bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers
Authors: Chen Weihsu C. , Yuan Julie S. , Xing Yan , Mitchell Amanda , Mbong Nathan , Popescu Andreea C. , McLeod Jessica , Gerhard Gitte , Kennedy James A. , Bogdanoski Goce , Lauriault Stevan , Perdu Sofie , Merkulova Yulia , Minden Mark D. , Hogge Donna E. , Guidos Cynthia , Dick John E. , Wang Jean C.Y. 
Published: February 2016

Abstract
Many promising new cancer drugs proceed through preclinical testing and early-phase trials only to fail in late-stage clinical testing. Thus, improved models that better predict survival outcomes and enable the development of biomarkers are needed to identify patients most likely to respond to and benefit from therapy. Here, we describe a comprehensive approach in which we incorporated biobanking, xenografting, and multiplexed phospho-flow (PF) cytometric profiling to study drug response and identify predictive biomarkers in acute myeloid leukemia (AML) patients. To test the efficacy of our approach, we evaluated the investigational JAK2 inhibitor fedratinib (FED) in 64 patient samples. FED robustly reduced leukemia in mouse xenograft models in 59% of cases and was also effective in limiting the protumorigenic activity of leukemia stem cells as shown by serial transplantation assays. In parallel, PF profiling identified FED-mediated reduction in phospho-STAT5 (pSTAT5) levels as a predictive biomarker of in vivo drug response with high specificity (92%) and strong positive predictive value (93%). Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-responsive samples. Notably, this outcome could be predicted by the status of pSTAT5 signaling, which was unaffected by RUX treatment. Consistent with this observed discrepancy, PF analysis revealed that FED exerted its effects through multiple JAK2-independent mechanisms. Collectively, this work establishes an integrated approach for testing novel anticancer agents that captures the inherent variability of response caused by disease heterogeneity and in parallel, facilitates the identification of predictive biomarkers that can help stratify patients into appropriate clinical trials. Cancer Res; 76(5); 1214–24. ©2016 AACR.
Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation
Authors: Hedayati Mohammad , Haffner Michael C. , Coulter Jonathan B. , Raval Raju R. , Zhang Yonggang , Zhou Haoming , Mian Omar , Knight Emma J. , Razavi Nina , Dalrymple Susan , Isaacs John T. , Santos Aileen , Hales Russell , Nelson William G. , Yegnasubramanian Srinivasan , DeWeese Theodore L. 
Published: February 2016

Abstract
Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR).
Experimental Design: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models.
Results: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice.
Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310–9. ©2016 AACR.
See related commentary by Chua and Bristow, p. 3124
Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors
Authors: Macaulay Valentine M. , Middleton Mark R. , Eckhardt S. Gail , Rudin Charles M. , Juergens Rosalyn A. , Gedrich Richard , Gogov Sven , McCarthy Sean , Poondru Srinivasu , Stephens Andrew W. , Gadgeel Shirish M. 
Published: February 2016

Abstract
Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib.
Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1–3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100–150 mg once daily; and a non–small cell lung cancer (NSCLC) expansion cohort.
Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug–drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study &gt;12 weeks.
Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897–907. ©2016 AACR.
T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin
Authors: Dziegielewska Barbara , Casarez Eli V. , Yang Wesley Z. , Gray Lloyd S. , Dziegielewski Jaroslaw , Slack-Davis Jill K. 
Published: February 2016

Abstract
Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type calcium (Ca2+) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca2+ channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca2+ channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the antiapoptotic gene survivin (BIRC5). Analysis of intracellular signaling revealed mibefradil reduced AKT phosphorylation, increased the levels and nuclear retention of FOXO transcription factors that repress BIRC5 expression, and decreased the expression of FOXM1, which promotes BIRC5 expression. Combining carboplatin with mibefradil synergistically increased apoptosis in vitro. Importantly, mibefradil rendered platinum-resistant ovarian tumors sensitive to carboplatin in a mouse model of peritoneal metastasis. Together, the data provide rationale for future use of T-type channel antagonists together with platinum agents for the treatment of ovarian cancer. Mol Cancer Ther; 15(3); 460–70. ©2016 AACR.
EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib
Authors: De Andrade James P. , Park Jung M. , Gu Vivian W. , Woodfield George W. , Kulak Mikhail V. , Lorenzen Allison W. , Wu Vincent T. , Van Dorin Sarah E. , Spanheimer Philip M. , Weigel Ronald J. 
Published: February 2016

Abstract
Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers, and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, P &lt; 0.01), combined KD reduced proliferation greater than either alone (52% reduction, P &lt; 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C, and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated through the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response. Mol Cancer Ther; 15(3); 503–11. ©2016 AACR.
Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer
Authors: Ishida Michihiro , Kagawa Shunsuke , Shimoyama Kyoko , Takehara Kiyoto , Noma Kazuhiro , Tanabe Shunsuke , Shirakawa Yasuhiro , Tazawa Hiroshi , Kobayashi Hisataka , Fujiwara Toshiyoshi 
Published: February 2016

