bluuebunny/crossref_metadata_2025 huggingface dataset:
Can semiology predict psychogenic nonepileptic seizures? a prospective study
Authors: Syed Tanvir U. , LaFrance W. Curt , Kahriman Emine S. , Hasan Saba N. , Rajasekaran Vijayalakshmi , Gulati Deepak , Borad Samip , Shahid Asim , Fernandez‐Baca Guadalupe , Garcia Naiara , Pawlowski Matthias , Loddenkemper Tobias , Amina Shahram , Koubeissi Mohamad Z.
Published: December 2010

Objective:

Reducing health and economic burdens from diagnostic delay of psychogenic nonepileptic seizures (PNES) requires prompt referral for video electroencephalography (VEEG) monitoring, the diagnostic gold standard. Practitioners make VEEG referrals when semiology suggests PNES, although few semiological signs are supported by well‐designed studies, and most VEEG studies neglect to concurrently measure how accurately seizure witnesses can ascertain semiology. In this study, we estimate the value of eyewitness‐reported and video‐documented semiology for predicting PNES, and we measure accuracy of eyewitness reports.

Methods:

We prospectively interviewed eyewitnesses of seizures in patients referred for VEEG monitoring, to inquire about 48 putative PNES and ES signs. Multiple, EEG‐blinded, epileptologists independently evaluated seizure videos and documented the presence/absence of signs. We used generalized estimating equations to identify reliable video‐documented PNES and ES signs, and we compared eyewitness reports with video findings to assess how accurately signs are reported. We used logistic regression to determine whether eyewitness reports could predict VEEG‐ascertained seizure type.

Results:

We analyzed 120 seizures (36 PNES, 84 ES) from 35 consecutive subjects. Of 45 video‐documented signs, only 3 PNES signs (“preserved awareness,” “eye flutter,” and “bystanders can intensify or alleviate”) and 3 ES signs (“abrupt onset,” “eye‐opening/widening,” and postictal “confusion/sleep”) were significant and reliable indicators of seizure type. Eyewitness reports of these 6 signs were inaccurate and not statistically different from guessing. Consequentially, eyewitness reports of signs did not predict VEEG‐ascertained diagnosis. We validated our findings in a second, prospective cohort of 36 consecutive subjects.

Interpretation:

We identified 6 semiological signs that reliably distinguish PNES and ES, and found that eyewitness reports of these signs are unreliable. We offer suggestions to improve the accuracy of eyewitness reports. ANN NEUROL 2011;
Dietary wheat germ oil influences gene expression in larvae and eggs of the oriental fruit fly
Authors: Coudron Thomas A. , Chang Chiou Ling , Goodman Cynthia L. , Stanley David
Published: December 2010

Changes in animal nutrition, particularly essential dietary components, alter global gene expression patterns. Our goal is to identify molecular markers that serve as early indicators of the quality of insect culture media. Markers of deficient culture media will increase the efficiency of developing optimal systems for mass rearing beneficial insects and some pest species because decisions on culture media quality can be made without waiting through one or several life cycles. The objective of our current study is to discover molecular markers of essential dietary lipid deficiency in the oriental fruit fly, Bactrocera dorsalis. We reared groups of fruit flies separately on media either devoid of or supplemented with wheat germ oil (WGO) and analyzed gene expression in third instar larvae and F1 eggs using 2D electrophoresis. Gel densitometry revealed significant changes in expression levels of genes encoding eight proteins in larvae and 22 proteins in eggs. We identified these proteins by using mass spectrometry (MALDI TOF/TOF) and bioinformatic analyses of the protein sequences. Among these, we identified one gene encoding the receptor of activated C Kinase 1 (RACK1) that increased in expression by 6.8‐fold in eggs from adults that were reared as larvae on media supplemented with WGO. RACK1 is an essential component of at least three intracellular signal transduction pathways, making it a good molecular marker candidate of lipid deficiency in fruit flies and possibly many other insect species. © 2010 Wiley Periodicals, Inc.
Der Einfluß des Lösungsmittels auf die Teilreaktionen bei der radikalischen Polymerisation des Methylmethacrylates
Authors: Fischer J. P. , Mücke G. , Schulz G. V.
Published: December 2010

Mit Hilfe der Methode der intermittierenden Belichtung (Sektormethode) in Kombination mit Stationärmessungen wird eine Absolutbestimmung der Geschwindigkeitskonstanten aller am Polymerisationsprozeß beteiligten Elementarreaktionen durchgeführt. Hierbei wird die Viskosität des Lösungsmittels insgesamt um den Faktor 170 und der Polymerisationsgrad um den Faktor 20 variiert. Es zeigt sich, daß die Radikalausbeute (efficiency) bei Erhöhung der Viskosität absinkt und daß die Geschwindigkeitskonstante des Kettenabbruchs umgekehrt proportional der Viskosität und vollkommen unabhängig vom Polymerisationsgrad der Polymerradikale ist.

