bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling
Authors: Hohwieler Meike , Illing Anett , Hermann Patrick C , Mayer Tobias , Stockmann Marianne , Perkhofer Lukas , Eiseler Tim , Antony Justin S , Müller Martin , Renz Susanne , Kuo Chao-Chung , Lin Qiong , Sendler Matthias , Breunig Markus , Kleiderman Susanne M , Lechel André , Zenker Martin , Leichsenring Michael , Rosendahl Jonas , Zenke Martin , Sainz Bruno , Mayerle Julia , Costa Ivan G , Seufferlein Thomas , Kormann Michael , Wagner Martin , Liebau Stefan , Kleger Alexander 
Published: September 2016

ObjectiveThe generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment.DesignWe designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.ResultsExtensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro,but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids.ConclusionsTaken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.
Impact of thrombus length on recanalization and clinical outcome following mechanical thrombectomy in acute ischemic stroke
Authors: Seker Fatih , Pfaff Johannes , Wolf Marcel , Schönenberger Silvia , Nagel Simon , Herweh Christian , Pham Mirko , Bendszus Martin , Möhlenbruch Markus A 
Published: September 2016

PurposeThe impact of thrombus length on recanalization in IV thrombolysis for acute intracranial artery occlusion has been well studied. Here we analyzed the influence of thrombus length on the number of thrombectomy maneuvers needed for recanalization, intraprocedural complications, recanalization success, and clinical outcome after mechanical thrombectomy.MethodsWe retrospectively analyzed angiographic and clinical data from 72 consecutive patients with acute occlusion of the M1 segment of the middle cerebral artery who were treated with mechanical thrombectomy using stent retrievers. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction score of 2b or 3. Good neurological outcome was defined as a modified Rankin Scale score of ≤2 at 90 days after stroke onset.ResultsMean thrombus length was 13.4±5.2 mm. Univariate binary logistic regression did not show an association of thrombus length with the probability of a good clinical outcome (OR 0.95, 95% CI 0.84 to 1.03, p=0.176) or successful recanalization (OR 0.92, 95% CI 0.81 to 1.05, p=0.225). There was no significant correlation between thrombus length and the number of thrombectomy maneuvers needed for recanalization (p=0.112). Furthermore, thrombus length was not correlated with the probability of intraprocedural complications (p=0.813), including embolization in a new territory (n=3).ConclusionsIn this study, thrombus length had no relevant impact on recanalization, neurological outcome, or intraprocedural complications following mechanical thrombectomy of middle cerebral artery occlusions. Therefore, mechanical thrombectomy with stent retrievers can be attempted with large clots.
Advanced analytical techniques for studying the morphology and chemistry of Proterozoic microfossils
Authors: Wacey David , Battison Leila , Garwood Russell J. , Hickman-Lewis Keyron , Brasier Martin D. 
Published: September 2016

Abstract
This paper outlines the suite of advanced multi-scalar techniques currently available in the toolkit of the modern Proterozoic palaeobiologist. These include non-intrusive and non-destructive optical, laser and X-ray techniques, plus more destructive ion beam and electron beam methods. Together, these provide morphological, mineralogical and biochemical data at flexible spatial scales from that of an individual atom to the largest Proterozoic microfossils. An overview is given of each technique and a case study from the exceptionally well-preserved Torridonian biota of NW Scotland is presented. This microfossil assemblage was first recognized over a century ago, but its great diversity and evolutionary importance has only recently come to light, due in no small part to the research efforts of Martin Brasier.
Ediacaran pre-placozoan diploblasts in the Avalonian biota: the role of chemosynthesis in the evolution of early animal life
Authors: Dufour Suzanne C. , McIlroy Duncan 
Published: September 2016

