bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer
Authors: Krishnamurthy Anuradha , Dasari Arvind , Noonan Anne M. , Mehnert Janice M. , Lockhart Albert C. , Leong Stephen , Capasso Anna , Stein Mark N. , Sanoff Hanna K. , Lee James J. , Hansen Aaron , Malhotra Usha , Rippke Sarah , Gustafson Daniel L. , Pitts Todd M. , Ellison Kim , Davis S. Lindsey , Messersmith Wells A. , Eckhardt S. Gail , Lieu Christopher H. 
Published: July 2018

Abstract
MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program–approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib “run-in” to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.
Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398–407. ©2018 AACR.
The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
Authors: Iglesias-Gato Diego , Thysell Elin , Tyanova Stefka , Crnalic Sead , Santos Alberto , Lima Thiago S. , Geiger Tamar , Cox Jürgen , Widmark Anders , Bergh Anders , Mann Matthias , Flores-Morales Amilcar , Wikström Pernilla 
Published: July 2018

Abstract
Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.
Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.
Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair–related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.
Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433–44. ©2018 AACR.
R1 Regulates Prostate Tumor Growth and Progression By Transcriptional Suppression of the E3 Ligase HUWE1 to Stabilize c-Myc
Authors: Lin Tzu-Ping , Li Jingjing , Li Qinlong , Li Xiangyan , Liu Chunyan , Zeng Ni , Huang Jen-Ming , Chu Gina Chia-Yi , Lin Chi-Hung , Zhau Haiyen E. , Chung Leland W.K. , Wu Boyang Jason , Shih Jean C. 
Published: July 2018

Abstract

Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis.

Implications:
These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.
Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer
Authors: Eke Iris , Makinde Adeola Y. , Aryankalayil Molykutty J. , Reedy Jessica L. , Citrin Deborah E. , Chopra Sunita , Ahmed Mansoor M. , Coleman C. Norman 
Published: July 2018

Abstract

Adaptation of tumor cells to radiotherapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted 2 months later. Integrins are transmembrane cell adhesion molecules that are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2–10 Gy) or a multifractionated regimen (2–10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (ITGB1 and ITGB4) were upregulated after radiation in vitro and in vivo. This overexpression lasted for more than 2 months and was dose dependent. Moreover, radiation-induced upregulation of β1 and β4 integrin resulted in significantly increased tumor cell death after treatment with inhibitory antibodies. Combined, these findings indicate that long-term tumor adaptation to radiation can result in an increased susceptibility of surviving cancer cells to molecular targeted therapy due to a radiation-induced overexpression of the target.

Implications:
Radiation induces dose- and schedule-dependent adaptive changes that are targetable for an extended time; thus suggesting radiotherapy as a unique strategy to orchestrate molecular processes, thereby providing new radiation-drug treatment options within precision cancer medicine.
Temperament and Character Inventory in Bipolar Disorder versus Healthy Controls and Modulatory Effects of 3 Key Functional Gene Variants
Authors: Porcelli Stefano , Marsano Agnese , Caletti Elisabetta , Sala Michela , Abbiati Vera , Bellani Marcella , Perlini Cinzia , Rossetti Maria Gloria , Mandolini Gian Mario , Pigoni Alessandro , Paoli Riccardo Augusto , Piccin Sara , Lazzaretti Matteo , Fabbro Dora , Damante Giuseppe , Bonivento Carolina , Ferrari Clarissa , Rossi Roberta , Pedrini Laura , Serretti Alessandro , Brambilla Paolo ,   GECOBIP Group
Published: July 2018

