bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression
Authors: Keasey Matthew P , Kang Seong Su , Lovins Chiharu , Hagg Theo
Published: May 2013

Background

Ciliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Here, we defined an inhibitory integrin signaling pathway.

Results

The integrin substrates laminin, fibronectin and vitronectin, but not collagen, thrombospondin or fibrinogen, reduced CNTF expression in C6 astroglioma cells. Antibodies against αv and β5, but not α6 or β1, integrin induced CNTF. Together, the ligand and antibody specificity suggests that CNTF is repressed by αvβ5 integrin. Antibodies against Thy1, an abundant neuronal surface protein whose function is unclear, induced CNTF in neuron-astrocyte co-cultures indicating that it is a neuroglial CNTF repressor. Inhibition of the integrin signaling molecule Focal Adhesion Kinase (FAK) or the downstream c-Jun N-terminal kinase (JNK), but not extracellular regulated kinase (ERK) or p38 MAPK, greatly induced CNTF mRNA and protein expression within 4 hours. This selective inhibitory pathway phosphorylated STAT3 on its inhibitory ser-727 residue interfering with activity of the pro-transcription Tyr-705 residue. STAT3 can activate CNTF transcription because it bound to its promoter and FAK antagonist-induced CNTF was reduced by blocking STAT3. Microinjection of FAK inhibitor directly into the brain or spinal cord in adult mice rapidly induced CNTF mRNA and protein expression. Importantly, systemic treatment with FAK inhibitors over 3 days induced CNTF in the subventricular zone and increased neurogenesis.

Conclusions

Neuron-astroglia contact mediated by integrins serves as a sensor to enable rapid neurotrophic responses and provides a new pharmacological avenue to exploit the neuroprotective properties of endogenous CNTF.
Reduced graphene oxide aerogel with high-rate supercapacitive performance in aqueous electrolytes
Authors: Si Weijiang , Wu Xiaozhong , Zhou Jin , Guo Feifei , Zhuo Shuping , Cui Hongyou , Xing Wei
Published: May 2013

Reduced graphene oxide aerogel (RGOA) is synthesized successfully through a simultaneous self-assembly and reduction process using hypophosphorous acid and I2 as reductant. Nitrogen sorption analysis shows that the Brunauer-Emmett-Teller surface area of RGOA could reach as high as 830 m2 g−1, which is the largest value ever reported for graphene-based aerogels obtained through the simultaneous self-assembly and reduction strategy. The as-prepared RGOA is characterized by a variety of means such as scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. Electrochemical tests show that RGOA exhibits a high-rate supercapacitive performance in aqueous electrolytes. The specific capacitance of RGOA is calculated to be 211.8 and 278.6 F g−1 in KOH and H2SO4 electrolytes, respectively. The perfect supercapacitive performance of RGOA is ascribed to its three-dimensional structure and the existence of oxygen-containing groups.
A diagnostic window for the treatment of acute graft-versus-host disease prior to visible clinical symptoms in a murine model
Authors: Bäuerlein Carina A , Riedel Simone S , Baker Jeanette , Brede Christian , Garrote Ana-Laura Jordán , Chopra Martin , Ritz Miriam , Beilhack Georg F , Schulz Stephan , Zeiser Robert , Schlegel Paul G , Einsele Hermann , Negrin Robert S , Beilhack Andreas
Published: May 2013

Background

Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.

Methods

Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.

Results

We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.

Conclusions

Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
Comparative pathogenesis of type 1 (European genotype) and type 2 (North American genotype) porcine reproductive and respiratory syndrome virus in infected boar
Authors: Han Kiwon , Seo Hwi Won , Park Changhoon , Oh Yeonsu , Kang Ikjae , Chae Chanhee
Published: May 2013

Background

Porcine reproductive and respiratory syndrome virus (PRRSV) now has two main genotypes, genotype 1 (European) and genotype 2 (North American). There is a lack of data on the comparison of pathogenicity of the two genotypes in boars. The objectives of the present study were to evaluate the amount of PRRSV present in semen over time and compare the viral distribution and microscopic lesions of type 1 and type 2 PRRSV-infected boars.

Methods

Twenty-four 8-month-old PRRSV-naïve Duroc boars were randomly allocated to 3 treatment groups. The boars in groups 1 (n = 9) and 2 (n = 9) were intranasally inoculated with type 1 or type 2 PRRSV, respectively. The boars in groups 1 (n = 6) served as negative controls. Semen and blood samples were collected up to 35 days post-inoculation (dpi), and necropsies were performed on 14, 21, and 35 dpi.

