bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes following corticosteroid administration in patients with delayed diagnosis of spinal arteriovenous fistulas
Authors: Nasr Deena M , Brinjikji Waleed , Rabinstein Alejandro A , Lanzino Giuseppe 
Published: June 2016

Background and purposeThere have been several previously reported cases of acute progression of myelopathic symptoms in patients with spinal arteriovenous fistula (SAVF) treated with intravenous methylprednisolone. This usually occurs during or immediately following steroid administration. We examined a small case series of patients with SAVF treated with epidural, oral, or intravenous steroids to determine the association between steroid administration and clinical outcomes in these patients.MethodsFollowing Institutional Review Board approval, we conducted a retrospective review of patients with angiographically-confirmed SAVF who received intravenous, oral, or epidural corticosteroids for treatment of their symptoms. We studied patient-reported motor and sensory function following steroid administration using both the modified Rankin Scale and the Aminoff Motor Disability Scale.ResultsTwenty-one patients with SAVF were included in this study. Thirteen patients (61.9%) had intravenous methylprednisolone administered, four patients (19.0%) had epidural steroid injections, and six patients (28.6%) had oral prednisone. Among patients who received intravenous methylprednisolone, seven (53.8%) reported acute worsening of symptoms during or immediately following steroid administration. Among the patients receiving epidural steroids, none reported worsening and one patient reported short-term relief. Among the patients receiving oral steroids, one reported acute worsening of symptoms. Worsened deficits did not consistently resolve after steroid discontinuation.ConclusionsOur study suggests that intravenous methylprednisolone can cause immediate worsening of motor and sensory symptoms when administered to patients with SAVF. Steroid administration should be avoided in patients with a myelopathy secondary to an untreated SAVF because neurological worsening may not be fully reversible.
Significant reduction of left atrial volume concomitant with clinical improvement after percutaneous transluminal septal myocardial ablation for drug-refractory hypertrophic obstructive cardiomyopathy, and its precise detection with multidetector CT
Authors: Maekawa Yuichiro , Akita Keitaro , Tsuruta Hikaru , Yamada Yoshitake , Hayashida Kentaro , Yuasa Shinsuke , Murata Mitsushige , Jinzaki Masahiro , Fukuda Keiichi 
Published: June 2016

ObjectiveIn patients with hypertrophic obstructive cardiomyopathy (HOCM), left atrial (LA) volume measurement is very important to provide prognostic information. Recent studies demonstrated that multidetector CT (MDCT) is useful to assess the changes in LA volume. Our aim was to examine the utility of a follow-up cardiac MDCT for long-term evaluation of the effect of percutaneous transluminal septal myocardial ablation (PTSMA) on LA volume.MethodsWe studied a consecutive cohort of 20 patients with drug-refractory symptomatic HOCM after PTSMA. We evaluated LA volume analyses with cardiac MDCT on patients who underwent PTSMA as compared to echocardiography.ResultsBefore PTSMA, 75% of all patients had heart failure-associated symptoms in the New York Heart Association functional class III/IV. All patients experienced relief from heart failure-associated symptoms after PTSMA. Cardiac MDCT showed significant reduction in the index of maximum LA volume during follow-up compared to before PTSMA in the same way as in echocardiography (93.6±34.1 mL/m2vs 82.6±35.3 mL/m2, p=0.035). A Bland-Altman plot showed small mean differences and limits of agreement in the measurements of the index of maximum LA volume before and after PTSMA between echocardiography and MDCT.ConclusionsThe follow-up cardiac MDCT was a useful tool to evaluate the effectiveness of PTSMA on reduction of LA volume. Cardiac MDCT might provide comparable measurements of the LA volume in patients with drug-refractory symptomatic HOCM before and after PTSMA compared to echocardiography.
Relationship between selected perinatal paratuberculosis management interventions and passive transfer of immunity in dairy calves
Authors: McAloon C. G. , Whyte P. , O'Grady L. , Lorenz I. , Green M. G. , Hogan I. , Johnson A. , Doherty M. L. 
Published: June 2016

The objective of this cohort study was to assess the relationship between perinatal calf management practices relevant to the control of paratuberculosis and passive transfer of immunoglobulin in calves born in an endemically infected Irish dairy herd. Data from 176 calves were used to assess the effect of time spent in the calving area, individual versus non‐designated calving and colostrum pasteurisation on serum total protein, zinc sulphate turbidity, globulin and γ‐glutamyltransferase. In addition, the effects of colostrum quality, volume of colostrum fed, method of colostrum administration and calving season on passive transfer were quantified. Serum samples were collected as part of routine herd health monitoring from calves aged between one and seven days. Multivariate linear and logistic regression models were used to assess the effect of each variable on the test result and failure of passive transfer as determined using a cut‐off point for each diagnostic test. Colostrum pasteurisation and calving area were not significantly associated with passive transfer, whereas increased time spent in the calving pen was consistently associated with a detrimental effect. In addition, a strong seasonal effect was apparent, which appeared to be unrelated to colostrum quality and calf management. The authors are unaware of published studies documenting such a significant seasonal effect on passive transfer.
MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development
Authors: Eso Yuji , Takai Atsushi , Matsumoto Tomonori , Inuzuka Tadashi , Horie Takahiro , Ono Koh , Uemoto Shinji , Lee Kyeryoung , Edelmann Winfried , Chiba Tsutomu , Marusawa Hiroyuki 
Published: June 2016

