bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss, transition and trust: perspectives of terminally ill patients and their oncologists when transferring care from the hospital into the community at the end of life
Authors: Smith Clare , Bosanquet Nick , Riley Julia , Koffman Jonathan
Published: June 2016

Introduction

Most people prefer to die at home. However, most continue to die in hospital. Little is known about the impact on the patient of transferring care from acute sector specialist follow-up to the community. In one cancer centre, a new service—Hospital2Home was set up to facilitate this transfer of care. This study aimed to explore patients’ and oncologists’ perspectives of the meanings involved in this transition.

Methods

Qualitative study using semistructured one-to-one interviews with 8 terminally ill cancer patients and 13 oncologists. The interviews were audio recorded, transcribed verbatim and analysed using the framework approach.

Results

3 main themes were identified: loss, transition and community care. The theme of loss referred to losses associated with the end of treatment and losses associated with the familiar safe relationship between the patient and oncologist. Transition refers to the change from hospital-led to community-based care. Barriers to transition included patient and family acceptance, attachment and concerns about community services. Transition was more acceptable if initiated in a gradual manner. Community care: participants found the Hospital2Home service crucial in establishing new trustworthy relationships between community providers and the patient.

Conclusions

Transfer of care from the acute sector to the community represents a delicate crossroad where complex notions of loss should not be underestimated. A gradual transfer of care may improve this if the patient's condition allows. Therefore, introductions to the community team should be timely, and a staggered transfer should be planned. This would improve the experience of the patient, carer and oncologist.
Ambient temperature as a trigger of preterm delivery in a temperate climate
Authors: Cox Bianca , Vicedo-Cabrera Ana M , Gasparrini Antonio , Roels Harry A , Martens Evelyne , Vangronsveld Jaco , Forsberg Bertil , Nawrot Tim S
Published: June 2016

Background

Recent evidence suggests that elevated ambient temperatures may trigger preterm delivery. Since results from studies in temperate climates are inconclusive, we investigated the association between temperature and the risk of preterm birth in Flanders (Belgium).

Methods

We used data on 807 835 singleton deliveries (January 1998–July 2011). We combined a quasi-Poisson model with distributed lag non-linear models to allow for delayed and non-linear temperature effects, accounting for the daily pregnancies at risk and their gestational age distribution.

Results

For moderate heat (95th vs 50th centile) up to 1 day before delivery (lag 0–1), the risk of preterm birth increased by 8.5% (95% CI 2.4% to 15.0%) when minimum temperature increased from 8.3°C to 16.3°C and by 9.6% (95% CI 1.1% to 18.7%) when maximum temperature increased from 14.7°C to 26.5°C. Corresponding estimates for extreme heat (99th vs 50th centile) were 15.6% (95% CI 4.8% to 27.6%) for minimum temperature (19.0°C vs 8.3°C) and 14.5% (95% CI 0.5% to 30.6%) for maximum temperature (30.7°C vs 14.7°C). Despite the increased risk of preterm birth associated with cold at lag 2 (and lag 1 for minimum temperature), cumulative cold effects were small. The per cent change in preterm birth associated with moderate cold (5th vs 50th centile) up to 3 days before delivery (lag 0–3) was 2.1% (95% CI −4.1% to 8.7%) for minimum temperature (−2.0°C vs 8.3°C) and 0.6% (95% CI −7.3% to 9.2%) for maximum temperature (2.5°C vs 14.7°C).

Conclusions

Even in a temperate climate, ambient temperature may trigger preterm delivery, suggesting that pregnant women should avoid temperature extremes.
Aneurysm outflow angle at MRA as discriminant for accurate diagnosis and differentiation between small sidewall cerebral aneurysms and infundibula
Authors: Sun Ling-Jun , Li Yong-Dong , Li Ming-Hua , Wang Wu , Gu Bin-Xian
Published: June 2016

Objective

To evaluate whether the aneurysm outflow angle (OA) at MR angiography (MRA) might serve as discriminant for accurate diagnosis of, and differentiation between, small sidewall cerebral aneurysms (SCAs) and infundibula.

Methods

Between June 2007 and July 2015, 426 consecutive patients with SCAs completed both an MRA and DSA examination. Of these, 156 patients with small SCAs and 52 patients with infundibula were included in this study. A patient with an OA ≥90° was defined as having a SCA, while those with OA <90° were defined as having an infundibulum.