Results

There were no significant differences in the genomic copy number of PRRSV, microscopic testicular lesion score, number of PRRSV-positive germ cells, or number of apoptotic cells between the type 1 and type 2 PRRSV-infected boars throughout the experiment. Histopathological changes were manifested by the desquamation of spermatocytes and the presence of multinucleated giant cells in seminiferous tubules of both type 1 and type 2 PRRSV-infected boars. The distribution of PRRSV-positive cells was focal; the virus was found in single germ cells or small clusters of germ cells, localized to the spermatogonia, spermatocytes, spermatids, and non-sperm cells in type 1 and type 2 PRRSV-infected boars.

Conclusions

The results of this study demonstrated that two genotypes of PRRSV do not have significantly different virulence toward the male reproductive system of pigs.
Lack of SF3B1 R625 mutations in cutaneous melanoma
Authors: Schilling Bastian , Bielefeld Nicola , Sucker Antje , Hillen Uwe , Zimmer Lisa , Schadendorf Dirk , Zeschnigk Michael , Griewank Klaus G
Published: May 2013

Background

Melanoma is a deadly disease affecting people worldwide. Genetic studies have identified different melanoma subtypes characterized by specific recurrently mutated genes and led to the successful clinical introduction of targeted therapies. Hotspot mutations in SF3B1 were recently reported in uveal melanoma. Our aim was to see if these mutations also occur in cutaneous melanoma.

Findings

We analyzed a cohort of 85 cutaneous melanoma including 22 superficial spreading, 24 acral-lentiginous, 36 nodular, and 3 lentigo-maligna melanomas. Exon 14 of SF3B1, containing the site of recurrent mutations described in uveal melanoma, was sequenced in all samples. Additionally, NRAS exon 1 and 2 and BRAF exon 15 were sequenced in all, KIT exons 9, 11, 13, 17, and 18 in 30 samples. High numbers of BRAF and NRAS mutations were identified with frequencies varying according to melanoma subtype. None of the samples were found to harbor a SF3B1 mutation.

Conclusions

We conclude that recurrent mutations in codon 625 of SF3B1 as reported in uveal melanoma are not present in most types of cutaneous melanoma. This highlights the genetic differences between cutaneous and uveal melanoma and the need for subtype specific therapeutic approaches.
Vocal cord paralysis secondary to spontaneous internal carotid dissection: Case report and systematic review of the literature
Authors: Nguyen TT Jean , Zhang Han , Dziegielewski Peter T , Seemann Robert
Published: May 2013

Objectives

To present a rare case of unilateral vocal cord paralysis (VCP) secondary to spontaneous internal carotid artery dissection and to perform a literature review.

Case report

A 35-year-old male presented to the emergency department with acute onset hoarseness and dysphagia. History, physical exam and laryngoscopy revealed left sided VCP without obvious cause. Magnetic Resonance Imaging (MRI) demonstrated a left internal carotid artery dissection of unknown etiology. Neurovascular surgery was consulted and treatment with aspirin was initiated. The dysphagia and hoarseness resolved in 12 weeks with long-term neurosurgery follow-up as the management plan.

Methods

Systematic literature review was conducted by 3 independent reviewers. Since 1988 only 9 cases of VCP due to internal carotid artery dissection have been reported. These were reviewed for: demographics, diagnostic method, treatment and vocal cord function.

Results

7 patients had unilateral while 2 had bilateral VCP. MRI was used for diagnosis in 7 cases and 5 cases utilized a type of angiography. All received antithrombotic treatment with 5 out of the 9 patients experiencing vocal cord recovery in an average of 7.2 weeks.

Conclusion

MRI is crucial in the work-up of idiopathic VCP. If an ipsilateral internal carotid artery dissection is found, antithrombotic treatment is initiated with an expectation that vocal cord mobility is likely to return.
Defining publication bias: protocol for a systematic review of highly cited articles and proposal for a new framework
Authors: Müller Katharina Felicitas , Briel Matthias , D’Amario Alexandra , Kleijnen Jos , Marusic Ana , Wager Elizabeth , Antes Gerd , von Elm Erik , Lang Britta , Motschall Edith , Gloy Viktoria , Schwarzer Guido , Altman Doug , Meerpohl Joerg J , Bassler Dirk
Published: May 2013

Background

Selective publication of studies, which is commonly called publication bias, is widely recognized. Over the years a new nomenclature for other types of bias related to non-publication or distortion related to the dissemination of research findings has been developed. However, several of these different biases are often still summarized by the term 'publication bias'.

