bluuebunny/crossref_metadata_2025 huggingface dataset:
Watch and learn
Authors: Roth Aaron , Ullman Jonathan , Wu Zhiwei Steven
Published: November 2015

A
Stackelberg game
is played between a
leader
and a
follower.
The leader first chooses an action, and then the follower plays his best response, and the goal of the leader is to pick the action that will maximize his payoff given the follower's best response. Stackelberg games capture, for example, the following interaction between a retailer and a buyer. The retailer chooses the
prices
of the goods he produces, and then the buyer chooses to buy a utility-maximizing bundle of goods. The goal of the retailer here is to set prices to maximize his profit---his revenue minus the production cost of the purchased bundle. It is quite natural that the retailer in this example would not know the buyer's utility function. However, he does have access to
revealed preference
feedback---he can set prices, and then observe the purchased bundle and his own profit. We give algorithms for efficiently solving, in terms of both computational and query complexity, a broad class of Stackelberg games in which the follower's utility function is unknown, using only "revealed preference" access to it. This class includes the profit maximization problem, as well as the optimal tolling problem in nonatomic congestion games, when the latency functions are unknown. Surprisingly, we are able to solve these problems even though the corresponding maximization problems are not concave in the leader's actions.
Algorithmic game theory and econometrics
Authors: Syrgkanis Vasilis
Published: November 2015

The traditional econometrics approach for inferring properties of strategic interactions that are not fully observable in the data, heavily relies on the assumption that the observed strategic behavior has settled at an equilibrium. This assumption is not robust in complex economic environments such as online markets where players are typically unaware of all the parameters of the game in which they are participating, but rather only learn their utility after taking an action. Behavioral models from online learning theory have recently emerged as an attractive alternative to the equilibrium assumption and have been extensively analyzed from a theoretical standpoint in the algorithmic game theory literature over the past decade. In this letter we survey two recent works, [Nekipelov et al. 2015, Hoy et al. 2015], in which we take a learning agent approach to econometrics, i.e. infer properties of the game, such as private valuations or efficiency of observed allocation, by only assuming that the observed repeated behavior is the outcome of a no-regret learning algorithm, rather than a static equilibrium. In both works we apply our methods to datasets from Microsoft's sponsored search auction system.
Dogs as a Model for Cancer
Authors: Gardner Heather L. , Fenger Joelle M. , London Cheryl A.
Published: November 2015

Spontaneous cancers in client-owned dogs closely recapitulate their human counterparts with respect to clinical presentation, histological features, molecular profiles, and response and resistance to therapy, as well as the evolution of drug-resistant metastases. In several instances the incorporation of dogs with cancer into the preclinical development path of cancer therapeutics has influenced outcome by helping to establish pharmacokinetic/pharmacodynamics relationships, dose/regimen, expected clinical toxicities, and ultimately the potential for biologic activity. As our understanding regarding the molecular drivers of canine cancers has improved, unique opportunities have emerged to leverage this spontaneous model to better guide cancer drug development so that therapies likely to fail are eliminated earlier and therapies with true potential are optimized prior to human studies. Both pets and people benefit from this approach, as it provides dogs with access to cutting-edge cancer treatments and helps to insure that people are given treatments more likely to succeed.
Ion Channels in Development and Cancer
Authors: Bates Emily
Published: November 2015

Ion channels have emerged as regulators of developmental processes. In model organisms and in people with mutations in ion channels, disruption of ion channel function can affect cell proliferation, cell migration, and craniofacial and limb patterning. Alterations of ion channel function affect morphogenesis in fish, frogs, mammals, and flies, demonstrating that ion channels have conserved roles in developmental processes. One model suggests that ion channels affect proliferation and migration through changes in cell volume. However, ion channels have not explicitly been placed in canonical developmental signaling cascades until recently. This review gives examples of ion channels that influence developmental processes, offers a potential underlying molecular mechanism involving bone morphogenetic protein (BMP) signaling, and finally explores exciting possibilities for manipulating ion channels to influence cell fate for regenerative medicine and to impact disease.
Toward a Synthesis of Developmental Biology with Evolutionary Theory and Ecology
Authors: Sommer Ralf J. , Mayer Melanie G.
Published: November 2015

The evolutionary conservation of developmental mechanisms is a truism in biology, but few attempts have been made to integrate development with evolutionary theory and ecology. To work toward such a synthesis, we summarize studies in the nematode model Pristionchus pacificus, focusing on the development of the dauer, a stress-resistant, alternative larval stage. Integrative approaches combining molecular and genetic principles of development with natural variation and ecological studies in wild populations have identified a key role for a developmental switch mechanism in dauer development and evolution, one that involves the nuclear hormone receptor DAF-12. DAF-12 is a crucial regulator and convergence point for different signaling inputs, and its function is conserved among free-living and parasitic nematodes. Furthermore, DAF-12 is the target of regulatory loops that rely on novel or fast-evolving components to control the intraspecific competition of dauer larvae. We propose developmental switches as paradigms for understanding the integration of development, evolution, and ecology at the molecular level.
Cystic Neoplasms of the Pancreas
Authors: Chandwani Rohit , Allen Peter J.
Published: November 2015

