bluuebunny/crossref_metadata_2025_split huggingface dataset:
The National Violent Death Reporting System: overview and future directions
Authors: Blair Janet M , Fowler Katherine A , Jack Shane P D , Crosby Alexander E 
Published: December 2015

ObjectiveTo describe the National Violent Death Reporting System (NVDRS). This is a surveillance system for monitoring the occurrence of homicides, suicides, unintentional firearm deaths, deaths of undetermined intent, and deaths from legal intervention (excluding legal executions) in the US.DesignThis report provides information about the history, scope, data variables, processes, utility, limitations, and future directions of the NVDRS.ResultsThe NVDRS currently operates in 32 states, with the goal of future expansion to all 50 states, the District of Columbia, and US territories. The system uses existing primary data sources (death certificates, coroner/medical examiner reports, and law enforcement reports), and links them together to provide a comprehensive picture of the circumstances surrounding violent deaths.ConclusionsThis report provides an overview of the NVDRS including a description of the system, discussion of its expanded capability, the use of new technologies as the system has evolved, how the data are being used for violence prevention efforts, and future directions.
Infective endocarditis in intravenous drug users: a review article
Authors: Colville Thomas , Sharma Vishal , Albouaini Khaled 
Published: December 2015

Abstract
Approximately 10% of infective endocarditis (IE) involves the right side of the heart with the majority of these cases occurring in intravenous drug users. Patients are less likely to present with classical IE signs of a new murmur and peripheral stigmata, are more frequently immunocompromised and often have significant social difficulties. These factors result in both diagnostic and therapeutic challenges in this patient group that are not often seen in other patient populations with IE.
Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer
Authors: Farren Matthew R. , Mace Thomas A. , Geyer Susan , Mikhail Sameh , Wu Christina , Ciombor Kristen , Tahiri Sanaa , Ahn Daniel , Noonan Anne M. , Villalona-Calero Miguel , Bekaii-Saab Tanios , Lesinski Gregory B. 
Published: December 2015

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate &lt;7% and is ultimately refractory to most treatments. To date, an assessment of immunologic factors relevant to disease has not been comprehensively performed for treatment-naïve patients. We hypothesized that systemic immunologic biomarkers could predict overall survival (OS) in treatment-naïve PDAC patients.
Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry.
Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62).
Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565–74. ©2015 AACR.
Molecular Pathways: Mechanism of Action for Talimogene Laherparepvec, a New Oncolytic Virus Immunotherapy
Authors: Kohlhapp Frederick J. , Kaufman Howard L. 
Published: December 2015

AbstractOncolytic viruses are native or engineered viruses that preferentially replicate in and lyse cancer cells. Selective tumor cell replication is thought to depend on infection of neoplastic cells, which harbor low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling elements. These changes allow more efficient viral replication, and with selected deletion of specific viral genes, replication in normal cells with activated PKR may not be possible. Direct tumor cell lysis, release of soluble tumor antigens, and danger-associated molecular factors are all thought to help prime and promote tumor-specific immunity. Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type I and is the first oncolytic virus to demonstrate a clinical benefit in patients with melanoma. T-VEC has also been evaluated for the treatment of head and neck cancer, pancreatic cancer, and likely other types of cancer will be targeted in the near future. T-VEC has been modified for improved safety, tumor-selective replication, and induction of host immunity by deletion of several viral genes and expression of human granulocyte-macrophage colony stimulating factor. Although the mechanism of action for T-VEC is incompletely understood, the safety profile of T-VEC and ability to promote immune responses suggest future combination studies with other immunotherapy approaches including checkpoint blockade through PD-1, PD-L1, and CTLA-4 to be a high priority for clinical development. Oncolytic viruses also represent unique regulatory and biosafety challenges but offer a potential new class of agents for the treatment of cancer. Clin Cancer Res; 22(5); 1048–54. ©2015 AACR.
Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia
Authors: Nemoto Atsushi , Saida Satoshi , Kato Itaru , Kikuchi Jiro , Furukawa Yusuke , Maeda Yasuhiro , Akahane Koshi , Honna-Oshiro Hiroko , Goi Kumiko , Kagami Keiko , Kimura Shinya , Sato Yuko , Okabe Seiichi , Niwa Akira , Watanabe Kenichiro , Nakahata Tatsutoshi , Heike Toshio , Sugita Kanji , Inukai Takeshi 
Published: December 2015

