bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes
Authors: Choe Jung-Yoon , Park Ki-Yeun , Park Sung-Hoon , Lee Sang-Il , Kim Seong-Kyu 
Published: February 2013

Abstract
Introduction
This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.

Methods
The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.

Results
We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.

Conclusions
These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.
MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes
Authors: Matsukawa Tetsuya , Sakai Tadahiro , Yonezawa Tomo , Hiraiwa Hideki , Hamada Takashi , Nakashima Motoshige , Ono Yohei , Ishizuka Shinya , Nakahara Hiroyuki , Lotz Martin K , Asahara Hiroshi , Ishiguro Naoki 
Published: February 2013

Abstract
Introduction
Increased expression of aggrecanase-1 (ADAMTS-4) has emerged as an important factor in osteoarthritis (OA) and other joint diseases. This study aimed to determine whether the expression of ADAMTS-4 in human chondrocytes is regulated by miRNA.

Methods
MiRNA targets were identified using bioinformatics. Chondrocytes were isolated from knee cartilage and treated with interleukin-1 beta (IL-1β). Gene expression was quantified using TaqMan assays and protein production was determined by immunoblotting. Luciferase reporter assay was used to verify interaction between miRNA and target messenger RNA (mRNA).

Results
In silico analysis predicted putative target sequence of miR-125b on ADAMTS-4. MiR-125b was expressed in both normal and OA chondrocytes, with significantly lower expression in OA chondrocytes than in normal chondrocytes. Furthermore, IL-1β-induced upregulation of ADAMTS-4 was suppressed by overexpression of miR-125b in human OA chondrocytes. In the luciferase reporter assay, mutation of the putative miR-125b binding site in the ADAMTS-4 3'UTR abrogated the suppressive effect of miR125.

Conclusions
Our results indicate that miR-125b plays an important role in regulating the expression of ADAMTS-4 in human chondrocytes and this identifies miR-125b as a novel therapeutic target in OA.
Anti-matrix metalloproteinase-9 DNAzyme decreases tumor growth in the MMTV-PyMT mouse model of breast cancer
Authors: Hallett Miranda A , Teng Bin , Hasegawa Hisashi , Schwab Luciana P , Seagroves Tiffany N , Pourmotabbed Tayebeh 
Published: February 2013

Abstract
Introduction
Despite continued improvements in diagnosis, surgical techniques, and chemotherapy, breast cancer patients are still overcome by cancer metastasis. Tumor cell proliferation, invasion and metastasis are mediated, at least in part, through degradation of basement membrane by neutral matrix metalloproteinases (MMP) produced by tumor and stromal cells. Evidence suggests that MMP-9 plays a significant role in breast tumor cell invasion and metastasis. DNAzymes or catalytic oligonucleotides are new classes of gene targeting molecules that bind and cleave a specific mRNA, resulting in decreased protein expression.

Methods
The application of anti-MMP-9 DNAzyme (AM9D) for the treatment of primary and metastatic breast cancer was evaluated in vitro and in vivo using MDA-MB-231 cells and the MMTV-PyMT transgenic breast cancer mouse model. Spontaneously developed mammary tumors in MMTV-PyMT transgenic mice were treated intratumorally with naked AM9D, once a week for 4 weeks. The stability of DNAzyme was determined in vitro and in vivo using fluorescently labeled DNAzyme.

Results
AM9D specifically inhibited expression of MMP-9 in MDA-MB-231 cells resulting in reduced invasive property of these cells by 43%. Weekly intratumoral treatment of spontaneously developed mammary tumors in MMTV-PyMT transgenic mice was sufficient to significantly reduce the rate of tumor growth and final tumor load in a dose dependent and statistically significant manner (P < 0.05). This decrease in tumor growth was correlated with decreased MMP-9 protein production within the treated tumor tissues. Tumors treated with AM9D were also less vascularized and contained more apoptotic cells compared to control and untreated tumors.

