bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical value of serum TPS in gynecological malignancies
Authors: Salman T. , El-Ahmady O. , Sawsan M.R. , Nahed M.H.
Published: March 2018

This study included 75 cases; 39 with gynecological cancer of different types, stages, and grades (14 ovarian, 11 endometrial, 9 cervical, and 5 vulvovaginal); 23 patients with benign gynecological diseases and 13 normal healthy controls. Serum TPS was estimated using the ELISA kit supplied by Beki Diagnostic AB, Bromma, Sweden. The results of the present study revealed that serum TPS was significantly elevated in cancer patients followed by those with benign diseases. When the cutoff values were adjusted to 137 and 101 U/L, we obtained sensitivities of 56.4% and 82.1% at specifities of 100% and 85%, respectively. The benign diseases group had false positive rates of 13% and 34.8%, respectively. When considering tumor site, vulvo vaginal cancer showed the highest sensitivity (80%) followed by cervical (66.7%), ovarian (50%), and lastly endometrial cancer (45.5%). Serial measurement of TPS was shown to be of important value in the post-surgical follow-up of cancer patients.
Correlation between pS2 protein positivity, steroid receptor status and other prognostic factors in breast cancer
Authors: Racca S. , Conti G. , Pietribiasi F , Stramignoni D. , Tampellini M. , Valetto M.R. , Ghezzo F. , Di Carlo F.
Published: March 2018

The cytosolic levels of pS2, an estrogen-regulated protein, were measured in 100 cases of primary breast cancer and related to several conventional histological and biochemical prognostic factors. The data were statistically analyzed on the basis of two different cutoff points for pS2: 4 and 11 ng/mg of cytosolic proteins. pS2 positivity (cutoff 11 ng/mg) was shown to be associated with smaller tumor size (p = 0.05), a higher differentiation grade (p = 0.007) and a smaller number of mitoses (p = 0.004), but not with menopausal status, lymph node involvement, cathepsin D levels, or proliferative activity determined by the monoclonal antibody Ki67. With the cutoff of 4 ng/mg, the statistical significance was confirmed only for the number of mitoses (p = 0.03), which was also the most closely related covariate in multivariate analysis (p = 0.008). As regards steroid receptor status, a significant difference was observed between pS2+ and pS2– cases (Chi-square = 8.9; p - 0.04, cutoff 4 ng/mg). In conclusion, pS2 positivity, being preferentially expressed in hormone-dependent cells and related to other well-known positive markers, may either indicate a good prognosis or predict responsiveness to endocrine treatment.
Serum levels of procollagen type I carboxyterminal extension peptide in cancer patients with bone metastases
Authors: Santi I. , Monti M. , Viganò A. , D'aprile E. , Rampoldi E. , Castellani L. , Accinni R. , Cunietti E.
Published: March 2018

Serum levels of procollagen type I carboxy-terminal extension peptide (PICP) reflect the synthesis of type I collagen. As PICP is produced by osteoblasts and is not incorporated into bone matrix, serum PICP levels have been suggested as a marker of bone formation. In 37 cancer patients (21 men and 16 women; age: 72.4±8.6 (mean±SD) years) with bone metastases and 23 women (age: 77.3+6.64 years) as controls, the following biochemical variables were measured: serum PICP, calcium (Ca), phosphorus, alkaline phosphatase (AP) and tartrate-resistant acid phosphatase (TRAP), and urinary hydroxyproline and calcium corrected for creatinine excretion.

Higher serum levels of PICP were observed in cancer patients than in controls (245±177 μg/l vs 121.7±36 μg/l, p<0.01). Cancer patients also had higher AP levels than controls (704±755 U/l vs 216.5±56 U/l, p<0.01). Abnormal PICP and AP serum concentrations (above the mean+2SD of controls) were found in 46% and 51% of patients, respectively. Moreover, patients showed significantly lower serum calcium concentrations (p<0.001), and higher TRAP and hydroxyproline levels although statistical significance was not reached. In the patients, PICP was correlated directly with AP (r=0.50, p<0.01) and TRAP (r=0.34, p<0.05). In conclusion, patients with bone metastases have increased bone turnover as shown by serum markers. Serum PICP may be used as an adjunctive, non-invasive index to assess bone metabolism. However, the clinical usefulness of PICP in cancer patients needs further evaluation.
Immunohistochemical Staining of Metastatic Ductal Carcinomas of the Breast by Monoclonal Antibodies used in Imaging and Therapy: A Comparative Study
Authors: Howell L.P. , Denardo S.J. , Levy N.B. , Lund J. , Denardo G.L.
Published: March 2018

