquid nitrogen and stored at −80°C until analysis by multiplex assays on a Luminex system.
The ELISpot assay protocol has been described previously (18). Briefly, to isolate lymphocytes, the splenocytes were layered over lymphocyte separation medium (Lonza) and then centrifuged at 600 × g for 15 minutes. The purified and washed lymphocytes were resuspended in improved minimum essential medium (Invitrogen) containing 10% FBS (HyClone), 50 μg/mL streptomycin, and 50 U/mL penicillin (Invitrogen) before cell number counting and viability assessment using an Auto T4 Cellometer (Nexcelom Bioscience).
Lymphocytes (1 × 106/well) were seeded into a 96-well microplate, which was included in the Mouse IFNγ ELISpot Kit (R&D Systems), and incubated in triplicate at 37°C overnight with no peptide (medium only), BP25 peptide, or scrambled peptide (BP1–424). All peptides were prepared in culture medium containing antibiotics at a final concentration of 5 μg/mL. The ELISpot microplates were then developed according to the manufacturer's instructions.
Serum cytokine and immune responses to tecemotide
A total of 31 mixed-sex C57BL/6 hMUC1.Tg mice (9 weeks of age) were used to determine whether serum cytokine and immune responses to tecemotide treatment could be assessed following four doses of tecemotide. Mice received four weekly 10-μg doses of either tecemotide (24 mice) or placebo (7 mice) by s.c. injection (100 μL injection volume) at rotating sites using a 25-gauge needle. Three days before starting immunotherapy or placebo treatment, all mice received a single 100-mg/kg dose of cyclophosphamide by i.p. injection. Vials of lyophilized tecemotide or placebo (300 μg each) were reconstituted in 3 mL sterile 0.9% saline within 24 hours before each dose. A total of 11 mice (8 tecemotide and 3 placebo), 10 mice (8 tecemotide and 2 placebo), and 10 mice (8 tecemotide and 2 placebo) were euthanized by CO2 asphyxiation for the collection of blood at 6, 24, and 48 hours, respectively, following the fourth dose of tecemotide or placebo. Blood was collected by cardiac puncture, placed in clotting tubes, allowed to clot for 30 minutes, and then serum was isolated by centrifugation at 3,500 × g for 10 minutes at 4°C. Serum was flash-frozen in liquid nitrogen and stored at −80°C until analysis by multiplex cytokine assay as described above. For ELISpot analysis, spleens were collected from selected mice 24 and 48 hours following the fourth dose of tecemotide or placebo.
Effects of cisplatin/tecemotide combination therapy on lung tumor development, serum cytokines, and immune response
To determine the effect of cisplatin chemotherapy on serum cytokines and the development of lung cancer when used in combination with tecemotide, a previously described hMUC1.Tg lung cancer mouse model was used (18). A total of 80 male C57BL/6 hMUC1.Tg mice began urethane induction at approximately 6 weeks of age. All mice received 10 weekly doses of urethane (0.75 mg/g) by i.p. injection (100 μL) using a 25-gauge needle. In week 23, approximately 7 weeks after the last dose of urethane, mice were randomized into four treatment groups of 20 mice each such that the average weight in each group was approximately equal; the four groups were control, tecemotide, cisplatin, and tecemotide + cisplatin. In week 24, mice in the tecemotide groups began their first 8-week cycle of treatment, 3 days after receiving a single 100-mg/kg dose of cyclophosphamide by i.p. injection. Tecemotide was prepared as described above and administered weekly (10 μg doses) for 8 weeks. Tecemotide cycle 2 began in week 34, approximately 3 weeks following the end of cycle 1, and continued through the end of the study. We showed previously that an antitumor response to tecemotide requires at least two 8-week cycles (18). Just as in cycle 1, a single 100-mg/kg i.p. injection of cyclophosphamide was administered 3 days before the first dose of tecemotide in cycle 2. Concomitant with tecemotide therapy, mice in the cisplatin groups received four cycles of chemotherapy given 4 weeks apart. Each cisplatin cycle consisted of two 2.5-mg/kg doses given by i.p. injection (100 μL) 48 hours apart. Cisplatin cycles 1 to 4 were administered in weeks 24, 28, 32, and 37, respectively. Before each dose, a fresh solution of cisplatin was prepared in sterile 0.9% saline and used within 1 hour.
At the conclusion of the study in week 41, all but 4 mice in each group were euthanized 48 hours after the last dose of tecemotide in cycle 2 for the collection of blood and lungs. Serum was isolated and stored as described. After blood collection, the lungs were harvested for the preparation of whole mounts. The lungs were first inflated with 10% neutral buffered formalin (Thermo Fisher Scientific Inc.), then separated into the five lobes, placed in tissue cassettes, and fixed in formalin for 48 hours, followed by 70% ethanol. Completed lung whole mounts were blinded and then examined by a pathologist to determine the numbers of tumor foci. The remaining 4 mice in each treatment group received an additional dose of tecemotide 48 hours before being euthanized for the collection of blood, spleens, and lungs. Spleens from these mice were processed for ELISpot analysis.
Lymphocyte dose response to RTX
Fifteen mixed-sex C57BL/6 hMUC1.Tg mice (6 weeks of age) were used to determine the effects of increasing doses of radiation on lymphocyte count and serum cytokines. Mice were divided into five groups of 3 mice each, viz., control, 2-, 4-, 6-, and 8-Gy doses of RTX. Sixteen hours following radiation exposure, all mice were euthanized for the collection of blood and spleens. Serum was isolated and stored, and spleens were collected and processed for lymphocyte counts as described in ELISpot analysis. RTX was performed as described in “Radiation treatment.”
Time course of lymphocyte recovery following RTX
The effects of an 8-Gy dose of radiation on lymphocyte counts and serum cytokines were followed from 16 hours to 20 days after exposure to assess the time course of lymphocyte recovery. A total of 40 mixed-sex hMUC1.Tg C57BL/6 mice (7 weeks of age) were assigned to five groups of 8 mice each, viz., 16 hours, 48 hours, 7, 9, and 20 days. Within each group, there were 4 control and 4 radiation-treated mice. All mice assigned to RTX were exposed to an 8-Gy dose of radiation as described above. At the scheduled time points following RTX, all mice within each group were euthanized as described above for the collection of blood and spleens. Serum was isolated and stored, and spleens were processed for lymphocyte counts.
Effects of concurrent RTX on the immune response to tecemotide
To determine the effects of RTX delivered simultaneously with tecemotide on the immune response to tecemotide and on serum cytokines, 60 mixed-sex hMUC1.Tg C57BL/6 mice (∼8 weeks of age) were assigned to four groups as follows: control (n = 10), RTX (n = 10), tecemotide (n = 20), and tecemotide + RTX (n = 20). Mice in the tecemotide groups received a total of four weekly 10-μg doses as described above. Three days before starting tecemotide treatment, all mice in the tecemotide groups received a single 100-mg/kg dose of cyclophosphamide by i.p. injection. Three days after the third dose of tecemotide, all mice in the RTX groups were exposed to an 8-Gy dose of radiation. Mice were administered the fourth and final dose of tecemotide 48 hours after RTX, and then all mice were euthanized as described for the collection of blood and spleens 48 hours after the last dose of tecemotide. Serum was isolated and stored, and spleens were processed for lymphocyte counts and ELISpot analysis.
In the study of the effects of cisplatin/tecemotide combination therapy on lung tumor development, serum cytokines, and immune response, a one-way ANOVA with Bonferroni multiple comparisons test was used to analyze serum levels of IFNγ. The ELISpot data in this study were analyzed using a two-way ANOVA with a Bonferroni multiple comparisons test. To analyze lung tumor foci data, an unpaired, two-tailed Student t test was used. In the study assessing the time course of lymphocyte recovery following RTX, an unpaired, two-tailed Student t test was used to assess differences in lymphocyte cell counts and the multiplex serum IFNγ data. To assess lymphocyte cell counts and IFNγ serum cytokine data in the study evaluating the effects of concurrent RTX on the immune response to tecemotide, a one-way ANOVA with a Bonferroni multiple comparisons test was used. For the ELISpot data in this study, a two-way ANOVA with the Bonferroni multiple comparisons test was used. All statistical analyses were performed using GraphPad Prism 5 software version 5. A P ≤0.05 was considered significant for all analyses.
Serum cytokine profile of concurrent tecemotide/cisplatin combination therapy
In our previous study, we showed that tecemotide treatment resulted in a significant antitumor effect following the administration of two 8-week cycles with cyclophosphamide pretreatment in a urethane-induced hMUC1.Tg lung tumor mouse model (18). Here, the effectiveness of cisplatin combined with tecemotide in lung cancer was examined. Before this study, a pilot study was performed by administering four doses of tecemotide to healthy hMUC1.Tg mice and then analyzing the serum cytokines at different time points after the final dose to validate the timing of the serum cytokine and immune responses in relationship with tecemotide dosing. The results showed that serum IFNγ was increased 6 to 48 hours after tecemotide treatment compared with placebo (Fig. 1A). Statistical significance of these increases could not be determined because of limited numbers of placebo mice (n = 2) at each time point. Therefore, tecemotide was administered 48 hours before each analysis endpoint in the cisplatin/tecemotide combination study design (Fig. 2A). A specific IFNγ immune response to the MUC1 peptide was observed in the pilot study by ELISpot analysis 48 hours following the fourth dose of tecemotide (Fig. 1B), although this difference was not significant. While the pilot study showed that tecemotide-induced serum cytokine release lasts for at least 48 hours, only a modestly increased level of IFNγ was observed in the sera of lung tumor–bearing mice after two cycles of tecemotide treatment (Fig. 2B) in the current study, which is consistent with our previous report (18). However, levels of IFNγ in the tecemotide + cisplatin–treated mice were significantly elevated compared with those with placebo control, tecemotide, or cisplatin-alone treatments (Fig. 2B).
