bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bicyclic Peptides as a New Modality for Imaging and Targeting of Proteins Overexpressed by Tumors
Authors: Eder Matthias , Pavan Silvia , Bauder-Wüst Ulrike , van Rietschoten Katerine , Baranski Ann-Christin , Harrison Helen , Campbell Spencer , Stace Catherine L. , Walker Edward H. , Chen Liuhong , Bennett Gavin , Mudd Gemma , Schierbaum Ursula , Leotta Karin , Haberkorn Uwe , Kopka Klaus , Teufel Daniel P. 
Published: January 2019

Abstract

Molecular imaging of cancers using probes specific for tumor-associated target proteins offers a powerful solution for providing information regarding selection of targeted therapy, patient stratification, and response to therapy. Here we demonstrate the power of bicyclic peptides as targeting probes, exemplified with the tumor-overexpressed matrix metalloproteinase MT1-MMP as a target. A bicyclic peptide with subnanomolar affinity towards MT1-MMP was identified, and its radioconjugate showed selective tumor uptake in an HT1080 xenograft mouse model. Proteolytic stabilization of the peptide by chemical modification significantly enhanced the in vivo tumor signal [from 2.5%ID/g to 12%ID/g at 1 hour post injection (p.i.)]. Studies using mouse xenograft models with different cell lines show a robust correlation between tumor signals and in vivo MT1-MMP expression levels. Fatty acid modification of the bicyclic peptide extended its circulating half-life, resulting in increased tumor signals (36%ID/g at 6 hours p.i.). Comparative work with an equipotent radiolabeled MT1-MMP targeting antibody demonstrated starkly differential biodistribution and tumor accumulation properties, with the tumor signal slowly increasing to 6.2%ID/g within 48 hours. The rapid tumor penetration characteristics of bicyclic peptides, coupled with high potency and chemical versatility, thus offer high-contrast imaging probes for clinical diagnostics with compelling additional potential in targeted therapy.
Significance: This work demonstrates the potential of bicyclic peptides as a platform for the development of high-contrast imaging probes for potential use in clinical cancer diagnostics and molecularly targeted therapeutics.
Growth Factor–Independent 1 Is a Tumor Suppressor Gene in Colorectal Cancer
Authors: Chen Min-Shan , Lo Yuan-Hung , Chen Xi , Williams Christopher S. , Donnelly Jessica M. , Criss Zachary K. , Patel Shreena , Butkus Joann M. , Dubrulle Julien , Finegold Milton J. , Shroyer Noah F. 
Published: January 2019

Abstract

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor–independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1F/F; CDX2-cre) and crossed them with ApcMin/+ mice (ApcMin/+; Gfi1F/F; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (ApcMin/+; Gfi1F/F; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon.

Implications:
These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis.
Chemoprevention of Lung Carcinogenesis by Dietary Nicotinamide and Inhaled Budesonide
Authors: Galbraith Arthur R. , Seabloom Donna E. , Wuertz Beverly R. , Antonides Jennifer D. , Steele Vernon E. , Wattenberg Lee W. , Ondrey Frank G. 
Published: January 2019

Abstract
Nicotinamide, the amide form of vitamin B3, and budesonide, a synthetic glucocorticoid used in the treatment of asthma, were evaluated to determine their individual and combinational chemopreventive efficacy on benzo(a)pyrene-induced lung tumors in female A/J mice. Nicotinamide fed at a dietary concentration of 0.75% significantly inhibited tumor multiplicity. Nicotinamide by aerosol inhalation at doses up to 15 mg/kg/day did not result in a statistically significant reduction in tumor multiplicity. Finally, dietary nicotinamide was administered with aerosol budesonide and tumor multiplicity reduced by 90% at 1 week and 49% at 8 weeks post last carcinogen dose. We conclude nicotinamide is an effective and safe agent for lung cancer dietary prevention at both early- and late-stage carcinogenesis and that efficacy is increased with aerosol budesonide. Combination chemoprevention with these agents is a well-tolerated and effective strategy which could be clinically advanced to human studies.
Human Papillomavirus (HPV) 16/18 E6 Oncoprotein Expression in Infections with Single and Multiple Genotypes
Authors: Wu Zeni , Li Ting-Yuan , Jiang Mingyue , Yu Lulu , Zhao Jing , Wang Hairui , Zhang Xun , Chen Wen , Qiao Youlin 
Published: January 2019