Abstract
The large, enigmatic members of the Ediacaran biota have received much attention regarding their possible affinities and mode of life. Fossil evidence reveals that many Ediacaran animals, such as the rangeomorphs, were characterized by extensive surface areas, lived in close association with the seafloor and were non-motile. We argue for the presence of a simple, diploblastic body plan in these early animals and discuss the means by which they probably derived nutrients from chemosynthetic bacteria thriving at the sediment–water interface. We consider that the large surface area of some Ediacaran organisms in the Avalonian biota may have been an adaptation for maximizing a phagocytotic or chemosymbiotic surface. Ediacaran animals probably increased the availability of oxygen along their ventral surface either by diffusion or ciliary pumping. This increased supply of oxygen to the sediment is inferred to have simultaneously increased the productivity of their food source (chemosynthetic bacteria) and restricted the build-up of toxic sulphides in the pore waters below their bodies. This is an example of a very simple form of ecosystem engineering.
v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1
Authors: Ju Xiaoming , Jiao Xuanmao , Ertel Adam , Casimiro Mathew C. , Di Sante Gabriele , Deng Shengqiong , Li Zhiping , Di Rocco Agnese , Zhan Tingting , Hawkins Adam , Stoyanova Tanya , Andò Sebastiano , Fatatis Alessandro , Lisanti Michael P. , Gomella Leonard G. , Languino Lucia R. , Pestell Richard G. 
Published: September 2016

Abstract
Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1–regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, epitope characteristics, and prostatosphere formation. Cyclin D1 was induced by v-Src, and Src kinase induction of Trop2 ICD nuclear accumulation required cyclin D1. Cyclin D1 induced abundance of the Trop2 proteolytic cleavage activation components (PS2, TACE) and restrained expression of the inhibitory component of the Trop2 proteolytic complex (Numb). Patients with prostate cancer with increased nuclear Trop2 ICD and cyclin D1, and reduced Numb, had reduced recurrence-free survival probability (HR = 4.35). Cyclin D1, therefore, serves as a transducer of v-Src–mediated induction of Trop2 ICD by enhancing abundance of the Trop2 proteolytic activation complex. Cancer Res; 76(22); 6723–34. ©2016 AACR.
Visualizing Epithelial–Mesenchymal Transition Using the Chromobody Technology
Authors: Maier Julia , Traenkle Bjoern , Rothbauer Ulrich 
Published: September 2016

AbstractThe epithelial–mesenchymal transition (EMT) is a complex cellular program involved in the progression of epithelial cancers to a metastatic stage. Along this process, epithelial traits are repressed in favor of a motile mesenchymal phenotype. A detailed characterization and monitoring of EMT-related processes is required for the design of screening strategies needed to develop novel antimetastatic therapies. Overexpression of the canonical EMT biomarker vimentin correlates with increased tumor growth and invasiveness, as well as with reduced patient survival across various epithelial cancers. Moreover, recent findings have demonstrated an active role of vimentin in regulating and reorganizing the cellular architecture toward a migratory and invasive phenotype. However, current studies suffer from a lack of appropriate methods to trace the induction and dynamics of vimentin in cell-based assays. Recently, we have reported a novel intrabody (chromobody)–based approach to study the spatiotemporal organization of endogenous vimentin upon induction of EMT by high-content imaging. In this review, we discuss the relevance of the chromobody technology with regard to the visualization of EMT-related processes in living systems. Cancer Res; 76(19); 5592–6. ©2016 AACR.
Administration of Non-Torsadogenic human Ether-à-go-go-Related Gene Inhibitors Is Associated with Better Survival for High hERG–Expressing Glioblastoma Patients
Authors: Pointer Kelli B. , Clark Paul A. , Eliceiri Kevin W. , Salamat M. Shahriar , Robertson Gail A. , Kuo John S. 
Published: September 2016