Five monoclonal antibodies (MoAbs) (L6, 170H.82, 155, BrE-3 and BR96), most of which have been previously shown to target breast cancer and not normal tissues by immunoscintigraphic imaging, were evaluated for their frequency and pattern of immunohistochemical staining in 67 to 116 metastatic lesions from patients with ductal carcinoma of the breast. Immunoperoxidase staining in 75% or more of the cells occurred in 56/116 (48%) for L6, 44189 (49%) for Br, -96, 58/102 (57%) for 155, 62/99 (84%) for 170H.82, and 65.67 (97%) for BrE-3. With the first three MoAbs, an additional 6-10% of the tumors showed staining in 50-75% of tumor cells. These results illustrate that most patients with metastatic ductal carcinoma have cancer tissue in which a high percent of cells will react to several of these selected MoAbs that target different epitopes. The high expression of the MoAb targets throughout the tumor tissue makes these antibodies potential candidates to carry immunologically directed radioimmunotherapy and is an aid in selecting patients for treatment..
Steroid receptors in pleural effusions of advanced breast cancer patients
Authors: Branković-Magić M. , Nešković-Konstantinović Z. , Nikolić-Vukosavljević D. , Spužić I.
Published: March 2018

The steroid receptor content in breast carcinoma correlates with the responsiveness of malignant cells to endocrine manipulation. Although the steroid receptor status of the primary tumor is mostly used to select systemic therapy, it was suggested that steroid receptor content should be evaluated in metastatic lesions whenever possible. In this study the estrogen and progesterone receptor content was determined biochemically in 38 pleural effusions from advanced breast cancer patients. In 17/38 patients the steroid receptor status was assessed twice during the course of the disease - at diagnosis in the primary tumor/lymph nodes, and subsequently in metastatic pleural effusion fluid. A trend towards lower receptor values in pleural fluids was evident. There was no correlation between pleural steroid receptor content and pleural response to endocrine or chemo/endocrine therapy, indicating that the usefulness of effusional steroid receptors for therapy planning of advanced breast cancer could not be confirmed in this study.
Clinical utility of hyaluronic acid values in serum and bronchoalveolar lavage fluid as tumor marker for bronchogenic carcinoma
Authors: Hernández J.R. Hernández , García J.M. García , Muñíz M.A. Martínez , Monclus M.T. Allende , Morell A. Ruibal
Published: March 2018

Various authors have proposed the use of hyaluronic acid (HA) as a tumor marker. In order to analyze its usefulness as a marker in bronchogenic carcinoma, the most common carcinoma in men, we determined the HA values in serum and bronchoalveolar lavage fluid (BAL). We performed prospective studies on two groups of patients: 81 diagnosed as having bronchial carcinoma and 34 with benign respiratory diseases.

HA values were higher in patients with cancer than in those with benign diseases (serum: 79.8 ng/ml vs 63.7 ng/ml; BAL: 927 ng/mg vs 522 ng/mg). Also, the percentage of patients with levels exceeding the established cutoff was greater in the group with cancer than in the group with benign diseases (serum: 24.6 vs 17.6; BAL: 25.3 vs 3). Statistically significant differences in these percentages were found in BAL (p<0.01). Patients with extended small cell carcinoma had higher HA values (p=0.04) than those with limited disease, and the percentage of patients with abnormal HA values was larger in the group with extended disease than in the group with limited disease (p=0.004). The serial determinations of HA values in serum reflected the clinical evolution after treatment in 73% of the small cell carcinomas. Most of the patients with benign diseases whose HA values exceeded the cutoff level suffered from acute infectious dis-eases. Once these cases were excluded, the specificity of HA value determination in the diagnosis of carcinoma was very high (serum 96%, BAL 100%). The determination of HA levels in serum or BAL did not have any prognostic value in this study.

We conclude that the HA levels in serum and BAL could be of interest as a tumor marker, especially in patients with small cell carcinoma.
Evaluation of the serum markers CEA, NSE, TPS and CYFRA 21.1 in lung cancer
Authors: Giovanella L. , Ceriani L. , Bandera M. , Beghe B. , Roncari G.
Published: March 2018

We investigated the role of tumor markers CEA, NSE, TPS and CYFRA 21.1 in lung cancer diagnosis and staging in 169 patients with histologically confirmed lung cancer (43 SCLC and 126 NSCLC). In SCLC patients NSE and CYFRA 21.1 showed the highest senstitivity and their combination improve significantly the diagnostic sensitivity and accuracy. In NSCLC patients CYFRA 21.1 showed the highest sensitivity and global accuracy and no markers association was as effective as CYFRA 21.1 alone. Based on data from our study it can be concluded that in patients with suspected lung cancer the serum NSE and CYFRA 21.1 assay is a suitable association to confirm the clinical hypothesis. NSE in SCLC and CYFRA 21.1 in NSCLC are useful in the evaluation of disease extent and successive treatment planning.
Tumor Markers in the Diagnosis, Monitoring and Therapy of Pancreatic Cancer: State of the Art
Authors: Plebani M. , Basso D. , Panozzo M.P. , Fogar P. , Del Favero G. , Naccarato R.
Published: March 2018