Specific MUC1 immune response to tecemotide with and without cisplatin treatment
To determine whether cisplatin treatment would affect the tecemotide-induced specific immune response, lymphocytes from mice in each treatment group in the cisplatin/tecemotide combination study were isolated to perform an IFNγ ELISpot analysis. As shown in Fig. 2C, lymphocytes from tecemotide-treated mice had a significant and specific IFNγ immune response to the MUC1 peptide, but not to the scrambled peptide. In addition, tecemotide following cisplatin treatment also induced a significant, MUC1-specific immune response, whereas cisplatin-alone did not induce an immune response (Fig. 2C). The difference between tecemotide-alone and tecemotide + cisplatin was not statistically significant.
Additive tumor-suppressive effects of tecemotide/cisplatin combination treatment
MUC1.Tg mice treated with urethane developed lung adenomas with a tumor incidence rate of 100%. The number of tumor foci was significantly lower in the tecemotide- and cisplatin-treated mice than in the untreated mice (Fig. 3). Interestingly, an additive reduction in the number of lung tumor foci was observed with simultaneous tecemotide and cisplatin treatment compared with the single treatment groups (Fig. 3). Compared with the control group, the additive reduction induced by the tecemotide and cisplatin combination was highly significant (P < 0.0001). The reduction in tumor foci induced by the combination was also statistically significant compared with both tecemotide (P < 0.01) and cisplatin (P < 0.05) alone.
Immune recovery following RTX
Lymphocytes are known to be among the most radiosensitive cells in the body. A limitation of our current study design is that although we focus the radiation dose on the thoracic region, part of the spleen is still irradiated. To determine the dose–response effects of radiation on lymphocytes, cell counts were assessed 16 hours after exposure to increasing doses of radiation. As shown in Fig. 4A, the lowest dose of radiation (2 Gy) did not affect cell numbers, while lymphocyte counts decreased in a dose–response fashion following 4, 6, and 8 Gy of radiation (Fig. 4A). These differences, however, did not reach the level of statistical significance. To assess the time course of lymphocyte recovery following RTX, lymphocyte counts from 16 hours to 20 days following exposure to a radiation dose of 8 Gy were evaluated. Lymphocyte counts did not begin to recover until 9 days after exposure (Fig. 4B). Full recovery of lymphocytes was observed 20 days after exposure (Fig. 4B). In addition, serum IFNγ was significantly increased (Fig. 4C) 16 hours after exposure to radiation at a dose of 8 Gy. This may be the result of a nonspecific effect of ionizing radiation on IFNγ production, as suggested by previously published studies (22, 23).
Effects of concomitant RTX on the immune response to tecemotide
To determine the effects of simultaneous application of RTX and tecemotide on the immune response to tecemotide and on serum cytokines, 60 mixed-sex hMUC1.Tg C57BL/6 mice (∼8 weeks of age) were assigned to four groups as follows: control (n = 10), RTX 8 Gy (n = 10), tecemotide (n = 20), and tecemotide + RTX (n = 20). Consistent with the observation of reduced lymphocyte counts following RTX in the above studies, cell counts in the RTX-treated mice were significantly suppressed (Fig. 5A) 4 days after exposure to a radiation dose of 8 Gy. Serum IFNγ concentrations were significantly elevated in tecemotide-treated animals 48 hours following the last dose of tecemotide (Fig. 5B). Although IFNγ levels were reduced in the tecemotide + RTX–treated mice compared with mice treated with tecemotide alone, the difference was not statistically significant. IFNγ ELISpot analysis showed that RTX treatment had no appreciable effect on the immune response to tecemotide, with both the tecemotide-alone and tecemotide + RTX–treated mice showing a specific and significant immune response to the MUC1 peptide (Fig. 5C).
In the present study, a human MUC1 transgenic lung cancer mouse model was used to examine the effectiveness of cisplatin and tecemotide used in combination, and whether cisplatin or local radiation treatment affects the immune response to tecemotide. In agreement with our previous study (18), two 8-week cycles of tecemotide treatment produced a significant reduction in the number of lung tumor foci. Cisplatin-alone treatment had a comparable effect. As is hypothesized for cyclophosphamide, the effects of chemotherapy on the number and function of regulatory T cells (Treg) may be involved in cisplatin's antitumor effects. A recent study suggests that some chemotherapeutic regimens, such as docetaxel in metastatic breast cancer and castration-resistant prostate cancer, and the combination of cisplatin and vinorelbine in NSCLC, may suppress Treg activity and increase the ratio of T-effector cells to Tregs, while other therapeutic regimens have mixed effects on Tregs, such as tamoxifen combined with leuprolide in breast cancer, and sunitinib in metastatic renal cell carcinoma (24). Clinically, and in the present study, low-dose cyclophosphamide is administered 3 days before starting each cycle of tecemotide. Cyclophosphamide has been shown to reduce both the number of Tregs (25–29) and their immunosuppressive functionality in mice (28) and humans (26). Preclinical data suggest that cisplatin, administered at full therapeutic doses, has a similar effect on Tregs (30, 31) and may prove useful in combination with immunotherapy. Cisplatin has been shown to alter the phenotype of tumor cells (32–34), resulting in increased sensitivity to CTL. Although Treg and CTL activities were not addressed in this study, we did observe an additive inhibitory effect on lung tumor foci with the combination of cisplatin and tecemotide. The tumor-suppressive effects of tecemotide and the combination of cisplatin and tecemotide were associated with a specific and significant immune response to the MUC1 antigen, which suggests that cisplatin does not interfere with the immune response to tecemotide and vice versa. As expected, a MUC1-specific immune response was not observed with cisplatin-alone, which is consistent with cisplatin having a nonspecific tumor inhibitory effect. Furthermore, the observed additive reduction in lung tumor foci following treatment with the combination of tecemotide and cisplatin suggests that tecemotide may improve the chemotherapeutic effects of agents such as cisplatin (35).
The inflammatory responses induced by RTX for cancer can exert dual effects. Although they can promote the growth and metastasis of tumors, they can also activate immune response mechanisms that may limit tumor growth (36). Our results showed that when mice were exposed to radiation, a dose–response suppression of lymphocytes lasting up to 9 days was observed at doses up to 8 Gy delivered to the thoracic region. Interestingly, even with lymphocyte suppression, a strong immune response was still observed when radiation was administered simultaneously with tecemotide. Taken together, the results of these studies show that the transgenic lung cancer mouse model may prove useful in determining the most efficacious combinations of RTX, chemotherapy, and tecemotide immunotherapy (37).
Finally, the results of the global phase III START trial of tecemotide in stage III NSCLC were recently made available (21). Although the primary objective of prolonging OS was not met, predefined subgroup analyses revealed that patients previously treated with concomitant CRT received a clinically meaningful prolongation of OS. In contrast, patients who were previously treated with sequential CRT seemed to receive no benefit from tecemotide therapy. In this trial, tecemotide was well tolerated, with no safety concerns identified and no evidence of immune-related, treatment-emergent adverse events. The biologic mechanisms underlying these different treatment outcomes are not presently understood. Although the studies described here were not designed to address these concerns, they demonstrated the suitability of the model for use in studies that will attempt to discern the mechanism(s) responsible for these clinical results.
In conclusion, the results of these studies showed that (i) tecemotide combined with cisplatin caused a modest, yet significant reduction in the number of lung tumor foci; (ii) cisplatin did not interfere with the immune response to tecemotide; and (iii) mice treated with localized concomitant radiation maintained a strong immune response to tecemotide. Although the translational relevance of the observed additive reduction in lung tumor foci is presently unknown, it was important to show that tecemotide did not interfere with the efficacy of cisplatin, which is one of the key first-line agents used in the treatment of NSCLC, and that the immune response to tecemotide is maintained with concomitant radiation treatment. If properly sequenced, the addition of RTX to cisplatin chemotherapy and tecemotide may further increase the CTL-driven antitumor activity.
Disclosure of Potential Conflicts of Interest
M.W. DeGregorio is principal investigator of a research grant received from Merck KGaA, and M. Wolf is an employee of Merck KGaA. No potential conflicts of interest were disclosed by the other authors.
Conception and design: C.-J. Kao, G.T. Wurz, A.M. Monjazeb, M. Wolf, M.W. DeGregorio
Development of methodology: C.-J. Kao, G.T. Wurz, A.M. Monjazeb, D.P. Vang, M.W. DeGregorio
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.-J. Kao, G.T. Wurz, A.M. Monjazeb, D.P. Vang, M.W. DeGregorio
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.-J. Kao, G.T. Wurz, A.M. Monjazeb, D.P. Vang, S.M. Griffey, M.W. DeGregorio
Writing, review, and/or revision of the manuscript: C.-J. Kao, G.T. Wurz, A.M. Monjazeb, D.P. Vang, M. Wolf, M.W. DeGregorio
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.-J. Kao, G.T. Wurz, D.P. Vang, T.B. Cadman, S.M. Griffey, M. Wolf, M.W. DeGregorio
Study supervision: C.-J. Kao, M.W. DeGregorio
The authors thank Drs. Martin Falk, Christoph Helwig, Andreas Schröder, and Christoph Bogedain for their editorial assistance. The authors also thank Melinda Zmerzlikar and Lauren Wilke at the UC Davis Mouse Biology Program.
This research was supported by a research grant from Merck KGaA, Darmstadt, Germany.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