Eine Deutung der Radikalausbeute wird im Rahmen des Käfigeffektes versucht. Der Befund über den Kettenabbruch wird durch einen Modellmechanismus erklärt, der eine praktisch unbehinderte gegenseitige Durchdringung der Polymermoleküle bei der Selbstdiffusion voraussetzt.
Developmental defects of coronary vasculature in rat embryos administered bis‐diamine
Authors: Hanato Takashi , Nakagawa Masao , Okamoto Nobuhiko , Nishijima Setsuko , Fujino Hidetoshi , Shimada Morimi , Takeuchi Yoshihiro , Imanaka‐Yoshida Kyoko
Published: December 2010

BACKGROUND: Conotruncal anomalies are often associated with abnormal coronary arteries. Although bis‐diamine is known to induce conotruncal defects, its pathological effects on coronary vascular development have not been demonstrated. This study sought to assess the teratogenic effects of bis‐diamine on coronary vascular development and the pathogenesis of this anomalous association. METHODS AND RESULTS: A single 200 mg dose of bis‐diamine was administered to pregnant Wistar rats at 10.5 days of gestation. Fifty‐two embryos from 10 mother rats underwent morphological analysis of the coronary arteries. Three embryos each were removed from four mothers on embryonic days (ED) 14.5, 15.5, 16.5, and 17.5 and used for immunohistochemical studies using the anti‐vascular cell adhesion molecule (VCAM)‐1 antibody. Conotruncal anomalies were detected in 48 of 52 embryos, and an aplastic or hypoplastic left coronary artery was found in all of them. In control embryos at ED 16.5, VCAM‐1‐positive epicardial cells were transformed into mesenchymal cells in vascular plexus, which appeared to differentiate into the endothelial cells of coronary vasculature. In the heart at ED 17.5, coronary vasculature was well developed and connected with coronary ostia near the aorta. However, poor epicardial–mesenchymal transformation and subsequent differentiation was revealed in bis‐diamine‐treated embryos at EDs 16.5 and 17.5, causing abnormal development of the coronary vasculature and incomplete connections with coronary ostia of the aorta. CONCLUSIONS: Anomalous coronary arteries in the bis‐diamine‐treated embryos are induced by the disruption of epicardial–mesenchymal transformation and subsequent poor development of coronary vasculature. Incomplete hatching of the coronary ostium is associated with abnormal truncal division. Birth Defects Res (Part B) 92:10–16, 2011. © 2010 Wiley‐Liss, Inc.
Systematic review of percutaneous catheter drainage as primary treatment for necrotizing pancreatitis
Authors: van Baal M C , van Santvoort H C , Bollen T L , Bakker O J , Besselink M G , Gooszen H G
Published: December 2010

Background

The role of percutaneous catheter drainage (PCD) in patients with (infected) necrotizing pancreatitis was evaluated.

Methods

A systematic literature search was performed. Inclusion criteria were: consecutive cohort of patients with necrotizing pancreatitis undergoing PCD as primary treatment for peripancreatic collections; indication for PCD either (suspected) infected necrosis or symptomatic sterile pancreatic necrosis; and outcomes reported to include percentage of infected peripancreatic collections, need for additional surgical necrosectomy, complications and deaths. Exclusion criteria were: cohort of fewer than five patients; cohort included patients with chronic pancreatitis; selected subgroup of patients with acute pancreatitis studied, such as those with pseudocysts, pancreatic abscesses and/or exclusively sterile pancreatic necrosis; and cohort in which PCD was combined with another minimally invasive strategy and results for PCD alone not reported separately.

Results

Eleven studies, including 384 patients, fulfilled the inclusion criteria. Only one study was a randomized controlled trial; most others were retrospective case series. Four studies reported on the presence of organ failure before PCD; this occurred in 67·2 per cent of 116 patients. Infected necrosis was proven in 271 (70·6 per cent) of 384 patients. No additional surgical necrosectomy was required after PCD in 214 (55·7 per cent) of 384 patients. Complications consisted mostly of internal and external pancreatic fistulas. The overall mortality rate was 17·4 per cent (67 of 384 patients). Nine of 11 studies reported mortality separately for patients with infected necrosis undergoing PCD; the mortality rate in this group was 15·4 per cent (27 of 175).

Conclusion

A considerable number of patients can be treated with PCD without the need for surgical necrosectomy.
Sustainable Performance with Values‐Based Shared Leadership: A Case Study of a Virtuous Organization
Authors: Manz Charles C. , Manz Karen P. , Adams Stephen B. , Shipper Frank
Published: December 2010

This article presents a qualitative case study of Herman Miller Inc., a “Virtuous Organization” and leading innovator and manufacturer in the business furniture industry. It adds to the literature by examining the role shared leadership can play in fostering sustainable performance in one organization that has a track record of virtuous organizational behaviour and long‐term success. Herman Miller has survived and thrived in the face of multiple setbacks. Our findings suggest two primary values potentially moderate the relationship between shared leadership and sustainable performance: (a) an ongoing creative process, and (b) recognition of every organization member as a valuable resource. We propose a conceptual model and offer preliminary qualitative evidence supporting key components and relationships implied by the model. Copyright © 2010 ASAC. Published by John Wiley & Sons, Ltd.
Integrated Synthetic, Pharmacological, and Computational Investigation ofcis‐2‐(3,5‐Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4
Authors: Christov Christo , González‐Bulnes Patricia , Malhaire Fanny , Karabencheva Tatyana , Goudet Cyril , Pin Jean‐Philippe , Llebaria Amadeu , Giraldo Jesús
Published: December 2010

2‐(3,5‐Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of1was reported to reside in thecisdiastereomer with equal potency between its enantiomeric forms (Niswender et al.,Mol. Pharmacol.2008,74, 1345–1358). In the present study, the asymmetric synthesis of each of thecisenantiomers was performed, and their activities were compared with that of the racemictrans. In our assays, thecisenantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemictrans. High‐level quantum chemical calculations were carried out to characterize the structures of minimum energy in all‐isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of1that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R,2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R,2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.
Bioavailability of EPA and DHA delivered by gelled emulsions and soft gel capsules
Authors: Haug Ingvild J. , Sagmo Lise B. , Zeiss Daniel , Olsen Inge C. , Draget Kurt I. , Seternes Tore
Published: December 2010