The present review focuses on the utility of serum tumor markers in screening, diagnosis, prognosis and monitoring of pancreatic cancer. Serum determination of all tumor markers studied offers no help in screening or early diagnosis of pancreatic cancer. For diagnosis, blood group-related antigens, in particular CA 19-9, are considered the best indicators of this neoplasm. However, as occurs with other glycoproteic tumor markers, the circulating levels of CA 19-9 are significantly influenced by jaundice, probably because its liver metabolism is reduced. Therefore, the finding of elevated CA 19-9 levels in jaundiced patients has to be evaluated with caution. Since pancreatic cancer recurrences are not susceptible to treatment, the clinical role of widespread use of tumor marker determination in follow-up programs is limited and calls for a critical evaluation.
Vascular Endothelial Growth Factor (VEGF) Serum Levels during Cancer Immunotherapy with IL-2: Preliminary Considerations
Authors: Lissoni P. , Fumagalli L. , Giani L. , Rovelli F. , Confalonieri G , Pescia S.
Published: March 2018

Neoangiogenesis has been proven to play a fundamental role in promoting cancer spread, and vascular endothelial growth factor (VEGF) is known to represent one of the most important angiogenic factors. The present study was planned to investigate changes in VEGF secretion in cancer patients undergoing immunotherapy with IL-2, with the aim of establishing whether VEGF variations play a role in mediating the IL-2-induced control of neoplastic diseases. The study involved 14 metastatic renal cell cancer patients treated with IL-2 immunotherapy (6 million IU/day subcutaneously for 6 days/week for 4 weeks). The clinical response consisted of partial response (PR) in 3, stable disease (SD) in 6 and progressive disease (PD) in the remaining 5 patients. VEGF serum levels were measured by an enzyme immunoassay designed to determine both bound and unbound VEGF. No significant changes in VEGF mean levels occurred during IL-2 therapy. Moreover, neither in patients with PR or SD nor in those with PD did the mean serum levels of VEGF change significantly in response to IL-2. This preliminary study seems to exclude that changes in the angiogenic factor VEGF may play a role in mediating the therapeutic efficacy of IL-2 cancer immunotherapy. However, since the method of measurement used in our study was designed to detect the total amount of VEGF, it cannot be excluded that changes in the free fraction of the molecule may occur during IL-2 cancer immunotherapy.
How Tumor Markers are used in the Routine Follow-up of Breast and Colorectal Cancer. A Survey of 29 Italian Hospitals
Authors: Gion M. , Barioli P. , Ponti A. , Torri V. , Mione R. , Dittadi R.
Published: March 2018

The impact of tumor markers on the outcome of several malignancies is still under debate. This relative uncertainty leads to a subjective approach to their use. Monitoring the use of tumor markers is a valuable tool to identify the need for educational policies. We conducted a survey to evaluate how tumor markers are routinely used in the follow-up of patients with breast, colorectal and ovarian carcinoma. The former two malignancies are considered in the present paper. We surveyed 35 Italian hospitals; 29 (83%, accounting for 26,622 hospital beds) filled in and returned the questionnaire. Overall, 467,361 tumor marker requests were scrutinized by the surveyed hospitals. We found a wide variability in the type and number of routinely used markers, the cutoff points chosen, and the clinical decisions taken on the basis of marker results. In addition, we observed a relative lack of communication between clinicians and clinical pathologists in around 50% of the surveyed hospitals. In these cases clinical information was not provided to the laboratory and methodological aspects were not communicated to clinicians. From the findings of the present study we conclude that the cooperation between clinicians and clinical pathologists must improve before guidelines for the use of tumor marker assays can be framed and the compliance with these guidelines can be checked. Request forms for tumor marker assays should therefore be designed to contain clinical information and the quality of filling in request forms with clinical data should be carefully monitored.
Dehydroepiandrosterone Sulfate (DHEAS) Secretion in Early and Advanced Solid Neoplasms: Selective Deficiency in Metastatic Disease
Authors: Lissoni P. , Rovelli F. , Giani L. , Mandala M. , Meregalli S. , Barni S. , Confalonieri G , Bonfanti A.
Published: March 2018

Several endogenous hormones have been proven to stimulate cancer growth, whereas at present very few hormones are known to display oncostatic activity. The most widely investigated antitumor hormone is the pineal indole melatonin (MLT), and cancer progression has been shown to be associated with a decline in MLT secretion. Recently, another hormone, the adrenal steroid dehydroepiandrosterone-sulfate (DHEAS), has appeared to exert antitumor effects similar to those previously described for MLT In addition, experimental studies suggest a diminished DHEAS production with neoplastic progression. This preliminary study was performed to evaluate the daily secretion of DHEAS in a group of early and advanced cancer patients. The study included 70 patients with solid tumors (gastrointestinal tract tumors: 28; breast cancer: 24; non-small cell lung cancer: 18), 28 without and 42 with distant metastases. The serum levels of DHEAS were measured by RIA in blood samples collected in the morning. The control group consisted of 100 age- and sex-matched healthy subjects. No significant difference in mean serum levels of DHEAS was observed between controls and non-metastatic patients. In contrast, metastatic patients, irrespectively of tumor histotype, showed significantly lower mean levels of DHEAS with respect to either controls or non-metastatic patients. Moreover, metastatic patients with visceral locations showed significantly lower values of DHEAS than those with bone or soft-tissue metastases. This preliminary study would suggest there to be a deficiency in the daily DHEA secretion in patients with disseminated cancer. Further studies evaluating circadian DHEAS secretion in relation to that of the pineal hormone MLT will be required to better define the biological significance of the advanced cancer-related decline in endogenous DHEAS production.
Blood Concentrations of Interleukin-15 in Cancer Patients and Their Variations during Interleukin-2 Immunotherapy: Preliminary Considerations
Authors: Lissoni P. , Rovelli F. , Mandalà M. , Barni S.
Published: March 2018