<b><i>Background:</i></b> Bipolar disorder (BD) has been associated with temperamental and personality traits, although the relationship is still to be fully elucidated. Several studies investigated the genetic basis of temperament and character, identifying catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF), and serotonin transporter (5-HTT) gene variants as strong candidates. <b><i>Methods:</i></b> In the GECO-BIP study, 125 BD patients and 173 HC were recruited. Subjects underwent to a detailed assessment and the temperament and character inventory 125 items (TCI) was administrated. Three functional genetic variants within key candidate genes (COMT rs4680, BDNF rs6265, and the serotonin-transporter-linked polymorphic region (5-HTTLPR)) were genotyped. Univariate and multivariate analyses were performed. <b><i>Results:</i></b> Compared to HC, BD patients showed higher scores in novelty seeking (NS; <i>p </i>= 0.001), harm avoidance (HA; <i>p</i> &#x3c; 0.001), and self transcendence (St; <i>p</i> &#x3c; 0.001), and lower scores in self directness (<i>p</i> &#x3c; 0.001) and cooperativeness (<i>p</i> &#x3c; 0.001) TCI dimensions. Concerning the genetic analyses, COMT rs4680 was associated with NS in the total sample (<i>p</i> = 0.007) and in the male subsample (<i>p</i> = 0.022). When performing the analysis in the HC and BD samples, the association was confirmed only in HC (<i>p</i> = 0.012), and in the HC male subgroup in particular (<i>p </i>= 0.004). BDNF rs6265 was associated with St in the BD group (<i>p</i> = 0.017). <b><i>Conclusion:</i></b> COMT rs4680 may modulate NS in males in the general population. This effect was not detected in BD patients, probably because BD alters the neurobiological basis of some TCI dimensions. BDNF rs6265 seems to modulate St TCI dimension only in BD patients, possibly modulating the previously reported association between rs6265 and BD treatment response. Further studies are needed to confirm our findings.
Da rua para os palcos, relações insuspeitas entre dança popular e dança teatral (Resenha de Marianna Monteiro)
Authors: Rocha Ewelter 
Published: July 2018

A relação conflituosa entre uma suposta “natureza dançante” do povo brasileiro e a participação apenas remota que a dança de palco ocupa no cenário cultural do Brasil constitui a provocação inicial que motivou Marianna Monteiro a realizar sua pesquisa, oportunamente nominada Dança popular: espetáculo e devoção. Como preconizado no subtítulo, a investigação lida com vetores aparentemente opostos – advindos da velha dialética do sagrado e do profano – contudo, marcados por relações insuspeitas, em que política, economia, estética e religião se interceptam nos processos formativos das danças populares brasileiras, considerados pela autora como parte integrante da expansão do Estado Moderno português, entre os séculos XVI e XVIII. A pesquisa é fruto da tese de doutorado apresentada ao Departamento de Filosofia da Faculdade de Filosofia, Letras e Ciências Humanas da Universidade de São Paulo (FFLCH-USP), sob orientação da professora Olgária Feres Matos.
As imagens e a potência dos encontros
Authors: Santos Carolina Junqueira dos 
Published: July 2018

O livro A experiência da imagem na etnografia, resultado de pesquisas realizadas pelo GRAVI – Grupo de Antropologia Visual /USP, aborda, a partir de artigos e filmes, os mais diversos usos da imagem dentro de uma perspectiva antropológica, procurando novas linguagens e possibilidades visuais para a etnografia.
BORÇ HEDEFLEMESİ REJİMİ VE MAKROEKONOMİK PERFORMANS
Authors: ÇETİN İrem 
Published: July 2018

Çalışmada, borç hedeflemesi rejimin, makroekonomik
performans üzerindeki etkilerinin, politik makroekonomi modelleri kullanılarak,
merkez bankasının bağımsız olduğu kurumsal yapıda araştırılması amaçlanmıştır.
Bu çerçevede, çalışmada, ilk olarak borç hedeflemesinin, politik
istikrarsızlığın arttığı durumda makroekonomik sonuçları incelenmektedir. Daha
sonra, daha sıkı borç hedeflemesinin ekonomik performans üzerindeki etkileri
değerlendirilmektedir. Çalışmada, son olarak, seçim sonuçlarına ilişkin belirsizlik
durumunda, borç hedeflemesi politikasının makroekonomik etkileri analiz
edilmektedir. Çalışmadan elde edilen sonuçlara
göre, politik istikrarsızlık sonucu mali sürdürülebilirlik problemleri ile
karşı karşıya kalan ekonomilerde kamu borcunun makul bir seviyede seyretmesini
sağlayacak bir borç hedeflemesi rejimi, politik istikrarsızlığın zamanlar arası
maliyetinin azaltılmasına yardımcı olmaktadır.
The Heart of Heresy: Inquisition, Medicine, and False Sanctity
Authors: Bouley Bradford 
Published: July 2018