Cystic neoplasms of the pancreas are being identified at an increasing frequency largely due to the increased use of abdominal cross-sectional imaging. These neoplasms represent a heterogeneous group of tumors with various genetic alterations, molecular features, and risks of malignancy. Despite the use of high-resolution radiographic studies, endoscopic evaluation, cyst fluid analysis, and novel molecular diagnostics, many of these lesions remain difficult to classify without operative resection. These diagnostic challenges are coupled with an improving but limited understanding of the natural history of these neoplasms. Treatment of pancreatic cystic neoplasms therefore remains controversial but consists largely of a selective tumor-specific approach to surgical resection. Future research remains necessary to better discriminate the biological behavior of these tumors in order to more appropriately select patients for operative intervention.
Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases
Authors: Whitaker Ryan M. , Corum Daniel , Beeson Craig C. , Schnellmann Rick G.
Published: November 2015

Mitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of mitochondrial homeostasis through the balance of mitochondrial turnover, fission and fusion, and generation of new mitochondria via mitochondrial biogenesis is critical for tissue health. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by mitochondrial dysfunction. However, owing to the complexity of mitochondrial assembly and maintenance, identification of specific activators of mitochondrial biogenesis has been difficult. This review provides an overview of the role of mitochondrial dysfunction in acute and chronic diseases, details the current state of therapeutics for the stimulation of mitochondrial biogenesis and their effects on disease outcomes, describes new screening methodologies to identify novel stimulators and noncanonical pathways of mitochondrial biogenesis, and discusses potential hurdles of mitochondrial biogenesis as a therapeutic strategy.
Genome Editing: A New Approach to Human Therapeutics
Authors: Porteus Matthew
Published: November 2015

The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.
CCR 20th Anniversary Commentary: Circulating Tumor Cells in Prostate Cancer
Authors: Mehra Niven , Zafeiriou Zafeiris , Lorente David , Terstappen Leon W.M.M. , de Bono Johann S.
Published: November 2015

Circulating tumor cells (CTC) have substantial promise for multipurpose biomarker studies in prostate cancer. The IMMC-38 trial conducted by de Bono and colleagues, which was published in the October 1, 2008, issue of Clinical Cancer Research, demonstrated for the first time that CTCs are the most accurate and independent predictor of overall survival in metastatic prostate cancer. Since the publication of prospective trials demonstrating prognostic utility, CTCs have been utilized for nucleic acid analyses, for protein analyses, and in intermediate endpoint studies. CTC studies are also now facilitating the analysis of intrapatient heterogeneity. Clin Cancer Res; 21(22); 4992–5. ©2015 AACR.

See related article by de Bono et al., Clin Cancer Res 2008;14(19) October 1, 2008;6302–9
BCL-2 Antagonism to Target the Intrinsic Mitochondrial Pathway of Apoptosis
Authors: Gibson Christopher J. , Davids Matthew S.
Published: November 2015

Despite significant improvements in treatment, cure rates for many cancers remain suboptimal. The rise of cytotoxic chemotherapy has led to curative therapy for a subset of cancers, though intrinsic treatment resistance is difficult to predict for individual patients. The recent wave of molecularly targeted therapies has focused on druggable-activating mutations, and is thus limited to specific subsets of patients. The lessons learned from these two disparate approaches suggest the need for therapies that borrow aspects of both, targeting biologic properties of cancer that are at once distinct from normal cells and yet common enough to make the drugs widely applicable across a range of cancer subtypes. The intrinsic mitochondrial pathway of apoptosis represents one such promising target for new therapies, and successfully targeting this pathway has the potential to alter the therapeutic landscape of therapy for a variety of cancers. Here, we discuss the biology of the intrinsic pathway of apoptosis, an assay known as BH3 profiling that can interrogate this pathway, early attempts to target BCL-2 clinically, and the recent promising results with the BCL-2 antagonist venetoclax (ABT-199) in clinical trials in hematologic malignancies. Clin Cancer Res; 21(22); 5021–9. ©2015 AACR.

See all articles in this CCR Focus section, “Cell Death and Cancer Therapy.”
How Do Cytotoxic Lymphocytes Kill Cancer Cells?
Authors: Martínez-Lostao Luis , Anel Alberto , Pardo Julián
Published: November 2015

In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed. Clin Cancer Res; 21(22); 5047–56. ©2015 AACR.

See all articles in this CCR Focus section, “Cell Death and Cancer Therapy.”
A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer
Authors: Ma Cynthia X. , Luo Jingqin , Naughton Michael , Ademuyiwa Foluso , Suresh Rama , Griffith Malachi , Griffith Obi L. , Skidmore Zachary L. , Spies Nicholas C. , Ramu Avinash , Trani Lee , Pluard Timothy , Nagaraj Gayathri , Thomas Shana , Guo Zhanfang , Hoog Jeremy , Han Jing , Mardis Elaine , Lockhart Craig , Ellis Matthew J.
Published: November 2015

Purpose: This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER+) breast cancer.