In addition to the better known cytokines IL-2 and IL-12, IL-15, which is mainly produced by macrophages, is a new antitumor cytokine with a mechanism of action similar to that of IL-2. At present, however, there are no data about IL-15 secretion in cancer patients. This study was carried out to evaluate IL-15 blood concentrations in patients with early or advanced cancer and their possible variations in response to IL-2 cancer immunotherapy. The study included 40 patients with solid tumors, 24 of whom had metastatic disease. In addition, IL-15 secretion was evaluated during subcutaneous low-dose IL-2 therapy (6 million IU/day for 6 days/week for 4 weeks) in 14 metastatic renal cell cancer patients by collecting blood samples at weekly intervals. The control group consisted of 40 age-matched healthy subjects. Serum levels of IL-15 were measured by an enzyme immunoassay. No significant difference in mean serum levels of IL-15 was observed between cancer patients and controls. Moreover, the mean serum levels of IL-15 found in metastatic cancer patients were not significantly different from those found in patients with limited disease. Finally, no significant changes in mean levels of IL-15 occurred during IL-2 cancer immunotherapy. This preliminary study would suggest that IL-15 secretion is substantially within the normal range in cancer patients, both in early and advanced disease, and no variation seems to occur in response to IL-2 administration.
Regulation of CA 125 Expression in Cultured Human Carcinoma Cells
Authors: Marth C. , Zeimet A.G. , Widschwendter M. , Daxenbichler G.
Published: March 2018

CA 125 shedding is not a constitutive and stable process but may be affected by cell cycle and cell proliferation as well as by various growth factors and cytokines. Interferons, interleukin-1β, tumor necrosis factor-α and transforming growth factor-α have been shown to induce while glucocorticoids and transforming growth factor-β have been shown to suppress the release of the tumor marker CA 125 from ovarian carcinoma cells. Several endogenous as well as exogenous factors may affect CA 125 biosynthesis; however, a major question remains whether this observed modulation of CA 125 expression in vitro is of clinical importance.
Overview: Quality Control of Tumor Marker Assays
Authors: Kruse R. , Geilenkeuser W.-J. , Röhle G.
Published: March 2018

Data from interlaboratory surveys for the determination of CA 125 (1987 to 1998) show large differences depending on the commercial kit used. Samples of the same material produced different analytical results in different interlaboratory surveys, thus showing that some kits did not have a satisfactory rate of reproducibility over a longer period of time.
Hormonal Regulation of MUC1 Expression
Authors: Seregni E. , Botti C. , Bajetta E. , Ferrari L. , Martinetti A. , Nerini-Molteni S. , Bombardieri E.
Published: March 2018

Several circulating mucinous markers, including CA 15.3, MCA, CA 459, CASA, and Truquant BR, are secreted products of the polymorphic MUC1 gene, and are used as diagnostic tools in patients with breast cancer. In clinical practice the measurement of the levels of these markers in the blood can give important information on the tumor's response to treatment and its biological behavior during disease monitoring. Since the marker levels reflect the activity of the tumor, it is important to know all factors influencing the production/secretion and the blood concentrations of MUC1 mucin. Recent findings suggest that MUC1 gene expression is regulated by steroid hormones and other substances present in the serum. Such observations are very important not only because of their biological significance but also for their clinical implications, as one approach to breast cancer therapy is based on chemical hormone manipulation. Nevertheless, we have preliminarily demonstrated that endocrine treatment in breast cancer patients does not influence the circulating CA 15.3 serum levels, so changes in marker levels are related only to the clinical evolution of the tumor.
Apoptosis and Bcl-2 Expression in Relation to Age, Tumor Characteristics and Prognosis in Breast Cancer
Authors: Holmqvist P. , Lundström M. , Stål O. ,   THE SOUTH-EAST SWEDEN BREAST CANCER GROUP, Arnesson L.-G. , Nordenskjöld B. , Nordenskjöld K. , Malmström A. , Bång H. , Källström A.-Ch. , Einarsson E. , Norberg B. , Adlouni W. , Henning Å. , Sundquist M. , Tejler G.
Published: March 2018

