bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Treatment and Insurance on Socioeconomic Disparities in Survival after Adolescent and Young Adult Hodgkin Lymphoma: A Population-Based Study
Authors: Keegan Theresa H.M. , DeRouen Mindy C. , Parsons Helen M. , Clarke Christina A. , Goldberg Debbie , Flowers Christopher R. , Glaser Sally L. 
Published: January 2016

Abstract
Background: Previous studies documented racial/ethnic and socioeconomic disparities in survival after Hodgkin lymphoma among adolescents and young adults (AYA), but did not consider the influence of combined-modality treatment and health insurance.
Methods: Data for 9,353 AYA patients ages 15 to 39 years when diagnosed with Hodgkin lymphoma during 1988 to 2011 were obtained from the California Cancer Registry. Using multivariate Cox proportional hazards regression, we examined the impact of sociodemographic characteristics [race/ethnicity, neighborhood socioeconomic status (SES), and health insurance], initial combined-modality treatment, and subsequent cancers on survival.
Results: Over the 24-year study period, we observed improvements in Hodgkin lymphoma–specific survival by diagnostic period and differences in survival by race/ethnicity, neighborhood SES, and health insurance for a subset of more recently diagnosed patients (2001–2011). In multivariable analyses, Hodgkin lymphoma–specific survival was worse for Blacks than Whites with early-stage [HR: 1.68; 95% confidence interval (CI): 1.14–2.49] and late-stage disease (HR: 1.68; 95% CI, 1.17–2.41) and for Hispanics than Whites with late-stage disease (HR: 1.58; 95% CI, 1.22–2.04). AYAs diagnosed with early-stage disease experienced worse survival if they also resided in lower SES neighborhoods (HR: 2.06; 95% CI, 1.59–2.68). Furthermore, more recently diagnosed AYAs with public health insurance or who were uninsured experienced worse Hodgkin lymphoma–specific survival (HR: 2.08; 95% CI, 1.52–2.84).
Conclusion: Our findings identify several subgroups of Hodgkin lymphoma patients at higher risk for Hodgkin lymphoma mortality.
Impact: Identifying and reducing barriers to recommended treatment and surveillance in these AYAs at much higher risk of mortality is essential to ameliorating these survival disparities. Cancer Epidemiol Biomarkers Prev; 25(2); 264–73. ©2016 AACR.
Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2
Authors: Terashima Masato , Togashi Yosuke , Sato Katsuaki , Mizuuchi Hiroshi , Sakai Kazuko , Suda Kenichi , Nakamura Yu , Banno Eri , Hayashi Hidetoshi , De Velasco Marco A. , Fujita Yoshihiko , Tomida Shuta , Mitsudomi Tetsuya , Nishio Kazuto 
Published: January 2016

Abstract
Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets.
Experimental design: Fifty surgically resected non–small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro.
Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type–overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K–overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor.
Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. Clin Cancer Res; 22(14); 3663–71. ©2016 AACR.
Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer
Authors: Jabbour-Leung Natalie A. , Chen Xian , Bui Tuyen , Jiang Yufeng , Yang Dong , Vijayaraghavan Smruthi , McArthur Mark J. , Hunt Kelly K. , Keyomarsi Khandan 
Published: January 2016

Abstract
Triple-negative breast cancer (TNBC) is an aggressive malignancy in which the tumors lack expression of estrogen receptor, progesterone receptor, and HER2. Hence, TNBC patients cannot benefit from clinically available targeted therapies and rely on chemotherapy and surgery for treatment. While initially responding to chemotherapy, TNBC patients are at increased risk of developing distant metastasis and have decreased overall survival compared with non-TNBC patients. A majority of TNBC tumors carry p53 mutations, enabling them to bypass the G1 checkpoint and complete the cell cycle even in the presence of DNA damage. Therefore, we hypothesized that TNBC cells are sensitive to cell-cycle–targeted combination therapy, which leaves nontransformed cells unharmed. Our findings demonstrate that sequential administration of the pan-CDK inhibitor roscovitine before doxorubicin treatment is synthetically lethal explicitly in TNBC cells. Roscovitine treatment arrests TNBC cells in the G2–M cell-cycle phase, priming them for DNA damage. Combination treatment increased frequency of DNA double-strand breaks, while simultaneously reducing recruitment of homologous recombination proteins compared with doxorubicin treatment alone. Furthermore, this combination therapy significantly reduced tumor volume and increased overall survival compared with single drug or concomitant treatment in xenograft studies. Examination of isogenic immortalized human mammary epithelial cells and isogenic tumor cell lines found that abolishment of the p53 pathway is required for combination-induced cytotoxicity, making p53 a putative predictor of response to therapy. By exploiting the specific biologic and molecular characteristics of TNBC tumors, this innovative therapy can greatly impact the treatment and care of TNBC patients. Mol Cancer Ther; 15(4); 593–607. ©2016 AACR.
Gastric Adenocarcinomas Express the Glycosphingolipid Gb3/CD77: Targeting of Gastric Cancer Cells with Shiga Toxin B-Subunit
Authors: Geyer Philipp Emanuel , Maak Matthias , Nitsche Ulrich , Perl Markus , Novotny Alexander , Slotta-Huspenina Julia , Dransart Estelle , Holtorf Anne , Johannes Ludger , Janssen Klaus-Peter 
Published: January 2016