Methods/Design

As part of the OPEN Project (To Overcome failure to Publish nEgative fiNdings) we will conduct a systematic review with the following objectives:

- To systematically review highly cited articles that focus on non-publication of studies and to present the various definitions of biases related to the dissemination of research findings contained in the articles identified.

- To develop and discuss a new framework on nomenclature of various aspects of distortion in the dissemination process that leads to public availability of research findings in an international group of experts in the context of the OPEN Project.

We will systematically search Web of Knowledge for highly cited articles that provide a definition of biases related to the dissemination of research findings. A specifically designed data extraction form will be developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article.

For the development of a new framework we will construct an initial table listing different levels and different hazards en route to making research findings public. An international group of experts will iteratively review the table and reflect on its content until no new insights emerge and consensus has been reached.

Discussion

Results are expected to be publicly available in mid-2013. This systematic review together with the results of other systematic reviews of the OPEN project will serve as a basis for the development of future policies and guidelines regarding the assessment and prevention of publication bias.
Intranuclear inclusions in a fragile X mosaic male
Authors: Pretto Dalyir I , Hunsaker Michael R , Cunningham Christopher L , Greco Claudia M , Hagerman Randi J , Noctor Stephen C , Hall Deborah A , Hagerman Paul J , Tassone Flora
Published: May 2013

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels ofFMR1mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of anFMR1premutation (55–200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45–54 CGG repeats) as well as in a subject with a full mutation with mosaicism.

Here, we report on molecular and clinical data of a maleFMR1mosaic individual with full and premutation alleles. Molecular analysis ofFMR1and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of bothFMR1mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.

The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutationFMR1alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.
Treatment with CNX-011-67, a novel GPR40 agonist, delays onset and progression of diabetes and improves beta cell preservation and function in male ZDF rats
Authors: Gowda Nagesh , Dandu Anilkumar , Singh Jaideep , Biswas Sanghamitra , Raghav Vijaya , Lakshmi Mudigere N , Shilpa Pavagada C , Sunil Venkategowda , Reddy Ashokkumar , Sadasivuni Manojkumar , Aparna Kumaraswamy , Verma Mahesh Kumar , Moolemath Yoganand , Anup Mammen O , Venkataranganna Marikunte V , Somesh Baggavalli P , Jagannath Madanahalli R
Published: May 2013

Background

The role of G protein-coupled receptor (GPR40), which is highly expressed in pancreatic beta cells, has been studied extensively in the amelioration of beta cell dysfunction in T2D using rat and mouse islets, beta cell lines and in animal models of diabetes. But its potential as a therapeutic target has not been fully explored. This aim of the study is to evaluate the therapeutic potential of CNX-011-67, a highly selective, potent and orally bioavailable GPR40 agonist, in controlling diabetes and other metabolic parameters.

Methods

Seven week old male ZDF rats were treated with either vehicle or CNX-011-67, 5 mg/kg twice daily, for seven weeks. The animals were subjected to oral glucose tolerance and insulin tolerance tests. Plasma glucose, insulin, triglyceride, HbA1c, fructosamine and free fatty acids were measured at selected time points. Pancreas from control and treated animals were subjected to insulin and pancreatic and duodenal homeobox 1 (PDX1) immunohistochemistry and were also evaluated by electron microscopy. Also the potential impact of CNX-011-67 on islet insulin secretion, content, ATP levels and markers of both glucose oxidation, beta cell health in rat islets under chronic glucolipotoxic conditions was evaluated.

Results

Treatment of male ZDF rats with CNX-011-67 for 7 weeks significantly enhanced insulin secretion in response to oral glucose load, delayed the onset of fasting hyperglycemia by 3 weeks, reduced nonfasting glucose excursions, fasting free fatty acids and triglyceride levels. A significant increase in PDX1 expression and insulin content and reduction in plasma fructosamine, HOMA-IR, and beta cell apoptosis were observed. CNX-011-67 improves glucose mediated insulin secretion, insulin gene transcription and islet insulin content in cultured rat islets under chronic glucolipotoxic condition. Also enhanced glucose oxidation in the form of increased islet ATP content and overall improvement in beta cell health in the form of reduced expression of stress markers (TXNIP and CHOP mRNA) were observed.