Abstract
Purpose: Glioblastoma is the most malignant primary brain tumor, with a median survival of less than 2 years. More effective therapeutic approaches are needed to improve clinical outcomes.
Experimental Design: Glioblastoma patient-derived cells (GPDC) were isolated from patient glioblastomas and implanted in mice to form xenografts. IHC was performed for human Ether-à-go-go-Related Gene (hERG) expression and tumor proliferation. Sphere-forming assays with the hERG blocker E-4031 were performed on a high and low hERG–expressing lines. A glioblastoma tissue microarray (TMA; 115 patients) was used to correlate hERG expression with patient survival. Clinical data were analyzed to determine whether patient survival was affected by incidental administration of hERG inhibitory drugs and the correlative effect of patient glioblastoma hERG expression levels.
Results: hERG expression was upregulated in glioblastoma xenografts with higher proliferative indices. High hERG–expressing GPDCs showed a reduction in sphere formation when treated with hERG inhibitors compared with low hERG–expressing GPDCs. Glioblastoma TMA analysis showed worse survival for glioblastoma patients with high hERG expression versus low expression—43.5 weeks versus 60.9 weeks, respectively (P = 0.022). Furthermore, patients who received at least one hERG blocker had a better survival rate compared with patients who did not (P = 0.0015). Subgroup analysis showed that glioblastoma patients with high hERG expression who received hERG blockers had improved survival (P = 0.0458). There was no difference in survival for low hERG–expressing glioblastoma patients who received hERG blockers (P = 0.4136).
Conclusions: Our findings suggest that hERG is a potential glioblastoma survival marker, and that already approved drugs with non-torsadogenic hERG inhibitory activity may potentially be repurposed as adjuvant glioblastoma therapy in high hERG–expressing glioblastoma patients. Clin Cancer Res; 23(1); 73–80. ©2016 AACR.
See related commentary by Arcangeli and Becchetti, p. 3
Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient–Derived Xenografts and Mesothelin as a Biomarker of Tumor Response
Authors: Zhang Jingli , Khanna Swati , Jiang Qun , Alewine Christine , Miettinen Markku , Pastan Ira , Hassan Raffit 
Published: September 2016

Abstract
Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of mesothelin as a biomarker of tumor response.
Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time points to determine whether its levels correlated with tumor response.
Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41 × 103 to 346 × 103 mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.
Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. Clin Cancer Res; 23(6); 1564–74. ©2016 AACR.
B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm
Authors: Schaheen Basil , Downs Emily A. , Serbulea Vlad , Almenara Camila C.P. , Spinosa Michael , Su Gang , Zhao Yunge , Srikakulapu Prasad , Butts Cherié , McNamara Coleen A. , Leitinger Norbert , Upchurch Gilbert R. , Meher Akshaya K. , Ailawadi Gorav 
Published: September 2016

Objective—
B-cell depletion therapy is widely used for treatment of cancers and autoimmune diseases. B cells are abundant in abdominal aortic aneurysms (AAA); however, it is unknown whether B-cell depletion therapy affects AAA growth. Using experimental models of murine AAA, we aim to examine the effect of B-cell depletion on AAA formation.

Approach and Results—
Wild-type or apolipoprotein E–knockout mice were treated with mouse monoclonal anti-CD20 or control antibodies and subjected to an elastase perfusion or angiotensin II infusion model to induce AAA, respectively. Anti-CD20 antibody treatment significantly depleted B1 and B2 cells, and strikingly suppressed AAA growth in both models. B-cell depletion resulted in lower circulating IgM levels, but did not affect the levels of IgG or cytokine/chemokine levels. Although the total number of leukocyte remained unchanged in elastase-perfused aortas after anti-CD20 antibody treatment, the number of B-cell subtypes was significantly lower. Interestingly, plasmacytoid dendritic cells expressing the immunomodulatory enzyme indole 2,3-dioxygenase were detected in the aortas of B-cell–depleted mice. In accordance with an increase in indole 2,3-dioxygenase+ plasmacytoid dendritic cells, the number of regulatory T cells was higher, whereas the expression of proinflammatory genes was lower in aortas of B-cell–depleted mice. In a coculture model, the presence of B cells significantly lowered the number of indole 2,3-dioxygenase+ plasmacytoid dendritic cells without affecting total plasmacytoid dendritic cell number.