This study presents data comparing the bioavailability of DHA and EPA delivered by two different formulations: One group received TAG fish oil in traditional soft gel capsules, whereas the other group received the TAG oil as droplets trapped inside a gelatin matrix (gelled emulsions). The incremental area under the curve (AUC0–26 h) of EPA and EPA + DHA in blood plasma from the gelled emulsions was significantly increased by 44.9 and 43.3%, respectively, compared to soft gel capsules. The maximum incremental concentration of EPA and EPA + DHA was significantly increased by 100.4 and 105.6%, respectively, compared to soft gel capsules. These results suggest that improved bioavailability of EPA and DHA may be achieved by incorporating emulsified TAG fish oil in a gel matrix prior to oral ingestion.

Practical applications: This study presents a new type of vehicle for the delivery of PUFAs. The vehicles are soft and chewable with the possibility of adding flavours, sweeteners and colour, and this makes the vehicles ideal for delivery of PUFAs to consumers having problems swallowing large capsules or cod liver oil. The vehicles are already applied in products in several countries, including Norway.
Radical Intramolecular Arylation of Pyridinium Salts: A Straightforward Entry to 7‐Hydroxypyrido[2,1‐a]isoquinolinylium Salts
Authors: Castillo Rafael R. , Burgos Carolina , Vaquero Juan J. , Alvarez‐Builla Julio
Published: December 2010

The synthesis of 7‐hydroxypyrido[2,1‐a]isoquinolinylium salts can be achieved in moderate yields by intramolecular radical arylation of pyridinium salts obtained from substituted pyridines and o‐bromophenacyl bromides.
Kalman filtering and smoothing for model‐based signal extraction that depend on time‐varying spectra
Authors: Koopman Siem Jan , Wong Soon Yip
Published: December 2010

We develop a flexible semi‐parametric method for the introduction of time‐varying parameters in a model‐based signal extraction procedure. Dynamic model specifications for the parameters in the model are not required. We show that signal extraction based on Kalman filtering and smoothing can be made dependent on time‐varying sample spectra. Our new procedure starts with specifying the time‐varying spectrum as a semi‐parametric flexible spline function that can be formulated in state space form and can be treated by multivariate Kalman filter and smoothing methods. Next we show how a time series decomposition model can be made dependent on a time‐varying sample spectrum in a frequency domain analysis. The key insight is that the spectral likelihood function depends on the sample spectrum. The estimates of the model parameters are obtained by maximizing the spectral likelihood function. A time‐varying sample spectrum leads to a time‐varying spectral likelihood and hence we obtain time‐varying parameter estimates. The time series decomposition model with the resulting time‐varying parameters reflect the time‐varying spectrum accurately. This approach to model‐based signal extraction includes a bootstrap procedure to compute confidence intervals for the time‐varying parameter estimates. We illustrate the methodology by presenting a business cycle analysis for three quarterly US macroeconomic time series between 1947 and 2010. The empirical study provides strong evidence that the cyclical properties of macroeconomic time series have been changing over time. Copyright © 2010 John Wiley & Sons, Ltd.
Transoral robotic surgery and human papillomavirus status: Oncologic results
Authors: Cohen Marc A. , Weinstein Gregory S. , O'Malley Bert W. , Feldman Michael , Quon Harry
Published: December 2010

Background

Patients with oropharyngeal squamous cell carcinoma (OPSCC) have been shown to have distinct outcome profiles based on their human papillomavirus (HPV) status. The purpose of this study was to assess HPV‐related outcomes after transoral robotic surgery (TORS) with adjuvant therapy as indicated.

Methods

This study consisted of a retrospective review of 50 patients with OPSCC within a prospective single‐arm cohort study. Outcome measures included HPV status, margin status, relapse pattern, and survival.

Results

Thirty‐seven patients were HPV‐positive (74.0%) with 34 patients (91.9%) being serotype‐16. Negative margins were achieved in 92.3% (HPV‐negative) and 94.6% (HPV‐positive). In the HPV‐negative group, there were no local recurrences and 1 patient had both regional and distant recurrence (7.7%). In the HPV‐positive group, there were no local or regional recurrences and 2 patients (5.4%) had distant recurrences. There were no statistically significant differences in survival between the 2 cohorts (overall survival, disease‐specific survival, disease‐free survival).

Conclusion

TORS as a primary surgical modality, followed by adjuvant therapy as indicated, offers disease control in both HPV‐negative and HPV‐positive groups. We believe that multi‐institutional studies are warranted to further evaluate this novel approach for patients who are HPV negative and HPV positive. © 2010 Wiley Periodicals, Inc. Head Neck, 2011
Oral maxillary squamous carcinoma: An indication for neck dissection in the clinically negative neck
Authors: Montes David M. , Carlson Eric R. , Fernandes Rui , Ghali G. E. , Lubek Joshua , Ord Robert , Bell Bryan , Dierks Eric , Schmidt Brian L.
Published: December 2010

Background

This multicenter study was undertaken to characterize the metastatic behavior of oral maxillary squamous carcinoma and to determine the role of selective neck dissection.