Conclusions

These findings, suggest that long-term oral therapy with CNX-011-67 could be of clinical value to provide good glycemic control and improve islet beta cell function.
CD70–CD27 ligation between neural stem cells and CD4+ T cells induces Fas–FasL-mediated T-cell death
Authors: Lee Eun Mi , Hurh Sunghoon , Cho Bumrae , Oh Kook-Hwan , Kim Seung U , Surh Charles D , Sprent Jonathan , Yang Jaeseok , Kim Jae Young , Ahn Curie
Published: May 2013

Introduction

Neural stem cells (NSCs) are among the most promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. One of the remaining obstacles for NSC therapy is to overcome the alloimmune response on NSCs by the host.

Methods

To investigate the mechanisms of immune modulatory function derived from the interaction of human NSCs with allogeneic T cells, we examined the immune regulatory effects of human NSCs on allogeneic T cells in vitro.

Results

Significantly, NSCs induced apoptosis of allogeneic T cells, in particular CD4+ T cells. Interaction of CD70 on NSCs and CD27 on CD4+ T cells mediated apoptosis of T cells. Thus, blocking CD70–CD27 interaction prevented NSC-mediated death of CD4+ T cells.

Conclusions

We present a rational explanation of NSC-induced immune escape in two consecutive stages. First, CD70 constitutively expressed on NSCs engaged CD27 on CD4+ T cells, which induced Fas ligand expression on CD4+ T cells. Second, CD4+ T-cell apoptosis was followed by Fas–Fas ligand interaction in the CD4+ T cells.
Methylphenidate and/or a Nursing Telephone Intervention for Fatigue in Patients With Advanced Cancer: A Randomized, Placebo-Controlled, Phase II Trial
Authors: Bruera Eduardo , Yennurajalingam Sriram , Palmer J. Lynn , Perez-Cruz Pedro E. , Frisbee-Hume Susan , Allo Julio A. , Williams Janet L. , Cohen Marlene Z.
Published: May 2013

Purpose

Cancer-related-fatigue (CRF) is common in advanced cancer. The primary objective of the study was to compare the effects of methylphenidate (MP) with those of placebo (PL) on CRF as measured using the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) fatigue subscale. The effect of a combined intervention including MP plus a nursing telephone intervention (NTI) was also assessed.

Patients and Methods

Patients with advanced cancer with a fatigue score of ≥ 4 out of 10 on the Edmonton Symptom Assessment Scale (ESAS) were randomly assigned to one of the following four groups: MP+NTI, PL+NTI, MP + control telephone intervention (CTI), and PL+CTI. Methylphenidate dose was 5 mg every 2 hours as needed up to 20 mg per day. The primary end point was the median difference in FACIT-F fatigue at day 15. Secondary outcomes included anxiety, depression, and sleep.

Results

One hundred forty-one patients were evaluable. Median FACIT-F fatigue scores improved from baseline to day 15 in all groups: MP+NTI (median score, 4.5; P = .005), PL+NTI (median score, 8.0; P < .001), MP+CTI (median score, 7.0; P = .004), and PL+CTI (median score, 5.0; P = .03). However, there were no significant differences in the median improvement in FACIT-F fatigue between the MP and PL groups (5.5 v 6.0, respectively; P = .69) and among all four groups (P = .16). Fatigue (P < .001), nausea (P = .01), depression (P = .02), anxiety (P = .01), drowsiness (P < .001), appetite (P = .009), sleep (P < .001), and feeling of well-being (P < .001), as measured by the ESAS, significantly improved in patients who received NTI. Grade ≥ 3 adverse events did not differ between MP and PL (40 of 93 patients v 29 of 97 patients, respectively; P = .06).

Conclusion

MP and NTI alone or combined were not superior to placebo in improving CRF.
Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type K-RAS Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial
Authors: Siu Lillian L. , Shapiro Jeremy D. , Jonker Derek J. , Karapetis Chris S. , Zalcberg John R. , Simes John , Couture Felix , Moore Malcolm J. , Price Timothy J. , Siddiqui Jehan , Nott Louise M. , Charpentier Danielle , Liauw Winston , Sawyer Michael B. , Jefford Michael , Magoski Nadine M. , Haydon Andrew , Walters Ian , Ringash Jolie , Tu Dongsheng , O'Callaghan Chris J.
Published: May 2013

Purpose

The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity.

Patients and Methods

Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m2 intravenous loading dose followed by weekly maintenance of 250 mg/m2 plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS).