Experimental Design: Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.

Results: Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%–74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations in AKT1 and ESR1 did not exclude treatment response.

Conclusions: Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER+ breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features. Clin Cancer Res; 22(7); 1583–91. ©2015 AACR.
Recombinant Hepatitis B Vaccine Adjuvanted With AS04 in Dialysis Patients: A Prospective Cohort Study
Authors: Fabrizi Fabrizio , Tarantino Antonio , Castelnovo Claudia , Martin Paul , Messa PierGiorgio
Published: November 2015

Background/Aims: Patients undergoing maintenance dialysis have an unsatisfactory response to vaccination, including to hepatitis B vaccine. A recombinant HB vaccine containing a new adjuvant system AS04 (HBV-AS04) has been recently developed; a few data exist on the immunogenicity and safety of HBV-AS04 among patients undergoing regular dialysis. All hepatitis B virus-seronegative patients with undetectable antibody against HBsAg undergoing maintenance dialysis at two units were prospectively included. Methods: Patients received four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle) at months 0,1,2, and 3. Anti-HB surface antibody concentrations were measured at intervals of 1, 2, 3, 4, and 12 months. Univariate and multivariate analyses determined which parameters predicted immunologic response to HBV-AS04 vaccine. Results: 102 patients were enrolled and 91 completed the study. At completion of the vaccination schedule, using per-protocol analysis, 76 of 91 (84%) had antibody titers ≥10 mIU/mL with anti-HBs geometric antibody concentrations (GMCs) of 385.25 mIU/mL. The sero-protection rate at month 12 was 84% (48/57) with lower GMCs (62.74 mIU/mL, P<0.0001). Multivariate analysis revealed a detrimental role of age on the immune response to HB-AS04 vaccine (F Ratio, 4.04; P<0.04). Tolerance to HBV-AS04 was good and only minor side-effects were observed. Conclusions: HBV-AS04 vaccine was highly immunogenic in our cohort of patients on maintenance dialysis even if a significant number of non-responders is still present. Prospective studies with HBV-AS04 on larger study groups and with longer follow-ups are under way.
Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells
Authors: Stamoula Eleni , Vavilis Theofanis , Aggelidou Eleni , Kaidoglou Aikaterini , Cheva Angeliki , Mellidis Kyriakos , Lazou Antigone , Haitoglou Costas , Albani Maria , Kritis Aristeidis
Published: November 2015

Background/Aims: Increasing amounts of the neurotransmitter glutamate are associated with excitotoxicity, a phenomenon related both to homeostatic processes and neurodegenerative diseases such as multiple sclerosis. Methods: PC12 cells (rat pheochromocytoma) were treated with various concentrations of the non-essential amino acid glutamate for 0.5-24 hours. The effect of glutamate on cell morphology was monitored with electron microscopy and haematoxylin-eosin staining. Cell survival was calculated with the MTT assay. Expression analysis of chaperones associated with the observed phenotype was performed using either Western Blotting at the protein level or qRT-PCR at the mRNA level. Results: Administration of glutamate in PC12 cells in doses as low as 10 μM causes an up-regulation of GRP78, GRP94 and HSC70 protein levels, while their mRNA levels show the opposite kinetics. At the same time, GAPDH and GRP75 show reduced protein levels, irrespective of their transcriptional rate. On a cellular level, low concentrations of glutamate induce an autophagy-mediated pro-survival phenotype, which is further supported by induction of the autophagic marker LC3. Conclusion: The findings in the present study underline a discrete effect of glutamate on neuronal cell fate depending on its concentration. It was also shown that a low dose of glutamate orchestrates a unique expression signature of various chaperones and induces cell autophagy, which acts in a neuroprotective fashion.
Rapid Upregulation of Orai1 Abundance in the Plasma Membrane of Platelets Following Activation with Thrombin and Collagen Related Peptide
Authors: Liu Guilai , Liu Guoxing , Chen Hong , Alzoubi Kousi , Umbach Anja T. , Gawaz Meinrad , Stournaras Christos , Lang Florian
Published: November 2015