Methods

A retrospective, multicenter study of patients surgically treated for oral maxillary squamous carcinoma was completed. Data collected included primary tumor location, cervical lymph node status, and neck failure rate.

Results

The study included 146 patients. The adjusted regional metastatic rate was 31.4%. Of those N0 (clinically negative) necks treated with or without neck dissection, 14.4% developed cervical metastasis. Within the cohort, 7.5% of patients died with distant disease. The regional salvage rate was 52.9%. None of the patients with locoregional failures were salvaged.

Conclusions

Maxillary palatal, alveolar, and gingival squamous carcinomas exhibit aggressive regional metastatic behavior. Surgical salvage rates for neck failure are low; therefore, selective neck dissection (levels I–III) is recommended at the time of resection of T2, T3, and T4 maxillary squamous carcinomas. © 2010 Wiley Periodicals, Inc. Head Neck, 2011
Grid cell hexagonal patterns formed by fast self‐organized learning within entorhinal cortex
Authors: Mhatre Himanshu , Gorchetchnikov Anatoli , Grossberg Stephen
Published: December 2010

Grid cells in the dorsal segment of the medial entorhinal cortex (dMEC) show remarkable hexagonal activity patterns, at multiple spatial scales, during spatial navigation. It has previously been shown how a self‐organizing map can convert firing patterns across entorhinal grid cells into hippocampal place cells that are capable of representing much larger spatial scales. Can grid cell firing fields also arise during navigation through learning within a self‐organizing map? This article describes a simple and general mathematical property of the trigonometry of spatial navigation which favors hexagonal patterns. The article also develops a neural model that can learn to exploit this trigonometric relationship. This GRIDSmap self‐organizing map model converts path integration signals into hexagonal grid cell patterns of multiple scales. GRIDSmap creates only grid cell firing patterns with the observed hexagonal structure, predicts how these hexagonal patterns can be learned from experience, and can process biologically plausible neural input and output signals during navigation. These results support an emerging unified computational framework based on a hierarchy of self‐organizing maps for explaining how entorhinal‐hippocampal interactions support spatial navigation. © 2010 Wiley Periodicals, Inc.
7,8‐dihydroxyflavone, a TrkB receptor agonist, blocks long‐term spatial memory impairment caused by immobilization stress in rats
Authors: Andero Raül , Daviu Núria , Escorihuela Rosa Maria , Nadal Roser , Armario Antonio
Published: December 2010

Post‐traumatic stress disorder (PTSD) patients show cognitive deficits, but it is unclear whether these are a consequence of the pathology or a pre‐existing factor of vulnerability to PTSD. Animal models may help to demonstrate whether or not exposure to certain stressors can actually induce long‐lasting (LL; days) impairment of hippocampus‐dependent memory tasks and to characterize neurobiological mechanisms. Adult male rats were exposed to 2‐h immobilization on boards (IMO), a severe stressor, and spatial learning in the Morris water maze (MWM) was studied days later. Exposure to IMO did not modify learning or short‐term memory in the MWM when learning started 3 or 9 days after IMO, but stressed rats did show impaired long‐term memory at both times, in accordance with the severity of the stressor. New treatments to prevent PTSD symptoms are needed. Thus, considering the potential protective role of brain‐derived neurotrophic factor (BDNF) on hippocampal function, 7,8‐dihydroxyflavone (7,8‐DHF), a recently characterized agonist of the BDNF receptor TrkB, was given before or after IMO in additional experiments. Again, exposure to IMO resulted in LL deficit in long‐term memory, and such impairment was prevented by the administration of 7,8‐DHF either 2 h prior IMO or 8 h after the termination of IMO. The finding that IMO‐induced impairment of spatial memory was prevented by pharmacological potentiation of TrkB pathway with 7,8‐DHF even when the drug was given 8 h after IMO suggests that IMO‐induced impairment is likely to be a LL process that is strongly dependent on the integrity of the BDNF‐TrkB system and is susceptible to poststress therapeutic interventions. 7,8‐DHF may represent a new therapeutic approach for early treatment of subjects who have suffered traumatic experiences. © 2010 Wiley Periodicals, Inc.
Update on extracorporeal photopheresis in heart and lung transplantation
Authors: Marques Marisa B. , Schwartz Joseph
Published: December 2010

Transplant rejection of solid organs remains a threat to thousands of patients despite modern immunosuppressive regimens. The currently available drugs are associated with severe complications such as hypertension, diabetes mellitus, renal failure, risk of infections, and malignancies among many others and, often enough, still allow episodes of rejection. New and less‐toxic immunologic measures are desperately needed to accomplish the desired tolerance to the transplant without the undesirable side effects. Extracorporeal photopheresis (ECP) has been shown to benefit especially patients with cardiac transplants, but also those who received lung allografts. ECP likely modulates the recipient's antigen‐specific immune responses and inflammation in transplantation by in vivo generation of apoptotic leukocytes. This review will highlight the need for ECP, how it is thought to act, and the published evidence for its role in cardiac and pulmonary transplantation. J. Clin. Apheresis, 2011. © 2010 Wiley‐Liss, Inc.
Oncogenic role of RUNX3 in head and neck cancer
Authors: Kudo Yasusei , Tsunematsu Takaaki , Takata Takashi
Published: December 2010

Cumulative evidences show that Runt‐related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor‐β (TGF‐β)‐induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer. J. Cell. Biochem. 112: 387–393, 2011. © 2010 Wiley‐Liss, Inc.
Inducible expression of Runx2 results in multiorgan abnormalities in mice
Authors: He Nan , Xiao Zhousheng , Yin Tong , Stubbs Jason , Li Linheng , Quarles L. Darryl
Published: December 2010