Abstract
Factors that differentiate risk of cervical cancer associated with infection with single versus multiple HPV types are yet undefined. We hypothesize that E6 oncoprotein is one determining factor. This cross-sectional, multicenter study was performed between 2013 and 2017. A total of 1,781 women were recruited from six hospitals. Samples were tested for presence of 14 types of high-risk HPV DNA. HPV16/18-positive samples were also tested for HPV16/18-E6 oncoprotein. Of 1,781 subjects, 687 (38.6%) tested positive for HPV16/18. HPV16/18 single infections were associated with higher E6 positivity rates compared with multiple infections only for cancer cases (HPV16: 92.2% vs. 76.5%; HPV18: 93.9% vs. 62.1%) but not for normal histopathology or cervical intraepithelial neoplasia. In HPV16/18 coinfection subjects, the positivity rate was 42.9% for HPV16-E6 and 42.9% for HPV18-E6. The combined positivity rate of either HPV16-E6 or HPV18-E6 among HPV16/18 coinfection subjects was 78.6%, similar with HPV16 (74.8%) and HPV18 (79.5%) single-infection subjects. The positivity rates of HPV16/18 E6 oncoprotein varied depending on the HPV-type composition in multiple infection (“clusters”) including HPV types other than 16 and 18. Multiple infection clusters most likely to express HPV16-E6 and HPV18-E6 were HPV16/52 (61.5%) and HPV18/52 (66.7%), and the less were HPV16/45 (10.0%) and HPV18/51 (16.7%), respectively. Patterns of E6 oncoprotein expression varied depending on clustering types. However, expression was greatest in women with single HPV-type infections compared with those with multiple HPV types regardless of histopathology. Our findings provided new insight of natural history of cervical cancer.
Impact of 12/15-Lipoxygenase on Brain Injury After Subarachnoid Hemorrhage
Authors: Gaberel Thomas , Gakuba Clément , Zheng Yi , Lépine Matthieu , Lo Eng H. , van Leyen Klaus 
Published: January 2019

Background and Purpose—
Subarachnoid hemorrhage (SAH) is a devastating form of stroke. Oxidative stress contributes to brain injury, but the mechanisms have been poorly studied. Here, we evaluated the role of 12/15-lipoxygenase (12/15-LOX), an enzyme known to cause cell death in ischemic stroke, on brain injury in a mouse model of SAH.

Methods—

C57Bl6 wild-type mice and
Alox15
knockout mice were subjected to SAH using a direct blood injection technique. In SAH wild-type mice, half received the 12/15-LOX inhibitor ML351 and half received vehicle. Immunohistochemistry, brain edema, blood-brain barrier leakage and functional outcomes were assessed 1 and 3 days after SAH induction.

Results—

SAH led to increased 12/15-LOX in macrophages of the brain parenchyma, adjacent to the subarachnoid blood. Neuronal cell death after SAH was reduced by ML351 and in
Alox15
knockout mice. Similarly, SAH induced brain edema, which was 12/15-LOX dependent. Finally,
Alox15
gene knockout and inhibitor treatment in wild-type mice with SAH led to an improved behavioral outcome.