Results

DSA identified 172 SCAs in 156 patients and 55 infundibula in 52 patients. The average OA on MRA was 102.96°±13.36° (range 60°–151°) in 172 SCAs of 156 patients. An OA of ≥90° was seen for 159 (92.4%) small SCAs in 147 patients, while an OA of <90° was observed for 13 SCAs. The average OA on MRA was 69.05°±14.26° (range 35–107°) in 55 infundibula of 52 patients. An OA of ≥90° was seen in one patient with one infundibulum; while an OA of <90° was observed for 54 infundibula (98.2%) in 51 patients. The average OA in SCAs (n=172) was greater than the average OA in infundibula (n=55; 102.96° vs 69.05°, p<0.001).

Conclusions

The OA at MRA could serve as discriminant for accurate diagnosis of, and differentiation between, small SCAs and infundibula.
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 purpose

There 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.

Methods

Following 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.

Results

Twenty-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.

Conclusions

Our 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

Objective

In 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.

Methods

We 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.

Results

Before 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.

Conclusions

The 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.
Quantitative dating of Pleistocene deposits of the Kyrenia Range, northern Cyprus: implications for timing, rates of uplift and driving mechanisms
Authors: Palamakumbura Romesh N. , Robertson Alastair H. F. , Kinnaird Tim C. , van Calsteren Peter , Kroon Dick , Tait Jenny A.
Published: June 2016

The Kyrenia Range underwent tectonically driven uplift during the Pliocene to Pleistocene in response to the interaction of various tectonic processes. To understand the tectonic processes driving the uplift and how this is related to uplift of other areas of the Eastern Mediterranean, uranium-series disequilibrium and optically stimulated luminescence dating were applied to marine and non-marine terrace deposits exposed on the northern flank of the range. Palaeomagnetism and strontium isotope dating were used in conjunction to date the final stages of the marine environment adjacent to the Kyrenia Range prior to major surface uplift. Uplift rates range from >1.2 mm a
−1
, inferred during the Early Pleistocene, to <0.2 mm a
−1
during the Late Pleistocene. The new data show that the Kyrenia Range was uplifted contemporaneously with the Troodos Massif in southern Cyprus. The uplift of the Kyrenia Range appears to have been significantly faster than that affecting other comparable regions in the easternmost Mediterranean during the Pleistocene (e.g. Lebanon coast; southern Anatolian plateau). The driving mechanism for the uplift of both the Kyrenia Range and the Troodos Massif is inferred to be the collision of the Eratosthenes Seamount with the Cyprus trench to the south of Cyprus.

Supplementary material
:
Details of the methods used are available at
https://doi.org/10.6084/m9.figshare.c.3260977
.
Cell adhesion during bullet motion in capillaries
Authors: Takeishi Naoki , Imai Yohsuke , Ishida Shunichi , Omori Toshihiro , Kamm Roger D. , Ishikawa Takuji
Published: June 2016

A numerical analysis is presented of cell adhesion in capillaries whose diameter is comparable to or smaller than that of the cell. In contrast to a large number of previous efforts on leukocyte and tumor cell rolling, much is still unknown about cell motion in capillaries. The solid and fluid mechanics of a cell in flow was coupled with a slip bond model of ligand-receptor interactions. When the size of a capillary was reduced, the cell always transitioned to “bullet-like” motion, with a consequent decrease in the velocity of the cell. A state diagram was obtained for various values of capillary diameter and receptor density. We found that bullet motion enables firm adhesion of a cell to the capillary wall even for a weak ligand-receptor binding. We also quantified effects of various parameters, including the dissociation rate constant, the spring constant, and the reactive compliance on the characteristics of cell motion. Our results suggest that even under the interaction between P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin, which is mainly responsible for leukocyte rolling, a cell is able to show firm adhesion in a small capillary. These findings may help in understanding such phenomena as leukocyte plugging and cancer metastasis.
Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis
Authors: Yang Jie , Xiang Fei , Cai Peng-Cheng , Lu Yu-Zhi , Xu Xiao-Xiao , Yu Fan , Li Feng-Zhi , Greer Peter A. , Shi Huan-Zhong , Zhou Qiong , Xin Jian-Bao , Ye Hong , Su Yunchao , Ma Wan-Li
Published: June 2016

Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis.
Genome-wide identification of quantitative trait transcripts for blood traits in the liver samples of a White Duroc × Erhualian F2pig resource population
Authors: Xu Pan , Cui Leilei , Huang Tao , Zhang Zhen , Yang Bin , Chen Congying , Huang Lusheng , Duan Yanyu
Published: June 2016

Blood cell counts are important clinical indicators for health status. The liver plays a crucial role in food digestion and metabolism and is also a blood-forming organ. Here, we conducted a whole-genome quantitative trait transcript (QTT) analysis on 497 liver samples for 16 hematological traits in a White Duroc × Erhualian F2pig resource population. A total of 20,108 transcripts were explored to detect their association with hematological traits. By using Spearman correlation coefficients, we identified 1,267 QTTs for these 16 hematological traits at the significance threshold of P < 0.001. We found 31 candidate genes for erythrocyte and leukocyte-related traits by a look-up of human and pig genome-wide association study results. Furthermore, we constructed coexpression networks for leukocyte-related QTTs using weighted gene coexpression analysis. These QTTs were clustered into two to eight modules. The highest connection strength in intramodules was identified in a module for white blood cell count. In the module, USP18, RSAD2, and OAS1 appeared to be important genes involved in interferon-stimulated innate immune system. The findings improve our understanding of intrinsic relationships between the liver and blood cells and provide novel insights into the potential therapeutic targets of hematologic diseases.
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

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

The 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

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

The 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

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

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

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

Purpose: 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

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.
DNA Methylome Analyses Implicate Fallopian Tube Epithelia as the Origin for High-Grade Serous Ovarian Cancer
Authors: Klinkebiel David , Zhang Wa , Akers Stacey N. , Odunsi Kunle , Karpf Adam R.
Published: June 2016

High-grade serous ovarian cancer (HGSC) is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been suggested as the tissue of origin: ovarian surface epithelia (OSE) and fallopian tube epithelia (FTE). We hypothesized that the DNA methylome of HGSC should more closely resemble the methylome of its tissue of origin. To this end, we profiled HGSC (n = 10), and patient-matched OSE and FTE (n = 5) primary fresh-frozen tissues, and analyzed the DNA methylome using Illumina 450K arrays (n = 20) and Agilent Sure Select methyl-seq (n = 7). Methylomes were compared using statistical analyses of differentially methylated CpG sites (DMC) and differentially methylated regions (DMR). In addition, methylation was evaluated within a variety of different genomic contexts, including CpG island shores and Homeobox (HOX) genes, due to their roles in tissue specification. Publicly available HGSC methylome data (n = 628) were interrogated to provide additional comparisons with FTE and OSE for validation. These analyses revealed that HGSC and FTE methylomes are significantly and consistently more highly conserved than are HGSC and OSE. Pearson correlations and hierarchal clustering of genes, promoters, CpG islands, CpG island shores, and HOX genes all revealed increased relatedness of HGSC and FTE methylomes. Thus, these findings reveal that the landscape of FTE more closely resembles HGSC, the most common and deadly EOC subtype.

Implications: DNA methylome analyses support the hypothesis that HGSC arise from the fallopian tube and that due to its tissue-specificity and biochemical stability, interrogation of the methylome may be a valuable approach to examine cell/tissue lineage in cancer. Mol Cancer Res; 14(9); 787–94. ©2016 AACR.
Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting
Authors: Aguirre Andrew J. , Meyers Robin M. , Weir Barbara A. , Vazquez Francisca , Zhang Cheng-Zhong , Ben-David Uri , Cook April , Ha Gavin , Harrington William F. , Doshi Mihir B. , Kost-Alimova Maria , Gill Stanley , Xu Han , Ali Levi D. , Jiang Guozhi , Pantel Sasha , Lee Yenarae , Goodale Amy , Cherniack Andrew D. , Oh Coyin , Kryukov Gregory , Cowley Glenn S. , Garraway Levi A. , Stegmaier Kimberly , Roberts Charles W. , Golub Todd R. , Meyerson Matthew , Root David E. , Tsherniak Aviad , Hahn William C.
Published: June 2016

The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest. By examining single-guide RNAs that map to multiple genomic sites, we found that this cell response to CRISPR/Cas9 editing correlated strongly with the number of target loci. These observations indicate that genome targeting by CRISPR/Cas9 elicits a gene-independent antiproliferative cell response. This effect has important practical implications for the interpretation of CRISPR/Cas9 screening data and confounds the use of this technology for the identification of essential genes in amplified regions.