Conclusions
These results show that targeting and down regulation of MMP-9 by AM9D could prove useful as a therapy against breast carcinoma tumor growth and invasion.
Phenotypic flexibility in migrating bats: seasonal variation in body composition, organ sizes and fatty acid profiles
Authors: McGuire Liam P. , Fenton M. Brock , Guglielmo Christopher G. 
Published: February 2013

SUMMARYMany species of bats migrate long distances, but the physiological challenges of migration are poorly understood. We tested the hypothesis that migration is physiologically demanding for bats by examining migration-related phenotypic flexibility. Both bats and birds are endothermic, flying vertebrates; therefore, we predicted that migration would result in similar physiological trade-offs. We compared hoary bats (Lasiurus cinereus) during spring migration and summer non-migratory periods, comparing our results with previous observations of birds. Migrating bats had reduced digestive organs, enlarged exercise organs, and fat stores had higher proportions of polyunsaturated fatty acids (PUFAs). These results are consistent with previous studies of migrating birds; however, we also found sex differences not typically associated with bird migration. Migrating female hoary bats increased the relative size of fat stores by reducing lean body components, while males maintained the same relative amount of fat in both seasons. The ratio of n-6 to n-3 PUFA in flight muscle membrane increased in migrating males and decreased in migrating females, consistent with males using torpor more frequently than females during spring migration. Enlarged exercise organs, reduced digestive organs and changes in adipose tissue composition reflect the elevated energetic demands of migration. Sex-specific patterns of fat storage and muscle membrane composition likely reflect challenges faced by females that migrate while pregnant. Our results provide some of the first insights into the physiological demands of bat migration and highlight key differences between bats and birds.
Regulatory polymorphisms in CYP2C19 affecting hepatic expression
Authors: Sanford Jonathan C. , Guo Yingying , Sadee Wolfgang , Wang Danxin 
Published: February 2013

Abstract

Background: Cytochrome P450 2C19 is responsible for the metabolism of many drugs, including the activation of clopidogrel. The allele CYP2C19*17 is associated with ultra-rapid metabolizer phenotypes by increasing gene transcription. This study tests to what extent CYP2C19*17 enhances CYP2C19 expression in human liver and whether additional regulatory variants contribute to variation in CYP2C19 expression.

Methods: CYP2C19 mRNA was measured with quantitative real-time PCR (qRT-PCR), enzyme activity as metabolic velocity with S-mephenytoin as the substrate and allelic mRNA expression ratio with SNaPshot in human livers. CYP2C19 transcribed exons and a 4kb promoter region were sequenced using IonTorrent PGM or Sanger sequencing and screened for polymorphisms associated with total hepatic CYP2C19 mRNA, enzyme activity and allelic mRNA ratios.

Results: Livers heterozygote and homozygous for CYP2C19*17 had mRNA levels 1.8-fold (p=0.028) and 2.9-fold (p=0.006), respectively, above homozygous reference allele livers. CYP2C19*17 heterozygotes were also associated with increased allelic mRNA expression (allelic ratio ~1.8-fold, SD±0.6, p<0.005), whereas CYP2C19 enzyme activity was elevated 2.3-fold, with borderline significance (p=0.06) in CYP2C19*17 carriers. One liver sample of African ancestry displayed a 2-fold allelic expression ratio, and another sample, a ~12-fold increase in metabolic velocity. Neither case was accounted for by *17, which indicates the presence of additional regulatory variants.