Conclusions—
12/15-LOX is overexpressed in macrophages after SAH in mice, and inhibition of the 12/15-LOX pathway decreases brain injury and improves neurological outcome. This study suggests 12/15-LOX as a novel therapeutic target to limit brain injury after SAH.
Reducing Risk for Gestational Diabetes Mellitus (GDM) Through a Preconception Counseling Program for American Indian/Alaska Native Girls: Perceptions From Women With Type 2 Diabetes or a History of GDM
Authors: Stotz Sarah , Charron-Prochownik Denise , Terry Martha Ann , Gonzales Kelly , Moore Kelly ,   For the Stopping GDM Study Group
Published: January 2019

Purpose American Indian and Alaska Native (AIAN) women are disproportionately affected by gestational diabetes mellitus (GDM). GDM is a risk factor for subsequent diagnosis of type 2 diabetes (T2D) in both mother and offspring, yet there is minimal research being conducted in this population. The purpose of this portion of a larger 5-year study is to examine AIAN women’s experiences of having GDM or T2D during pregnancy, inform the development of a GDM risk reduction and preconception counseling (PC) program tailored to AIAN girls, and enhance mother-daughter communication and support within the program. Methods AIAN women with TD2 or a history of GDM (N = 5) were interviewed to understand their unique perspectives on diabetes and pregnancy, behaviors to reduce risk, and content for a PC education program for AIAN girls. Interviews were digitally recorded, transcribed verbatim, and analyzed using the constant comparison method to construct themes across the interviews. Results Four primary themes were constructed: lack of knowledge on GDM and GDM risk factors, importance of AIAN culture for health and wellness, suggestions for communication with AIAN girls to reduce risk of GDM, and the emotional impact of GDM diagnosis. Conclusions Participants wished they had known about risk factors for GDM and how to reduce their own risk of developing GDM. Findings from this study have been used to adapt an existing PC program, originally developed for non-AIAN girls with diabetes, for AIAN girls who do not have diabetes but have risk factors for developing GDM in future pregnancies.
Against Financial Derivatives: Towards an Ethics of Representation
Authors: Hawkes David 
Published: January 2019

Financial derivatives dominate the twenty-first century economy. Such instruments are performative signs, in the sense that they do not refer to any substantial use-value but rather carry their value within themselves. Financial derivatives thus represent a movement towards the autonomy of representation in the economic sphere, which parallels the rise of performative representation in linguistics and philosophy. The independent power of signs has historically been subjected to severe ethical criticism. To imagine that signs can do things has always been denounced as magic, idolatry and fetishism. In the economic sphere the autonomous reproduction of financial signs has been criticized as ‘usury.’ In order to achieve an ethical perspective on the rise to power of financial derivatives, and also on the wider power of signs in postmodernity, we would do well to revive such forms of moral semiotics, and to apply them to the autonomous representations of our own era. JEL: A12, A13, B14, E44, Z13
The Psychometric Properties of the Kessler Psychological Distress Scale (K6) in an Epidemiological Sample of Canadian Youth
Authors: Ferro Mark A. 
Published: January 2019

Objective: This study (1) describes the distribution of Kessler Psychological Distress Scale (K6) scores in an epidemiological sample of youth, (2) reports its item correlations and internal consistency reliability, (3) tests for measurement invariance by age (youth vs. adults) and sex, and (4) examines its predictive power for past-year psychiatric disorders. Method: Youth aged 15 to 19 years ( n = 2010) and adults aged 20 to 64 years ( n = 2010) from the Canadian Community Health Survey–Mental Health who completed the K6 were included. Past-year psychiatric disorders were measured using the World Health Organization Composite International Diagnostic Interview 3.0 (WHO-CIDI). Polychoric correlation matrices and ordinal reliability coefficients were calculated to assess internal consistency of the K6, and confirmatory factor analysis was used to test for measurement invariance. Area under the curves (AUCs) were computed to determine the extent to which the K6 predicted a positive screen on the WHO-CIDI. Results: K6 scores showed a J-shaped distribution, with >50% of youth having scores ≤3. Item and total scores were higher for females versus males. Item correlations were robust (0.31-0.78) and internal consistency was high (α = 0.86). Full measurement invariance was demonstrated between youth and adults, as well as between male and female youth. The K6 was a strong predictor of major depressive episode (AUC = 0.848), generalized anxiety disorder (AUC = 0.847), and bipolar disorder (AUC = 0.853). Conclusions: The K6 is a valid and reliable measure of psychological distress among youth. Its brevity and robust predictive power for psychiatric disorder confirm its utility in clinical and community settings to identify youth needing comprehensive psychiatric assessment.
“I Didn’t Need People’s Negative Thoughts”: Women With Intellectual and Developmental Disabilities Reporting Attitudes Toward Their Pregnancy
Authors: Potvin Lynne A. , Barnett Barbara M. , Brown Hilary K. , Cobigo Virginie 
Published: January 2019