Background: Blood platelets accomplish primary hemostasis following vascular injury and contribute to the orchestration of occlusive vascular disease. Platelets are activated by an increase of cytosolic Ca2+-activity ([Ca2+]i), which is accomplished by Ca2+-release from intracellular stores and subsequent store operated Ca2+ entry (SOCE) through Ca2+ release activated Ca2+ channel moiety Orai1. Powerful activators of platelets include thrombin and collagen related peptide (CRP), which are in part effective by activation of small G- protein Rac1. The present study explored the influence of thrombin and CRP on Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i) in platelets drawn from wild type mice. Methods: Orai1 protein surface abundance was quantified utilizing CF™488A conjugated antibodies, and [Ca2+]i was determined with Fluo3-fluorescence. Results: In resting platelets, Orai1 protein abundance and [Ca2+]i were low. Thrombin (0.02 U/ml) and CRP (5ug/ml) within 2 min increased [Ca2+]i and Orai1 protein abundance at the platelet surface. [Ca2+]i was further increased by Ca2+ ionophore ionomycin (1 µM) and by store depletion with the sarcoendoplasmatic Ca2+ ATPase inhibitor thapsigargin (1 µM). However, Orai1 protein abundance at the platelet surface was not significantly affected by ionomycin and only slightly increased by thapsigargin. The effect of thrombin and CRP on Orai1 abundance and [Ca2+]i was significantly blunted by Rac1 inhibitor NSC23766 (50 µM). Conclusion: The increase of [Ca2+]i following stimulation of platelets with thrombin and collagen related peptide is potentiated by ultrarapid Rac1 sensitive translocation of Orai1 into the cell membrane.
Synergistic Effects of a Mixture of Glycosaminoglycans to Inhibit Adipogenesis and Enhance Chondrocyte Features in Multipotent Cells
Authors: Petrov Petar D. , Granados Nuria , Chetrit Carles , Martínez-Puig Daniel , Palou Andreu , Bonet M. Luisa
Published: November 2015

Background/Aims: Multipotent mesenchymal stem cells affect homeostasis of adipose and joint tissues. Factors influencing their differentiation fate are of interest for both obesity and joint problems. We studied the impact of a mixture of glycosaminoglycans (GAGs) (hyaluronic acid: dermatan sulfate 1:0.25, w/w) used in an oral supplement for joint discomfort (Oralvisc™) on the differentiation fate of multipotent cells. Methods: Primary mouse embryo fibroblasts (MEFs) were used as a model system. Post-confluent monolayer MEF cultures non-stimulated or hormonally stimulated to adipogenesis were chronically exposed to the GAGs mixture, its individual components or vehicle. The appearance of lipid laden cells, lipid accumulation and expression of selected genes at the mRNA and protein level was assessed. Results: Exposure to the GAGs mixture synergistically suppressed spontaneous adipogenesis and induced the expression of cartilage extracellular matrix proteins, aggrecan core protein, decorin and cartilage oligomeric matrix protein. Hormonally-induced adipogenesis in the presence of the GAGs mixture resulted in decreased adipogenic differentiation, down-regulation of adipogenic/lipogenic factors and genes for insulin resistance-related adipokines (resistin and retinol binding protein 4), and up-regulation of oxidative metabolism-related genes. Adipogenesis in the presence of dermatan sulfate, the minor component of the mixture, was not impaired but resulted in smaller lipid droplets and the induction of a more complete brown adipocyte-related transcriptional program in the cells in the adipose state. Conclusions: The Oralvisc™ GAGs mixture can tip the adipogenic/chondrogenic fate balance of multipotent cells away from adipogenesis while favoring chondrocyte related gene expression. The mixture and its dermatan sulfate component also have modulatory effects of interest on hormonally-induced adipogenesis and on metabolic and secretory capabilities of adipose cells.
BRCA Mutation-Related and Claudin-Low Breast Cancer: Blood Relatives or Stepsisters?
Authors: Madaras Lilla , Balint Nora , Gyorffy Balazs , Tokes Anna-Maria , Barshack Iris , Yosepovich Ady , Friedman Eitan , Paluch-Shimon Shani , Zippel Dov , Baghy Kornelia , Timar Jozsef , Kovalszky Ilona , Kulka Janina , Szasz Attila Marcell
Published: November 2015

Background: BRCA mutation-associated (BRCAmut) breast cancer represents a heterogeneous group displaying certain molecular features. Claudin-low breast cancers (CLBC) overlap with characteristics of BRCAmut tumors; therefore, we have investigated whether these are identical subtypes. Methods: Using public gene expression data, CLDN, CDH1, 9-cell line claudin-low predictor (9CLCLP) and PAM50 expression was evaluated in BRCAmut and BRCA wild-type (BRCAwt) breast cancer cases focusing on their possible overlap with the CLBC subtype. A separate formalin-fixed, paraffin-embedded (FFPE) cohort of 22 BRCAmut and 19 BRCAwt tumor tissues was used for immunohistochemical examination of AR, CD24, CD44, CK5/6, claudin-1, -3, -4 and -7, E-cadherin, EGFR, estrogen receptor (ER), EZH2, HER2, Ki67, p53, progesterone receptor (PgR) and vimentin expression. Results: In the data sets, CLDN1 (ROC = 0.785, p < 0.001), CDH1 (ROC = 0.785, p < 0.001), CLDN7 (ROC = 0.723, p < 0.001), CLDN3 (ROC = 0.696, p = 0.020) and CLDN4 (ROC = 0.685, p = 0.027) were expressed at higher level in BRCAmut than BRCAwt tumor tissue. The PAM50 subtype differed from the assigned immunohistochemistry (IHC)-based subtype in 30%. Based on accessible 9CLCLP predictor genes, BRCAmut breast cancer does not display the claudin-low phenotype. Utilizing FFPE samples, claudins were evidently expressed in both BRCAmut and BRCAwt cases. However, at the protein level, only claudin-3 expression was higher in BRCAmut tumors, while claudin-1, -4 and -7 and E-cadherin expression was lower compared to BRCAwt cases. A CD24low/CD44high phenotype was found in BRCAmut tumors upon comparison with BRCAwt cases (p < 0.001 and p = 0.001, respectively). Conclusions: There is a prominent correlation between the genes under focus herein and BRCA mutation status. BRCAmut tumors bear stem cell characteristics displaying a distinct cell adhesion molecule profile characterized by high expression of CDH1 and CLDN4 according to public gene expression data set analysis, and higher claudin-3 expression as detected by IHC; thus, BRCAmut breast carcinomas are not identical with the previously identified claudin-low subtype of breast cancer.
Is It Contralateral Axillary Metastasis or Occult Breast Cancer: A Confusing Case Report
Authors: Son Yong Gi , Kim Woon Won , Kim Ki Hoon , Kim Jin Soo
Published: November 2015

