bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice
Authors: Ikeguchi Eri , Harada Norio , Kanemaru Yoshinori , Sankoda Akiko , Yamane Shunsuke , Iwasaki Kanako , Imajo Masamichi , Murata Yuki , Suzuki Kazuyo , Joo Erina , Inagaki Nobuya 
Published: May 2018

Fat accumulation with aging is a serious problem; glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, age-related changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter [GIP-green fluorescent protein (GFP) knock-in heterozygous (GIPgfp/+)] mice. Aged 1-yr-old GIPgfp/+ mice exhibited a phenotype of fat accumulation, insulin resistance, and GIP hypersecretion compared with young (3–4 mo old) GIPgfp/+ mice. In aged mice, K-cell number in the small intestine and the mRNA expression levels of GIP and transcriptional factor pancreatic and duodenal homeobox-1 (Pdx1) in K cells were increased. K-cell number, GIP mRNA expression and content in small intestine, and GIP secretion were decreased after posteriori suppression of Pdx1 using intestine-specific gene transfer. Thus, Pdx1 positively regulates GIP mRNA and K-cell number in small intestine. Increased Pdx1 expression might be involved in GIP hypersecretion with aging. NEW & NOTEWORTHY Age-related changes of glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) secretion and K cells were investigated. We found that K-cell number and GIP and pancreatic and duodenal homeobox-1 (Pdx1) expression in K cells were increased in aged mice, which showed greater GIP secretion compared with young mice. In addition, we have succeeded in posteriori suppression of Pdx1 in small intestine using the method of intestine-specific gene transfer, and showed that K-cell number, GIP expression, and GIP secretion were decreased in the Pdx1-knockdown intestine.
Force properties of skinned cardiac muscle following increasing volumes of aerobic exercise in rats
Authors: Boldt Kevin R. , Rios Jaqueline L. , Joumaa Venus , Herzog Walter 
Published: May 2018

The positive effects of chronic endurance exercise training on health and performance have been well documented. These positive effects have been evaluated primarily at the structural level, and work has begun to evaluate mechanical adaptations of the myocardium. However, it remains poorly understood how the volume of exercise training affects cardiac adaptation. To gain some understanding, we subjected 3-mo-old Sprague-Dawley rats ( n = 23) to treadmill running for 11 wk at one of three exercise volumes (moderate, high, and extra high). Following training, hearts were excised and mechanical testing was completed on skinned trabecular fiber bundles. Performance on a maximal fitness test was dose dependent on training volume, where greater levels of training led to greater performance. No differences were observed between animals from any group for maximal active stress and passive stress at a sarcomere length of 2.2 µm. Heart mass and passive stress at sarcomere lengths beyond 2.4 µm increased in a dose-dependent manner for animals in the control and moderate- and high-duration groups. However, hearts from animals in the extra high-duration group presented with inhibited responses for heart mass and passive stress, despite performing greatest on a graded treadmill fitness test. These results suggest that heart mass and passive stress adapt in a dose-dependent manner, until exercise becomes excessive and adaptation is inhibited. Our findings are in agreement with the beneficial role exercise has in cardiac adaptation. However, excessive exercise comes with risks of maladaptation, which must be weighed against the desire to increase performance. NEW & NOTEWORTHY For the first time, we present findings on cardiac trabecular muscle passive stiffness and show the effect of excessive exercise on the heart. We demonstrated that heart mass increases with exercise until a maximum, after which greater exercise volume results in inhibited adaptation. At paraphysiological lengths, passive stiffness increases with exercise but to a lesser degree with excessive training. Despite greater performance on graded exercise tests, animals in the highest trained group exhibited possible maladaptation.
MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis
Authors: Trissal Maria C. , Wong Terrence N. , Yao Juo-Chin , Ramaswamy Rahul , Kuo Iris , Baty Jack , Sun Yaping , Jih Gloria , Parikh Nishi , Berrien-Elliott Melissa M. , Fehniger Todd A. , Ley Timothy J. , Maillard Ivan , Reddy Pavan R. , Link Daniel C. 
Published: May 2018