The extent of apoptosis and the expression of Bcl-2 was investigated in tumor samples from 165 women who underwent surgery for primary breast carcinoma between 1989 and 1990 in South-East Sweden. Apoptosis was assessed by a DNA fragmentation assay for flow cytometry. Bcl-2 protein expression was analyzed with immunocytochemistry Bcl-2 immunoreactivity correlated with estrogen receptor (ER) and progesterone receptor (PgR) positivity and was inversely correlated with p53 accumulation. Apoptosis increased with patient age and a high degree of apoptosis was negatively associated with Bcl-2 immunostaining. Apoptosis showed no significant correlation with any of the other variables studied, including prognosis. The group with Bcl-2-positive tumors tended to have a lower risk of distant recurrence than others, but the association of Bcl-2 with recurrence was different in groups divided by ER and PgR status. Whereas Bcl-2 positivity indicated a low recurrence rate among PgR-negative patients, in the PgR-positive group, those with Bcl-2-positive tumors showed a non significantly higher recurrence rate than Bcl-2-negative cases. In the PgR-positive group, Bcl-2-positive tumors also appeared more frequently to be lymph node positive and DNA aneuploid. The results suggest that hormone receptor status is of importance for the prognostic role of Bcl-2. Likewise, patient age merits consideration when apoptosis is studied in human cancer.
Tissue Quantification of CA 125 in Epithelial Ovarian Cancer
Authors: De La Cuesta R. , Maestro M.L. , Solana J. , Vidart J.A. , Escudero M. , Iglesias E. , Valor R.
Published: March 2018

The objectives of this study were the determination of CA 125 in the cytosol of healthy and carcinomatous ovarian tissue by immunoanalysis, analysis of its correlation with the biological characteristics of ovarian carcinoma, determination of serum CA 125 levels, and study of the prognostic value of the marker in cytosol. The levels of the marker depend not only on the tumor's production rate, so its determination in tissue can indicate more accurately if the tumor is a producer of the marker and establish its value for the prognosis of the disease. Determination of CA 125 in tissue was performed by immunoanalysis in 50 ovarian epithelial cancer samples, 13 benign pathology samples and 32 healthy ovary samples. The presurgical serum level of the marker was also obtained. The correlation between the CA 125 level in the cytosol and the different biological characteristics of the ovarian carcinoma, the serum levels of the marker and survival were analyzed. The CA 125 level proved to be higher in malignant tissue (p<0.0001). There was a significant association between the tissue marker and histological type (high CA 125 was associated with serous and endometrioid tumors) and between the marker and survival. No relation with stage was found. There was a correlation between the CA 125 level in the cytosol and serum, both variables being dependent, with a correlation coefficient of 0.44. This good correlation speaks in favor of the usefulness of CA 125 determination in serum in the follow-up of ovarian cancer. Tumors having high tissue expression of CA 125 were found to have a double relative risk of death, independently of tumor stage.
Changes in Lymphocyte Number during Cancer Chemotherapy and Their Relation to Clinical Response
Authors: Lissoni P. , Fumagalli L. , Paolorossi F. , Mandalà M.
Published: March 2018

Since hematologic examination during cancer chemotherapy is generally limited to the evaluation of neutrophil and platelet numbers, at present there are no clear data about the possible prognostic significance of changes in lymphocyte number in relation to the clinical efficacy of chemotherapy itself. To obtain some preliminary data about this issue, we have evaluated changes in lymphocyte number and percentage in a group of 50 advanced non-small cell lung cancer patients treated with three cycles of cisplatin (20 mg/m2/day) plus etoposide (100 mg/m2/day) i.v for three days every 21 days. The clinical response consisted of partial response (PR) in nine (18%), stable disease (SD) in 18 (36%) and progressive disease (PD) in the remaining 23 (46%) patients. The lymphocyte percentage increased during chemotherapy, without, however, a significant difference with respect to the pretreatment values. In contrast, the mean number of lymphocytes observed after the first chemotherapeutic cycle significantly decreased in patients with PD, whereas it increased in patients with PR or SD, even though the difference did not reach statistical significance. These preliminary data, which have to be confirmed in a large number of patients and in patients treated with other chemotherapeutic schedules for different tumor types, seem to suggest that a chemotherapy-induced decline in lymphocyte number may be associated with a lack of efficacy of chemotherapy itself.
Generation of Expression Plasmids for Angiostatin, Endostatin and Timp-2 for Cancer Gene Therapy
Authors: Indraccolo S. , Minuzzo S. , Gola E. , Habeler W. , Carrozzino F. , Noonan D. , Albini A. , Santi L. , Amadori A. , Chieco-Bianchi L.
Published: March 2018

Antiangiogenic therapy may represent a promising approach to cancer treatment. Indeed, the efficacy of endogenous angiogenesis inhibitors, including angiostatin, endostatin and TIMPs, has been demonstrated in many types of solid tumors in animal models. In view of the possible problems associated with long-term administration of inhibitors as recombinant proteins, we propose their delivery as nucleic acids through a gene therapy approach. To this end, eukaryotic expression constructs for murine angiostatin and endostatin as well as human TIMP-2 were generated, and characterized in vitro. All constructs carry the relevant cDNAs under the control of the strong HCMV promoter/enhancer, and cleavable leader signals to allow protein secretion. Expression of the angiogenesis inhibitors was detected by in vitro transcription/translation experiments as well as transfection of 293T cells, followed by Western blotting (WB) or radioimmunoprecipitation analysis of both cell lysates and supernatants (SNs). These constructs might be used for in vivo intramuscular delivery of plasmid DNA and as a set of reagents for the development of retroviral as well as adeno-associated viral (AAV) vectors expressing angiogenesis inhibitors.
Animated Images and Animated Objects in the Toy Story Franchise: Reflexively and Intertextually Transgressive Mimesis
Authors: Geal Robert
Published: March 2018