AbstractS-phase progression of the cell cycle is accelerated in tumors through various genetic abnormalities, and, thus, pharmacologic inhibition of altered cell-cycle progression would be an effective strategy to control tumors. In the current study, we analyzed the antileukemic activity of three available small molecules targeting CDK4/CDK6 against lymphoid crisis of chronic myeloid leukemia (CML-LC) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), and found that all three molecules showed specific activities against leukemic cell lines derived from CML-LC and Ph+ ALL. In particular, PD0332991 exhibited extremely high antileukemic activity against CML-LC and Ph+ ALL cell lines in the nanomolar range by the induction of G0–G1 arrest and partially cell death through dephosphorylation of pRb and downregulation of the genes that are involved in S-phase transition. As an underlying mechanism for favorable sensitivity to the small molecules targeting CDK4/CDK6, cell-cycle progression of Ph+ lymphoid leukemia cells was regulated by transcriptional and posttranscriptional modulation of CDK4 as well as Cyclin D2 gene expression under the control of BCR-ABL probably through the PI3K pathway. Consistently, the gene expression level of Cyclin D2 in Ph+ lymphoid leukemia cells was significantly higher than that in Ph− lymphoid leukemia cells. Of note, three Ph+ ALL cell lines having the T315I mutation also showed sensitivity to PD0332991. In a xenograft model, PD0332991, but not imatinib, suppressed dissemination of Ph+ ALL having the T315I mutation and prolonged survival, demonstrating that this reagent would be a new therapeutic modality for relapsed CML-LC and Ph+ ALL patients after treatment with tyrosine kinase inhibitors. Mol Cancer Ther; 15(1); 94–105. ©2015 AACR.
Activation of EGFR Bypass Signaling by TGFα Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells
Authors: Tani Tetsuo , Yasuda Hiroyuki , Hamamoto Junko , Kuroda Aoi , Arai Daisuke , Ishioka Kota , Ohgino Keiko , Miyawaki Masayoshi , Kawada Ichiro , Naoki Katsuhiko , Hayashi Yuichiro , Betsuyaku Tomoko , Soejima Kenzo 
Published: December 2015

Abstract
Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non–small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFα, one of the EGFR ligands, was significantly increased and knockdown of TGFα restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling. Mol Cancer Ther; 15(1); 162–71. ©2015 AACR.
Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues
Authors: Zhu Charles , Bandekar Amey , Sempkowski Michelle , Banerjee Sangeeta Ray , Pomper Martin G. , Bruchertseifer Frank , Morgenstern Alfred , Sofou Stavroula 
Published: December 2015

Abstract
This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of α-particle emitters by using different radionuclide carriers in the setting of targeted antivascular α-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the α-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four α-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of α-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of α-particle emitters. Mol Cancer Ther; 15(1); 106–13. ©2015 AACR.
AT2R Gene Delivered by Condensed Polylysine Complexes Attenuates Lewis Lung Carcinoma after Intravenous Injection or Intratracheal Spray
Authors: Alhakamy Nabil A. , Ishiguro Susumu , Uppalapati Deepthi , Berkland Cory J. , Tamura Masaaki 
Published: December 2015

Abstract
Transfection efficiency and toxicity concerns remain a challenge for gene therapy. Cell-penetrating peptides (CPP) have been broadly investigated to improve the transfection of genetic material (e.g., pDNA and siRNA). Here, a synthetic CPP (polylysine, K9 peptide) was complexed with angiotensin II type 2 receptor (AT2R) plasmid DNA (pAT2R) and complexes were condensed using calcium chloride. The resulting complexes were small (∼150 nm) and showed high levels of gene expression in vitro and in vivo. This simple nonviral formulation approach showed negligible cytotoxicity in four different human cell lines (cervix, breast, kidney, and lung cell lines) and one mouse cell line (a lung cancer cell line). In addition, this K9-pDNA-Ca2+ complex demonstrated cancer-targeted gene delivery when administered via intravenous injection or intratracheal spray. The transfection efficiency was evaluated in Lewis lung carcinoma (LLC) cell lines cultured in vitro and in orthotopic cancer grafts in syngeneic mice. Immunohistochemical analysis confirmed that the complex effectively delivered pAT2R to the cancer cells, where it was expressed mainly in cancer cells along with bronchial epithelial cells. A single administration of these complexes markedly attenuated lung cancer growth, offering preclinical proof-of-concept for a novel nonviral gene delivery method exhibiting effective lung tumor gene therapy via either intravenous or intratracheal administration. Mol Cancer Ther; 15(1); 209–18. ©2015 AACR.
A Novel Inhibitor of Topoisomerase I Is Selectively Toxic for a Subset of Non–Small Cell Lung Cancer Cell Lines
Authors: Zubovych Iryna O. , Sethi Anirudh , Kulkarni Aditya , Tagal Vural , Roth Michael G. 
Published: December 2015