Results

A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively.

Conclusion

Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Bepler Gerold , Williams Charles , Schell Michael J. , Chen Wei , Zheng Zhong , Simon George , Gadgeel Shirish , Zhao Xiuhua , Schreiber Fred , Brahmer Julie , Chiappori Alberto , Tanvetyanon Tawee , Pinder-Schenck Mary , Gray Jhanelle , Haura Eric , Antonia Scott , Fischer Juergen R.
Published: May 2013

Purpose

We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Eligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS).

Results

Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months).

Conclusion

This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.
International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease
Authors: Terpos Evangelos , Morgan Gareth , Dimopoulos Meletios A. , Drake Matthew T. , Lentzsch Suzanne , Raje Noopur , Sezer Orhan , García-Sanz Ramón , Shimizu Kazuyuki , Turesson Ingemar , Reiman Tony , Jurczyszyn Artur , Merlini Giampaolo , Spencer Andrew , Leleu Xavier , Cavo Michele , Munshi Nikhil , Rajkumar S. Vincent , Durie Brian G.M. , Roodman G. David
Published: May 2013

Purpose

The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease.

Methodology

An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members.

Recommendations

Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.
Healthy human CSF promotes glial differentiation of hESC-derived neural cells while retaining spontaneous activity in existing neuronal networks
Authors: Kiiski Heikki , Äänismaa Riikka , Tenhunen Jyrki , Hagman Sanna , Ylä-Outinen Laura , Aho Antti , Yli-Hankala Arvi , Bendel Stepani , Skottman Heli , Narkilahti Susanna
Published: May 2013

The possibilities of human pluripotent stem cell-derived neural cells from the basic research tool to a treatment option in regenerative medicine have been well recognized. These cells also offer an interesting tool for in vitro models of neuronal networks to be used for drug screening and neurotoxicological studies and for patient/disease specific in vitro models. Here, as aiming to develop a reductionistic in vitro human neuronal network model, we tested whether human embryonic stem cell (hESC)-derived neural cells could be cultured in human cerebrospinal fluid (CSF) in order to better mimic the in vivo conditions. Our results showed that CSF altered the differentiation of hESC-derived neural cells towards glial cells at the expense of neuronal differentiation. The proliferation rate was reduced in CSF cultures. However, even though the use of CSF as the culture medium altered the glial vs. neuronal differentiation rate, the pre-existing spontaneous activity of the neuronal networks persisted throughout the study. These results suggest that it is possible to develop fully human cell and culture-based environments that can further be modified for various in vitro modeling purposes.
Isotope incorporation in broad-snouted caimans (crocodilians)
Authors: Caut Stephane
Published: May 2013

The trophic ecology and migration of vertebrate species have been increasingly studied using stable isotope analysis. However, this approach requires knowledge on how dietary isotopic values are reflected in consumers' tissues. To date, this information has only been obtained for a handful of ectotherms; in particular, little is known about crocodilians. In this study, diet-tissue discrimination factors (DTDFs) and carbon and nitrogen stable isotope turnover rates were estimated for plasma, red blood cells (RBCs), and muscle obtained from broad-snouted caimans (Caiman latirostris). Individuals were fed two different control diets for 189 days. DTDFs for δ15N (Δ15N) and δ13C (Δ13C) ranged from −2.24‰ to 0.39‰ and from −0.52‰ to 1.06‰, respectively. Isotope turnover rates in tissues, expressed as half-lives, ranged from 11 to 71 days, with plasma<muscle<RBCs. Δ15N was found to be particularly small, even when compared to values found for other ectotherms, a result that may be linked to the unique excretion physiology of crocodilians. These stable isotope incorporation data should help inform future interpretations of isotopic values obtained in the field for this taxon.
Raft endocytosis of autocrine motility factor regulates mitochondrial dynamics via rac1 signaling and the gp78 ubiquitin ligase
Authors: Shankar Jay , Kojic Liliana D. , St-Pierre Pascal , Wang Peter T. C. , Fu Min , Joshi Bharat , Nabi Ivan R.
Published: May 2013