This article explores how animation can manipulate a reflexive intertextual framework which relates to religious prohibitions on artistic mimesis that might replicate and threaten God’s creative act. Animated films are most intertextually reflexive, in these terms, when they narrativize the movement of diegetic objects from another medium which also transgresses God’s prohibition: sculpture. In the media of both sculpture and animation, the act of mimesis is transgressive in fundamentally ontological terms, staging the illusion of creation by either replicating the form of living creatures in three-dimensional sculpture, or by giving the impression of animating the inanimate in two-dimensional film. Both media can generate artworks that directly comment on these processes by using narratives about the creative act which not only produce the illusion of life, but which produce diegetically real life itself. Such artworks are intensely reflexive, and engage with one another in an intertextual manner. The article traces this process from the pre-historic and early historic religious, mythic and philosophical meditations which structure ideas about mimetic representations of life, via Classical and Early Modern sculpture, through a radical proto-feminist revision crystallizing around the monstrous consequences of the transgression in Mary Shelley’s Frankenstein, and finally into film and more specifically animation. The article culminates with a relatively detailed account of these processes in the Toy Story franchise, which is a heightened example of how animation can stage a narrative in which ostensibly inanimate sculpted toys move of their own volition, and of how this double form of animation does this reflexively, by ontologically performing the toys’ animating act. The animated films analysed also engage with the transgressive and monstrous consequences of this double form of animation, which derive from the intertextual life of those narratives that challenge God’s prohibition on mimesis.
Snow White and the Seven Dwarfs, Cinderella and Sleeping Beauty: The Components of Costume Design in Disney’s Early Hand-Drawn Animated Feature Films
Authors: Kalmakurki Maarit
Published: March 2018

Costumes in feature films can be deliberately used for narrative purposes to reveal or conceal something related to the plot, functioning as a key element for cinematic storytelling. Costume design in animation is an integral part of character creation; however, relatively little is known about the design process. Previous research concentrates on either the history of hand-drawn animation, the principles of making animated films or character construction. This article presents several key components of the animators’ costume design process in Walt Disney’s animated feature films Snow White and the Seven Dwarfs (1937), Cinderella (1950) and Sleeping Beauty (1959). The author demonstrates that the costume design in these films was a multi-layered process. For example, for Snow White, the costume silhouette of the final animation is visible in the early conceptual designs whereas, for Cinderella or Princess Aurora, the principal character animators designed the final costume. Additionally, the slow production time influenced the style of the costumes: small details on costumes and complex constructions were not used as it would have taken too long for them to be drawn. The article also reveals that animators used live-action filming and rotoscoping as tools for designing costumes. Furthermore, costumes that were used in pre-production filming for rotoscope were different in their construction from everyday garments. The work of a costume designer existed in the character design process, although not as a separate profession. This article aims to highlight the importance of characters’ costumes in Disney’s early hand-drawn animated films and the different ways costumes have been designed for animated characters.
Jan Švankmajer’s Don Šajn (1970): Puppets as intimate objects
Authors: Sera Mareike
Published: March 2018

The puppet form has caught the imagination of many artists and writers. However, coming to terms with this riddling figuration is difficult. As a configuration characterized by tensions and conflicts, it eludes easy determination. This article focuses on the paradoxical nature of the puppet form: the tension in between the external bodily existence and the internal dramatic life of the puppet – two existential states that invest the puppet form with a perplexing double life. The paradox of renegotiating communicative flows between interior and exterior worlds is examined in relation to the phenomenon of intermediality. Amidst the intermedial concatenation of different modes of expression – puppetry, theatre, cinema and object animation – the puppet form acts as an intimate space. Concrete instances of medial interchanges carry metaphorically a long way towards the most intimate relation of knowing and feeling in resonance with the puppet form. Working with one of the finest examples of the use of puppetry in film, Jan Švankmajer’s Don Šajn (1970), these thoughts are developed through a series of readings ranging from the film critic Michael O’Pray’s view of the film, André Breton’s notion of communicating vessels, Deleuze’s concept of the baroque fold and Paul Ricoeur’s hermeneutic phenomenology.
A practical guide to medical ethics for intensivists
Authors: Innes Richard , Montgomery Hugh , Bolton Jim , Rowland Matthew , Hannam Andrew , Lindsay Simon , Sankey Paul
Published: March 2018

This series of articles provides a practical guide to dealing with the complex ethical and legal challenges we face in the provision of Intensive Care. They explain the implications of recent legal rulings and cases (such as "Montgomery" and the tragic case of Charlie Gard), and include discussion of clinical scenarios with which we are all familiar. Each article is written by those who are not only experts in their fields, but who also deal with these issues on a day-to-day basis.
Substance use in pregnancy: The medical challenge
Authors: Louw Kerry-Ann
Published: March 2018