domain: literature


text:
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Finland is the most sparsely-populated country in the European Union. In fact, there are more people living in the city of London that the country of Finland, which means that there is quite a lot riding on the effectiveness of online shopping and the national postal service, especially when it comes to shipping to Finland from the UK.
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Always Cheaper than the Royal Mail

domain: geography


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Four firearms remain missing after five were stolen from a Prince George home this week, which investigators believe was targeted.
Prince George RCMP Cst. Jennifer Cooper says Mounties were notified of a break-in at a home in the Miworth area on Monday (Dec. 14) after 6 p.m.
Cooper says one or more suspects went into the house and pried open a gun safe.
Five guns were taken and the matching magazines were also missing.
“Guns were clearly targeted in this break-and- enter,” Cooper said in a news release.
“Every gun owner should take all precautions to secure their firearms and should refrain from discussing locations and details of their guns with others.”
One of the guns taken was found in an alleyway yesterday by a member of the public.
Cooper said it was found among garbage, which could have been an attempt to hide the gun for later use.
Cooper is asking anyone with information about the events to call Prince George RCMP at 250-561-3300, anonymously contact Crime Stoppers at 1-800-222-8477 or go online to www.pgcrimestoppers.bc.ca.

domain: news


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“Anchorman 2” is borrowing a move from the “World War Z” playbook and will offer fans the chance to buy a “superticket,” which would allow them to see the film two days early.
Paramount, partnering with AMC Theaters and Fandango, announced the plan today, but did not offer up the price or any additional details. The so-called “supertickets” go on sale on Nov. 26, and fans can register to get info at AnchormanMovie.com.
Film is set for release on Dec. 20.
Paramount sold a similar ticket for “World War Z.” For $50, fans received an early 3D screening of the pic, one HD digital copy, one pair of “World War Z” custom RealD 3D glasses, a full-size limited-edition movie poster and a small popcorn.
As Variety reported back in July, four out of the five screenings for superticket holders were sold out (the fifth was at 80% capacity).

domain: entertainment


Craig Parry Wins the 2007 Australian Open
Sydney NSW (16 December 2007) Australian Craig Parry won his own national championship – The Australian Open – fittingly at The Australian Golf Club.
His first victory came here in the NSW open in 1987 and an added 20 more years experience helped him seal victory with a 20 foot par-saving putt on the 17th to stay at -11, vitrually assuring him of victory. He needed only a par 5 on the reachable finishing hole to pocket the $315 000 winner's cheque. A chip and two putts saw him home. Only James Nitties and Stuart Appelby stood between him and his first Australian Open. Both players had a chance to try to hole out their chip shots at the final to force a play off.
"This means a lot to me as an Australian" he said in an improptu TV interview afterwards.
Tied in 2nd place were young hopeful Won Joon Lee , 'Rookie of the Year ' Brandt Snedeker, Left-hander Nick O'Hern.