Gp78 is a cell surface receptor that also functions as an E3 ubiquitin ligase in the endoplasmic reticulum-associated degradation (ERAD) pathway. The Gp78 ligand, the glycolytic enzyme phosphoglucose isomerase (also called autocrine motility factor or AMF), functions as a cytokine upon secretion by tumor cells. AMF is internalized via a PI3K- and dynamin-dependent raft endocytic pathway to the smooth endoplasmic reticulum (ER), however the relationship between AMF and Gp78 ubiquitin ligase activity remains unclear. AMF uptake to the smooth ER is inhibited by the dynamin inhibitor, dynasore, reduced in Gp78 knockdown cells and induces the dynamin-dependent downregulation of its cell surface receptor. AMF uptake is Rac1-dependent, inhibited by expression of dominant-negative Rac1 and the Rac1 inhibitor NSC23766, and therefore distinct from Cdc42 and RhoA-dependent raft endocytic pathways. AMF stimulates Rac1 activation, that is reduced by dynasore treatment and absent in Gp78-knockdown cells and therefore requires Gp78-mediated endocytosis. AMF also prevents Gp78-induced degradation of the mitochondrial fusion proteins, Mitofusin 1 and 2 in a dynamin, Rac1 and PI3K-dependent manner. Gp78 induces mitochondrial clustering and fission in a ubiquitin ligase-dependent manner that is also reversed by AMF. The raft-dependent endocytosis of AMF therefore promotes Rac1/PI3K signaling that feeds back to promote AMF endocytosis and also inhibits the ability of Gp78 to target the mitofusins for degradation, thereby preventing Gp78-dependent mitochondrial fission. Through regulation of an ER-localized ubiquitin ligase, the raft-dependent endocytosis of AMF represents an extracellular regulator of mitochondrial fusion and dynamics.
Anomalous Ligand Acceleration on Cinchona-modified Pd/C during Asymmetric Hydrogenation of Properly Substituted Phenylcinnamic Acid
Authors: Ogawa Hiroyuki , Mameda Takuya , Misaki Tomonori , Okamoto Yasuaki , Sugimura Takashi
Published: May 2013

The hydrogenation of 4,4′-dimethoxy-α-phenylcinnamic acid over Pd/C showed a large ligand acceleration effect when a cinchonidine modifier was used; the hydrogen rate increased to 370% relative to the reaction rate on unmodified Pd/C and resulted in a 91% enantiomeric excess (ee). Another good substrate, 4-fluoro-2′-methoxyphenylcinnamic acid, also resulted in a high ee value of 92%; however, the rate increased only to 230% when this modifier was used. On the basis of the difference in the degree to which the reaction rate was accelerated, the eemax for each substrate was analyzed.
1,4-Addition Reaction of 5H-Oxazol-4-ones to Allenic Esters and Ketones Catalyzed by Chiral Guanidines
Authors: Jin Nari , Misaki Tomonori , Sugimura Takashi
Published: May 2013

In this paper, a chiral guanidine-catalyzed 1,4-addition reaction of 5H-oxazol-4-ones to allenic esters and ketones is described. 5H-Oxazol-4-ones substituted with a 2-chlorophenyl group were suitable pronucleophiles that gave high enantioselectivities. Subsequent hydrolysis of the obtained adduct gave the corresponding γ-butenolide ester without loss of enantiopurity and was transformed into (+)-crobarbatic acid in a few steps.
1:1 Co-crystallisation of 1,2,4,5-benzenetetracarboxylic acid (LH4) with isomeric 2,2′-dipyridyldisulfide (2-PA) and 4,4′-dipyridyldisulfide (4-PA)
Authors: Arman Hadi D. , Tiekink Edward R. T.
Published: May 2013

The 1 : 1 co-crystallisation experiments conducted between 1,2,4,5-benzenetetracarboxylic acid, LH4, and each of 2,2′-dipyridyldisulfide (2-PA) and 4,4′-dipyridyldisulfide (4-PA) resulted in the formation of two salts of distinct formulation, i.e. [LH4]0.5[2-PAH][LH3] (1) and [LH2][4-PAH2] (2), respectively, indicating that proton transfer had occurred during crystallisation. In 1, a framework structure constructed by hydrogen bonded (O—H … O) LH4 and LH3
-0 species defines channels in which reside 2-PAH cations that feature syn geometries and intramolecular N—H … N hydrogen bonds. By contrast, in 2, direct N—H … N links between cations and anions lead to zigzag supramolecular chains.
Direct Methanol Fuel Cell – Alternative Materials and Catalyst Preparation
Authors: Mitzel Jens , Arena Francesco , Walter Tanja , Stefener Manfred , Hempelmann Rolf
Published: May 2013

