bluuebunny/crossref_metadata_2025_split huggingface dataset:
MET Amplification and Exon 14 Splice Site Mutation Define Unique Molecular Subgroups of Non–Small Cell Lung Carcinoma with Poor Prognosis
Authors: Tong Joanna H. , Yeung Sai F. , Chan Anthony W.H. , Chung Lau Y. , Chau Shuk L. , Lung Raymond Wai Ming , Tong Carol Y. , Chow Chit , Tin Edith K.Y. , Yu Yau H. , Li Hui , Pan Yi , Chak Wing P. , Ng Calvin S.H. , Mok Tony S.K. , To Ka F. 
Published: February 2016

Abstract
Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non–small cell lung carcinoma (NSCLC).
Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (METΔ14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.
Results: METΔ14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. METΔ14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P &lt; 0.001). METΔ14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P &lt; 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except METΔ14. Oncogenic METΔ14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. METΔ14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both METΔ14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.
Conclusions: The high incidence of METΔ14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048–56. ©2016 AACR.
See related commentary by Drilon, p. 2832
Phase I Study of PSMA-Targeted Docetaxel-Containing Nanoparticle BIND-014 in Patients with Advanced Solid Tumors
Authors: Von Hoff Daniel D. , Mita Monica M. , Ramanathan Ramesh K. , Weiss Glen J. , Mita Alain C. , LoRusso Patricia M. , Burris Howard A. , Hart Lowell L. , Low Susan C. , Parsons Donald M. , Zale Stephen E. , Summa Jason M. , Youssoufian Hagop , Sachdev Jasgit C. 
Published: February 2016

Abstract
Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel.
Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively.
Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (&gt;20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors.
Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.
IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence,In VivoExpansion, and Enhanced Function
Authors: Vallera Daniel A. , Felices Martin , McElmurry Ron , McCullar Valarie , Zhou Xianzheng , Schmohl Joerg Uwe , Zhang Bin , Lenvik Alexander J. , Panoskaltsis-Mortari Angela , Verneris Michael R. , Tolar Jakub , Cooley Sarah , Weisdorf Daniel J. , Blazar Bruce R. , Miller Jeffrey S. 
Published: February 2016

AbstractPurpose: The effectiveness of NK cell infusions to induce leukemic remission is limited by lack of both antigen specificity and in vivo expansion. To address the first issue, we previously generated a bispecific killer engager (BiKE) containing single-chain scFv against CD16 and CD33 to create an immunologic synapse between NK cells and CD33+ myeloid targets. We have now incorporated a novel modified human IL15 crosslinker, producing a 161533 trispecific killer engager (TriKE) to induce expansion, priming, and survival, which we hypothesize will enhance clinical efficacy.Experimental Design: Reagents were tested in proliferation and functional assays and in an in vivo xenograft model of AML.Results: When compared with the 1633 BiKE, the 161533 TriKE induced superior NK cell cytotoxicity, degranulation, and cytokine production against CD33+ HL-60 targets and increased NK survival and proliferation. Specificity was shown by the ability of a 1615EpCAM TriKE to kill CD33-EpCAM+ targets. Using NK cells from patients after allogeneic stem cell transplantation when NK cell function is defective, the 161533 TriKE restored potent NK function against primary AML targets and induced specific NK cell proliferation. These results were confirmed in an immunodeficient mouse HL-60-Luc tumor model where the 161533 TriKE exhibited superior antitumor activity and induced in vivo persistence and survival of human NK cells for at least 3 weeks.Conclusions: Off-the-shelf 161533 TriKE imparts antigen specificity and promotes in vivo persistence, activation, and survival of NK cells. These qualities are ideal for NK cell therapy of myeloid malignancies or targeting antigens of solid tumors. Clin Cancer Res; 22(14); 3440–50. ©2016 AACR.See related commentary by Talmadge, p. 3419
Arresting the Inflammatory Drive of Chronic Lymphocytic Leukemia with Ibrutinib
Authors: Bachireddy Pavan , Wu Catherine J. 
Published: February 2016