Abstract
Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. We hypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)–mediated PIT induced selective cell death of HER2-ECD–transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700–mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. Mol Cancer Ther; 15(3); 402–11. ©2016 AACR.
Dopamine Modulation of Intertemporal Decision-making: Evidence from Parkinson Disease
Authors: Foerde Karin , Figner Bernd , Doll Bradley B. , Woyke Isabel C. , Braun Erin Kendall , Weber Elke U. , Shohamy Daphna 
Published: February 2016

Abstract
Choosing between smaller prompt rewards and larger later rewards is a common choice problem, and studies widely agree that frontostriatal circuits heavily innervated by dopamine are centrally involved. Understanding how dopamine modulates intertemporal choice has important implications for neurobiological models and for understanding the mechanisms underlying maladaptive decision-making. However, the specific role of dopamine in intertemporal decisions is not well understood. Dopamine may play a role in multiple aspects of intertemporal choices—the valuation of choice outcomes and sensitivity to reward delays. To assess the role of dopamine in intertemporal decisions, we tested Parkinson disease patients who suffer from dopamine depletion in the striatum, in either high (on medication, PDON) or low (off medication, PDOFF) dopaminergic states. Compared with both PDOFF and healthy controls, PDON made more farsighted choices and reduced their valuations less as a function of increasing time to reward. Furthermore, reduced discounting in the high dopaminergic state was robust across multiple measures, providing new evidence for dopamine's role in making decisions about the future.
Uses of strength-based interventions for people with serious mental illness: A critical review
Authors: Tse Samson , Tsoi Emily WS , Hamilton Bridget , O’Hagan Mary , Shepherd Geoff , Slade Mike , Whitley Rob , Petrakis Melissa 
Published: February 2016

Background: For the past 3 decades, mental health practitioners have increasingly adopted aspects and tools of strength-based approaches. Providing strength-based intervention and amplifying strengths relies heavily on effective interpersonal processes. Aim: This article is a critical review of research regarding the use of strength-based approaches in mental health service settings. The aim is to discuss strength-based interventions within broader research on recovery, focussing on effectiveness and advances in practice where applicable. Method: A systematic search for peer-reviewed intervention studies published between 2001 and December 2014 yielded 55 articles of potential relevance to the review. Results: Seven studies met the inclusion criteria and were included in the analysis. The Quality Assessment Tool for Quantitative Studies was used to appraise the quality of the studies. Our review found emerging evidence that the utilisation of a strength-based approach improves outcomes including hospitalisation rates, employment/educational attainment, and intrapersonal outcomes such as self-efficacy and sense of hope. Conclusion: Recent studies confirm the feasibility of implementing a high-fidelity strength-based approach in clinical settings and its relevance for practitioners in health care. More high-quality studies are needed to further examine the effectiveness of strength-based approaches.
An In Vitro Robotic Assessment of the Anterolateral Ligament, Part 2
Authors: Nitri Marco , Rasmussen Matthew T. , Williams Brady T. , Moulton Samuel G. , Cruz Raphael Serra , Dornan Grant J. , Goldsmith Mary T. , LaPrade Robert F. 
Published: February 2016

Background: Recent biomechanical studies have demonstrated that an extra-articular lateral knee structure, most recently referred to as the anterolateral ligament (ALL), contributes to overall rotational stability of the knee. However, the effect of anatomic ALL reconstruction (ALLR) in the setting of anterior cruciate ligament (ACL) reconstruction (ACLR) has not been biomechanically investigated or validated. Purpose/Hypothesis: The purpose of this study was to investigate the biomechanical function of anatomic ALLR in the setting of a combined ACL and ALL injury. More specifically, this investigation focused on the effect of ALLR on resultant rotatory stability when performed in combination with concomitant ACLR. It was hypothesized that ALLR would significantly reduce internal rotation and axial plane translation laxity during a simulated pivot-shift test compared with isolated ACLR. Study Design: Controlled laboratory study. Methods: Ten fresh-frozen cadaveric knees were evaluated with a 6 degrees of freedom robotic system. Knee kinematics were evaluated with simulated clinical examinations including a simulated pivot-shift test consisting of coupled 10-N·m valgus and 5-N·m internal rotation torques, a 5-N·m internal rotation torque, and an 88-N anterior tibial load. Kinematic differences between ACLR with an intact ALL, ACLR with ALLR, and ACLR with a deficient ALL were compared with the intact state. Single-bundle ACLR tunnels and ALLR tunnels were placed anatomically according to previous quantitative anatomic attachment descriptions. Results: Combined anatomic ALLR and ACLR significantly improved the rotatory stability of the knee compared with isolated ACLR in the face of a concurrent ALL deficiency. During a simulated pivot-shift test, ALLR significantly reduced internal rotation and axial plane tibial translation when compared with ACLR with an ALL deficiency. Isolated ACLR for the treatment of a combined ACL and ALL injury was not able to restore stability of the knee, resulting in a significant increase in residual internal rotation laxity. ALLR did not affect anterior tibial translation; no significant differences were observed between the varying ALL conditions with ACLR except between ACLR with an intact ALL and ACLR with a deficient ALL at 0° of flexion. Conclusion: In the face of a combined ACL and ALL deficiency, concurrent ACLR and ALLR significantly improved the rotatory stability of the knee compared with solely reconstructing the ACL. Clinical Relevance: Significant increases in residual internal rotation and laxity during the pivot-shift test may exist in both acute and chronic settings of an ACL deficiency and in patients treated with isolated ACLR for a combined ACL and ALL deficiency. For this subset of patients, surgical treatment of the ALL, in addition to ACLR, should be considered to restore knee stability.
Prospective Teachers’ Perceptions about the Concept of Sustainable Development and Related Issues in Oman
Authors: Ambusaidi Abdullah , Al Washahi Maryam 
Published: February 2016