Abstract
This paper examines the engagement of various officials and tribunals of the Roman Inquisition with the new anatomical studies of the early modern period. It argues that although inquisition officers were frequently very aware of the latest medical theories, they actively chose not to employ anatomical or medical evidence when evaluating the unusual physical symptoms that might be associated with false or affected sanctity. This attitude stands in contrast to the employment of anatomical knowledge by other ecclesiastical institutions – e.g. the Congregation of Rites – and suggests that the Inquisition held a different, and perhaps more modern, view about the relationship between natural knowledge and religion.
Contra medicos: Physicians Facing the Inquisition in Sixteenth-Century Venice
Authors: Celati Alessandra 
Published: July 2018

Abstract
Since the Middle Ages, ecclesiastical authorities considered medical activity worthy of their attention and control. During the Counter-Reformation, they toughened their disciplinary action, aware of the peculiarity of an ars that mixed together the cure of the body with the cure of the soul. Moreover, the authorities became increasingly suspicious of practitioners who were highly involved in the Reformation movement, and who distanced themselves from Catholicism in the epistemological premises of their work. By examining original sources from the Venetian Inquisition archive, this paper discusses the factors that put the Roman Church and the medical profession in op­­position to each other in the sixteenth century, and describes the professional solidarity put forward by physicians. It also examines the problematic relationship between doctors and the Inquisition, dealing with the former as effective agents of heretical propaganda.
Between Galen and St Paul: How Juan Huarte de San Juan Responded to Inquisitorial Censorship
Authors: Giglioni Guido 
Published: July 2018

Abstract
The Examen de ingenios para las sciencias, published in 1575 for the Spanish physician Juan Huarte de San Juan (1529/1530-1588), was a bold attempt to apply the principles of Galenic naturalism to a better understanding of human capabilities. Inevitably, the work also touched upon a number of theological issues, especially the delicate question of the interplay between natural abilities and supernatural gifts. When the treatise was included in the Portuguese Index of 1581, and then in the Spanish Indexes of 1583 and 1584, Huarte was allowed to amend some of his positions, as is evident in the second edition published posthumously in 1594. The aim of this article is to shed light on the identity of an ‘expurgated’ book by concentrating on some of the most significant changes in the Examen triggered by the intervention of the Spanish Inquisition. It will become apparent that Huarte’s response to censorship was not acquiescence or dissembling, but active engagement with the inquisitorial challenge.
Chara kirghisorum (Charales): lectotypification, first reliable record in Europe and update of species distribution in Russia
Authors: ROMANOV ROMAN E. , ABDULLIN SHAMIL R. 
Published: July 2018

Charophytes are commonly easily recognizable plants irrespective of their size due to the recurrent combination of very similar parts within their thalli. A few species are outstanding due to their unusual whip-like appearance with regularly distributed small nodules on the stems formed with whorls of short and nearly rudimentary branchlets. The central and north-European Chara filiformis A. Braun in Hertzsch (1855: 81) and mainly Middle-Asian C. kirghisorum Lessing (1834: 212) are examples of this distinctive habit. The species differ essentially in gametangia arrangement as well as in their distribution range. Monoecious C. filiformis does not have reliable records east of Pskov Oblast of Russia (29° E), while dioecious C. kirghisorum is unknown west of Orenburg Oblast of Russia (58° E) (Hollerbach 1941; Hollerbach & Krassavina 1983; LE!, PSK!). Therefore, they may be recognized as vicariate species.
Modification of Polar Low Development by Orography and Sea Ice
Authors: Sergeev Denis , Renfrew Ian A. , Spengler Thomas 
Published: July 2018

ABSTRACTThe life cycles of intense high-latitude mesoscale cyclones and polar lows are strongly shaped by their ambient environments. This study focuses on the influence of the orography of Svalbard and the sea ice cover in the Norwegian and Barents Seas on polar low development. We investigate two typical polar lows that formed near Svalbard during northerly cold-air outbreaks. Each case is simulated using the Met Office Unified Model with convection-permitting grid spacing. A series of sensitivity experiments is conducted with an artificially changed land mask, orography, and sea ice distribution. We find that Svalbard acts to block stably stratified air from the ice-covered Arctic Ocean, and as an additional source of low-level cyclonic vorticity aiding polar low genesis and intensification. A decrease in sea ice cover west of Svalbard results in a moderate intensification of the polar lows, particularly for the more convectively driven case, while an increase in the sea ice cover significantly hinders their development. These experiments exemplify that polar mesoscale cyclones in the northeast Atlantic can withstand large perturbations in the surface conditions (such as the removal of Svalbard) and still develop to sufficient intensity to be labeled as polar lows. However, there is a sensitivity to Svalbard’s orography and surrounding sea ice cover, illustrated by a clear modulation of polar low genesis and development.
Congenital Hypothyroid Screening in Term Neonates Using Cord Blood TSH
Authors: Bhatia Ravi , Rajwaniya Dinesh 
Published: July 2018