Abstract
The clinical success of agents targeting the B-cell receptor signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. Clin Cancer Res; 22(7); 1547–9. ©2016 AACR.
See related article by Niemann et al., p. 1572
ABT-414, an Antibody–Drug Conjugate Targeting a Tumor-Selective EGFR Epitope
Authors: Phillips Andrew C. , Boghaert Erwin R. , Vaidya Kedar S. , Mitten Michael J. , Norvell Suzanne , Falls Hugh D. , DeVries Peter J. , Cheng Dong , Meulbroek Jonathan A. , Buchanan Fritz G. , McKay Laura M. , Goodwin Neal C. , Reilly Edward B. 
Published: February 2016

AbstractTargeting tumor-overexpressed EGFR with an antibody–drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2–7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4); 661–9. ©2016 AACR.
Immunotherapy and Oncogenic Pathways: The PTEN Connection
Authors: Rizvi Naiyer A. , Chan Timothy A. 
Published: February 2016

Abstract
Summary: Peng and colleagues describe the effects of PTEN inactivation on antitumor immunity and response to immune checkpoint blockade in melanoma. These results shed light on the intricate interplay between oncogenic pathways and antitumor immune response. Cancer Discov; 6(2); 128–9. ©2016 AACR.
See related article by Peng et al., p. 202.
Descriptions of four new species of Dicopomorpha Ogloblin (Hymenoptera: Chalcidoidea: Mymaridae) from India with a key to Indian species
Authors: Rameshkumar A. , Manickavasagam S. 
Published: February 2016

<p>Four new species of <em>Dicopomorpha </em>Ogloblin (Hymenoptera: Chalcidoidea: Mymaridae), <em>D. albithorax</em>, <em>D. funiculata</em>,<em> D. longiscapa </em> and <em>D. minuta </em>are described and illustrated. A key to the Indian species of <em>Dicopomorpha </em>is provided.</p><div> </div>
Platelet Control of Fibrin Distribution and Microelasticity in Thrombus Formation Under Flow
Authors: Swieringa Frauke , Baaten Constance C.F.M.J. , Verdoold Remco , Mastenbroek Tom G. , Rijnveld Niek , van der Laan Koen O. , Breel Ernst J. , Collins Peter W. , Lancé Marcus D. , Henskens Yvonne M.C. , Cosemans Judith M.E.M. , Heemskerk Johan W.M. , van der Meijden Paola E.J. 
Published: February 2016

Objective—
Platelet- and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood.

Approach and Results—
Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factor–triggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet–fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B.

Conclusions—
Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects.
Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis
Authors: Babaev Vladimir R. , Ding Lei , Zhang Youmin , May James M. , Lin P. Charles , Fazio Sergio , Linton MacRae F. 
Published: February 2016

Objective—
The IκB kinase (IKK) is an enzyme complex that initiates the nuclear factor κB transcription factor cascade, which is important in regulating multiple cellular responses. IKKα is directly associated with 2 major prosurvival pathways, PI3K/Akt and nuclear factor κB, but its role in cell survival is not clear. Macrophages play critical roles in the pathogenesis of atherosclerosis, yet the impact of IKKα signaling on macrophage survival and atherogenesis remains unclear.

Approach and Results—

Here, we demonstrate that genetic IKKα deficiency, as well as pharmacological inhibition of IKK, in mouse macrophages significantly reduces Akt S
473
phosphorylation, which is accompanied by suppression of mTOR complex 2 signaling. Moreover, IKKα null macrophages treated with lipotoxic palmitic acid exhibited early exhaustion of Akt signaling compared with wild-type cells. This was accompanied by a dramatic decrease in the resistance of IKKα
−/−
monocytes and macrophages to different proapoptotic stimuli compared with wild-type cells. In vivo, IKKα deficiency increased macrophage apoptosis in atherosclerotic lesions and decreased early atherosclerosis in both female and male low-density lipoprotein receptor (LDLR)
−/−
mice reconstituted with IKKα
−/−
hematopoietic cells and fed with the Western diet for 8 weeks compared with control LDLR
−/−
mice transplanted with wild-type cells.

Conclusions—
Hematopoietic IKKα deficiency in mouse suppresses Akt signaling, compromising monocyte/macrophage survival and this decreases early atherosclerosis.
Absence of Coronary Artery Calcium Identifies Asymptomatic Diabetic Individuals at Low Near-Term But Not Long-Term Risk of Mortality
Authors: Valenti Valentina , Hartaigh Bríain ó , Cho Iksung , Schulman-Marcus Joshua , Gransar Heidi , Heo Ran , Truong Quynh A. , Shaw Leslee J. , Knapper Joseph , Kelkar Anita A. , Sciarretta Sebastiano , Chang Hyuk-Jae , Callister Tracy Q. , Min James K. 
Published: February 2016

Background—
Data regarding coronary artery calcification (CAC) prognosis in diabetic individuals are limited to 5-years follow-up. We investigated the long-term risk stratification of CAC among diabetic compared with nondiabetic individuals.