Background Since the illegalization of involuntary sterilization of persons with intellectual and developmental disabilities, there has been an increase in childbearing in this population. However, women with intellectual and developmental disabilities continue to experience prejudicial attitudes toward their pregnancies. Objective To analyze the experiences of women with intellectual and developmental disabilities regarding their perceptions of support persons’ attitudes toward their pregnancies. Methods Three case studies derived from grounded theory research exploring perinatal social support received by women with intellectual and developmental disabilities. Using inductive content analysis, we further analyzed the perceptions of women with intellectual and developmental disabilities regarding support persons’ attitudes toward their pregnancies. Findings: The nature of interactions with support persons and women’s characteristics, such as help-seeking behaviors, disability, mental illness, and age, influenced support persons’ attitudes toward childbearing. Women preferred support from caregivers perceived as nonjudgmental and tended to restrict contact with persons perceived as prejudicial. However, some attitudes improved following positive interactions with the women. The relationship between support persons’ attitudes and the women’s help-seeking behaviors is thus complex. Conclusions Education of families and medical and social services practitioners and opportunities for positive contact should be further explored. Caseworkers of women with intellectual and developmental disabilities may have invaluable roles in facilitating positive interactions between women with intellectual and developmental disabilities and caregivers.
Validation of a new 2.5D radiographic index evaluating acetabular coverage using ACX software
Authors: Nishikino Shoichi , Koyama Hiroshi , Furuhashi Hiroki , Hoshino Hironobu , Matsuyama Yukihiro 
Published: January 2019

Background: Several radiographic signs have been described to assess acetabular coverage. However, plain radiographs only have 2 dimensions (2D) and cannot accurately show acetabular coverage. Questions/purposes: We developed the ACX Dynamics software to calculate the radial centre-edge angle (RCEA), which represents the acetabular coverage of the femoral head at each acetabular edge point on the radial plane. This study validated the accuracy of the RCEA, as calculated by ACX Dynamics, as a quantitative parameter for acetabular coverage. Patients and methods: We reviewed the anteroposterior (AP) pelvic radiographs and computed tomography (CT) of 650 hips from 325 patients who presented with chief complaint of symptoms at the hip joint. Of 109 hip radiographs (68 patients) that satisfied the criteria, 50 randomised, blinded AP pelvic radiographs were chosen. We determined the absolute RCEA difference (°) [= RCEA ACX (°) – RCEA CT (°)], determined the correlation between RCEA ACX (°) and RCEA CT (°), and examined the RCEA’s intra-observer and inter-observer reliability in 50 hips. Results: The absolute RCEA difference from A45° to P75° was 1.9–3.1°. The correlation between the RCEA ACX (°) and RCEA CT (°) was > 0.7 in all lesions ( p < 0.001). Using the intraclass correlation coefficient, the intra-observer reliability of the RCEA was 0.83–0.97 in the whole range, which is a highly reproducible and reasonable parameter, and the inter-observer reliability was > 0.80 in A45°–P0°. Conclusions: The RCEA ACX (°) can be used as a simple quantitative parameter for assessing acetabular coverage using AP pelvic radiograph.
Acute toxicity and teratogenicity of α-mangostin in zebrafish embryos
Authors: Kittipaspallop Wannakarn , Taepavarapruk Pornnarin , Chanchao Chanpen , Pimtong Wittaya 
Published: January 2019