Conclusions—
The present results demonstrate that B-cell depletion protects mice from experimental AAA formation and promotes emergence of an immunosuppressive environment in aorta.
TMEM16F-Mediated Platelet Membrane Phospholipid Scrambling Is Critical for Hemostasis and Thrombosis but not Thromboinflammation in Mice—Brief Report
Authors: Baig Ayesha A. , Haining Elizabeth J. , Geuss Eva , Beck Sarah , Swieringa Frauke , Wanitchakool Podchanart , Schuhmann Michael K. , Stegner David , Kunzelmann Karl , Kleinschnitz Christoph , Heemskerk Johan W.M. , Braun Attila , Nieswandt Bernhard 
Published: September 2016

Objective—
It is known that both platelets and coagulation strongly influence infarct progression after ischemic stroke, but the mechanisms and their interplay are unknown. Our aim was to assess the contribution of the procoagulant platelet surface, and thus platelet-driven thrombin generation, to the progression of thromboinflammation in the ischemic brain.

Approach and Results—
We present the characterization of a novel platelet and megakaryocyte-specific TMEM16F (anoctamin 6) knockout mouse. Reflecting Scott syndrome, platelets from the knockout mouse had a significant reduction in procoagulant characteristics that altered thrombin and fibrin generation kinetics. In addition, knockout mice showed significant defects in hemostasis and arterial thrombus formation. However, infarct volumes in a model of ischemic stroke were comparable with wild-type mice.

Conclusions—
Platelet TMEM16F activity contributes significantly to hemostasis and thrombosis but not cerebral thromboinflammation. These results highlight another key difference between the roles of platelets and coagulation in these processes.
Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population
Authors: Friedman Kevin G. , Gauvreau Kimberly , Hamaoka‐Okamoto Akiko , Tang Alexander , Berry Erika , Tremoulet Adriana H. , Mahavadi Vidya S. , Baker Annette , deFerranti Sarah D. , Fulton David R. , Burns Jane C. , Newburger Jane W. 
Published: September 2016

Background

The natural history of coronary artery aneurysms (
CAA
) after intravenous immunoglobulin (
IVIG
) treatment in the United States is not well described. We describe the natural history of
CAA
in
US
Kawasaki disease (
KD
) patients and identify factors associated with major adverse cardiac events (
MACE
) and
CAA
regression.

Methods and Results

We evaluated all
KD
patients with
CAA
at 2 centers from 1979 to 2014. Factors associated with
CAA
regression, maximum
CA
z
‐score over time (
z
Max), and
MACE
were analyzed. We performed a matched analysis of treatment effect on likelihood of
CAA
regression. Of 2860
KD
patients, 500 (17%) had
CAA
, including 90 with
CAA
z
‐score >10. Most (91%) received
IVIG
within 10 days of illness, 32% received >1
IVIG
, and 27% received adjunctive anti‐inflammatory medications.
CAA
regression occurred in 75%. Lack of
CAA
regression and higher
CAA
z
Max were associated with earlier era, larger
CAA
z
‐score at diagnosis, and bilateral
CAA
in univariate and multivariable analyses.
MACE
occurred in 24 (5%) patients and was associated with higher
CAA
z
‐score at diagnosis and lack of
IVIG
treatment. In a subset of patients (n=132) matched by age at
KD
and baseline
CAA
z
‐score, those receiving
IVIG
plus adjunctive medication had a
CAA
regression rate of 91% compared with 68% for the 3 other groups (
IVIG
alone,
IVIG
≥2 doses, or
IVIG
≥2 doses plus adjunctive medication).

Conclusions

CAA
regression occurred in 75% of patients.
CAA
z
‐score at diagnosis was highly predictive of outcomes, which may be improved by early
IVIG
treatment and adjunctive therapies.
MKEY, a Peptide Inhibitor of CXCL4‐CCL5 Heterodimer Formation, Protects Against Stroke in Mice
Authors: Fan Yifang , Xiong Xiaoxing , Zhang Yongming , Yan Dongmei , Jian Zhihong , Xu Baohui , Zhao Heng 
Published: September 2016

Background

MKEY
, a synthetic cyclic peptide inhibitor of
CXCL
4–
CCL
5 heterodimer formation, has been shown to protect against atherosclerosis and aortic aneurysm formation by mediating inflammation, but whether it modulates neuroinflammation and brain injury has not been studied. We therefore studied the role of
MKEY
in stroke‐induced brain injury in mice.