Runx2 is a transcription factor controlling skeletal development, and is also expressed in extraskeletal tissues where its function is not well understood. Existing Runx2 mutant and transgenic mouse models do not allow the necessary control of Runx2 expression to understand its functions in different tissues. We generated conditional, doxycyline‐inducible, triple transgenic mice (CMV‐Cre;ROSA26‐neoflox/+‐rtTA;Tet‐O‐Runx2) to investigate the effects of wide spread overexpression of Runx2. Osteoblasts isolated from CMV‐Cre;ROSA26‐neoflox/+‐rtTA; Tet‐O‐Runx2 mice demonstrated a dose‐dependent effect of doxycycline to stimulate Runx2 transgene expression. Doxycycline administration to CMV‐Cre;ROSA26‐neoflox/+‐rtTA;Tet‐O‐Runx2 mice induced Runx2 transgene expression in all tissues tested, with the highest levels observed in kidney, ovary, and bone. Runx2 overexpression resulted in deceased body size and reduced viability. With regard to bone, Runx2 overexpressing mice paradoxically displayed profound osteopenia and diminished osteogenesis. Induced expression of Runx2 in extraskeletal tissues resulted in ectopic calcification and induction of the osteogenic program in a limited number of tissues, including lung and muscle. In addition, the triple transgenic mice showed evidence of a myeloproliferative disorder and an apparent inhibition of lymphocyte development. Thus, overexpression of Runx2 both within and outside of the skeleton can have diverse biological effects. Use of tissue specific Cre mice will allow this model to be used to conditionally and inducibly overexpress Runx2 in different tissues and provide a means to study the post‐natal tissue‐ and cell context‐dependent functions of Runx2. J. Cell. Biochem. 112: 653–665, 2011. © 2010 Wiley‐Liss, Inc.
Loss of runt‐related transcription factor 3 causes development and progression of hepatocellular carcinoma
Authors: Shiraha Hidenori , Nishina Shin‐ichi , Yamamoto Kazuhide
Published: December 2010

Runt‐related transcription factor 3 (RUNX3) is reported as a tumor suppressor gene for gastric cancer, and may be important in the development of hepatocellular carcinoma (HCC). RUNX3 expression is frequently lost or decreased by hemizygous deletion or hypermethylation of its promoter lesion in HCC. The significance of decreased expression of RUNX3 in HCC has not been fully elucidated, but is likely related to dysfunction of cell cycle regulation, decrement of apoptosis, enhancement of angiogenesis, and development of epithelial–mesenchymal transition. RUNX3 is a promising candidate as a tumor suppressor gene for HCC. J. Cell. Biochem. 112: 745–749, 2011. © 2010 Wiley‐Liss, Inc.
Molecular mechanisms that produce secondary MDS/AML by RUNX1/AML1 point mutations
Authors: Harada Yuka , Harada Hironori
Published: December 2010

RUNX1/AML1 point mutations have been identified in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. A heterozygous germline mutation of the RUNX1 gene causes a familial platelet disorder with a predisposition to AML. RUNX1 mutations have also been detected with high frequency in minimally differentiated AML M0 subtypes and myelodysplastic/myeloproliferative neoplasms. Here we propose a new disease category of myelodysplastic neoplasms (MDN) consisting of MDS refractory anemia with excess blasts and AML with myelodysplasia‐related changes, including therapy‐related cases. RUNX1 mutations have been detected in about 20% of patients with “MDN”. Among the MDN cases, histories of radiation exposure, therapy‐related myeloid neoplasms after successful treatment for acute promyelocytic leukemia, and leukemic transformation of myeloproliferative neoplasms have been reported to have a strong association with RUNX1 mutations. The mutations occur in a normal, a receptive, or a disease‐committed hematopoietic stem cell. It is suspected that the “MDN” phenotypes are defined by the RUNX1 mutations in addition to some other abnormalities. J. Cell. Biochem. 112: 425–432, 2011. © 2010 Wiley‐Liss, Inc.
An autonomous BMP2 regulatory element in mesenchymal cells
Authors: Kruithof Boudewijn P.T. , Fritz David T. , Liu Yijun , Garsetti Diane E. , Frank David B. , Pregizer Steven K. , Gaussin Vinciane , Mortlock Douglas P. , Rogers Melissa B.
Published: December 2010

BMP2 is a morphogen that controls mesenchymal cell differentiation and behavior. For example, BMP2 concentration controls the differentiation of mesenchymal precursors into myocytes, adipocytes, chondrocytes, and osteoblasts. Sequences within the 3′untranslated region (UTR) of the Bmp2 mRNA mediate a post‐transcriptional block of protein synthesis. Interaction of cell and developmental stage‐specific trans‐regulatory factors with the 3′UTR is a nimble and versatile mechanism for modulating this potent morphogen in different cell types. We show here, that an ultra‐conserved sequence in the 3′UTR functions independently of promoter, coding region, and 3′UTR context in primary and immortalized tissue culture cells and in transgenic mice. Our findings indicate that the ultra‐conserved sequence is an autonomously functioning post‐transcriptional element that may be used to modulate the level of BMP2 and other proteins while retaining tissue specific regulatory elements. J. Cell. Biochem. 112: 666–674, 2011. © 2010 Wiley‐Liss, Inc.
Inhibition of HSP90‐dependent telomerase activity in amyloid β‐induced apoptosis of cerebral endothelial cells
Authors: Chiu Wen‐Ta , Shen Shing‐Chuan , Yang Liang‐Yo , Chow Jyh‐Ming , Wu Chin‐Yen , Chen Yen‐Chou
Published: December 2010