The direct methanol fuel cell is the most interesting fuel cell for mobile applications. The state-of-the-art materials in a practical direct methanol fuel cell are Nafion 115 as membrane, carbon black as catalyst support and PtRu and Pt, respectively, as electrocatalyst. However, many materials were under investigation as alternatives to these materials in the last two decades. The most promising materials are reviewed in this paper. In addition, the catalyst preparation methods are summarized for chemical and electrochemical methods separately. Furthermore, a new electrodeposition technique with a gel-type electrolyte is highlighted. By the use of this method, the catalyst loading on the cathode side can be reduced by 25%.
Building Brands Together: Emergence and Outcomes of Co-Creation
Authors: Ind Nicholas , Iglesias Oriol , Schultz Majken
Published: May 2013

Co-creation is a rapidly emerging area of research. However, there is a lack of understanding as to how organizations use co-creation to build relationships and generate value. How does participation emerge and what outcomes does it deliver? To generate insight into the co-creation process, we created an online brand community. Our findings show that people participate in a community because it offers them the chance to find fulfillment, to express their creativity, and to socialize. The findings have significant implications for marketing, branding, and research professionals because the research shows that managers have to see participants as integral to the brand.
On the Scientific Status of the Conscious Capitalism Theory
Authors: Wang Chong
Published: May 2013

This note is a response to Rajendra Sisodia's commentary on my article on the topic of Conscious Capitalism (in this issue of California Management Review). First, it raises new concerns based on Sisodia's commentary and challenges the scientific status of the Conscious Capitalism theory. It focuses on refutability, consistency, and generality, as these three characteristics are essential features of any scientific theory. Second, it responds to Sisodia's various comments.
Wnt signalling in pituitary development and tumorigenesis
Authors: Chambers T J G , Giles A , Brabant G , Davis J R E
Published: May 2013

Wnt signalling is activated in both pituitary organogenesis and its mature function. Wnt ligands and Wnt signalling pathways are critical for the regulation of the formation of the pituitary. In the mature pituitary, Wnt signalling pathways control cell activity and may stimulate cell proliferation in both physiological and pathological processes. This review compares Wnt signalling pathways active in the developing and mature pituitary and explores how this gives us further insight into the development of pituitary adenomas.
SMAD3 regulates the diverse functions of rat granulosa cells relating to the FSHR/PKA signaling pathway
Authors: Li Yexia , Jin Yujie , Liu Yuxia , Shen Chunyan , Dong Jingxia , Xu Jian
Published: May 2013

The function of Smad3, a downstream signaling protein of the transforming growth factor β (TGFβ) pathway, in ovarian follicle development remains to be elucidated. The effects of Smad3 on ovarian granulosa cells (GCs) in rat were studied. Female rats (21 days of age Sprague–Dawley) received i.p. injections of pregnant mare serum gonadotropin, and GCs were harvested for primary culture 48 h later. These cells were engineered to overexpress or knockdown Smad3, which were validated by immunohistochemistry and western blot. The expression of proliferating cell nuclear antigen (PCNA), cyclin D2, TGFβ receptor II (TGFβRII), protein kinase A (PKA), and FSH receptor (FSHR) was also detected by western blotting. Cell cycle and apoptosis of GCs were assayed by flow cytometry. The level of estrogen secreted by GCs was detected by ELISA. Smad3 overexpression promoted estrogen production and proliferation while inhibiting apoptosis of GCs. Reduction in Smad3 by RNAi resulted in reduced estrogen production and proliferation and increased apoptosis of GCs. Manipulation of Smad3 expression also resulted in changes in FSHR and PKA expression, suggesting that the effects of Smad3 on follicle development are related to FSHR-mediated cAMP signaling.
Protein Z, an anticoagulant protein with expanding role in reproductive biology
Authors: Almawi Wassim Y , Al-Shaikh Fatima S , Melemedjian Ohannes K , Almawi Ahmad W
Published: May 2013

Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factors VII, IX, and X, protein C and protein S), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa through the serpin PZ-dependent protease inhibitor (ZPI). PZ deficiency is associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and is linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for the PZ–ZPI complex in the regulation of physiological pregnancy has been demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily decline toward delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcomes (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) has been reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcomes is not clear, but it is multifactorial. It may be attributed to the anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies). PZ deficiency has also been reported to be constitutional, and a number of variants in thePROZ(PZ) gene andSERPINA10(ZPI) gene are linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcomes and acquired and constitutional PZ–ZPI deficiency, in order to understand whether or not PZ deficiency could be considered as a risk factor for poor pregnancy outcomes.
Health of Children Classified as Underweight by CDC Reference but Normal by WHO Standard
Authors: Meyers Alan , Joyce Katherine , Coleman Sharon M. , Cook John T. , Cutts Diana , Ettinger de Cuba Stephanie , Heeren Timothy C. , Rose-Jacobs Ruth , Black Maureen M. , Casey Patrick H. , Chilton Mariana , Sandel Megan , Frank Deborah A. ,   on behalf of Children’s HealthWatch
Published: May 2013