Methods and Results

MKEY
was injected into mice after stroke with 60 minutes of middle cerebral artery occlusion. Infarct volume and neurological deficit scores were measured. Protein levels of
CCL
5 and its receptor
CCR
5 were detected by Western blot and fluorescence‐activated cell sorting (
FACS
), respectively. Numbers of microglia‐derived macrophages (MiMΦs) and monocyte‐derived MΦs (MoMΦs) in the brain, and their subsets, based on the surface markers
CD
45,
CD
11b,
CCR
2,
CX
3
CR
1, and Ly6C, were analyzed by
FACS
. MΦs and neutrophil infiltration in the ischemic brain were stained with
CD
68 and myeloperoxidase (
MPO
), respectively, and assessed by immunofluorescent confocal microscopy. The results showed that expressions of
CCL
5 and its receptor
CCR
5, were increased in the ischemic brain after stroke.
MKEY
injection significantly reduced infarct sizes and improved neurological deficit scores measured 72 hours after stroke. In addition,
MKEY
injection inhibited the number of MoMΦs, but not MiMΦs, in the ischemic brain. Furthermore,
MKEY
inhibited protein expression levels of Ly6C,
CCR
2, and
CX
3
CR
1 on MoMΦs. Lastly, the confocal study also suggests that the number of
CD
68‐positive MΦs and
MPO
‐positive neutrophils was inhibited by
MKEY
injection.

Conclusions

MKEY
injection protects against stroke‐induced brain injury, probably by inhibiting MoMΦ‐mediated neuroinflammation.
Sex Differences in Survival From Out‐of‐Hospital Cardiac Arrest in the Era of Regionalized Systems and Advanced Post‐Resuscitation Care
Authors: Bosson Nichole , Kaji Amy H. , Fang Andrea , Thomas Joseph L. , French William J. , Shavelle David , Niemann James T. 
Published: September 2016

Background
The purpose of this study was to evaluate sex differences in out‐of‐hospital cardiac arrest (OHCA) characteristics, interventions, and outcomes.

Methods and Results
This is a retrospective analysis from a regionalized cardiac arrest system. Data on patients treated for OHCA are reported to a single registry, from which all adult patients were identified from 2011 through 2014. Characteristics, treatment, and outcomes were evaluated with stratification by sex. The adjusted odds ratio (OR) for survival with good neurological outcome (cerebral performance category 1 or 2) was calculated for women compared to men. There were 5174 out‐of‐hospital cardiac arrests (OHCAs; 3080 males and 2094 females). Women were older, median 71 (interquartile range [IQR], 59–82) versus 66 years (IQR, 55–78). Despite similar frequency of witnessed arrest, women were less likely to present with a shockable rhythm (22% vs 35%; risk difference [RD], 13%; 95% CI, 11–15), have ST‐segment elevation myocardial infarction (23% vs 32%; RD, 13%; 95% CI, 7–11), or receive coronary angiography (11% vs 25%; RD, 14%; 95% CI, 12–16), percutaneous coronary intervention (5% vs 14%; RD, 9%; 95% CI, 7–11), or targeted temperature management (33% vs 40%; RD, 7%; 95% CI, 4–10). Women had decreased survival to discharge (33% vs 40%; RD, 7%; 95% CI, 4–10) and a lower proportion of good neurological outcome (16% vs 24%; RD, 8%; 95% CI, 6–10). In multivariable modeling, female sex was not associated with decreased survival with good neurological outcome (OR, 0.9; 95% CI, 0.8–1.1).

Conclusions
Sex‐related differences in OHCA characteristics and treatment are predictors of survival outcome disparities. With adjustment for these factors, sex was not associated with survival or neurological outcome after OHCA.