Abstract
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB–dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2−/−AID+, ALB-MSH2−/−, and ALB-AID+ mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2−/−AID+ mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383–93. ©2016 AACR.
Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy
Authors: Mattina James , MacKinnon Nathalie , Henderson Valerie C. , Fergusson Dean , Kimmelman Jonathan 
Published: June 2016

AbstractThe validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose–response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies. Cancer Res; 76(16); 4627–36. ©2016 AACR.
Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency
Authors: Zhao Fang , Sucker Antje , Horn Susanne , Heeke Christina , Bielefeld Nicola , Schrörs Barbara , Bicker Anne , Lindemann Monika , Roesch Alexander , Gaudernack Gustav , Stiller Mathias , Becker Jürgen C. , Lennerz Volker , Wölfel Thomas , Schadendorf Dirk , Griewank Klaus , Paschen Annette 
Published: June 2016

Abstract
Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA class I loss in both metastases originated from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I haplotype-deficient lesion developed in year 3 of stage IV disease that acquired resistance toward dominant CD8+ T-cell clonotypes targeting stage III tumor cells. At an early stage, melanoma cells showed a dedifferentiated c-Junhigh/MITFlow phenotype, possibly associated with immunosuppression, which contrasted with a c-Junlow/MITFhigh phenotype of T cell–edited tumor cells derived from late metastases. In summary, our work shows how tumor recurrences after long-term latency evolve toward T-cell resistance by independent genetic events, as a means for immune escape and immunotherapeutic resistance. Cancer Res; 76(15); 4347–58. ©2016 AACR.
Definition of a Novel Feed-Forward Mechanism for Glycolysis-HIF1α Signaling in Hypoxic Tumors Highlights Aldolase A as a Therapeutic Target
Authors: Grandjean Geoffrey , de Jong Petrus R. , James Brian P. , Koh Mei Yee , Lemos Robert , Kingston John , Aleshin Alexander , Bankston Laurie A. , Miller Claudia P. , Cho Eun Jeong , Edupuganti Ramakrishna , Devkota Ashwini , Stancu Gabriel , Liddington Robert C. , Dalby Kevin N. , Powis Garth 
Published: June 2016

AbstractThe hypoxia-inducible transcription factor HIF1α drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1α transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1α signaling. Negative regulation of HIF1α by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1α transcriptional coactivator p300. Notably, of the HIF1α-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small-molecule inhibitor of aldolase A was sufficient to increase overall survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis–HIF-1α feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid tumors. Cancer Res; 76(14); 4259–69. ©2016 AACR.
A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy
Authors: Makvandi Mehran , Xu Kuiying , Lieberman Brian P. , Anderson Redmond-Craig , Effron Samuel Sander , Winters Harrison D. , Zeng Chenbo , McDonald Elizabeth S. , Pryma Daniel A. , Greenberg Roger A. , Mach Robert H. 
Published: June 2016

Abstract
Despite the availability of PARP inhibitors for cancer therapy, a biomarker to clearly stratify patients for selection of this treatment remains lacking. Here we describe a radiotracer-based method that addresses this issue, using the novel compound [125I]KX1 as a PARP-1–selective radiotracer that can accurately measure PARP-1 expression in vitro and in vivo. The pharmacologic properties of the PARP radiotracer [125I]KX1 was characterized in multiple cell lines where single-agent sensitivity was correlated with [125I]KX1 binding to PARP-1. In vivo evaluation of [125I]KX1 verified in vitro results, validating PARP radiotracers to define PARP-1 enzyme expression as an in vivo biomarker. Notably, PARP-1 expression as quantified by [125I]KX1 correlated positively with the cytotoxic sensitivity of cell lines evaluated with PARP inhibitors. Overall, our results defined a novel technology with the potential to serve as a companion diagnostic to identify patients most likely to respond therapeutically to a PARP inhibitor. Cancer Res; 76(15); 4516–24. ©2016 AACR.
Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation
Authors: Schwartz Hila , Blacher Eran , Amer Malak , Livneh Nir , Abramovitz Lilach , Klein Anat , Ben-Shushan Dikla , Soffer Shelly , Blazquez Raquel , Barrantes-Freer Alonso , Müller Meike , Müller-Decker Karin , Stein Reuven , Tsarfaty Galia , Satchi-Fainaro Ronit , Umansky Viktor , Pukrop Tobias , Erez Neta 
Published: June 2016

Abstract
Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood–brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse. Cancer Res; 76(15); 4359–71. ©2016 AACR.
Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma
Authors: Roife David , Dai Bingbing , Kang Ya'an , Rios Perez Mayrim V. , Pratt Michael , Li Xinqun , Fleming Jason B. 
Published: June 2016