Substance use contributes significantly to the global burden of disease. Growing numbers of women use nicotine, alcohol, and illicit substances. Women are the most vulnerable to problematic substance use in their reproductive years. The first 1000 days of life, starting at conception, have been established as a critical window of time for long-term health and development. Substance use in pregnancy is associated with negative pregnancy and child health outcomes. The impact of antenatal substance use on these outcomes needs to be considered within a challenging and complex context. This review provides an overview of the current literature on the impact of substances on pregnancy and child outcomes as well as the evidence and guidelines on screening and interventions for women using substances during pregnancy.
The ethics of Carr and Wendt: Fairness and peace
Authors: Pashakhanlou Arash Heydarian
Published: March 2018

The, classical realist writings of E.H. Carr and constructivist publications of Alexander Wendt are extraordinarily influential. While they have provoked a great number of reactions within the discipline of International Relations, the ethical dimensions of their works have rarely been studied at length. This article seeks to remedy this lack of examination by engaging in an in-depth scrutiny of the moral concerns of these two mainstream International Relations scholars. On investigation, it is revealed that Carr demonstrates a strong commitment to the ethical principle of fairness and Wendt a moral concern for the prevention of the use of organized violence. These concerns are shared by Rawlsians and cosmopolitans in International Relations, and these findings may thereby encourage closer engagement between these diverse communities that rarely speak to one another and strengthen disciplinary research on morals.
“Gaus’s choice”: The Open Society as an ideal
Authors: Singer Abraham
Published: March 2018

Gaus has recently offered a novel argument for an open society, connecting it to recent methodological debates regarding ideal and non-ideal theory. The argument, briefly put, is that political philosophies based upon the search for an ideal to anchor their critical and prescriptive ambitions, so-called “ideal theories,” are bound to fail. The best possible case for doing ideal theory should lead us to recognize that such endeavors are conceptually incoherent or lead to morally perverse outcomes. Consequently, the best way to approximate a knowledge of the optimal institutional state of affairs is to organize institutions around the goal of maximizing perspectival diversity, what Gaus calls the “Open Society,” not according to an ideal blueprint. I argue that precisely because ideal theory has the problems that Gaus skillfully illuminates, we should be skeptical about the picture he paints of the Open Society.
No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a
Authors: Havrdová Eva , Arnold Douglas L , Bar-Or Amit , Comi Giancarlo , Hartung Hans-Peter , Kappos Ludwig , Lublin Fred , Selmaj Krzysztof , Traboulsee Anthony , Belachew Shibeshih , Bennett Iain , Buffels Regine , Garren Hideki , Han Jian , Julian Laura , Napieralski Julie , Hauser Stephen L , Giovannoni Gavin
Published: March 2018

Background

No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).

Objective

The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.

Methods

NEDA was assessed in a modified intent-to-treat population ( n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β‐1a; 44 μg).

Results

NEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% ( p < 0.001), from Week 0‒24 by 33% ( p < 0.001) and from Week 24‒96 by 72% ( p < 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p < 0.001).

Conclusion

Superior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.
Hand function and recurrence after limited fasciectomy for Dupuytren’s contracture: Long-term follow-up
Authors: Bergovec Marko , Jelicic Josko , Oljaca Ana , Bilic Ranko
Published: March 2018

Purpose:

The aim of this study was to analyze long-term results after limited fasciectomy for Dupuytren’s contracture.

Methods:

The study included 34 patients (52 rays), with an average follow-up of 9.5 years (range: 7–13 years). Range of motion, functional status, recurrence, and complications were recorded.

Results:

Preoperative metacarpophalangeal joint (MCPJ) contracture (median: 35°, range: 0–90°) improved postoperatively to full extension in all but one patient, with no recurrence at the most recent follow-up. Preoperative proximal interphalangeal joint (PIPJ) contractures (median: 52°, range: 5–100°) were initially corrected, but recurred with time (median: 25°, range 0°–80°). Hand function was assessed using the Disabilities of the Arm, Shoulder and Hand questionnaire. Postoperative hand function improved (median: 0, range: 0–27), compared to preoperative function (median: 20, range: 0–51). Hand function worsened with time (at most recent follow-up: median: 3, range: 0–40), mainly due to PIPJ contracture recurrence, but function remained better than before surgery.

Conclusion:

Limited fasciectomy is an effective treatment method for MCPJ, with full correction achievable in both the short and long term. Regarding the PIPJ, treatment outcomes seem to be multifactorial. Further clarification is required to distinguish between local recurrence and remaining contracture of the PIPJ.
Prolonged Exposure of CBA/Ca Mice to Moderately Loud Noise Can Cause Cochlear Synaptopathy but Not Tinnitus or Hyperacusis as Assessed With the Acoustic Startle Reflex
Authors: Pienkowski Martin
Published: March 2018