Abstract
Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. Mir142 loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of Mir142 increased ASH1L protein expression and consequently resulted in the aberrant maintenance of Hoxa gene expression in myeloid-committed hematopoietic progenitors. Mir142 loss also enhanced the disease-initiating activity of IDH2-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing HOXA9/A10 expression during normal myeloid differentiation. AML-associated loss-of-function mutations of MIR142 disrupt this negative signaling pathway, resulting in sustained HOXA9/A10 expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.
Significance: These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. Cancer Res; 78(13); 3510–21. ©2018 AACR.
The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis
Authors: Magkrioti Christiana , Oikonomou Nikos , Kaffe Eleanna , Mouratis Marios-Angelos , Xylourgidis Nikos , Barbayianni Iliana , Megadoukas Petros , Harokopos Vaggelis , Valavanis Christos , Chun Jerold , Kosma Alexandra , Stathopoulos Georgios T. , Bouros Evangelos , Bouros Demosthenes , Syrigos Konstantinos , Aidinis Vassilis 
Published: May 2018

Abstract
Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor–like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane–induced and the genetically engineered K-rasG12D–driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras-G12D–driven lung cancer pathogenesis.
Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634–44. ©2018 AACR.
Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo
Authors: Laszlo Viktoria , Valko Zsuzsanna , Kovacs Ildiko , Ozsvar Judit , Hoda Mir Alireza , Klikovits Thomas , Lakatos Dora , Czirok Andras , Garay Tamas , Stiglbauer Alexander , Helbich Thomas H. , Gröger Marion , Tovari Jozsef , Klepetko Walter , Pirker Christine , Grusch Michael , Berger Walter , Hilberg Frank , Hegedus Balazs , Dome Balazs 
Published: May 2018

Abstract
Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting.
Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM.
Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro. Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels.
Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo. These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. Clin Cancer Res; 24(15); 3729–40. ©2018 AACR.
EGFRvIII–Stat5 Signaling Enhances Glioblastoma Cell Migration and Survival
Authors: Roos Alison , Dhruv Harshil D. , Peng Sen , Inge Landon J. , Tuncali Serdar , Pineda Michael , Millard Nghia , Mayo Zachary , Eschbacher Jennifer M. , Loftus Joseph C. , Winkles Jeffrey A. , Tran Nhan L. 
Published: May 2018

Abstract
Glioblastoma multiforme (GBM) is the most common brain malignancies in adults. Most GBM patients succumb to the disease less than 1 year after diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radioresistant and chemoresistant properties to the tumor cells; therefore, there is a critical need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat signaling pathway. Here, it is reported that EGFRvIII activates Stat5 and GBM invasion by inducing the expression of a previously established mediator of glioma cell invasion and survival: fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is Stat5 dependent and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon Src–MEK/ERK–Stat3 activation. Notably, treatment of EGFRvIII-expressing GBM cells with the FDA-approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration and survival. Because EGFR inhibitors display limited therapeutic efficacy in GBM patients, the EGFRvIII–Stat5–Fn14 signaling pathway represents a node of vulnerability in the invasive GBM cell populations.
Implications: Targeting critical effectors in the EGFRvIII–Stat5–Fn14 pathway may limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival. Mol Cancer Res; 16(7); 1185–95. ©2018 AACR.
Establishing the Transient Mass Balance of Thrombosis
Authors: Zhu Shu , Chen Jason , Diamond Scott L. 
Published: May 2018

Objective—
We investigated the coregulation of thrombin and fibrin as blood flows over a procoagulant surface.

Approach and Results—

Using microfluidic perfusion of factor XIIa-inhibited human whole blood (200 s
−1
wall shear rate) over a 250-μm long patch of collagen/TF (tissue factor; ≈1 molecule per μm
2
) and immunoassays of the effluent for F1.2 (prothrombin fragment 1.2), TAT (thrombin–antithrombin complex), and D-dimer (post–end point plasmin digest), we sought to establish the transient mass balance for clotting under venous flow. F1.2 (but almost no free thrombin detected via TAT assay) continually eluted from clots when fibrin was allowed to form. Low-dose fluorescein-Phe-Pro-Arg-chloromethylketone stained fibrin-bound thrombin—a staining ablated by anti–γ′-fibrinogen or the fibrin inhibitor glypro-arg-pro but highly resistant to 7-minute buffer rinse, demonstrating tight binding of thrombin to γ′-fibrin. With fibrin polymerizing for 500 seconds, 92 000 thrombin molecules and 203 000 clot-associated fibrin monomer equivalents were generated per TF molecule (or per μm
2
). Fibrin reached 15 mg/mL in the pore space (porosity ≈0.5) of a 15-μm-thick thrombus core by 500 seconds and 30 mg/mL by 800 seconds. For a known rate of ≈60 FPA (fibrinopeptide-A) per thrombin per second, each thrombin molecule generated only 3 fibrin monomer equivalents during 500 seconds, indicating an intraclot thrombin half-life of ≈70 ms, much shorter than its diffusional escape time (≈10 seconds). By 800 seconds, gly-pro-arg-pro allowed 4-fold more F1.2 generation, consistent with gly-pro-arg-pro ablating fibrin’s antithrombin-I activity and facilitating thrombin-mediated FXIa activation.