Methods and Results—

Nine thousand seven hundred and fifteen asymptomatic individuals undergoing CAC scoring were followed for a median (interquartile range) of 14.7 (13.9–15.6) years. The incidence density rate and hazard ratios with 95% confidence intervals were used to calculate all-cause mortality. Incremental prognostic utility of CAC was evaluated using the area under the receiver operator characteristic curve and net reclassification improvement. Diabetics (54.7±10.8 years; 59.4% male) comprised 8.3% of the cohort (n=810), of which 188 (23.2%) died. For CAC=0, the rate of mortality was similar between diabetic and nondiabetic individuals for the first 5 years (
P
>0.05), with a nonlinear increased risk of mortality for diabetics after 5 years (
P
<0.05). The adjusted risk of death for those in the highest (CAC>400) versus the lowest (CAC=0) category of CAC increased by a hazards of 4.64 (95% confidence interval =3.74–5.76) and 3.41 (95% confidence interval =2.22–5.22) for nondiabetic and diabetic individuals, respectively. The presence of CAC improved discrimination (area under the receiver operator characteristic curve range: 0.73–0.74;
P
<0.01) and reclassification (category-free net reclassification improvement range: 0.53–0.50;
P
<0.001) beyond conventional risk factors in nondiabetic and diabetic individuals, respectively.

Conclusions—
CAC=0 is associated with a favorable 5-year prognosis for asymptomatic diabetic and nondiabetic individuals. After 5 years, the risk of mortality increases significantly for diabetic individuals even in the presence of a baseline CAC=0.
Temporal Course of Dynamic Cerebral Autoregulation in Patients With Intracerebral Hemorrhage
Authors: Ma Hongyin , Guo Zhen-Ni , Liu Jia , Xing Yingqi , Zhao Ren , Yang Yi 
Published: February 2016

Background and Purpose—
Cerebral autoregulation is crucial in patients with intracerebral hemorrhage. Dynamic cerebral autoregulation is probably altered in acute intracerebral hemorrhage; however, the temporal course of dynamic cerebral autoregulation and its correlation with clinical factors and outcomes are poorly understood.

Methods—
Forty-three acute supratentorial intracerebral hemorrhage patients (53.7±10.0 years old, 30 men) were enrolled for serial measurements performed on days 1 to 2, 4 to 6, 10 to 12, and 30 days after ictus. Noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously using transcranial Doppler and a servo-controlled plethysmograph, respectively. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference (PD), gain, and the rate of recovery of cerebral blood flow velocity. Results were compared with healthy controls and correlated with clinical factors and the 90-day outcome.

Results—
PD did not differ between affected and unaffected hemispheres over time. A significant lower PD (indicating dynamic cerebral autoregulation impaired) was found in bilateral hemispheres on days 1 to 2, 4 to 6, and 10 to 12, followed by later recovery on day 30. Lower bilateral PD on days 1 to 2 was associated with poorer Glasgow Coma Scale score at that time. Lower affected-side PD on days 4 to 6 was an independent predictive value for a poorer modified Rankin Scale at 90 days.

Conclusions—
In patients with supratentorial intracerebral hemorrhage, dynamic cerebral autoregulation is bilaterally impaired lasting at least 10 to 12 days and recovers within a month. Individual PD value is associated with clinical status at acute stage and affected-side PD on days 4 to 6 can be an independent predictor for clinical outcome.
Peripheral Blood
MCEMP1
Gene Expression as a Biomarker for Stroke Prognosis
Authors: Raman Kripa , O’Donnell Martin J. , Czlonkowska Anna , Duarte Yan Carlos , Lopez-Jaramillo Patricio , Peñaherrera Ernesto , Sharma Mike , Shoamanesh Ashkan , Skowronska Marta , Yusuf Salim , Paré Guillaume 
Published: February 2016

Background and Purpose—
A limitation when making early decisions on stroke management is the lack of rapid diagnostic and prognostic testing. Our study sought to identify peripheral blood RNA biomarkers associated with stroke. The secondary aims were to assess the discriminative capacity of RNA biomarkers for primary stroke type and stroke prognosis at 1-month.