We report the case of a 43-year-old woman with primary left breast cancer presenting metastatic lymphadenopathy in the contralateral axilla. This patient represents a diagnostic and therapeutic challenge because primary breast cancer, occult contralateral breast cancer, and extra-mammary primary lesion can all be the source of the contralateral axillary metastasis. Left breast-conserving surgery, left sentinel lymph node biopsy, right breast mass excision, and right axillary lymph node dissection were performed. Immunohistochemical analysis revealed that the left breast cancer specimen was positive for estrogen receptor (ER) and progesterone receptor (PR), but negative for human epidermal growth factor receptor 2 (HER2). In contrast, the right axillary lymphadenopathy specimen was negative for ER and PR, but positive for HER2. Further investigation revealed no evidence of occult primary cancers or extra-mammary tumors. After surgical intervention, the patient was treated with adjuvant chemotherapy, adjuvant radiation therapy, and targeted therapy with trastuzumab. Two years after diagnosis, she is free of disease and presently being treated with tamoxifen.
Butylated Hydroxyanisole Potently Inhibits Rat and Human 11β-Hydroxysteroid Dehydrogenase Type 2
Authors: Li Linxi , Wu Ying , Wu Xiaolong , Wang Huang , Bai Yanfang , Wang Xiudi , Akingbemi Benson T. , Huang Ping , Ge Ren-Shan
Published: November 2015

Butylated hydroxyanisole (BHA) is a widely used antioxidant for food preservation. 11β-hydroxysteroid dehydrogenases, isoforms 1 (HSD11B1) and 2 (HSD11B2) have been demonstrated to be the regulators of the local level of active glucocorticoid, which has a broad range of physiological actions. In this study, the potency of BHA was tested for the inhibition of HSD11B1 and HSD11B2 in rat and human tissues. BHA showed potent inhibition of HSD11B2 with the half maximal inhibitory concentration calculated at 13.99 and 69.25 µmol/l for the rat and human, respectively. Results showed that BHA competitively inhibited HSD11B2 when a steroid substrate was used. However, it served as a mixed inhibition factor when the cofactor NAD+ was used. In contrast, the potency of BHA to inhibit both rat and human HSD11B1 was diminished, with the concentration of 100 μmol/l causing no inhibitory effect on the isoform. In conclusion, we observed that BHA is a selective inhibitor of HSD11B2, implying that this agent may cause excessive glucocorticoid action in local tissues such as kidney and placentas.
Clinical Presentation and Genetic Paradigm of Diffuse Infiltrating Retinoblastoma: A Review
Authors: Traine Peter G. , Schedler Katharina J. , Rodrigues Eduardo B.
Published: November 2015

Retinoblastoma is the most common childhood cancer. Thanks to modern technology and good medical access, mortality in Europe has decreased to about 5%. Diffuse infiltrating retinoblastoma is a very rare subtype of this neoplasm and is characterized by its atypical growth pattern. Diffuse infiltrating retinoblastoma may mimic other more innocuous diseases and may therefore be misdiagnosed. The purpose of this paper was to provide a short review of the main symptoms of diffuse infiltrating retinoblastoma presenting to the ophthalmologist and give a comparison to typical retinoblastoma. The second purpose was to set up a discussion of the genetic paradigm of diffuse infiltrating retinoblastoma. It has often been described to occur sporadically; however, in the last years, it has been shown that it might be heritable. A literature search concerning diffuse infiltrating retinoblastoma considering English, German and Spanish cases and case series identified 77 patients. Moreover, an overview of general data, main symptoms, clinical findings and initial working diagnoses or referral diagnoses is given. Males were significantly more often affected than females. Diffuse infiltrating retinoblastoma can be heritable. Genetic analysis should be offered to the patient and relatives. Interdisciplinary medical follow-up care is needed to detect associated cancers.
Integrating Personalized Medicine in the Canadian Environment: Efforts Facilitating Oncology Clinical Research
Authors: Syme Rachel , Carleton Bruce , Leyens Lada , Richer Etienne
Published: November 2015