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Natural gardening encompasses a lot of methods. It handles objects such as seeds, equipment, techniques, and other this sort of issues. There are so a lot of approaches that you can expand your personal organic backyard, possibly for enjoyment or for bettering your total diet plan. This write-up has tips that can assist you locate what you need to have.
For the tumble time, plant a handful of drop edible plants in your yard containers. Lovely selections of kale and mustard greens, have lovely shades of greens and purples and provide diverse textures to the arrangement. Include a number of edible pansies to deliver shade to the inexperienced textures. The combination is fetching and will last nicely into the winter season.
Spend in a digital PH tester. Avoid liquid PH kits (the coloration coded types) as they are likely to be considerably less accurate. It is extremely easy for 1st time end users to botch readings. Also, do not use soil PH examination kits as they are unreliable and are not intended for residence use.
You can test the viability of your seeds by soaking them overnight. Drop them into a container of drinking water and maintain them in a dark place for a day. Check the area of the seeds. If they sank to the base, they are usable. If they float the the leading, they may be dead.
To eliminate off aphids on rose vegetation, spray them with a powdered milk and drinking water combination (one/3 cup powdered milk to one particular quart drinking water). When the combination is sprayed, the aphids get caught in the liquid and sooner or later die. Every handful of months spray down the roses with water to rinse off the mixture and reapply it if required.
To spice up a dull yard, consider making use of climbing plants. garden bridge challenge A climbing plant can incorporate visible curiosity to a fence or tree and are a fantastic way to cover any unattractive constructions. As an extra reward, most climbing plants are really minimal routine maintenance. Kiwi vine, climbing snapdragon and early morning glories are all fantastic alternatives.
If you develop roses or rosebushes, spray them with a remedy of 1/three cup powdered milk in about a quart of h2o after a week or so. The run milk solution will be sticky on the leaves and stems of your roses which will trap aphids and defend your roses.
Acquire a wheelbarrow and kneeling stool to perform with in the garden. In order to relieve pressure on your knees when gardening, often use a tiny backyard stool to be more relaxed. As effectively, gardening can include some large lifting and relocating, so a sturdy wheelbarrow can really make that element much more effortless.
If you do not like chemical insect repellants you must consider using herbs instead. Herbs like chives can be used in location of the chemical insect repellants to keep bugs from taking in your flowers and create. You can grow chives oneself or get them at your nearby grocery keep.
When beginning your organic backyard garden, a wonderful suggestion is to make positive you have the proper timing when sowing your seeds. If your timing is off when planting a distinct plant, you will have really disappointing results. If you make certain you have your timing correct, you will likely be happy with your outcomes.
To preserve air flowing via your compost pile, stand a large PVC pipe with punched holes in the heart of your pile so the air flows up and down the pipe, and then via the holes straight into the pile. The air movement aids your soil decomposers develop the warmth required to jumpstart the decay process.
Don’t be alarmed at the quantity of natural fertilizer you may possibly want to use. Natural fertilizers include a lower share of vitamins and minerals for every device fat than their synthetic counterparts. Simply because of this, it will probably be required to implement a lot more quantity of organic fertilizer than is standard for synthetic fertilizers.
To aid unfold mulch simply, you can use a flat-head rake or a bow. If you are using a rake, you must use the rakes tined edge to pull and distribute your mulch. Use the flat side of the rake to even your mulch on the bed. You will want to use a mild push then pull action.
When increasing your personal natural crops, you ought to move your seedlings absent from any air vents or radiators instantly on germination. garden bridge approved This is simply because your seedlings do not want to be genuinely heat like germinating seeds do. They need to have to be cooler in get for them to grow in the greatest way.
Any type of gardening aids you get in tune with the atmosphere, but organic and natural gardening normally takes this concept to the up coming amount. garden bay bridge wedding When you do this kind of gardening, you will start off to have a very good concept of the complete procedure of planting from begin to complete.
When planting your tomatoes in your organic and natural yard, you need to constantly make certain that you stake the tomato vegetation as substantial as you possibly can when you are transplanting them. The reason is simply because doing this will eliminate the roots of the plants from getting ruined in the course of the transplanting approach.
Make sure that you take special care of new crops that you lately planted in your natural yard. There must be no noticeable bare soil around any new vegetation. Constantly take care to go over them with a layer of some sort of mulch or any coarse or loose organic and natural content.
When planting an natural and organic backyard, be positive to use a weed-free mulch in your yard. Weeds will inevitably spring up in the empty dust, so laying down a layer of mulch will give you a a lot essential barrier in opposition to individuals weeds. This will support you to handle undesired progress and spend significantly less time weeding.
In conclusion, natural gardening is a quite broad subject that handles a whole lot of gardening merchandise and strategies. There are some appropriate techniques and wrong techniques to implement this understanding, but there is so considerably possible for creating your backyard garden exclusive. Ideally, this post has presented you some tips on how to make natural gardening work for you.

domain: agronomy


The 12th annual Georgia Literary Festival in 2010 will be hosted by Statesboro, officials at the Georgia Center for the Book recently announced.
WASHINGTON - Federal health authorities on Saturday urged consumers to avoid eating cookies, cakes, ice cream and other foods that contain peanut butter until authorities can learn more about a deadly outbreak of salmonella contamination.
Most peanut butter sold in jars at supermarkets appears to be safe, said Stephen Sundlof, head of the Food and Drug Administration's food safety center.
O.H. and Kanda Daniel of Bellville are pleased to announce the forthcoming marriage of their daughter, Erin Elizabeth Daniel, to Joshua Anthony Masters, son of Tony and Rebecca Masters of Statesboro.
Mr. and Mrs. Wes and Frances Allen of Fort Smith, Ark., announce the engagement of their daughter, Jenna Mays Allen of Statesboro, to Charles Brandon Sherrod, son of Mr. and Mrs. Charles A. Sherrod and the late Brenda Sherrod.
Mr. and Mrs. Lance Hodges of Statesboro, Ga., announce the engagement of their daughter, Brandi Marie Hodges of Statesboro, to Linton Andrew Forrest Harvey, son of Mr. and Mrs. Mike Harvey of Pembroke, Ga.
Shelly Maline Hendrix and Jason Douglas Wamba were united in marriage on the evening of September 20, 2008. The wedding took place at Meldrim Woods Plantation, where the Rev. Ray Jenkins officiated.
Mr. and Mrs. William R. Schafer of Brooklet announce the engagement of their daughter, Hope Elise of Brooklet, to Clint Allen Crosby, son of Mr. and Mrs. Harold M. Crosby.
(Note: All information included in this report is taken from law enforcement incident reports and arrest records, which are public records and available for review at any and all local law enforcement agencies. Not every arrest leads to a conviction. Guilt or innocence is determined by the court system.)
Studio Statesboro Vodcast - Friday, January 16, 2008
Evermore Farms in Brooklet will play host to its team's largest show in history this weekend as they welcome the Interscholastic Equestrian Association (IEA). It will be the first home show of 2009 for the Evermore Farms team, with classes scheduled for Saturday and Sunday.
Auditioning for the Georgia All-State Band is one of the most prestigious and toughest competitions high school musicians face each year. To earn first chair in your instrument - beating out about 1,000 of the most talented musicians in the state - is a remarkable achievement. To do it twice is almost unheard of.
Featuring the Farmers and Merchants Bank MVP of the Week
NEW YORK - A US Airways plane crashed into the frigid Hudson River on Thursday after striking a bird that disabled two engines, sending 150 on board scrambling onto rescue boats, authorities say. No deaths or serious injuries were immediately reported.
Federal Aviation Administration spokeswoman Laura Brown said US Airways Flight 1549 had just taken off from LaGuardia Airport enroute to Charlotte, North Carolina, when the crash occurred in the river near 48th Street in New York City.
Studio Statesboro Vodcast - Thursday, January 15, 2008
Though the current seeding may not indicate it, Friday's game between Emanuel County Institute and Macon County is a true one versus two matchup.
In front of a packed gymnasium for their first dual meet of the season, Bulloch Academy romped Metter High School 72-12 for their first win ...
TUSCALOOSA, Ala. - Jim McElwain never had a quarterback at Alabama quite like Jalen Hurts.
NEW YORK - The Los Angeles Dodgers, Latin American teenagers and Cubans approaching their mid-20s were losers in baseball's new labor contract, which includes stiffer ...
WASHINGTON - The most extreme tornado outbreaks are mysteriously spawning many more twisters than they did decades ago, a new study claimed.
INDIANAPOLIS - Donald Trump saluted workers, owners and himself Thursday at a Carrier plant in Indiana, declaring that a deal to keep a local plant open ...
Mr. George Thomas Holloway Sr.
WASHINGTON - "Made in the same factory as peanuts." ''May contain traces of tree nuts." A new report says the hodgepodge of warnings that a food ...
BIRMINGHAM, Ala. - Tornadoes that dropped out of the night sky killed five people in two states and injured at least a dozen more early Wednesday ...
Folks can enjoy all-you-can-eat pizza and watch live wrestling matches in Statesboro Saturday, and help make Christmas happen for children who would not have any ...
The Mercer Bears piled up a 23-6 lead after just one quarter of action and never looked back, defeating the Georgia Southern women's basketball ...
Welcome to more smarter stats! We've finally come full circle on this season's advanced stats tutorial.
NEW YORK - Bruce Arena opened a binder to a page with 48 names, his depth chart for the U.S. soccer team.
PARADISE ISLAND, Bahamas - Kentucky spent November romping its way to lopsided wins and leaving little doubt who should be the No. 1-ranked team in the ...
"Free Coffee for Free People" will be held Thursday from 6-9 p.m. at Three Tree Coffee on South Main Street in Statesboro.