Congenital hypothyroidism remains one of the most common preventable causes of mental retardation among children. Screening for congenital hypothyroidism remains one of the most cost-effective tools to prevent mental retardation in the population. Umbilical cord blood thyroid-stimulating hormone (TSH) levels remain an attractive and a practical step for screening for congenital hypothyroidism. Aims: To find normative values of cord blood TSH for the study group. To use cord blood TSH levels as a marker for the screening of congenital hypothyroidism. Methodology: Cord blood of 1824 neonates who were of term gestation, weighed greater than 2.5 kg at birth, and whose mothers were off thyroid medication were a part of the study group. Umbilical cord blood was collected at the time of delivery and TSH was estimated. All babies who had a cord blood TSH value >20 mIU/L were called bay on day 7 of life for a full thyroid profile. Results: Cord blood samples of 1824 neonates were tested for TSH. The male to female ratio was 979:845 = 1.15:1. The birth weights ranged between 2.5 and 4.5 kg with an average birth weight of 2.811 kg. The mean (SD) TSH value was 7.725 (8.99). TSH values ranged between 1.2 and 100 mIU/ml. TSH values corresponding to the 3rd, 10th, 25th, 50th, 90th, 95th, and 97th percentile were 2.32, 3.03, 4.05, 5.67, 7.5, 12, 20.63, and 30.88 respectively. Out of the 88 babies recalled for repeat testing, 80 babies turned up; eventually, 1 turned out to be hypothyroid on repeat testing. The incidence of congenital hypothyroidism in our study was 1 in 1824. Conclusion: To conclude, we can safely use the cord blood TSH value >20 mIU/L as a cutoff value for the purpose of screening for congenital hypothyroidism. For logistic angles, a higher cutoff of >30mIU/L can be used. Large population-based studies are required to establish normative values for cord blood TSH in our country.
Evaluation of the Effect of Warm and Humidified Oxygen as Compared to the Humidified Oxygen Alone in Neonates and Children with Respiratory Distress
Authors: Yadav Ashok K , Gupta Girish 
Published: July 2018

Introduction: Respiratory distress is common for which oxygen forms the mainstay of treatment and is given as humidified oxygen to newborn and children. The aim of the present study is to evaluate and compare the effect of warm and humidified oxygen with humidified oxygen alone in neonates and children with respiratory distress. Materials and Methods: For this study, 60 neonates and 60 children (2-12 years) with respiratory distress were enrolled. Oxygen supplementation was given as humidified oxygen for initial stabilization for 2 hours as per the extant practice and subsequently, neonates and children were divided into two subgroups for schema of evaluation and comparison as warm and humidified followed by humidified oxygen for 2 hours and again warm (36°C-38°C) and humidified oxygen and reversed for other schema. Results were analyzed using two-tailed t-test. Results: A majority of neonates were preterms ( n = 32; 53.33%) and respiratory distress syndrome ( n = 20; 33.33%) was the commonest cause followed by transient tachypnea of newborn ( n = 18; 30%), perinatal asphyxia ( n = 6; 10%), and meconium aspiration syndrome ( n = 5; 8.33%). A majority of neonates had moderate respiratory distress with Downe’s score of 4.13 ± 2.01 and responded well to supplemental oxygen alone. The difference of the Downe’s score was not statistically significant when compared at 2 hours, 4 hours, and 6 hours ( P > .05). Among the children with respiratory distress (asthma), the largest subgroup ( n = 13; 36.1%) had moderate to severe exacerbation at presentation. The difference of the respiratory distress score was not statistically significant when compared at 2 hours, 4 hours, and 6 hours ( P > .05). Conclusion: The current method of humidified oxygen delivery can be continued for oxygen therapy of neonates. Stand-alone humidifier with warmidification is useful when used as high flow nasal cannula for its additional effect of positive airway pressure. Multicentric and larger randomized control trials may provide further evidence on the subject issue.