There is currently a rapid evolution of clinical practices based on the introduction of patient stratification and molecular diagnosis that is likely to improve health outcomes. Building on a strong research base, complemented by strong support from clinicians and health authorities, the oncology field is at the forefront of this evolution. Yet, clinical research is still facing many challenges that need to be addressed in order to conduct necessary studies and effectively translate medical breakthroughs based on personalized medicine into standards of care. Leveraging its universal health care system and on resources developed to support oncology clinical research, Canada is well positioned to join the international efforts deployed to address these challenges. Available resources include a broad range of structures and funding mechanisms, ranging from direct clinical trial support to post-marketing surveillance. Here, we propose a clinical model for the introduction of innovation for precision medicine in oncology that starts with patients' and clinicians' unmet needs to initiate a cycle of discovery, validation, translation and sustainability development.
Spontaneous Pneumoperitoneum due to Constipation
Authors: Yamana Ippei , Noritomi Tomoaki , Takeno Shinsuke , Hashimoto Tatsuya , Sato Keisuke , Shimaoka Hideki , Yamaguchi Ryosuke , Ishii Fumiaki , Yamada Teppei , Yamashita Yuichi
Published: November 2015

We report a rare case of spontaneous pneumoperitoneum. An 82-year-old Japanese male patient was referred to our hospital because of constipation and abdominal pain. Abdominal computed tomography revealed a large amount of feces in the colon and rectum, and free air in the abdomen. Based on these findings, the patient was diagnosed with gastrointestinal perforation. Emergency exploratory laparotomy was performed. Neither perforation nor ischemic changes were recognized in the digestive tract. The patient's defecation was managed postoperatively until discharge on the 13th postoperative day. The authors assumed that free air, which was released after a mucosal injury due to the internal pressure caused by the presence of a large amount of feces in the colon and rectum, had penetrated the bowel wall through the bowel mucosa. We herein report the present case while also reviewing the pertinent literature.
Interleukin-1 cluster combined genotype and restenosis after balloon angioplasty
Authors: Marculescu Rodrig , Mlekusch Wolfgang , Exner Markus , Sabeti Schila , Michor Stefanie , Rumpold Helmut , Mannhalter Christine , Minar Erich , Wagner Oswald , Schillinger Martin
Published: November 2015

The interleukin-1 system is fundamentally involved in the pathogenesis of restenosis after percutaneous transluminal angioplasty (PTA). In order to further define the clinical impact of genetic variation in this potent proinflammatory pathway we investigated the joint effects of two single nucleotide polymorphisms in the interleukin-1 beta gene [IL-1B(–511) and IL-1B(+3954)] and a variable number tandem repeat polymorphism in intron 2 of the interleukin 1 receptor antagonist gene (IL-1RN VNTR) on postintervention inflammation and occurrence of restenosis in 183 consecutive patients who underwent successful femoropopliteal PTA. C-reactive protein (CRP) and serum amyloid A (SAA) were determined pre- and 48 hours postintervention. Patients were followed up to 12 months for the occurrence of postangioplasty restenosis (≥50 %). When analyzed separately, none of the polymorphisms was associated either with inflammation or restenosis. However, when the IL-1B (–511) and the IL-1RN VNTR genotypes were combined, a highly significant relationship was observed: Non-carriers of the two repeat allele of the IL-1RN VNTR (IL-1RN*2) who were heterozygous and homozygous for the IL-1B (–511)T allele exhibited a gradually increased inflammatory response and a higher restenosis risk. In contrast, carriers of the IL-1RN*2 and the IL-1B (–511)T allele showed a significantly better outcome.

This remarkable gene dose-dependent association emphasizes the advantage of considering combinations of genetic markers rather that isolated polymorphisms in the analysis of multifactorial vascular disease.
Cambio Climático y Turismo: una aproximación a su estado de conocimiento
Authors: Mancilla Velasco Stephany , Osorio García Maribel , Serrano Barquín Rocío Del Carmen
Published: November 2015

Este artigo discute o estado do conhecimento sobre as mudanças climáticas e o turismo como um objeto de estudo, com o objectivo de caracterizar as tendências temáticas, disciplinar e metodológica, além de reconhecer os desafios para o seu desenvolvimento. Uma análise foi feita de documentos relacionados com este objeto de estudo, dos quais foram identificados os seguintes cinco linhas temáticas: impactos ecológicos e de vulnerabilidade; projeções e cenários futuros; atenuação e adaptação; efeitos económicos; e estudos de turistas/visitantes. A investigação descobriu sobre este tema definido para as teorias de sistemas complexos como o suporte mais exposição, como também mostram maior tendência para a utilização de metodologias quantitativas, com uma maior produção de estudos sobre o continente europeu.