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Hypopharyngeal Cancer Library
Learn about Hypopharyngeal Cancer
Hypopharyngeal cancer is a disease in which malignant (cancer) cells form in the tissues of the hypopharynx.
The hypopharynx is the bottom part of the pharynx (throat). The pharynx is a hollow tube about 5 inches long that starts behind the nose, goes down the neck, and ends at the top of the trachea (windpipe) and esophagus (the tube that goes from the throat to the stomach). Air and food pass through the pharynx on the way to the trachea or the esophagus.
Most hypopharyngeal cancers form in squamous cells, the thin, flat cells lining the inside of the hypopharynx. The hypopharynx has 3 different areas. Cancer may be found in 1 or more of these areas.
Hypopharyngeal cancer is a type of head and neck cancer.
Use of tobacco products and heavy drinking can affect the risk of developing hypopharyngeal cancer.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors include the following:
- Smoking tobacco.
- Chewing tobacco.
- Heavy alcohol use.
- Eating a diet without enough nutrients.
- Having Plummer-Vinson syndrome.
Signs and symptoms of hypopharyngeal cancer include a sore throat and ear pain.
These and other signs and symptoms may be caused by hypopharyngeal cancer or by other conditions. Check with your doctor if you have any of the following:
- A sore throat that does not go away.
- Ear pain.
- A lump in the neck.
- Painful or difficult swallowing.
- A change in voice.
Tests that examine the throat and neck are used to help diagnose hypopharyngeal cancer and find out whether the cancer has spread.
The following tests and procedures may be used:
- Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
- Physical exam of the throat: An exam in which the doctor feels for swollen lymph nodes in the neck and looks down the throat with a small, long-handled mirror to check for abnormal areas.
- Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
- CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the head, neck, chest, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
- PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. A PET scan and CT scan may be done at the same time. This is called a PET-CT.
- MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the head, neck, chest, and lymph nodes. This procedure is also called nuclear magnetic resonance imaging (NMRI).
- Endoscopy: A procedure used to look at areas in the throat that cannot be seen with a mirror during the physical exam of the throat. An endoscope (a thin, lighted tube) is inserted through the nose or mouth to check the throat for anything that seems unusual. Tissue samples may be taken for biopsy.
- Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer.
- Bone scan: A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner.
- Barium esophagogram: An x-ray of the esophagus. The patient drinks a liquid that contains barium (a silver-white metallic compound). The liquid coats the esophagus and x-rays are taken.
- Esophagoscopy: A procedure to look inside the esophagus to check for abnormal areas. An esophagoscope (a thin, lighted tube) is inserted through the mouth or nose and down the throat into the esophagus. Tissue samples may be taken for biopsy.
- Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope (a thin, lighted tube) is inserted through the nose or mouth into the trachea and lungs. Tissue samples may be taken for biopsy.
Certain factors affect prognosis (chance of recovery) and treatment options.
Prognosis depends on the following:
- The stage of the cancer (whether it affects part of the hypopharynx, involves the whole hypopharynx, or has spread to other places in the body). Hypopharyngeal cancer is usually detected in later stages because early signs and symptoms rarely occur.
- The patient's age, gender, and general health.
- The location of the cancer.
- Whether the patient smokes during radiation therapy.
Treatment options depend on the following:
- The stage of the cancer.
- Keeping the patient's ability to talk, eat, and breathe as normal as possible.
- The patient's general health.
Patients who have had hypopharyngeal cancer are at an increased risk of developing a second cancer in the head or neck. Frequent and careful follow-up is important.

domain: medical


Larry Burton's 160mph Wooden Wonder
When Good Isn't
The two-finger approach worked on all the controls and let me experience the airplane's slippery, silky control reaction. As with most planes of its size, control response is pronto, no lag, no inertia hang-up, no nothing. But at the same time, it is very, very precise. You can whip a wing up and bang into a 60 degree bank like you were a Blue Angel flying the landing break, and the controls let you stop it at the exact degree of bank you want.
At 2400 rpm we were indicating a pretty solid 150-155 mph (160 TAS), which Burton says takes about 6 gph. With 24 gallons on board that gives him an absolute range of 640 miles, no reserve.
Clean stalls were about as you'd expect, with the exception that it feels as if it really doesn't have enough elevator to hold it stalled, so it just sort of mushes. Gear and flaps down, it breaks much more cleanly with a fairly pronounced roll in one direction or the other. All of this is happening down around 50 mph, so it's no lunch eater.
In the pattern, all dirtied up, it did nothing that you wouldn't expect from a piece of factory iron. Even on final you could have made pretend it was a Bonanza/Arrow/Swift and made an absolutely perfect approach. The only place you'd have to watch your-self is in the actual flare. That little hummer sits so low to the deck that there's not only a tendency to flare a bit high, but it's easy to over-rotate as well.
At no time does the runway disappear, not even when flaring, so I did just as I'd told myself not to do, I rotated a bit too much and got it on tailwheel first, as if I were a Corsair jockey looking for number three wire. It tiptoed from gear to gear just a bit and settled down to follow what my feet were telling it to do. Aside from some reference problems which resulted in my eyes giving me the wrong info about how high my butt was off the runway, it was a very, very straightforward, easy to fly airplane. It's a credit to the basic design and to the modifications that Burton made that it fits together so well.
I suppose I should probably mention that I had originally intended to fly two Cavaliers, Burton's R.G. job and Verne Minzimer's '76 Grand Champion 102.5, but I somehow never got to catch Verne before he split for parts unknown (The So-Cal hinterlands). Both Burton's and Minzimer's are unreal examples of what regular people-type persons can whittle out in their garages. Also, I wanted see how a nearly stock Cavalier flies.
The Cavalier 102.5 is really nothing more than the old 1946 French Minicab cleaned up to use modern ideas of structures, materials and aesthetics. In terms of appearance, not much of the old Minicab remains. The Mini looked like a homebuilt Culver Cadet, which is to say it was a project, which took a lot of time and turned out ugly. The Cavalier modification sought to remedy the uglies. Even so, the Cavalier still has a cabin roof line that looks as if it was designed for pilots with pointed heads. Most Cavalier owners lower and streamline the cabin lines similar to the way Burton did on his.
The original Cavalier is sort of unique in that it's designed to be either a tri-gear or a taildragger or both. Supposedly you could build in two sets of gear mounts so you could fly it on Saturday with the nose wheel and, if anybody called you a limp wrist for flying a tri-gear, you could return on Sunday with a tailwheel, using the same gear legs and all.
At designed gross weight of 1500 pounds (890 empty) the stock Cavalier with tip tanks (24 gallons) carried about 12 pounds per square foot of wing. Burton's weighs 1100 pounds empty, so he's at a natural disadvantage in that area, but the cleaned up belly ought to make up for it. As it happens, most Cavaliers weigh 1000 pounds or more. Burton's gear mod required extensive rehashing of the inner wing panel to accommodate the T-33 hatch motor operated actuating system and the Czechovic CA-65 legs. He's drawn up plans for the unit and is currently trying to sell a few to make back some of the costs of building "Mistress."
That's always been the way with homebuilts, the more traditional ones anyway. You cart a surprisingly expensive stationwagon-load of lumber into your garage and years later, when the wrinkles around your eyes and the greying at your temples mark the passage of an inordinate amount of time, you tow the same lumber back out of the garage. This time it moves tail first, on its own wheels, out to the airport to feel out an entirely new environment . . . the sky.
Homebuilding is not quick, it's not easy and the results are often no longer suited to the builder. A man ages and his tastes change. An airplane is constant. So, the young man who may have wanted a zippy, tail-twisting biplane finds the man/machine match no longer dovetails. He now needs something a little more sedate/faster/ prettier/bigger. He needs something, which fits his changed tastes, whatever they may be.
With Larry Burton, when his airplane was done, he was a little older, a little greyer, just like the rest of us, but the dove-tail still matched. The spruce and fabric he'd laboriously loved for those years were still what he wanted. The Cavalier was still close to being the perfect airplane for him, it was still a material statement of an aerial emotion.
It was, after all, not by accident that he named it "His Mistress." BD For lots more pilot
reports like this one go to PILOT
For lots more pilot reports like this one go to PILOT REPORTS