Abstract
The B-subunit of the bacterial Shiga toxin (STxB), which is nontoxic and has low immunogenicity, can be used for tumor targeting of breast, colon, and pancreatic cancer. Here, we tested whether human gastric cancers, which are among the most aggressive tumor entities, express the cellular receptor of Shiga toxin, the glycosphingolipid globotriaosylceramide (Gb3/CD77). The majority of cases showed an extensive staining for Gb3 (36/50 cases, 72%), as evidenced on tissue sections of surgically resected specimen. Gb3 expression was detected independent of type (diffuse/intestinal), and was negatively correlated to increasing tumor–node–metastasis stages (P = 0.0385), as well as with markers for senescence. Gb3 expression in nondiseased gastric mucosa was restricted to chief and parietal cells at the bottom of the gastric glands, and was not elevated in endoscopic samples of gastritis (n = 10). Gb3 expression in established cell lines of gastric carcinoma was heterogeneous, with 6 of 10 lines being positive, evidenced by flow cytometry. STxB was taken up rapidly by live Gb3-positive gastric cancer cells, following the intracellular retrograde transport route, avoiding lysosomes and rapidly reaching the Golgi apparatus and the endoplasmic reticulum. Treatment of the Gb3-expressing gastric carcinoma cell line St3051 with STxB coupled to SN38, the active metabolite of the topoisomerase type I inhibitor irinotecan, resulted in &gt;100-fold increased cytotoxicity, as compared with irinotecan alone. No cytotoxicity was observed on gastric cancer cell lines lacking Gb3 expression, demonstrating receptor specificity of the STxB–SN38 compound. Thus, STxB is a highly specific transport vehicle for cytotoxic agents in gastric carcinoma. Mol Cancer Ther; 15(5); 1008–17. ©2016 AACR.
A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells
Authors: Lilienthal Nils , Lohmann Gregor , Crispatzu Giuliano , Vasyutina Elena , Zittrich Stefan , Mayer Petra , Herling Carmen Diana , Tur Mehmet Kemal , Hallek Michael , Pfitzer Gabriele , Barth Stefan , Herling Marco 
Published: January 2016

Abstract
The serine/threonine death-associated protein kinases (DAPK) provide pro-death signals in response to (oncogenic) cellular stresses. Lost DAPK expression due to (epi)genetic silencing is found in a broad spectrum of cancers. Within B-cell lymphomas, deficiency of the prototypic family member DAPK1 represents a predisposing or early tumorigenic lesion and high-frequency promoter methylation marks more aggressive diseases. On the basis of protein studies and meta-analyzed gene expression profiling data, we show here that within the low-level context of B-lymphocytic DAPK, particularly CLL cells have lost DAPK1 expression. To target this potential vulnerability, we conceptualized B-cell–specific cytotoxic reconstitution of the DAPK1 tumor suppressor in the format of an immunokinase. After rounds of selections for its most potent cytolytic moiety and optimal ligand part, a DK1KD-SGIII fusion protein containing a constitutive DAPK1 mutant, DK1KD, linked to the scFv SGIII against the B-cell–exclusive endocytic glyco-receptor CD22 was created. Its high purity and large-scale recombinant production provided a stable, selectively binding, and efficiently internalizing construct with preserved robust catalytic activity. DK1KD-SGIII specifically and efficiently killed CD22-positive cells of lymphoma lines and primary CLL samples, sparing healthy donor– or CLL patient–derived non-B cells. The mode of cell death was predominantly PARP-mediated and caspase-dependent conventional apoptosis as well as triggering of an autophagic program. The notoriously high apoptotic threshold of CLL could be overcome by DK1KD-SGIII in vitro also in cases with poor prognostic features, such as therapy resistance. The manufacturing feasibility of the novel CD22-targeting DAPK immunokinase and its selective antileukemic efficiency encourage intensified studies towards specific clinical application. Mol Cancer Ther; 15(5); 971–84. ©2016 AACR.
Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression
Authors: Bisi John E. , Sorrentino Jessica A. , Roberts Patrick J. , Tavares Francis X. , Strum Jay C. 
Published: January 2016

Abstract
Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first- and second-line treatment of small-cell lung cancer. Mol Cancer Ther; 15(5); 783–93. ©2016 AACR.
EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB
Authors: Civenni Gianluca , Longoni Nicole , Costales Paula , Dallavalle Cecilia , García Inclán Cristina , Albino Domenico , Nuñez Luz Elena , Morís Francisco , Carbone Giuseppina M. , Catapano Carlo V. 
Published: January 2016

Abstract
Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKβ and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-κB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKβ and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-κB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806–18. ©2016 AACR.
Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease
Authors: Bonaca Marc P. , Gutierrez J. Antonio , Creager Mark A. , Scirica Benjamin M. , Olin Jeffrey , Murphy Sabina A. , Braunwald Eugene , Morrow David A. 
Published: January 2016

Background—
Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type.