Although apoptosis induced by amyloid β (Aβ) has been identified, the effect of Aβ on telomerase activity in relation to apoptosis induction remains unclear. In the present study, Aβ1–40 and Aβ25–35, but not Aβ1–16 and Aβ35–25, reduce the viability of primary cerebral endothelial cells (CECs) in accordance with apoptosis induction. Increases in caspase 3 and PARP protein cleavage with reductions of the Bcl‐2/Bax protein ratio accompanied by a loss in the mitochondria membrane potential were identified in Aβ1–40 and Aβ25–35‐treated CECs. A significant decrease in intracellular telomerase activity by Aβ1–40 and Aβ25–35 was detected; meanwhile, reduced telomerase activity by telomerase reverse transcriptase (TERT) siRNA enhanced the cytotoxic effect of Aβ. The addition of serum might block the Aβ25–35‐induced cytotoxic effect via elevated telomerase activity in according with stimulating phospho‐AKT protein expression, which was blocked by adding AKT inhibitor LY294002. Decreases in heat shock protein 90 (HSP90) and its client proteins including TERT, AKT, p53, CDK4 were observed in Aβ1–40 and Aβ25–35, but not Aβ1–16 and Aβ35–25, ‐treated CECs. The knockdown of HSP90 gene expression by HSP90 siRNA significantly inhibits telomerase activity with decreasing TERT protein expression. The application of HSP90 activity inhibitor geldanamycin (GA) and radicicol (RD) potentiates the telomerase inhibition and apoptosis induction of Aβ in CECs. An increase in protein ubiquitination by Aβ25–35, but not Aβ35–25, treatment was examined, and Aβ‐inhibited HSP90 and TERT protein expression and telomerase activity was reversed by adding proteasome inhibitor, MG132. Additionally, increased TERT protein ubiquitination by Aβ25–35 was detected in CECs via immunoprecipitation/Western blotting analysis. The data of the present study firstly demonstrates that telomerase inhibition contributes to the apoptosis induction of Aβ in CECs. J. Cell. Physiol. 226: 2041–2051, 2011. © 2010 Wiley‐Liss, Inc.
Role of bone marrow‐derived progenitor cells in the maintenance and regeneration of dental mesenchymal tissues
Authors: Zhou Jing , Shi Songtao , Shi Yuanyuan , Xie Han , Chen Lei , He Yong , Guo Weihua , Wen Lingying , Jin Yan
Published: December 2010

While dental mesenchymal stem cells are well‐studied, the origin of these cells is still unclear. Bone marrow‐derived cells (BMDCs) have the potential to engraft into several tissues after injury, but whether they can become dental tissue‐specific progenitor cells under normal conditions and the relationship of these cells to the tissue‐resident cells are unknown. Thus, we transplanted green fluorescent protein (GFP)‐labeled BMDCs into irradiated wild‐type mice. We found that the engraftment of BMDCs participated in the regeneration and differentiated into periodontal specific cells after injury. Under normal conditions, there were more BMDCs engrafting into the dental mesenchymal tissue than other organs, in which the expression of stromal cell‐derived factor‐1 (SDF‐1) was significantly higher than in other organs, and the engraftment of cells increased with time. A small fraction of GFP+ cells maintained the mesenchymal stem cell phenotype positive for CD105, CD106, and CD90, which were significantly less than the tissue‐resident stem cells; meanwhile, GFP+/CD45+ cells were rare. Isolation and characterization of the dental pulp cells showed that the number of GFP+/Ki67+ cells were greater than the GFP−/Ki67+ cells. In addition, some GFP+ cells differentiated into the dental‐specific cells and expressed dental‐specific proteins, and can be found in the odontoblast layer after implantation of the apical bud. In conclusion, these data suggest that bone marrow progenitor cells communicate with dental tissues and become tissue‐specific mesenchymal progenitor cells to maintain tissue homeostasis. J. Cell. Physiol. 226: 2081–2090, 2011. © 2010 Wiley‐Liss, Inc.
VEGF inhibitor (Iressa) arrests histone deacetylase expression: Single‐cell cotransfection imaging cytometry for multi‐target‐multi‐drug analysis
Authors: Tak Yu Kyung , Naoghare Pravin K. , Han Eunyoung , Song Joon Myong
Published: December 2010