Abstract
Purpose: Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design.
Experimental Design: We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slices derived from pancreatic ductal adenocarcinoma PDX tumors were arrayed in a 96-well plate and screened against clinically relevant regimens within 3 to 5 days. The correlation between the sensitivities of tissue slices to the regimens and patients' clinical responses and outcome were statistically analyzed. The results of LTSA assay were further confirmed with biochemical methods in vitro and animal PDX model in vivo.
Results: The ex vivo tissue slices remain viable for at least 5 days, and the tumor parenchyma, including stroma, vascular structures, and signaling pathways, are all retained. The sensitivities of the ex vivo tissue slices to gemcitabine and irinotecan was consistent with the clinical responses and outcomes of the patients from whom the tumorgrafts were derived (r = 0.77; P = 0.0002). Retrospective analysis showed that the patients who received LTSA-sensitive regimens had remarkably longer progression-free survival than patients who received LTSA-resistant regimens (16.33 vs. 3.8 months; n = 18, P = 0.011).
Conclusions: The results from these PDX and LTSA methods reflect clinical patients' responses and could be used as a personalized strategy for improving systemic therapy effectiveness in patients with pancreatic cancer. Clin Cancer Res; 22(24); 6021–30. ©2016 AACR.
Radiotherapy for Non–Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues
Authors: Siva Shankar , Lobachevsky Pavel , MacManus Michael P. , Kron Tomas , Möller Andreas , Lobb Richard J. , Ventura Jessica , Best Nickala , Smith Jai , Ball David , Martin Olga A. 
Published: June 2016

AbstractPurpose: To study the response of irradiated and out-of-field normal tissues during localized curative intent radiotherapy.Experimental Design: Sixteen patients with non–small cell lung carcinoma (NSCLC) received 60 Gy in 30 fractions of definitive thoracic radiotherapy with or without concurrent chemotherapy. Peripheral blood lymphocytes (PBL) and eyebrow hairs were sampled prior, during, and after radiotherapy. Clinical variables of radiotherapy dose/volume, patient age, and use of chemoradiotherapy were tested for association with γ-H2AX foci, a biomarker of DNA damage that underlies cellular response to irradiation.Results: Radiotherapy induced an elevation of γ-H2AX foci in PBL, representing normal tissues in the irradiated volume, 1 hour after fraction one. The changes correlated directly with mean lung dose and inversely with age. γ-H2AX foci numbers returned to near baseline values in 24 hours and were not significantly different from controls at 4 weeks during radiotherapy or 12 weeks after treatment completion. In contrast, unirradiated hair follicles, a surrogate model for out-of-field normal tissues, exhibited delayed “abscopal” DNA damage response. γ-H2AX foci significantly increased at 24 hours post-fraction one and remained elevated during treatment, in a dose-independent manner. This observed abscopal effect was associated with changes in plasma levels of MDC/CCL22 and MIP-1α/CCL3 cytokines. No concordant changes in size and concentration of circulating plasma exosomes were observed.Conclusions: Both localized thoracic radiotherapy and chemoradiotherapy induce pronounced systemic DNA damage in normal tissues. Individual assessment of biologic response to dose delivered during radiotherapy may allow for therapeutic personalization for patients with NSCLC. Clin Cancer Res; 22(19); 4817–26. ©2016 AACR.See related commentary by Verma and Lin, p. 4763
FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes
Authors: Kessler Brittelle E. , Sharma Vibha , Zhou Qiong , Jing Xia , Pike Laura A. , Kerege Anna A. , Sams Sharon B. , Schweppe Rebecca E. 
Published: June 2016

Abstract
There are limited therapy options for advanced thyroid cancer, including papillary and anaplastic thyroid cancer (PTC and ATC). Focal adhesion kinase (FAK) regulates cell signaling by functioning as a scaffold and kinase. Previously, we demonstrated that FAK is overexpressed and activated in thyroid cancer cells and human PTC clinical specimens. However, it remains unclear whether patients with advanced thyroid cancer will benefit from FAK inhibition. Therefore, the dual functions of FAK in mediating protumorigenic processes and thyroid tumorigenesis were investigated. Evidence here shows that FAK expression predominantly regulates thyroid cancer cell growth, viability, and anchorage-independent growth. FAK inhibition, with PF-562,271 treatment, modestly reduced tumor volumes, while FAK depletion, through shRNA knockdown, significantly reduced tumor volumes in vivo. A role for FAK expression in tumor establishment was demonstrated in a model of PTC, where FAK knockdown tumors did not develop. FAK depletion also led to a significant decrease in overall metastatic burden. Interestingly, pretreatment with a FAK inhibitor resulted in a paradoxical increase in metastasis in a model of ATC, but decreased metastasis in a model of PTC. These data provide the first evidence that FAK expression is critical for the regulation of thyroid tumorigenic functions.
Implications: This study demonstrates that FAK expression, but not kinase activity alone, predominantly mediates thyroid tumor growth and metastasis, indicating that targeting the scaffolding function(s) of FAK may be an important therapeutic strategy for advanced thyroid cancer, as well as other FAK-dependent tumors. Mol Cancer Res; 14(9); 869–82. ©2016 AACR.