Significance: We found that the number of CRISPR/Cas9-induced DNA breaks dictates a gene-independent antiproliferative response in cells. These observations have practical implications for using CRISPR/Cas9 to interrogate cancer gene function and illustrate that cancer cells are highly sensitive to site-specific DNA damage, which may provide a path to novel therapeutic strategies. Cancer Discov; 6(8); 914–29. ©2016 AACR.

See related commentary by Sheel and Xue, p. 824.

See related article by Munoz et al., p. 900.

This article is highlighted in the In This Issue feature, p. 803
CRISPR Screens Provide a Comprehensive Assessment of Cancer Vulnerabilities but Generate False-Positive Hits for Highly Amplified Genomic Regions
Authors: Munoz Diana M. , Cassiani Pamela J. , Li Li , Billy Eric , Korn Joshua M. , Jones Michael D. , Golji Javad , Ruddy David A. , Yu Kristine , McAllister Gregory , DeWeck Antoine , Abramowski Dorothee , Wan Jessica , Shirley Matthew D. , Neshat Sarah Y. , Rakiec Daniel , de Beaumont Rosalie , Weber Odile , Kauffmann Audrey , McDonald E. Robert , Keen Nicholas , Hofmann Francesco , Sellers William R. , Schmelzle Tobias , Stegmeier Frank , Schlabach Michael R.
Published: June 2016

CRISPR/Cas9 has emerged as a powerful new tool to systematically probe gene function. We compared the performance of CRISPR to RNAi-based loss-of-function screens for the identification of cancer dependencies across multiple cancer cell lines. CRISPR dropout screens consistently identified more lethal genes than RNAi, implying that the identification of many cellular dependencies may require full gene inactivation. However, in two aneuploid cancer models, we found that all genes within highly amplified regions, including nonexpressed genes, scored as lethal by CRISPR, revealing an unanticipated class of false-positive hits. In addition, using a CRISPR tiling screen, we found that sgRNAs targeting essential domains generate the strongest lethality phenotypes and thus provide a strategy to rapidly define the protein domains required for cancer dependence. Collectively, these findings not only demonstrate the utility of CRISPR screens in the identification of cancer-essential genes, but also reveal the need to carefully control for false-positive results in chromosomally unstable cancer lines.

Significance: We show in this study that CRISPR-based screens have a significantly lower false-negative rate compared with RNAi-based screens, but have specific liabilities particularly in the interrogation of regions of genome amplification. Therefore, this study provides critical insights for applying CRISPR-based screens toward the systematic identification of new cancer targets. Cancer Discov; 6(8); 900–13. ©2016 AACR.

See related commentary by Sheel and Xue, p. 824.

See related article by Aguirre et al., p. 914.

This article is highlighted in the In This Issue feature, p. 803
A Novel Method Based on Teaching-Learning-Based Optimization for Recloser Placement with Load Model Consideration in Distribution System
Authors: Khajeh Ahmad Attari Sina , Bakhshipour Mohammad , Shakarami Mahmoudreza , Namdari Farhad
Published: June 2016

This paper proposed a novel technique based on teaching-learning-based optimization (TLBO) algorithm in order to find optimal placement of reclosers in the distribution networks which is applied to improve reliability. Reclosers use to eliminate transient faults, faults isolation, network management and enhance reliability to reduce customer outages. According to recloser role in network reliability, the cost for the installation and maintenance must be sustained by distribution companies. Therefore, selecting sufficient number and suitable location for reclosers are important issue. In this paper, the proposed objective function for optimal recloser number and placement has been formulated to improve three reliability indices which consists of three terms; i.e. System Average Interruption Frequency Index (SAIFI), System Average Interruption Duration Index (SAIDI) and Average Energy Not Supplied (AENS). Besides the load model effectiveness has been considered to the simulation. To verify the efficiency of proposed method, it has been conducted to IEEE 69-bus radial distribution system. The obtained simulation results demonstrate the reliability improvement.
Synchronverter Control for Parallel Operation of Cascaded H-Bridge Inverter
Authors: Hamza Amar , Altahir Sara , Yan Xiangwu
Published: June 2016