Conclusions—
Under flow, fibrinogen continually penetrates the clot, and γ′-fibrin regulates thrombin.
Coronary and Peripheral Vasomotor Responses to Mental Stress
Authors: Hammadah Muhammad , Kim Jeong Hwan , Al Mheid Ibhar , Samman Tahhan Ayman , Wilmot Kobina , Ramadan Ronnie , Alkhoder Ayman , Khayata Mohamed , Mekonnen Girum , Levantsevych Oleksiy , Bouchi Yasir , Kaseer Belal , Choudhary Fahad , Gafeer Mohamad M. , Corrigan Frank E. , Shah Amit J. , Ward Laura , Kutner Michael , Bremner J. Douglas , Sheps David S. , Raggi Paolo , Vaccarino Viola , Samady Habib , Mavromatis Kreton , Quyyumi Arshed A. 
Published: May 2018

Background

Coronary microvascular dysfunction may contribute to myocardial ischemia during mental stress (
MS
). However, the role of coronary epicardial and microvascular function in regulating coronary blood flow (
CBF
) responses during
MS
remains understudied. We hypothesized that coronary vasomotion during
MS
is dependent on the coronary microvascular endothelial function and will be reflected in the peripheral microvascular circulation.

Methods and Results

In 38 patients aged 59±8 years undergoing coronary angiography, endothelium‐dependent and endothelium‐independent coronary epicardial and microvascular responses were measured using intracoronary acetylcholine and nitroprusside, respectively, and after
MS
induced by mental arithmetic testing. Peripheral microvascular tone during
MS
was measured using peripheral arterial tonometry (Itamar Inc, Caesarea, Israel) as the ratio of digital pulse wave amplitude compared to rest (peripheral arterial tonometry ratio).
MS
increased the rate‐pressure product by 22% (±23%) and constricted epicardial coronary arteries by −5.9% (−10.5%, −2.6%) (median [interquartile range]),
P
=0.001, without changing
CBF
. Acetylcholine increased
CBF
by 38.5% (8.1%, 91.3%),
P
=0.001, without epicardial coronary diameter change (0.1% [−10.9%, 8.2%],
P
=not significant). The
MS
‐induced
CBF
response correlated with endothelium‐dependent
CBF
changes with acetylcholine (
r
=0.38,
P
=0.03) but not with the response to nitroprusside. The peripheral arterial tonometry ratio also correlated with the demand‐adjusted change in
CBF
during
MS
(
r
=−0.60,
P
=0.004), indicating similarity between the microcirculatory responses to
MS
in the coronary and peripheral microcirculation.

Conclusions

The coronary microvascular response to
MS
is determined by endothelium‐dependent, but not endothelium‐independent, coronary microvascular function. Moreover, the coronary microvascular responses to
MS
are reflected in the peripheral microvascular circulation.
Association of Basilar Bifurcation Aneurysms With Age, Sex, and Bifurcation Geometry
Authors: Zhang Xue-Jing , Gao Bu-Lang , Li Tian-Xiao , Hao Wei-Li , Wu Song-Shi , Zhang Dong-Hai 
Published: May 2018

Background and Purpose—
Basilar artery (BA) bifurcation aneurysms are common, but the correlation between BA bifurcation morphology and aneurysm formation remains to be established. Our purpose was to determine the association of BA bifurcation aneurysms with patient age, sex, bifurcation angle, and branch diameter.

Methods—
Three-dimensional angiographic data of 195 patients were used, including 59 patients with BA bifurcation aneurysms and 136 control subjects. The angles formed between left and right posterior cerebral arteries (φ1) and between posterior cerebral artery and BA (the smaller angle defined as φ2 and the larger one as φ3), arterial diameters, and BA bifurcation aneurysm geometric characters were examined.