This study aims to investigate, from the Omani’s prospective, teachers’ perceptions about the concept of sustainable development (SD) and three related issues (cultural diversity, renewable energy and equity). The sample consisted of 159 prospective teachers from Sultan Qaboos University. Data were collected via a questionnaire comprising a list of 41 SD points. The results showed that the main source of knowledge for prospective teachers concerning the concept of SD is school textbooks. They also showed that prospective teachers had high perceptions of the concept of SD and the three related issues. In addition, there are no statistical differences found between male and female prospective teachers’ perceptions about the concept of SD, cultural diversity and renewable energy. However, the results showed significant statistical differences between male and female prospective teachers in the equity domain. Finally, the results showed no statistical differences due to prospective teachers’ specializations (humanities versus science).
Predictors of Postoperative Wound Necrosis Following Primary Wound Closure of Open Ankle Fractures
Authors: Ovaska Mikko T. , Madanat Rami , Mäkinen Tatu J. 
Published: February 2016

Background: Most open malleolar ankle fracture wounds can be closed primarily after meticulous debridement. However, the development of wound necrosis following operative treatment of open malleolar ankle fractures can have catastrophic consequences. The aim of this study was to identify risk factors predisposing to postoperative wound necrosis following primary wound closure of open malleolar ankle fractures. Methods: A total of 137 patients with open malleolar ankle fractures were identified. The open fracture wound was primarily closed in 110 of 137 (80%) patients, and postoperative wound necrosis occurred in 18 (16%) of these patients. These patients were compared to the open fracture patients without wound necrosis. Twenty possible risk factors for the development of wound necrosis were studied with logistic regression analysis. Results: The variables that were independently associated with an increased risk for postoperative wound necrosis included ASA class ≥2, Gustilo grade III open injury, and the use of pulsatile lavage at index surgery. Conclusions: Our study showed that ASA class ≥2, Gustilo grade III open injury, and the use of pulsatile lavage at index surgery were the most important factors predisposing to postoperative wound necrosis following primary wound closure of open malleolar ankle fractures. The findings warrant a further study specifically comparing primary and delayed wound closure in patients with Gustilo grade III open malleolar ankle fractures and different ASA classes. Also, the role of pulsatile lavage should be re-evaluated. Level of Evidence: Level III, retrospective comparative series.
Chronic Spontaneous Urticaria (CSU)
Authors: Cheung Loretta Y. , Lynde Charles W. 
Published: February 2016

Background: Chronic spontaneous urticaria (CSU) is a skin disorder that is said to be “frustrating” and “difficult to treat.” It is characterized by recurrent hives for more than 6 weeks, and is further divided into spontaneous or inducible by physical stimuli.1 To better understand dermatologists’ perspective of this disorder, a survey was conducted with Canadian dermatologists. Methods: A detailed online practice survey was sent to all currently practicing Canadian dermatologists. Results: In all, 80 responses were received (response rate of 20%). Most respondents in Canada had treated patients with CSU (98.4%), with many of the patients having the disease last over 6 months (86.6%). A majority of the patients were female, with 84.1% of the respondents having over 50% of their patients as female. Most patients were over the age of 30 (74.2%). Of dermatologists, 85.7% felt that investigations were unhelpful in diagnosing CSU in a patient. Of respondents, 37.1% were not satisfied with current treatment methods of CSU, and 43.6% somewhat satisfied. Popular therapies included H1 and H2 antihistamines, oral corticosteroids, and montelukast. There were 16.1% of dermatologists who had over 50% of their patients refractory to treatment. Conclusions: There was a clear demographic preponderance for CSU patients with a majority as female over age 30. Investigations ordered for CSU patients do not seem to be helpful among dermatologists. Satisfaction with current therapies and investigations was quite low among Canadian dermatologists, suggesting new therapies are indicated.