Methods and Results—

The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis–Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39–0.86;
P
=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38–0.93;
P
=0.022). The efficacy of vorapaxar was consistent across types of ALI.

Conclusions—
In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00526474.
The sural nerve: Sonographic anatomy, variability and relation to the small saphenous vein in the setting of endovenous thermal ablation
Authors: Rodriguez-Acevedo Omar , Elstner Kristen , Zea Aaron , Diaz Jenny , Martinic Kui , Ibrahim Nabeel 
Published: January 2016

Background Neurological complications are well documented in association with both surgical stripping or disconnection and thermal ablation of the small saphenous vein. The sural nerve (medial sural cutaneous nerve) is most vulnerable due to its close relationship to the small saphenous vein. Objective This is a cross-sectional observational study of the sonographic anatomy of 115 Australian patients to determine the course of the sural nerve and its relationship to the small saphenous vein, and to identify its relevance in the thermal ablation of the small saphenous vein. Method Sonographic mapping of the right sural nerve was performed with a Philips L12.5 and Sonosite 10.5 MHz ultrasound machine on 115 patients. The sural nerve was traced proximally from the level of the lateral malleolus to the popliteal fossa in order to measure its distance from the small saphenous vein at four reference points in the lower leg. Results A total of 115 patients were studied (females 82, males 33). The sural nerve was identified in 100% of patients; 64 patients (55.7%) showed usual sural nerve anatomy, while 51 patients (44.3%) demonstrated a range of anatomical variations, including the sural nerve becoming epifascial at a higher point than usual. Conclusion The sural nerve was identifiable on duplex ultrasound in 100% of cases. Classic anatomical relations and the perceived protection of the sural nerve conferred by the deep fascia of the upper calf are unreliable. Preoperative strategies can help to approach and protect the sural nerve in the endovenous ablation setting.
Effectiveness of balance training programme in reducing the frequency of falling in established osteoporotic women: a randomized controlled trial
Authors: Mikó Ibolya , Szerb Imre , Szerb Anna , Poor Gyula 
Published: January 2016

Objective: To investigate the effect of a 12-month sensomotor balance exercise programme on postural control and the frequency of falling in women with established osteoporosis. Design: Randomized controlled trial where the intervention group was assigned the 12-month Balance Training Programme and the control group did not undertake any intervention beyond regular osteoporosis treatment. Subjects: A total of 100 osteoporotic women – at least with one osteoporotic fracture – aged 65 years old and above. Main measures: Balance was assessed in static and dynamic posture both with performance-based measures of balance, such as the Berg Balance Scale and the Timed Up and Go Test, and with a stabilometric computerized platform. Interventions: Patients in the intervention group completed the 12-month sensomotor Balance Training Programme in an outpatient setting, guided by physical therapists, three times a week, for 30 minutes. Results: The Berg Balance Scale and the Timed Up and Go Test showed a statistically significant improvement of balance in the intervention group ( p = 0.001 and p = 0.005, respectively). Balance tests using the stabilometer also showed a statistically significant improvement in static and dynamic postural balance for osteoporotic women after the completion of the Balance Training Programme. As a consequence, the one-year exercise programme significantly decreased the number of falls in the exercise group compared with the control group. Conclusion: The Balance Training Programme significantly improved the balance parameters and reduced the number of falls in postmenopausal women who have already had at least one fracture in the past.
Demographic factors associated with moral sensitivity among nursing students
Authors: Tuvesson Hanna , Lützén Kim 
Published: January 2016

Background: Today’s healthcare environment is often characterized by an ethically demanding work situation, and nursing students need to prepare to meet ethical challenges in their future role. Moral sensitivity is an important aspect of the ethical decision-making process, but little is known regarding nursing students’ moral sensitivity and its possible development during nursing education. Objectives: The aims of this study were to investigate moral sensitivity among nursing students, differences in moral sensitivity according to sample sub-group, and the relation between demographic characteristics of nursing students and moral sensitivity. Research design: A convenience sample of 299 nursing students from one university completed a questionnaire comprising questions about demographic information and the revised Moral Sensitivity Questionnaire. With the use of SPSS, non-parametric statistics, including logistic regression models, were used to investigate the relationship between demographic characteristics and moral sensitivity. Ethical considerations: The study followed the regulations according to the Swedish Ethical Review Act and was reviewed by the Ethics Committee of South-East Sweden. Findings: The findings showed that mean scores of nursing students’ moral sensitivity were found in the middle to upper segment of the rating scale. Multivariate analysis showed that gender (odds ratio = 3.32), age (odds ratio = 2.09; 1.73), and parental status (odds ratio = 0.31) were of relevance to nursing students’ moral sensitivity. Academic year was found to be unrelated to moral sensitivity. Discussion and conclusion: These demographic aspects should be considered when designing ethics education for nursing students. Future studies should continue to investigate moral sensitivity in nursing students, such as if and how various pedagogical strategies in ethics may contribute to moral sensitivity in nursing students.