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Community residents, Coalition Board members and Magnolia Project staff participated in the 2012 Annual Spring Conference of the National Healthy Start Association held recently in Washington D.C. The conference brought together representatives from the 103 federal Healthy Start programs across the country and featured an array of workshops and poster presentations, including one on the Coalition’s PhotoVoice project. Conference participants also had a chance to visit Capitol Hill to meet with U.S. Congressmen and Senators.
“It was truly an honor to meet the staff member of Senator Bill Nelson, and a staff member of Congresswoman Corrine Brown. The conference speakers were just so motivational and an encouragement to me,” said Gladys Rivers, a resident of New Town who was involved in the Strengthening the Voices of Women in New Town PhotoVoice project. She and fellow participant Dana Gregg represented the project at the poster session.
PhotoVoice is a grassroots process in which photography is used by regular citizens to promote social action in their community. It was implemented over 18 months in the New Town neighborhood of Jacksonville. Eight women, who were mothers or caregivers of children age 0-5, participated in the project, documenting neighborhood supports and challenges to raising a family. Photos taken by the women were featured in an ArtWalk exhibit last year. The women also advocated for changes to address the problems they identified in their neighborhood.
Also attending the national meeting were Carmen Ress and Isadora Howell, members of the Magnolia Project Community Council; Marsha Davis and Angelier Wright, Magnolia Project outreach staff, and Healthy Start Board members Joy Burgess and Rev. Tom Rodgers. Thomas Bryant, director of Institute for Public Health Informatics and Research at the Duval County Health Department, also attended and presented findings from a state study of the coalition-building process.

domain: sociology


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Hidden Objects : Paintings 1.1
If you like hidden object games, this one is totally for you. Indulge in awesome fun by finding hidden objects inside classic paintings of the old masters. Rack your brain and try to find the carefully hidden objects as fast as possible. Come on, take up the challenge.
* Hints available.
* 10 objects hidden in every painting.
* 20 classic paintings in all (5 free, remaining 15 available via an in-app purchase)

domain: artistic


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They’re truly scrumptious, truly truly scrumptious. Honest, truly, they are. Khloé Kardashian and True might be getting a KUWTK spinoff, and we cannot contain our excitement. Truly. (Ok—we’ll stop). But honestly, this is very cool and we’d love to Khloé’s sweet little baby on the reg. Plus, any new addition to their franchise will surely garner LOTS of attention because…well, they’re the Kardashians and the world can’t seem to spin without updates.
The Kardashian and Jenner girls have spent well over a decade having their lives on public display, and it’s looking like it won’t stop anytime soon. On Sunday evenings, fans gather for the inevitable drama that comes with watching KUWTK. This past Sunday was no exception. In the latest episode, which aired last night, Kim was hit with some backlash over her shapewear brand’s former name—Kimono. It was seen as extremely culturally insensitive. And then Kim and Kourtney had a fight over candy. Which, I mean, fair. Candy is v important guys. But the most interesting part of the episode was the clip of Kourtney and True which basically just served as a sneak peek of what’s to come.
Khloé and momager Kris Jenner sat down with producers to talk about a potential new collab. Khloé’s idea is to call the show Khloé and True Take The World. And it seems like the producers definitely want to pick it up. However, it will be aired in an entirely different platform that we’re used to. As opposed to other spinoffs like Kourtney & Kim Take Miami and Life Of Kylie, which were both aired on E!, this new spinoff may just go straight to the internet. Cut out the middle man. “We want to shoot and put this on the internet as soon as possible,” a producer told Khloé, suggesting the show may stream online instead of on E!. Considering most fans stream things online anyway, it does make a lot of sense in this modern era.
It’s unclear whether the show, if it gets the OK, will be on YouTube or another streaming platform. However, it’s pretty likely it will get picked up. I mean, who wouldn’t want to see more of this sweet face?
A true angel.


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The star went on a downward spiral after splitting from Ariana Grande in May.
10 Sep 2018
President Trump Puts the Cart Before the Taxpayers ... $300k for Secret Service Green Rides 9/6/2018 12:50 AM PDT EXCLUSIVE
Frankie Grande insists the tragic rapper was "wonderful" to his sister. [ad_2] Source link
Megyn Kelly Character in Ailes Movie Won't Be Rewritten ... In Wake of NBC Firing 10/26/2018 1:00 AM PDT EXCLUSIVE


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Development and promotion of nutritional labels for children
This grant provides partial support for the initial phase of a project to create and promote the first nutritional label for children. The goal of the label is to teach children ages 6-12 to seek out and use information about the food they eat so they will make better food decisions now and as adults. Nutritional habits established early in life can have a major impact on the development of degenerative diseases in adults including heart disease and cancer. The project will be cooperatively developed with the Food and Drug Administration. Dissemination will occur through a multimedia campaign. As a joint venture between the FDA and the communications industry, this project offers a special opportunity for the Foundation to join in support of an initiative that will have significant impact on the health of American children.
Amount Awarded $50,000.00
Awarded on: 1/16/1992
Time frame: 1/15/1992 - 9/30/1992
Grant Number: 19594


We’ve teamed up with 23 year old up-and-comer David Dann to bring you something fun this morning: his entire debut full length album free to stream and download, for the next 24 hours. Now, you know I’m no fan of vocal or progressive house, but there are always the special exceptions for me. I’ve been into his remixes for a few months now, and the full length had me as soon as David had sent it over. The quality and attention to detail in his production, coupled with an intricate and infectious sense of melody, put him on my list of artists to watch– I’ll be very surprised if this young producer isn’t playing very big rooms full of many people in the near future. Grab his full 11 track album, including his collaboration with C.C. Sheffield, his 7 track remix pack, and the premier of his latest video; all right here, today on GDD™.
This entire album will be available until 11AM PST tomorrow, September 12, 2012.
Did you miss the download window? Fret not, you can download all the remixes above and the full album is also available here:
All my best,


1.75 PCF FR CCMC
Touch 'n Seal Two Component 1.75 PCF FR CCMC foam is a closed cell spray foam insulation that provides Class A fire retardancy as well as air sealing and sound attenuating properties when used according to manufacturer’s directions. It is listed as CCMC 13600L as a bead-applied sealant.
Features & Benefits
- CCMC 13600L Evaluation Listing, for bead-applied sealant
- ASTM E-84 Class A Fire Resistance
- Maintains air seal
- Offers code officials, inspectors, and contractors evidence of code compliance
- Expands to fill small and large gaps, cracks and holes - reducing air exchanges
- Low odor
- Easy to carry using Rip 'n Go handle (Foam Kit 200 only)
- 15 month shelf life
Touch ‘n Seal 1.75 PCF FR CCMC spray foam is available in 3 convenient formats:
Disposable Foam Kits
CPDS Foam Kits
An instructional video featuring the Foam Kit 200 disposable foam kit with 1.75 PFC closed cell foam.