Results—

Women of 40 to 70 years of age are more vulnerable to BA bifurcation aneurysm formation than men. The φ1 bifurcation angle significantly increased (
P
<0.0001), whereas both φ2 and φ3 angles significantly decreased (
P
<0.0001 and
P
=0.09, respectively) with increase of patients’ age. Statistically significant (
P
<0.0001 and
P
=0.0002, respectively) positive correlations were observed between BA bifurcation branch diameter and aneurysm size. The φ1 angle was significantly (
P
<0.0001) wider in patients harboring BA bifurcation aneurysms than the control, whereas φ2 and φ3 angles in aneurysm group were significantly smaller than those in the control group (
P
<0.0001). The BA bifurcation aneurysms were mostly deviated toward the smaller φ2 angle side between φ2 and φ3 angles and deviated toward the smaller-diameter daughter posterior cerebral artery branch.

Conclusions—
BA bifurcation aneurysms are significantly associated with patients’ age, female sex, wider bifurcation angles, and smaller vascular diameter at the BA bifurcation.
the La Porte weather anomaly—fact or fiction?
Authors: Changnon Stanley A. 
Published: May 2018

A notable increase in precipitation, moderate rain days, thunderstorm days, and hail days has been occurring since 1925 at La Porte, Ind. Since La Porte is 30 miles east of the large complex of heavy industries at Chicago, there is a strong suggestion that the increases in precipitation conditions are due to inadvertent man-made modification.
If these increases are real, they serve as a good measure of the increase in convective precipitation that man could attain, at the same time pinpointing an excellent site for future meteorological studies of the exact causes of the increases. If the increases are fictional and result from exposure changes and observer error, they serve as an indication of the sizeable errors that may exist in some of our long-term climatological records.
The increase at La Porte is sizeable: during the 1951–1965 period La Porte had 31% more precipitation, 38% more thunderstorms, and 246% more hail days than did surrounding stations. Since 1925 the year-to-year fluctuations in the annual and warm season precipitation at La Porte show agreement with the temporal distribution of steel production in the Chicago area. After a careful assessment of all available climatological data, it was concluded that these sizeable increases were real and not fictional.
The Impact of Indian Ocean Mean-State Biases in Climate Models on the Representation of the East African Short Rains
Authors: Hirons Linda , Turner Andrew 
Published: May 2018

AbstractThe role of the Indian Ocean dipole (IOD) in controlling interannual variability in the East African short rains, from October to December, is examined in state-of-the-art models and in detail in one particular climate model. In observations, a wet short-rainy season is associated with the positive phase of the IOD and anomalous easterly low-level flow across the equatorial Indian Ocean. A model’s ability to capture the teleconnection to the positive IOD is closely related to its representation of the mean state. During the short-rains season, the observed low-level wind in the equatorial Indian Ocean is westerly. However, half of the models analyzed exhibit mean-state easterlies across the entire basin. Specifically, those models that exhibit mean-state low-level equatorial easterlies in the Indian Ocean, rather than the observed westerlies, are unable to capture the latitudinal structure of moisture advection into East Africa during a positive IOD. Furthermore, the associated anomalous easterly surface wind stress causes upwelling in the eastern Indian Ocean. This upwelling draws up cool subsurface waters, enhancing the zonal sea surface temperature gradient between west and east and strengthening the positive IOD pattern, further amplifying the easterly wind stress. This positive Bjerknes coupled feedback is stronger in easterly mean-state models, resulting in a wetter East African short-rain precipitation bias in those models.
Constrictive pericarditis: retrospective study of 109 patients
Authors: Kumawat Mukesh , Lahiri Tapan Kumar , Agarwal Damyanti 
Published: April 2018

Background Chronic constrictive pericarditis is the most common diastolic disorder of the heart. Non-elasticity of the pericardium with impaired cardiac diastolic function is constriction. Chronic constrictive pericarditis is the result of scarring and fibrosis in mid and late diastole. The clinical presentation is similar to that of right heart failure. Historically, the etiology is helpful but not diagnostic. Echocardiography and a hemodynamic study are the main diagnostic tools. A thick pericardium of more than 4 mm is not necessarily constrictive, but thickness ≥7 mm is highly specific for constrictive features. Pericardiectomy is usually associated with early normalization of hemodynamics, which can be achieved via a mid-sternotomy or left anterolateral thoracotomy. Methods Data of 109 patients who underwent pericardiectomy from January 1987 to June 2016 were reviewed retrospectively. Results The outcome of our 109 cases consisted of mortality in 2 patients only. Conclusion Progressive, fibrotic, thickened, adherent inflammatory changes in response to various pathologies of the pericardium impairing diastolic filling can be treated by pericardiectomy. Pericardiectomy can be achieved by a mid-sternotomy or anterolateral thoracotomy without any difference in outcome. The initial hemodynamic and clinical result may not always be dramatic but continued improvement is definite because of progressive enlargement of left ventricular dimensions.