Palavras-chave: turismo, alterações climáticas, estado do conhecimento.
O Planejamento Urbano e a Competitividade de Destinos Turísticos: uma análise desde a perspectiva do Modelo de Dwyer e Kim
Authors: Ruiz Thays Cristina Domareski , Gândara José Manoel
Published: November 2015

O estudo da competitividade vem sendo conduzido a partir de novos contextos, como por exemplo, o viés da competitividade de destinos turísticos, o que tem provocado significativas mudanças em termos de produção de conhecimento, mesclando áreas e proporcionando uma reflexão multidisciplinar. Este artigo tem como objetivo central analisar a relação entre o planejamento urbano e a competitividade de destinos turísticos desde a perspectiva do Modelo de Dwyer e Kim, contrastando diretamente estes dois conceitos atuais que se refletem no desenvolvimento das cidades, proporcionando uma reflexão sobre os temas. A metodologia do trabalho busca através do modelo de avaliação de competitividade de Dwyer e Kim (2003) e seus indicadores, determinar a relevância do planejamento urbano no desenvolvimento da competitividade nos destinos turísticos. O artigo identifica a influência e a relevância do planejamento urbano no desenvolvimento das cidades como destino turístico competitivo, através dos 42 indicadores presentes no modelo e que se relacionam diretamente com o planejamento urbano.

Palavras-Chave: desenvolvimento, planejamento urbano, competitividade, destinos turísticos.
Turismo e Desenvolvimento Local: a qualidade de vida sob a ótica da população do Arraial de Conceição do Ibitipoca- MG
Authors: Alves Monalisa Barbosa
Published: November 2015

O turismo é um fenômeno complexo. Constitui um conjunto de relações e mudanças de caráter econômico, ambiental, social, cultural e política. O presente trabalho apresenta uma discussão sobre a relação entre turismo, desenvolvimento local e qualidade de vida. Trata-se de um Estudo de Caso que teve como objetivo analisar em que medida as mudanças resultantes da intensificação do turismo no Arraial de Conceição do Ibitipoca, distrito de Lima Duarte - Minas Gerais resultaram em uma melhor qualidade de vida para a população local. O estudo se fundamentou em uma abordagem interdisciplinar, a partir de análise qualitativa, baseada em pesquisa bibliográfica e documental; pesquisa de campo composta por observação e entrevistas semi-estruturadas; análise de conteúdo. Os principais resultados revelaram que o desenvolvimento do turismo tem contribuído para mudanças socioculturais no local. Tendo estes aspectos positivos, como a geração de emprego e renda, desenvolvimento de infraestrutura e serviços, convivência com pessoas diferentes e vida social mais ativa. Segundo os moradores locais tais mudanças resultam na melhoria da qualidade de vida. No entanto, as mudanças também apresentam aspectos negativos, tais como: mudanças nos hábitos e costumes, uso de drogas, barulho, lixo, congestionamento de veículos, bares e restaurantes lotados e crescimento urbano desordenado. Os moradores não estão preparados para lidar com a dinâmica das mudanças. Para tal, é necessária uma capacitação dos moradores locais, maior participação local e melhorias na infraestrutura. Se devidamente planejado e pautado na realidade da localidade o turismo pode ser veículo de desenvolvimento e melhoria da qualidade de vida.Palavras-chave: turismo, desenvolvimento local, qualidade de vida.
Redes Interorganizacionais entre Fábricas de Objetos em Estanho no Mercado Turístico de São João del Rei- MG
Authors: Silva Gustavo Melo , Almeida Matheus Ribeiro de , Ferreira Renan Vilella
Published: November 2015

A cidade de São João del Rei concentra o maior número de fábricas de objetos em estanho da América Latina. Este sistema produtivo tradicional atualmente fornece souvenires para estabelecimentos comerciais especializados no atendimento aos turistas em São João del Rei e Tiradentes. Neste trabalho foi analisada esta realidade numa perspectiva sociológica estrutural a partir de suas redes interorganizacionais. Para alcançar este objetivo foram realizadas pesquisas bibliográficas e análises de dados primários e secundários coletados por meio de entrevistas e visitas às fábricas. Este campo organizacional foi analisado a partir de referencial teórico orientado para conceitos referentes à análise de redes sociais, tanto como categoria analítica como método de pesquisa. Os resultados possibilitaram caracterizar o mercado e o processo produtivo de peças artesanais de estanho, representando graficamente a rede e analisando sociometricamente a sua densidade e as medidas de centralidade dos atores deste mercado de souvenires em estanho dos destinos turísticos de São João del Rei e Tiradentes. Logo, podemos afirmar que o sistema produtivo em estanho pode ser analisado como uma estrutura social, sendo que seus atores exercem papéis nos relacionamentos socioeconômicos existentes que tem no turismo uma fonte de desenvolvimento regional. Ao final, foram feitas sugestões para novas pesquisas, propostas algumas recomendações para a melhoria da rede analisada e do mercado turístico local.Palavras-chave: Souvenires, desenvolvimento local, fábricas de souvenires em estanho, sociologia econômica e das organizações.
O Lazer nas Alianças Estratégicas de Resorts Brasileiros
Authors: Barbosa Marcos Aguiar , Isayama Helder Ferreira
Published: November 2015