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Accuracy evaluation of orthodontic movements with aligners: a prospective observational study
Progress in Orthodontics volume 23, Article number: 12 (2022)
Since their introduction in orthodontics, clear aligners have been appreciated by patients, including adults, for their comfort and low aesthetic impact. Despite the enormous mobilization of financial resources all over the world aimed at producing new product lines, few clinical studies or high-quality evidence have been produced regarding the real effectiveness of such treatment. Given the few limited kinds of research on the subject, this study aims to produce and critically evaluate other data, to establish the concrete reliability of clear aligners in orthodontic therapy.
Significant sample sizes were obtained for intrusion, vestibulo/lingual (V/L) crown tipping, and rotation. The overall accuracy for rotation resulted in 86%, ranging from 96% for maxillary central incisors to 70.4% for mandibular first premolars. The intrusion was registered only for anterior teeth; mean predictability was 92%, with the worst result being 86.7% for mandibular canines and the best being 98% for mandibular central incisors. V/L tipping was the most accurate movement: 93.1% of the prescribed movement was completed. Maxillary central incisors showed the lowest accuracy (80.7%), while mandibular central incisors were the highest (97.5%).
The present study provided reassuring data in support of the accuracy of the Invisalign® system. Vestibulo/lingual tipping was the most predictable movement, while rotation of canines, premolars, and lateral incisors were the least predictable. Intrusion resulted highly predictable up to 2 mm. When careful treatment planning follows a correct diagnosis, together with the use of auxiliary features and refinements, the planned results can be achieved in a clinically successful way. Authors believe that there is a major need for greater samples to overcome bias related to variables if we want to answer the unsolved questions, such as the predictability of severe malocclusions treatment.
Launched on the market in the late 1990s, today clear aligner therapy (CAT) has become a key part of orthodontics thanks to the use of a series of removable, clear thermoplastic appliances to be worn by patients instead of traditional fixed vestibular/lingual braces.
Kesling , who had developed a rubber-based tooth positioning appliance in 1946, was the forerunner of this system, until Align Technology (Santa Clara, CA, USA) patented clear aligners in 1998, introducing CAD/CAM technology into orthodontic treatments .
ClinCheck is the proprietary software by Align Technology that allows clinicians to plan the treatment digitally and predict the sequence of tooth movement, in terms of time, difficulty, and result. Therefore, through this 3D treatment planning software, the clinician can preview all tooth movements up to the final occlusion as well as showing them to the patient, which can be a great motivation tool.
Since their introduction in orthodontics, clear aligners have been appreciated by patients, including adults, for their comfort and low aesthetic impact. This success has encouraged manufacturers to improve the characteristics of their devices with the introduction of auxiliary features (power ridges, bite ramps, precision cuts, elastics), thus increasing the typologies and severity of malocclusions that can be treated with aligners [3,4,5,6]. Today many different cases are considered eligible for orthodontic therapy with these devices: moderate crowding, distalization, resolution of a deep overbite, narrow arches that can be expanded, major rotation, closing/opening of space, etc. .
However, despite the enormous mobilization of financial resources all over the world aimed at producing new product lines, few clinical studies or high-quality evidence have been produced regarding the real effectiveness of such treatment.
Among the first papers on Invisalign® (Align Technology), the study by Kravitz et al., evaluating the efficacy of tooth movement with removable polyurethane aligners , is one of the most relevant; his group reported a mean accuracy of 41%, the lowest accuracy occurred with extrusion (29.6%) while the highest accuracy occurred with lingual constriction (47.1%), which was the most accurate tooth movement obtained with clear aligners.
Among recent studies, Lombardo et al.  report a mean accuracy of movements obtained with F22® clear aligners of 73.6% being the rotation of the mandibular canines the least predictable movement, while the most predictable movements are the mesiodistal tipping of the upper molars and lower premolars.
When the available data are being assessed, clinicians should consider the heterogeneity of the literature in this context, since results refer to several different aligner companies .
Given the few limited kinds of research on the subject, this study aims to produce and critically evaluate other data, to establish the concrete reliability of clear aligners in orthodontic therapy.
The main difference between our study and the others available ones is that refinement trays will be included in the assessment, since the authors believe that these corrections are integral part of the treatment.
We set as the null hypothesis that there was no clinical difference between the majority of dental movements planned and the achieved ones.
Materials and methods
Trial design, participants, and settings
The present paper is a prospective observational study, approved by the Institutional Review Board of the University of Palermo General Hospital (A.O.U. Policlinico Paolo Giaccone; approval number 2/2020). The study was registered at the German Registry of Clinical Trials (DRKS-ID: DRKS00023865). Informed consent was obtained from all patients.
A total of 10 patients were treated with the same invisible orthodontic system (Invisalign®, Align Technology). The subjects selected for the study group were treated in a dental practice in Palermo (Italy).
The sample comprised 215 teeth (105 maxillary and 110 mandibular), which were analysed by overlapping three digital models (pre-treatment, real post-treatment, ideal post-treatment according to setup). The participants included 10 adult patients (3 men and 7 women), whose mean age was 34.8 ± 14.
First of all, a full medical history was documented, followed by a clinical examination. Secondly, diagnostic records—i.e. photographs, orthopantomography, and lateral teleradiographies—were taken to evaluate whether cases were eligible for aligner therapy or not. No fixed appliances or temporary anchorage devices (TADs) were used. Finally, patients deemed acceptable were treated with Invisalign®.
The inclusion and exclusion criteria for patient recruitment are reported in Table 1; all subjects were instructed to wear their aligners for 22 h per day and perform the correct oral hygiene procedures. Aligners were replaced every 7 days. In addition to the optimized attachments and interproximal reduction (IPR), auxiliaries (bite ramps, power ridges, elastics) were adopted according to the specific needs of each case (Table 2).
When patients completed their first set of aligners, each clinical case was re-evaluated and, if needed, a new ClinCheck simulation was made and a set of “refinement” aligners was used to accomplish all the treatment goals.
Patients needed an average of 25 refinement trays per arch before concluding their orthodontic therapy.
For each treated dental arch, pre-treatment (T0), post-treatment (T1), and planned post-treatment (Tp) digital casts were available. These 3D models were acquired as STL files via CEREC Omnicam (Dentsply Sirona, Italy) and superimposed by a single operator over stable reference points through Meshlab software (ISTI-CNR, Italy, 2021.05 version) (Fig. 1). Occlusal plane was main reference for superimpositions and vertical displacement measurement, once the models were placed in a 3D Cartesian grid and compared using trigonometry. Correct and repeatable spatial orientation of the models was granted by the use of sagittal and occlusal plane—which do not change after orthodontic treatment—as 3D references. Huanca et al.  described how occlusal plane is the best option to achieve a reliable and stable method for superimposition, as palatine folds could serve as reference points but only for the upper arch, while other dental structures could be affected by some movements.
Rhinoceros® software (Robert McNeel & Associates, USA) was used for examining linear and angular measurements of each tooth in a 3D Cartesian grid. Making sections of the superimposed digital casts allowed performing precise measurements.
The different tooth movements examined were: vestibulolingual tipping, mesiodistal tipping, rotation, and vertical displacement (intrusion/extrusion). Despite a major need for information on torque, such dental movement was not examined, as it would have needed a 3D computed tomography (CT) to be properly registered.
These superimpositions provided an accurate report on the reliability of the pre-treatment and post-treatment impressions and, above all, the discrepancies between planned treatment and actual results (Fig. 2).
The overall accuracy for every tooth and movement was calculated as follows:
Whenever accuracy exceeded 100% (as it occurred, for instance, when the vestibularization obtained in the lower-anterior region was greater than the predicted one), the excess was instead subtracted from 100%, obtaining only < 100% values which could be more easily read and interpreted.
Sections were made in a sagittal plane (Fig. 3) using the line passing through the central fossa of molars and premolars, the centre between the mesiodistal margins for the incisors, and the line passing through the cusp for the canines. Tooth inclination was calculated using the facial axis of the clinical crown (FACC) with respect to the occlusal plane.
Statistical analysis was performed using the statistical software package SPSS (SPSS Inc., USA).
Every measurement was repeated by two different trained operators, which allowed assessing that there was no systematic error and the registered values above 0.5 mm and 2° resulted highly reliable and repeatable.
Thus, values below 0.5 mm linear displacement and 2° angular movement were not registered, since they were far from clinical relevance. For every movement and tooth, the Wilcoxon rank-sum test was conducted and p values below 0.05 revealed when there was a statistically significant difference between the planned and the actual position of the examined tooth.
Table 3 shows accuracy percentages sorted by movement and tooth. Authors believed that every tooth should be analysed separately, as it displays unique radicular and crown morphologies as well as supporting alveolar bone histology. These issues must not be underestimated when the response of the teeth to orthodontic forces is being discussed.
Significant sample sizes were obtained for vertical apical displacement (intrusion), vestibulo/lingual (V/L) crown tipping, and rotation.