Abstract
SW044248, identified through a screen for chemicals that are selectively toxic for non–small cell lung cancer (NSCLC) cell lines, was found to rapidly inhibit macromolecular synthesis in sensitive, but not in insensitive, cells. SW044248 killed approximately 15% of a panel of 74 NSCLC cell lines and was nontoxic to immortalized human bronchial cell lines. The acute transcriptional response to SW044248 in sensitive HCC4017 cells correlated significantly with inhibitors of topoisomerases and SW044248 inhibited topoisomerase 1 (Top1) but not topoisomerase 2. SW044248 inhibited Top1 differently from camptothecin and camptothecin did not show the same selective toxicity as SW044248. Elimination of Top1 by siRNA partially protected cells from SW044248, although removing Top1 was itself eventually toxic. Cells resistant to SW044248 responded to the compound by upregulating CDKN1A and siRNA to CDKN1A sensitized those cells to SW044248. Thus, at least part of the differential sensitivity of NSCLC cells to SW044248 is the ability to upregulate CDKN1A. Mol Cancer Ther; 15(1); 23–36. ©2015 AACR.
Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor
Authors: Rosebeck Shaun , Alonge Mattina M. , Kandarpa Malathi , Mayampurath Anoop , Volchenboum Samuel L. , Jasielec Jagoda , Dytfeld Dominik , Maxwell Sean P. , Kraftson Stephanie J. , McCauley Dilara , Shacham Sharon , Kauffman Michael , Jakubowiak Andrzej J. 
Published: December 2015

Abstract
Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line–derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60–71. ©2015 AACR.
Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity
Authors: Yan Haoheng , Endo Yukinori , Shen Yi , Rotstein David , Dokmanovic Milos , Mohan Nishant , Mukhopadhyay Partha , Gao Bin , Pacher Pal , Wu Wen Jin 
Published: December 2015

Abstract
Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1–induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1–induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1–induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1–induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1–induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. Mol Cancer Ther; 15(3); 480–90. ©2015 AACR.
Mutated Pathways as a Guide to Adjuvant Therapy Treatments for Breast Cancer
Authors: Liu Yang , Hu Zhenjun , DeLisi Charles 
Published: December 2015

Abstract
Adjuvant therapy following breast cancer surgery generally consists of either a course of chemotherapy, if the cancer lacks hormone receptors, or a course of hormonal therapy, otherwise. Here, we report a correlation between adjuvant strategy and mutated pathway patterns. In particular, we find that for breast cancer patients, pathways enriched in nonsynonymous mutations in the chemotherapy group are distinct from those of the hormonal therapy group. We apply a recently developed method that identifies collaborative pathway groups for hormone and chemotherapy patients. A collaborative group of pathways is one in which each member is altered in the same—generally large—number of samples. In particular, we find the following: (i) a chemotherapy group consisting of three pathways and a hormone therapy group consisting of 20, the members of the two groups being mutually exclusive; (ii) each group is highly enriched in breast cancer drivers; and (iii) the pathway groups are correlates of subtype-based therapeutic recommendations. These results suggest that patient profiling using these pathway groups can potentially enable the development of personalized treatment plans that may be more accurate and specific than those currently available. Mol Cancer Ther; 15(1); 184–9. ©2015 AACR.
A Fast Hydrogen Sulfide–Releasing Donor Increases the Tumor Response to Radiotherapy
Authors: De Preter Géraldine , Deriemaeker Caroline , Danhier Pierre , Brisson Lucie , Cao Pham Thanh Trang , Grégoire Vincent , Jordan Bénédicte F. , Sonveaux Pierre , Gallez Bernard 
Published: December 2015

AbstractHydrogen sulfide (H2S) is the last gaseous transmitter identified in mammals, and previous studies have reported disparate conclusions regarding the implication of H2S in cancer progression. In the present study, we hypothesized that sodium hydrosulfide (NaHS), a fast H2S-releasing donor, might interfere with the mitochondrial respiratory chain of tumor cells, increase tumor oxygenation, and potentiate the response to irradiation. Using electron paramagnetic resonance (EPR) oximetry, we found a rapid increase in tumor pO2 after NaHS administration (0.1 mmol/kg) in two human tumor models (breast MDA-MB-231 and cervix SiHa), an effect that was due to a decreased oxygen consumption and an increased tumor perfusion. Tumors irradiated 15 minutes after a single NaHS administration were more sensitive to irradiation compared with those that received irradiation alone (increase in growth delay by 50%). This radiosensitization was due to the oxygen effect, as the increased growth delay was abolished when temporarily clamped tumors were irradiated. In contrast, daily NaHS injection (0.1 mmol/kg/day for 14 days) did not provide any effect on tumor growth in vivo. To understand these paradoxical data, we analyzed the impact of external factors on the cellular response to NaHS. We found that extracellular pH had a dramatic effect on the cell response to NaHS, as the proliferation rate (measured in vitro by BrdU incorporation) was increased at pH = 7.4, but decreased at pH = 6.5. Overall, our study highlights the complex role of environmental components in the response of cancer cells to H2S and suggests a new approach for the use of H2S donors in combination with radiotherapy. Mol Cancer Ther; 15(1); 154–61. ©2015 AACR.