Hearing loss changes the auditory brain, sometimes maladaptively. When deprived of cochlear input, central auditory neurons become more active spontaneously and begin to respond more strongly and synchronously to better preserved sound frequencies. This spontaneous and sound-evoked central hyperactivity has been postulated to trigger tinnitus and hyperacusis, respectively. Localized hyperactivity has also been observed after long-term exposure to noise levels that do not damage the cochlea. Adult animals exposed to bands of nondamaging noise exhibited suppressed spontaneous and sound-evoked activity in the area of primary auditory cortex (A1) stimulated by the exposure band but had increased spontaneous and evoked activity in neighboring A1 areas. We hypothesized that the cortically suppressed frequencies should for some time after exposure be perceived as less loud than before (hypoacusis), whereas the hyperactivity outside of the exposure band might lead to frequency-specific hyperacusis or tinnitus. To investigate this, adult CBA/Ca mice were exposed for >2 months to 8 to 16 kHz noise at 70 or 75 dB sound pressure level and tested for hypo-/hyperacusis and tinnitus using tone and gap prepulse inhibition of the acoustic startle reflex. Auditory brainstem responses and distortion product otoacoustic emissions showed evidence of cochlear synaptopathy after exposure at 75 but not 70 dB, putting a lower bound on damaging noise levels for CBA/Ca mice. Contrary to hypothesis, neither exposure significantly shifted startle results from baseline. These negative findings nevertheless have implications for startle test methodology and for the putative role of central hyperactivity in hyperacusis and tinnitus.
Adaptive Processes in Hearing
Authors: Santurette Sébastien , Christensen-Dalsgaard Jakob , Tranebjærg Lisbeth , Andersen Ture , Poulsen Torben , Dau Torsten
Published: March 2018

Our auditory environment is constantly changing and evolving over time, requiring us to rapidly adapt to a complex dynamic sensory input. This adaptive ability of our auditory system can be observed at different levels, from individual cell responses to complex neural mechanisms and behavior, and is essential to achieve successful speech communication, correct orientation in our full environment, and eventually survival. These adaptive processes may differ in individuals with hearing loss, whose auditory system may cope via “readapting” itself over a longer time scale to the changes in sensory input induced by hearing impairment and the compensation provided by hearing devices. These devices themselves are now able to adapt to the listener’s individual environment, attentional state, and behavior. These topics related to auditory adaptation, in the broad sense of the term, were central to the 6th International Symposium on Auditory and Audiological Research held in Nyborg, Denmark, in August 2017. The symposium addressed adaptive processes in hearing from different angles, together with a wide variety of other auditory and audiological topics. The papers in this special issue result from some of the contributions presented at the symposium.
Analyzing public opinions on death penalty abolishment
Authors: Ye Xinyue , Sharag-Eldin Adiyana , Spitzberg Brian , Wu Ling
Published: March 2018

A meme consists of any words or images in a text that can be replicated across communicators in the exchange of information. This study tests the Multilevel Model of Meme Diffusion (M3D) in a case study in the digital electronic technology that captures the controversial opinions regarding death penalty abolishment in Nebraska. The objective is to demonstrate that an internet-based study using social media data can be used to analyze and predict social processes engaging with phenomena in real space. The authors utilize the meme death_penalty in Twitter texts to predict public perception of death penalty abolishment in Nebraska. The M3D theory integrates the fields of geography and computer-mediated communication technology to explain and predict public opinion on the death penalty.
T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans
Authors: Toapanta Franklin R. , Bernal Paula J. , Kotloff Karen L. , Levine Myron M. , Sztein Marcelo B.
Published: March 2018

Background

Shigellosis persists as a public health problem worldwide causing ~ 165,000 deaths every year, of which ~ 55,000 are in children less than 5 years of age. No vaccine against shigellosis is currently licensed. The live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S (S. flexneri 2a; ΔguaBA, Δset, Δsen) demonstrated to be safe and immunogenic in phase 1 and 2 clinical trials. Earlier reports focused on humoral immunity. However, Shigella is an intracellular pathogen and therefore, T cell mediated immunity (T-CMI) is also expected to play an important role. T-CMI responses after CVD 1208S immunization are the focus of the current study.

Methods

Consenting volunteers were immunized orally (3 doses, 108 CFU/dose, 28 days apart) with CVD 1208S. T-CMI to IpaB was assessed using autologous EBV-transformed B-Lymphocytic cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines (IFN-γ, IL-2, IL-17A and TNF-α) and/or expression of the degranulation marker CD107a in 14 volunteers (11 vaccine and 3 placebo recipients).

Results

Following the first immunization, T-CMI was detected in CD8 and CD4 T cells obtained from CVD 1208S recipients. Among CD8 T cells, the T effector memory (TEM) and central memory (TCM) subsets were the main cytokine/CD107a producers/expressors. Multifunctional (MF) cells were also detected in CD8 TEM cells. Cells with 2 and 3 functions were the most abundant. Interestingly, TNF-α appeared to be dominant in CD8 TEM MF cells. In CD4 T cells, TEM responses predominated. Following subsequent immunizations, no booster effect was detected. However, production of cytokines/expression of CD107a was detected in individuals who had previously not responded. After three doses, production of at least one cytokine/CD107a was detected in 8 vaccinees (73%) in CD8 TEM cells and in 10 vaccinees (90%) in CD4 TEM cells.

Conclusions

CVD 1208S induces diverse T-CMI responses, which likely complement the humoral responses in protection from disease.

Trial registration This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT01531530)