α-Mangostin is the most active compound derived from the pericarps of mangosteen. A number of studies have reported its anticancer activity. However, only a few studies have investigated the toxicity of this compound; moreover, the teratogenicity of α-mangostin has not been reported. In this study, we evaluated the effects of α-mangostin on the development of zebrafish embryos. The exposure of zebrafish embryos to α-mangostin for 72 h dose-dependently induced mortality and abnormal development. The derived LC50 value of α-mangostin to zebrafish embryos at 72 h was 5.75 ± 0.26 μmol/L. We observed teratogenic effects in α-mangostin-treated embryos, characterized by axis malformation, bent tail, pericardial edema, yolk sac edema, sluggish circulation, and heart malformation. The percentages of the malformed embryos were 78.79% and 100% at 4.5 and 6 μM, respectively. α-Mangostin exposure also caused hemostasis in the ducts of Cuvier and a decreased heart rate in zebrafish embryos at 48 and 72 h post-fertilization. These results indicated that α-mangostin induced cardiac dysfunction in zebrafish embryos. In addition, a sub-lethal concentration and a lethal concentration (3 and 6 μM, respectively) were used to assess the compound effects on oxidative stress and embryonic erythropoiesis. α-Mangostin was found to decrease the level of reactive oxygen species (ROS) in zebrafish embryos. Furthermore, hemoglobin staining revealed a decrease in hemoglobin, which suggested that α-mangostin disrupted embryonic erythropoiesis in zebrafish. To our knowledge, the results of this study, for the first time, demonstrated that α-mangostin was potentially teratogenic and could disrupt embryonic ROS balance and erythropoiesis. Impact statement α-Mangostin has been reported to have anticancer properties both in vitro and in vivo models. Although there are several studies that evaluated the toxicity of the compound in rodent models, we are the first to evaluate the teratogenicity of α-mangostin. In the present work, we found that α-mangostin induced mortality and malformations in zebrafish embryos. In addition, we exhibited that the compound also disrupted the reactive oxygen species and hemoglobin levels. These findings suggest that α-mangostin may possibly cause the same adverse effects on human health. The mechanisms of these toxicological effects of the compound will be further elucidated and the effects found in zebrafish embryos need to be verified in other animal models.
Robot-Assisted Aortic Valve Replacement Using a Novel Sutureless Bovine Pericardial Prosthesis Proof of Concept as an Alternative to Percutaneous Implantation
Authors: Suri Rakesh M. , Burkhart Harold M. , Schaff Hartzell V. 
Published: January 2019

Objective Percutaneous aortic valve implantation within native valve calcium has progressed to clinical use despite the absence of data proving equivalence to complete surgical excision and prosthetic valve replacement. A novel self-expanding sutureless bovine pericardial prosthesis (Sorin Perceval) derived from a proven stented valve has been successfully used in humans recently through an open transaortic approach. We sought to develop a minimally invasive technique for native aortic valve excision and sutureless prosthetic aortic valve replacement using robot assistance. Methods The da Vinci S-HD system was used to open and suspend the pericardium anterior to the phrenic nerve in cadavers. A transthoracic cross-clamp was placed across the midascending aorta, following which a transverse aortotomy was made. The native aortic valve cusps were excised, and annular calcium was removed with robotic instruments. After placement of three guide sutures, the Perceval self-expanding pericardial prosthesis mounted on a flexible delivery system was inserted through a working port and lowered into the aortic annulus. Results Successful implantation of all valves was possible using a 3-cm right second intercostal space working port, along with two additional 1-cm instrument ports. A standard transverse aortotomy was sufficient for examination/debridement of the native aortic valve cusps, sizing of the annulus, and deployment of the nitinol-stented, bovine pericardial prosthesis. Delivery, seating, and stability of the device were easily confirmed above and below the aortic valve annulus using the robotic camera. Conclusions Complete excision of diseased native aortic valve cusps with robot assistance facilitates accurate and reproducible aortic valve replacement using a novel self-expanding sutureless version of a proven bovine pericardial prosthesis. This approach is comparable to the current surgical gold standard and is ready for clinical use as an alternative to percutaneous aortic valve implantation.