Multi‐target‐multi‐drug approaches are needed to accelerate the process of drug discovery screening and to design efficient therapeutic strategies against diseases that involve alterations in multiple cellular targets. Herein we report single‐cell cotransfection imaging cytometry to quantitatively screen drug‐induced off‐target effects. Vascular endothelial growth factor (VEGF) and histone deacetylase (HDAC) genes amplified from the genomic DNA were cloned in fluorescently tagged gene constructs (RFP‐HDAC/YFP‐VEGF). These gene constructs were cotransfected in HEK‐293 cells to explore the possibility of off‐target effects of 4‐phenylbutyrate and Iressa on the expression of VEGF and HDAC through single‐cell imaging cytometry. Iressa (10 µM) treatment at the time of cotransfection or 48 h after cotransfection of RFP‐HDAC/YFP‐VEGF plasmids in HEK‐293 cells resulted in off‐target effects on HDAC expression. These results suggest possible applications of Iressa in the treatment of diseases in which expression of both HDAC and VEGF should be inhibited. 4‐Phenylbutyrate (2.0 mM) did not show any off‐target effects on VEGF expression. The developed quantitative multicolor live single‐cell cotransfection imaging can be employed to select better drug combinations for faster screening and greater accuracy in multi‐target‐multi‐drug analysis by increasing the on‐target/desired off‐target effects and eliminating the undesirable off‐target effects. J. Cell. Physiol. 226: 2115–2122, 2011. © 2010 Wiley‐Liss, Inc.
HMGB‐1 induces IL‐6 production in human synovial fibroblasts through c‐Src, Akt and NF‐κB pathways
Authors: Hou Chun‐Han , Fong Yi‐Chin , Tang Chih‐Hsin
Published: December 2010

High mobility group box chromosomal protein 1 (HMGB‐1) is a widely studied, ubiquitous nuclear protein that is present in eukaryotic cells, and plays a crucial role in inflammatory response. However, the effects of HMGB‐1 on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in HMGB‐1‐induced IL‐6 production in human synovial fibroblast cells. HMGB‐1 caused concentration‐ and time‐dependent increases in IL‐6 production. HMGB‐1‐mediated IL‐6 production was attenuated by receptor for advanced glycation end products (RAGE) monoclonal antibody (Ab) or siRNA. Pretreatment with c‐Src inhibitor (PP2), Akt inhibitor and NF‐κB inhibitor (pyrrolidine dithiocarbamate and L‐1‐tosylamido‐2‐phenylenylethyl chloromethyl ketone) also inhibited the potentiating action of HMGB‐1. Stimulation of cells with HMGB‐1 increased the c‐Src and Akt phosphorylation. HMGB‐1 increased the accumulation of p‐p65 in the nucleus, as well as NF‐κB luciferase activity. HMGB‐1‐mediated increase of NF‐κB luciferase activity was inhibited by RAGE Ab, PP2 and Akt inhibitor or RAGE siRNA, or c‐Src and Akt mutant. Our results suggest that HMGB‐1‐increased IL‐6 production in human synovial fibroblasts via the RAGE receptor, c‐Src, Akt, p65, and NF‐κB signaling pathways. J. Cell. Physiol. 226: 2006–2015, 2011. © 2010 Wiley‐Liss, Inc.
Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells
Authors: De Luca Antonella , Gallo Marianna , Aldinucci Donatella , Ribatti Domenico , Lamura Luana , D'Alessio Amelia , De Filippi Rosaria , Pinto Antonio , Normanno Nicola
Published: December 2010

Increasing evidence suggests that bone marrow‐derived mesenchymal stem cells (MSCs) are recruited into the stroma of developing tumors where they contribute to cancer progression. MSCs produce different growth factors that sustain tumor‐associated neo‐angiogenesis. Since the majority of carcinomas secrete ligands of the epidermal growth factor receptor (EGFR), we assessed the role of EGFR signaling in regulating the release of angiogenic factors in MSCs. Treatment of human primary MSCs and of the human osteoblastic cell line hFOB with transforming growth factor α (TGF‐α), one of the main ligands of the EGFR, significantly induced activation of this receptor and of different intracellular signaling proteins, including the PI3K/AKT and the MEK/MAPK pathways. TGF‐α induced a significant increase in the levels of secretion of vascular endothelial growth factor in both MSCs and hFOB. Conditioned medium from TGF‐α treated MSCs showed an higher in vivo angiogenic effect as compared with medium from untreated cells. Treatment of MSCs with TGF‐α also produced a significant increase in the secretion of other angiogenic growth factors such as angiopoietin‐2, granulocyte‐colony stimulating factor, hepatocyte growth factor, interleukin (IL)‐6, IL‐8, and platelet‐derived growth factor‐BB. Using selective MEK and PI3K inhibitors, we found that both MEK/MAPK and the PI3K/AKT signaling pathways mediate the ability of TGF‐α to induce secretion of angiogenic factors in MSCs. Finally, stimulation with TGF‐α increased the ability of MSCs to induce migration of MCF‐7 breast cancer cells. These data suggest that EGFR signaling regulates the ability of MSCs to sustain cancer progression through the release of growth factors that promote neo‐angiogenesis and tumor cell migration. J. Cell. Physiol. 226: 2131–2138, 2011. © 2010 Wiley‐Liss, Inc.
Osteopontin controls endothelial cell migration in vitro and in excised human valvular tissue from patients with calcific aortic stenosis and controls
Authors: Poggio Paolo , Grau Juan B. , Field Benjamin C. , Sainger Rachana , Seefried William F. , Rizzolio Flavio , Ferrari Giovanni
Published: December 2010