A 21-levels cascaded H-bridge multilevel inverter topology based on three-phase voltage source inverter has been proposed as a superior replacement for conventional two-level in high voltage applications. In this work we have presented the usage of the new technique called virtual synchronous generator based synchronverter model to operate the multilevel inverter as synchronous generator, and to share active and reactive power automatically in case of parallel operated inverters of the same type. Carrier-based PWM is used to control each phase leg of the cascaded H-bridge multilevel inverter. This carrier-based PWM scheme is derived from the carrier phase disposition pulse width modulation strategy. By aid of MATLAB/Simulink package a simulation experiment is established to verify the performance of the proposed technique.

 
Automatic Voltage Generation Control for Two Area Power System Based on Particle Swarm Optimization
Authors: M. Ali Ali , Ebrahim M.A. , Moustafa Hassan M.A.
Published: June 2016

This article presentes a PID controller for two area power system equipped with both automatic generation control and automatic voltage regulator loops. The research has been done to control two area power systems with PSO optimized self-tuning PID controller. The comparison between different controllers and the suggested PSO based controller illustrates that the proposed controller can generate the best dynamic response for a step load change. For this purpose, MATLAB-Simulink software is used. The obtained results are promising.
Apply Optimarin Ballast System for Vietnam’s Fleet to Prevent Sea Pollution from Non-Indigenous Aquatic Species
Authors: Dang Dinh-Chien , Shu Ming-Hung , Hsu Bi-Min , Nguyen Thanh-Lam , Truong Phung-Kim , Nguyen Viet-Thanh
Published: June 2016

Marine species are usually transported from one area to another by the ballast water used to provide safe operation for vessels. After entering a new environment, they may cause damage to the local ecosystem, leading to the disruptions of the entire marine ecosystem, and seriously affecting not only biodiversity but also several industries such as fishing and aquaculture. Therefore, the United Nations (UN) considers the presence of non-indigenous oceanic species to be one of the top four serious threats to the global environment; and, how to effectively control the non-indigenous aquatic species has captivated the special attentions of several scientists worldwide. With the significant development in the maritime industry, strict requirements the control and management of ships’ ballast water and sediments set by The UN's International Maritime Organization (IMO) have well shaped the trend in installing ballast water treatment systems. Among them, Optimarin Ballast System is preferably used in practice. However, currently, Vietnam’s fleets use a different chemical method which is not utilized elsewhere in the world. Because it is not environmentally friendly and its effectiveness hasn’t been validated yet, this paper suggests the application of OBS in the Vietnam’s fleet in order to prevent sea pollution from non-indigenous aquatic species and minimize its associated negative impacts as well as make the Vietnam’s fleet comply with IMO requirements in protecting the global environment for sustainable development.
Background Modeling to Detect Foreground Objects Based on ANN and Spatio-Temporal Analysis
Authors: Kumar N. Satish , G Shobha
Published: June 2016

This paper presented an approach to building background model for moving object detection using unsupervised Artificial Neural Network (ANN) without any prior knowledge about foreground objects. First, using Local Binary Pattern (LBP) which is texture feature, builds a statistical Background Model using ANN, then, comparing the behavior of next incoming frame with model and decide each pixel whether is deviating from a model or not. And based on if method detects foreground objects then background model is updated to make this model adaptive. Also, spatial-temporal information has been exploited in this method to suppress sudden illumination variation and to suppress false foreground pixels.  It was demonstrated and proved, by qualitative and quantitative metrics that the newly presented approach is adaptive, generic and can address all issues and challenges for background subtraction. To evaluate the performance of the presented approach this paper compared with recent approaches by using standard metrics and proved that presented method outperforms many existing recent approaches.
Sparse Modeling with Applications to Speech Processing: A Survey
Authors: Omara Ahmed , Hefnawy Alaa , Zekry Abdelhalim
Published: June 2016

Nowadays, there has been a growing interest in the study of sparse approximation of signals. Using an over-complete dictionary consisting of prototype signals or atoms, signals are described by sparse linear combinations of these atoms. Applications that use sparse representation are many and include compression, source separation, enhancement, and regularization in inverse problems, feature extraction, and more. This article introduces a literature review of sparse coding applications in the field of speech processing.