When the sample did not result sufficiently represented, the teeth were excluded from the assessment.
Few data were available for both maxillary and mandibular molars, especially the mandibular second molars which were excluded from both intrusion and V/L tip measurements.
The overall accuracy for rotation resulted in 86%, ranging from 96% for the maxillary central incisors to 70.4% for the mandibular first premolars. Nearly half of the examined teeth completed a rotation with over 90% accuracy, while the remaining ones were placed between 80 and 90% (except the mandibular first premolars, with 70.4%).
The intrusion was registered only for anterior teeth, while the sample was not acceptable for posterior teeth. Mean predictability was 92%, with the worst result being 86.7% for the mandibular canines and the best being 98% for the mandibular central incisors.
V/L tipping was the most accurate movement: 93.1% of the prescribed movement was completed. Maxillary central incisors showed the lowest accuracy (80.7%), while mandibular central incisors were the highest (97.5%).
No statistically significant difference was found between planned and actual movement in the majority of cases (Table 4). The entire groups of intrusion and V/L tipping revealed a high precision since the planned and actual final positions resulted statistically homogeneous.
Nevertheless, some final positions were found to be significantly different from the predicted ones. In particular, p values < 0.05 were calculated for the intrusion of some teeth: maxillary lateral incisors, maxillary canines, mandibular lateral incisors, mandibular canines, maxillary first premolars, and mandibular first premolars.
The reliability of 3D digital planning has always been the centre of the debate over aligner therapy, since its introduction. At an early stage, in 2005, Djeu et al.  highlighted a clear difference between Invisalign® system and multibracket treatment, with the latter being significantly more effective in achieving good occlusal relationships and sagittal discrepancies. Recent systematic reviews, for instance, the 2019 study by Robertson et al. , found that clear aligners are as effective in the resolution of mild to moderate malocclusions as fixed orthodontics, although braces might be the best choice for complex malocclusions.
Different results throughout the years reflect the significant improvements in technology, software, and materials, not to mention the fact that new knowledge and experience allow clinicians to properly choose among aligners and other orthodontic tools.
The present study aims to give a reliable evaluation of how accurate Invisalign® can be in obtaining the prescribed movements. Appropriate sample size was obtained for rotation, intrusion of anterior teeth, and V/L tipping. Clinical experience and literature evaluation allow authors to maintain that these are the most prescribed movements when aligners are properly used. Major posterior intrusion, mesiodistal (M/D) translation, or torque movement are today considered contraindications  for the use of aligners, but the accuracy of the other movements is far from being clear.
Our results suggest that all examined movements can be achieved with high-rate precision, especially the intrusion of anterior teeth and V/L tipping, which showed an overall completion rate being, respectively, 92% and 93.1%, compared to prescription. Significantly lower results were obtained for rotation (86%) with the lowest accuracy regarding rotation of mandibular first premolars (70.4%).
Despite the great interest in the matter, little evidence has been produced regarding the exact amount of movements we can obtain from clear aligners with respect to the ones indicated in the 3D initial project.
Tepedino et al. , using Nuvola® system, put the focus on the importance of re-evaluation of results every 12 steps before proceeding to the next set of aligners. Among clinical papers, the study by Lombardo et al.  presents the most remarkable protocol and results: they obtained a mean accuracy of 73.6%. The least predictable movement was lower canine rotation, while the most predictable resulted to be the M/D tipping of lower premolars.
In 2015, Rossini et al.  found reduced predictability for rotations, especially for rounded teeth such as canine and premolars, and extrusion, while intrusion and distalization up to 1.5 mm proved to be more accurate.
What results from the most recent systematic reviews of the efficacy of tooth movement with Invisalign®, among which the prospective follow-up study by Haouil et al. , is that maximum efficiency is obtained in V/L tipping, while the lowest involves the rotation of the canines and premolars. However, though these findings are better than the data obtained in the previous part of this study , they do not change what we know about the most and least effective movements.
To our knowledge, our results may overcome the data already available in the literature, despite the fact strengths and weaknesses of clear aligners proved to be the same. Authors believe that this is due to the use of refinements, i.e. new sets of aligners worn by the patients when the first sequence did not lead to satisfying results. Refinements are the counterpart of finishing procedures in fixed appliances; several methods of completing a multibracket treatment are used , but the need for finishing in most cases is undisputed. Therefore, since refinements are common events during orthodontic treatment with Invisalign®, they should be included in the evaluation of accuracy as done in this study.
Furthermore, some auxiliary features helped in achieving prefigured treatments goals.
The majority of intrusions did not exceed 2 mm, which can explain, together with the frequent use of bite ramps and pressure areas, the extremely high success rates.
Since aligners biomechanics is based on the pressure generated by the deformation of the aligner’s surface over the crown of the tooth, it seems logical that V/L tipping was shown as the most accurate movement in most papers.
With regard to rotation, the recent adoption of optimized rotation attachments aimed to create a couple of forces and the momentum that the tooth needs to make a pure rotation on its axis. However, this strategy was not sufficient, as incomplete rotations were the main reason for the need for refinements in our sample. In these cases, the clinician found it useful to perform a slight IPR between canines and the adjacent teeth.
A key fact when interpreting these data is that no movement in orthodontics is pure, but each one consists of several components; when evaluating intrusion, if the tooth simultaneously goes through a vestibularization—implying a “relative” intrusion—the total amount of intrusion will be the sum of the two movements, and so on. Therefore, every result that isolates a single movement should be judged as a simplification of a complex reality, considering that studying the overall movement—as it should be made—would not lead to an advancement in our knowledge about what can and what cannot be predictably done through aligners.
The main limitation to this study is the reduced sample that did not allow the evaluation of major corrections, especially in posterior teeth that are infrequently involved in great movements. Nevertheless, many hybrid approaches are being tested to support posterior corrections in association with clear aligners; therefore, future papers are likely to bring innovations to this field.
A further limitation is the risk of overestimation of Invisalign® efficacy. The fact that no limits were put to the number of refinements used implied that from an average of 21,2 aligners per arch, the final mean number of steps per arch increased to 50. This meant that the planned movements were achieved, but at a higher cost of time than the initial evaluation. Nonetheless, the authors want to stress how this fact did not lead to periodontal problems, root resorption, or further economic costs, in contrast to what can occur with fixed appliances.
A last significant limitation is a knowledge that ClinCheck® cannot be used as a universal predictor of results. In fact, on the one hand, the huge amount of variables, in the response of the tissues to orthodontic forces, makes it impossible to predict an exact position; on the other hand, a 3D simulation can be used in combination with clinical expertise to set an initial goal as a starting point for the evaluation of the individual responses.
The present study provided reassuring data in support of the accuracy of the Invisalign® system; when careful treatment planning follows a correct diagnosis, together with the use of auxiliary features and refinements, the planned results can be achieved in a clinically successful way.
The data extrapolated from this analysis, however, agree with other studies, revealing a discrepancy between the planned movements and the results obtained.
Vestibulolingual tipping was the most predictable movement, reaching an accuracy of 95.9% for the lower arch and 94.6% for the upper arch. Intrusions reached a mean accuracy of 92.2% and 94.3% in the lower and upper arch, respectively. Rotations achieved a mean accuracy of 86.0%.
The least predictable movement was the rotation of the premolars, canines, and lateral incisors: the upper canine had a mean accuracy of 81.0%, the lateral incisor 80.9%, the second upper premolar 80.7%, the lower first premolar 70.4%.
There was no statistical significance among tooth movements, except for the rotation of upper and lower lateral incisors, canines, and premolars.
The intrusion was highly predictable up to 2 mm, above which the predictability of the movement was reduced.
In conclusion, the results obtained from this clinical study considerably contribute to the ongoing debate. It is desirable that in the future greater samples will be analysed to overcome bias related to variables (inter-and intra-arch differences, "relative" movements, radicular movement control), thus obtaining more reliable answers to the clinical questions that remain unsolved to date, the majority of which are related to the treatment of severe malocclusions.
Availability of data and materials
The data set supporting the conclusions of this article is included within the article. Further data sets are available from the corresponding author on reasonable request.
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Major and essential technical support in digital measurements was provided by Koident S.r.l.
The authors declare that no funding was received in the realization of this study.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of the University of Palermo General Hospital (A.O.U. Policlinico Paolo Giaccone; approval number 2/2020). Informed consent was obtained from every participant.
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Bilello, G., Fazio, M., Amato, E. et al. Accuracy evaluation of orthodontic movements with aligners: a prospective observational study. Prog Orthod. 23, 12 (2022). https://doi.org/10.1186/s40510-022-00406-7


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