OBJECTIVE:

To ascertain measures of health status among 6- to 24-month-old children classified as below normal weight-for-age (underweight) by the Centers for Disease Control and Prevention (CDC) 2000 growth reference but as normal weight-for-age by the World Health Organization (WHO) 2006 standard.

METHODS:

Data were gathered from children and primary caregivers at emergency departments and primary care clinics in 7 US cities. Outcome measures included caregiver rating of child health, parental evaluation of developmental status, history of hospitalizations, and admission to hospital at the time of visit. Children were classified as (1) not underweight by either CDC 2000 or WHO 2006 criteria, (2) underweight by CDC 2000 but not by WHO 2006 criteria, or (3) underweight by both criteria. Associations between these categories and health outcome measures were assessed by using multiple logistic regression analysis.

RESULTS:

Data were available for 18 420 children. For each health outcome measure, children classified as underweight by CDC 2000 but normal by WHO 2006 had higher adjusted odds ratios (aORs) of adverse health outcomes than children not classified as underweight by either; children classified as underweight by both had the highest aORs of adverse outcomes. For example, compared with children not underweight by either criteria, the aORs for fair/poor health rating were 2.54 (95% confidence interval: 2.20–2.93) among children underweight by CDC but not WHO and 3.76 (3.13–4.51) among children underweight by both.

CONCLUSIONS:

Children who are reclassified from underweight to normal weight in changing from CDC 2000 to WHO 2006 growth charts may still be affected by morbidities associated with underweight.
Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study
Authors: Keil Stefanie , Anjema Karen , van Spronsen Francjan J. , Lambruschini Nilo , Burlina Alberto , Bélanger-Quintana Amaya , Couce Maria L. , Feillet Francois , Cerone Roberto , Lotz-Havla Amelie S. , Muntau Ania C. , Bosch Annet M. , Meli Concetta A.P. , Billette de Villemeur Thierry , Kern Ilse , Riva Enrica , Giovannini Marcello , Damaj Lena , Leuzzi Vincenzo , Blau Nenad
Published: May 2013

OBJECTIVE:

Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries.

METHODS:

A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers.

RESULTS:

One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over ≤12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported.

CONCLUSIONS:

Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.
Accuracy of Point-of-Care Ultrasound for Diagnosis of Skull Fractures in Children
Authors: Rabiner Joni E. , Friedman Lana M. , Khine Hnin , Avner Jeffrey R. , Tsung James W.
Published: May 2013

OBJECTIVE:

To determine the test performance characteristics for point-of-care ultrasound performed by clinicians compared with computed tomography (CT) diagnosis of skull fractures.

METHODS:

We conducted a prospective study in a convenience sample of patients ≤21 years of age who presented to the emergency department with head injuries or suspected skull fractures that required CT scan evaluation. After a 1-hour, focused ultrasound training session, clinicians performed ultrasound examinations to evaluate patients for skull fractures. CT scan interpretations by attending radiologists were the reference standard for this study. Point-of-care ultrasound scans were reviewed by an experienced sonologist to evaluate interobserver agreement.

RESULTS:

Point-of-care ultrasound was performed by 17 clinicians in 69 subjects with suspected skull fractures. The patients’ mean age was 6.4 years (SD: 6.2 years), and 65% of patients were male. The prevalence of fracture was 12% (n = 8). Point-of-care ultrasound for skull fracture had a sensitivity of 88% (95% confidence interval [CI]: 53%–98%), a specificity of 97% (95% CI: 89%–99%), a positive likelihood ratio of 27 (95% CI: 7–107), and a negative likelihood ratio of 0.13 (95% CI: 0.02–0.81). The only false-negative ultrasound scan was due to a skull fracture not directly under a scalp hematoma, but rather adjacent to it. The κ for interobserver agreement was 0.86 (95% CI: 0.67–1.0).

CONCLUSIONS:

Clinicians with focused ultrasound training were able to diagnose skull fractures in children with high specificity.