Methods—
Whole-blood gene expression profiling was conducted on the discovery cohort: 129 first-time stroke cases that had blood sampling within 5 days of symptom onset and 170 control participants with no history of stroke.

Results—

Through multiple regression analysis, we determined that expression of the gene
MCEMP1
had the strongest association with stroke of 11 181 genes tested.
MCEMP1
increased by 2.4-fold in stroke when compared with controls (95% confidence interval, 2.0–2.8;
P
=8.2×10
−22
). In addition, expression was elevated in intracerebral hemorrhage when compared with ischemic stroke cases (
P
=3.9×10
−4
).
MCEMP1
was also highest soon after symptom onset and had no association with stroke risk factors. Furthermore,
MCEMP1
expression independently improved discrimination of 1-month outcome. Indeed, discrimination models for disability and mortality that included
MCEMP1
expression, baseline modified Rankin Scale score, and primary stroke type improved discrimination when compared with a model without
MCEMP1
(disability Net Reclassification Index, 0.76;
P
=3.0×10
−6
and mortality Net Reclassification Index, 1.3;
P
=1.1×10
−9
). Significant associations with
MCEMP1
were confirmed in an independent validation cohort of 28 stroke cases and 34 controls.

Conclusions—

This study demonstrates that peripheral blood expression of
MCEMP1
may have utility for stroke diagnosis and as a prognostic biomarker of stroke outcome at 1-month.
Quasi-Vertical Profiles—A New Way to Look at Polarimetric Radar Data
Authors: Ryzhkov Alexander , Zhang Pengfei , Reeves Heather , Kumjian Matthew , Tschallener Timo , Trömel Silke , Simmer Clemens 
Published: February 2016

AbstractA novel methodology is introduced for processing and presenting polarimetric data collected by weather surveillance radars. It involves azimuthal averaging of radar reflectivity Z, differential reflectivity ZDR, cross-correlation coefficient ρhv, and differential phase ΦDP at high antenna elevation, and presenting resulting quasi-vertical profiles (QVPs) in a height-versus-time format. Multiple examples of QVPs retrieved from the data collected by S-, C-, and X-band dual-polarization radars at elevations ranging from 6.4° to 28° illustrate advantages of the QVP technique. The benefits include an ability to examine the temporal evolution of microphysical processes governing precipitation production and to compare polarimetric data obtained from the scanning surveillance weather radars with observations made by vertically looking remote sensors, such as wind profilers, lidars, radiometers, cloud radars, and radars operating on spaceborne and airborne platforms. Continuous monitoring of the melting layer and the layer of dendritic growth with high vertical resolution, and the possible opportunity to discriminate between the processes of snow aggregation and riming, constitute other potential benefits of the suggested methodology.
Characteristics of the Spanish- and English-Language Self-Efficacy to Manage Diabetes Scales
Authors: Ritter Philip L. , Lorig Kate , Laurent Diana D. 
Published: February 2016

Purpose The purpose of this study was to examine the characteristics of the Spanish-language diabetes self-efficacy scale (DSES-S) and the English-language version (DSES). Methods This study consists of secondary data from 3 randomized studies that administered the DSES-S and DSES at 2 time points. The scales consist of 8 Likert-type 10-point items. Principal component analysis was applied to determine if the scales were unitary or consisted of subscales. Univariate statistics were used to describe the scales. Sensitivity to change was measured by comparing randomized treatment with control groups, where the treatment included methods designed to enhance self-efficacy. General linear models were used to examine the association between the scales and the 8 medical outcomes after controlling for demographic variables. Results Principal component analysis indicated that there were 2 subscales for both versions: self-efficacy for behaviors and self-efficacy to manage blood levels and medical condition. The measures had similar means across the 3 studies, high internal consistent reliability, values distributed across the entire range, and they showed no evidence of floor effects and little evidence of ceiling effects. The measures were sensitive to change. They were associated with several health indicators and behaviors at baseline, and changes were associated with changes in health measures. Conclusions The self-efficacy measures behaved consistently across the 3 studies and were highly reliable. Associations with medical indicators and behaviors suggested validity, although further study would be desirable to compare other measures of self-efficacy for people with type 2 diabetes. These brief scales are appropriate for measuring self-efficacy to manage diabetes.