O objetivo desse estudo foi diagnosticar o lazer nos resorts brasileiros na perspectiva da estratégia organizacional, especificamente no que se refere ao lazer nas alianças estratégicas. Foi utilizada a combinação das pesquisas bibliográfica, de campo e documental. A pesquisa de campo foi realizada junto a nove resorts e para a documental foram utilizados como fonte os sites dos estabelecimentos. O estudo mostra a complexidade do ambiente de negócio e organizacional nos quais estão imersos os resorts e o lazer. Revela como a conjuntura social e econômica, o mercado consumidor, os investidores, a natureza do negócio e a administração de cada organização estabelecem uma intricada rede de relações que é decisiva na participação do lazer nas estratégias organizacionais.Palavras chave: Lazer, Resort, Estratégia, Organização, Turismo.
Pesquisa de Demanda para Turismo de Base Comunitária: desafios à promoção do encontro entre comunidades e viajantes
Authors: Sancho Altair , Malta Guilherme
Published: November 2015

Neste trabalho, nos propomos a refletir sobre as especificidades, limitações e desafios inerentes às pesquisas de demanda direcionadas a viajantes interessados em vivenciar experiências de turismo de base comunitária. Tal objetivo teve como inspiração a experiência de uma pesquisa de demanda realizada no âmbito do Projeto de Turismo Comunitário Vale das Conquistas, município de Brumadinho, MG. Os procedimentos metodológicos envolveram o levantamento bibliográfico sobre turismo de base comunitária, segmentação de mercado e perfis de demanda turística e, também, análises de pesquisas secundárias, com vistas ao estabelecimento de parâmetros de investigação que subsidiaram a elaboração do modelo de questionário utilizado para a realização das pesquisas com demanda potencial em localidades turísticas próximas à área de abrangência do projeto. Os resultados estimularam importantes debates sobre os desafios de se realizar pesquisas de demanda potencial para esse público. Ao mesmo tempo, indicaram que os processos de formatação e comercialização de propostas de turismo de base comunitária devem priorizar estratégias voltadas à divulgação em mercados regionais, realização de pesquisas de demanda periódicas e investimento na disponibilização de informações de qualidade aos visitantes.
Pesquisa de Identificação do Perfil e Satisfação dos Turistas e Visitantes de Brasília Durante a Copa do Mundo 2014
Authors: Basso Karen Graziele Furlan , Andrade Thamyris Carvalho , Bittencourt Ariadne Pedra
Published: November 2015

O presente artigo versa sobre os resultados de pesquisa de demanda realizada durante a Copa do Mundo FIFA 2014 na cidade de Brasília, entre os dias 10 de junho a 19 de julho, em três pontos principais de coleta. A pesquisa foi realizada pela Secretaria de Turismo do Distrito Federal em caráter exploratório descritivo, resultando em um total de 9.728 entrevistados, sendo 6.765 visitantes nacionais e 3.499 visitantes internacionais. Entre os principais resultados obtidos, destacam-se o perfil dos visitantes, o montante de movimentação exclusivamente motivada pelo megaevento e os gastos médios realizados por estes turistas na Capital Federal. A título de conclusões, listam-se limitações e fragilidades observadas durante e após a realização da pesquisa, apontando possibilidades de aperfeiçoamentos em iniciativas futuras semelhantes. Ao final, procedimentos são fortemente recomendados a pesquisadores interessados neste tipo de pesquisa, tanto na etapa de planejamento como em sua execução e análise.
Em Busca da Definição de Reputação de Destinos Turísticos: significados e temas associados a partir da visão de profissionais
Authors: Coelho Mariana de Freitas , Gosling Marlusa
Published: November 2015

Pesquisadores de marketing turístico têm enfatizado a importância da imagem do destino turístico no processo de escolha de um lugar para visitar. No entanto, faltam pesquisas sobre reputação desses mesmos destinos turísticos, que pode ser usada como uma ferramenta para atrair visitantes potenciais. Autores como De Chernatony (1999), Gioia et al. (2000) e Torres et al. (2011) afirmam que o foco na imagem da marca evoca percepções recentes, que estão sujeitas a alterações. Portanto, estudos de reputação lidam com impressões mais consistentes do que a imagem do destino e consideram várias imagens percebidas ao longo do tempo. O método da pesquisa foi a abordagem qualitativa. O objetivo do artigo foi compreender o significado da reputação de destinos turísticos e seus temas associados. Quinze especialistas foram entrevistados e suas respostas foram classificadas em três áreas de conhecimento: Administração/Gestão, Marketing e Turismo. As respostas foram analisadas com base em Creswell (2007) e Bardin (2008) e os dados foram codificados em temas relacionados à literatura de reputação corporativa e reputação de destinos. Dentre os resultados, em geral, os entrevistados indicaram a associação de reputação e imagem e a importância do tempo para a formação da reputação. Além disso, o estudo identificou as peculiaridades apontadas por cada grupo, como por exemplo, uma ênfase no contexto social (Turismo), a importância da gestão (Administração/Gestão) e a avaliação de indivíduos ou grupos (Marketing). Finalmente, o estudo demonstrou que a reputação dos destinos turísticos é integrada a pelo menos quatro temas: comunicação, avaliação, diferenciação e tempo.