Calcific aortic stenosis (CAS) is a pathological condition of the aortic valve characterized by dystrophic calcification of the valve leaflets. Despite the high prevalence and mortality associated with CAS, little is known about its pathogenetic mechanisms. Characterized by progressive dystrophic calcification of the valve leaflets, the early stages of aortic valve degeneration are similar to the active inflammatory process of atherosclerosis including endothelial disruption, inflammatory cell infiltration, lipid deposition, neo‐vascularization and calcification. In the vascular system, the endothelium is an important regulator of physiological and pathological conditions; however, the contribution of endothelial dysfunction to valvular degeneration at the cellular and molecular level has received little attention. Endothelial cell (EC) activation and neo‐vascularization of the cusps characterizes all stages of aortic valvular degeneration from aortic sclerosis to aortic stenosis. Here we reported the role of osteopontin (OPN) in the regulation of EC activation in vitro and in excised tissue from CAS patients and controls. OPN is an important pro‐angiogenic factor in several pathologies. High levels of OPN have been demonstrated in both tissue and plasma of patients with aortic valve sclerosis and stenosis. The characterization of valvular ECs as a cellular target for OPN will help us uncover the pathogenesis of aortic valve degeneration and stenosis, opening new perspectives for the prevention and therapy of this prevalent disease. J. Cell. Physiol. 226: 2139–2149, 2011. © 2010 Wiley‐Liss, Inc.
A dominant mutation etiologic for human tricho‐dento‐osseous syndrome impairs the ability of DLX3 to downregulate ΔNp63α
Authors: Di Costanzo Antonella , Festa Luisa , Roscigno Giuseppina , Vivo Maria , Pollice Alessandra , Morasso Maria , La Mantia Girolama , Calabrò Viola
Published: December 2010

The homeodomain transcription factors play crucial roles in many developmental processes ranging from organization of the body plan to differentiation of individual tissues. The homeodomain protein Distal‐less‐3 (DLX3) has an essential role in epidermal stratification and development of ectodermal appendages, placenta and bones. A four‐nucleotide deletion in the human DLX3 gene is etiologic for the human hereditary tricho‐dento‐osseous (TDO) ectodermal dysplasia, a dominant syndrome characterized by abnormalities in hair, nails, teeth, and bones. We have previously demonstrated that DLX3 gene expression induces degradation of ΔNp63α, a specific product of the TP63 gene, a master regulator of multi‐layered epithelia. Here we show that the DLX3TDO mutant protein is unable to promote ΔNp63α protein degradation and impairs the expression of cell cycle regulatory proteins and skin differentiation markers. However, we found that in cell expressing equal amounts of mutant and wild‐type DLX3, ΔNp63α protein level is efficiently regulated implying that genetic heterozygosity at the DLX3 locus protects TDO patients from developing severe p63‐associated skin defects. J. Cell. Physiol. 226: 2189–2197, 2011. © 2010 Wiley‐Liss, Inc.
Adipogenic differentiation of human mesenchymal stromal cells is down‐regulated by microRNA‐369‐5p and up‐regulated by microRNA‐371
Authors: Bork Simone , Horn Patrick , Castoldi Mirco , Hellwig Isabelle , Ho Anthony D. , Wagner Wolfgang
Published: December 2010

Long‐term culture of human mesenchymal stromal cells (MSC) has implications on their proliferation and differentiation potential and we have demonstrated that this is associated with up‐regulation of the five microRNAs miR‐29c, miR‐369‐5p, miR‐371, miR‐499, and let‐7f. In this study, we examined the role of these senescence‐associated microRNAs for cellular aging and differentiation of MSC. Proliferation was reduced upon transfection with miR‐369‐5p, miR‐371, and miR‐499. Adipogenic differentiation was impaired by miR‐369‐5p whereas it was highly increased by miR‐371. This was accompanied by respective gene expression changes of some adipogenic key molecules (adiponectin and fatty acid‐binding protein 4 [FABP4]). Furthermore luciferase reporter assay indicated that FABP4 is a direct target of miR‐369‐5p. Microarray analysis upon adipogenic or osteogenic differentiation revealed down‐regulation of several microRNAs albeit miR‐369‐5p and miR‐371 were not affected. Expression of the de novo DNA methyltransferases DNMT3A and DNMT3B was up‐regulated by transfection of miR‐371 whereas expression of DNMT3A was down‐regulated by miR‐369‐5p. In summary, we identified miR‐369‐5p and miR‐371 as antagonistic up‐stream regulators of adipogenic differentiation and this might be indirectly mediated by epigenetic modifications. J. Cell. Physiol. 226: 2226–2234, 2011. © 2010 Wiley‐Liss, Inc.
The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts
Authors: Kemi Ole J. , Hoydal Morten A. , MacQuaide Niall , Haram Per M. , Koch Lauren G. , Britton Steven L. , Ellingsen Oyvind , Smith Godfrey L. , Wisloff Ulrik
Published: December 2010

The response of transverse (T)‐tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T‐tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (P < 0.01), with preserved T‐tubule density. Thus, the T‐tubules adapted to the physiologic hypertrophy. Next, we studied T‐tubules in a rat model of metabolic syndrome with pressure overload‐induced concentric left ventricle hypertrophy, evidenced by 15% (P < 0.01) increased cardiomyocyte size. These rats had only 85% (P < 0.01) of the T‐tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (P < 0.01); half to that in control rats, but the T‐tubule density remained unchanged. Finally, post‐myocardial infarction heart failure induced severe cardiac pathology, with a 70% (P < 0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (P < 0.01) reduced T‐tubule density. Exercise training reversed 50% (P < 0.01) of the pathologic hypertrophy, whereas the T‐tubule density increased by 40% (P < 0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (P < 0.01). Physiologic hypertrophy associated with conserved T‐tubule spacing (∼1.8–1.9 µm), whereas in pathologic hypertrophy, T‐tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T‐tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T‐tubules; exercise training reverses the remodeling and partly corrects the T‐tubule density. J. Cell. Physiol. 226: 2235–2243, 2011. © 2010 Wiley‐Liss, Inc.