Conclusions: Our findings confirm *17 as a regulatory polymorphism enhancing hepatic CYP2C19 expression 2-fold with potential to compensate for the loss of function allele CYP2C19*2. Additional regulatory factors may also enhance CYP2C19 expression in African American populations.
An ethical framework for the disposal of autologous stem cells
Authors: Petrini Carlo 
Published: February 2013

Abstract
The disposal of haematopoietic stem cells stored for autologous transplantation purposes becomes a problem for hospitals when the conditions for their preservation cease to exist. When these cells have been stored for a considerable time the problem often becomes an ethical one involving informed consent and is linked to at least two simultaneous circumstances: (i) the indications regarding disposal contained in available informed consent papers are either absent or too generic; (ii) the person who provided the sample can no longer be traced. This article proposes and discusses some of the ethical criteria for addressing this problem on the basis of the so-called “principles” of North American bioethics, and compares them with some of the principles and values proposed in other models of bioethics.
Effects of aqueous extract of Musa paradisiaca root on testicular function parameters of male rats
Authors: Yakubu Musa Toyin , Oyeyipo Theo Oyetayo , Quadri Ayodeji Luqman , Akanji Musbau Adewumi 
Published: February 2013

Abstract

Background: There is an age-long claim that the Musa paradisiaca root is used to manage reproductive dysfunction, most especially sexual dysfunction (as an aphrodisiac), but there are no data in the open scientific literature that have refuted or supported this claim and the effects of M. paradisiaca root on the testes. Therefore, this study was aimed at investigating the effect of oral administration of the aqueous extract of M. paradisiaca root on the testicular function parameters of male rat testes.

Methods: Sexually matured male albino rats (138.67±5.29 g) were randomly assigned into four groups, A, B, C, and D, that respectively received 0.5 mL (3.6 mL/kg body weight) of distilled water and 25, 50, and 100 mg/kg body weight of the extract, orally, once daily, for 14 days.

Results: The extract significantly increased (p<0.05) the testes-body weight ratio, total protein, sialic acid, glycogen, cholesterol, activities of alkaline phosphatase, γ-glutamyltransferase, acid phosphatase, and the concentration of testicular testosterone. In contrast, the extract decreased the concentrations of both luteinizing and follicle-stimulating hormones in the serum of the animals. The results revealed that oral administration of M. paradisiaca root extract at doses of 25, 50, and 100 mg/kg body weight enhanced the testosterone-dependent normal functioning of the testes.

Conclusions: Overall, the aqueous extract of M. paradisiaca stimulated the normal functioning of the testes and exhibited both androgenic and anabolic properties. The results may explain the rationale behind the folkloric beneficial effect of the plant in the management of reproductive dysfunction.
A discrepancy principle for generalized local regularization
of linear inverse problems
Authors: Brooks Cara D. , Lamm Patricia K. 
Published: February 2013

Abstract.
A modified version of the classical discrepancy principle
is formulated for use with generalized local regularization operators
of the form

ℛ
α

=

(

a
α

I
+

𝒜
α

)

-
1

T
α

${\mathcal {R}_\alpha = (a_\alpha I + \mathcal {A}_\alpha )^{-1}T_\alpha }$

for the approximate solution of linear inverse problems
in Banach space with deterministically modeled noise. The choice of the
local regularization parameter according to the a posteriori
parameter selection strategy is shown to result in a class of convergent
regularization methods and a general rate of convergence is
provided. As an example, the theory is applied to establish convergence
and convergence rates for approximations obtained using a zeroth-order
local regularization scheme with the modified principle for solving
Volterra convolution equations in

L
p

(
0
,
1
)

${{L^p(0,1)}}$

,

p
∈
(
1
,
∞
)

${{p \in (1,\infty )}}$

. A numerical example is provided to illustrate the practical use and
effectiveness of the method.
Selective Optogenetic Activation of Rostral Ventrolateral Medullary Catecholaminergic Neurons Produces Cardiorespiratory Stimulation in Conscious Mice
Authors: Abbott Stephen B. G. , DePuy Seth D. , Nguyen Thanh , Coates Melissa B. , Stornetta Ruth L. , Guyenet Patrice G. 
Published: February 2013

Activation of rostral ventrolateral medullary catecholaminergic (RVLM-CA) neurons e.g., by hypoxia is thought to increase sympathetic outflow thereby raising blood pressure (BP). Here we test whether these neurons also regulate breathing and cardiovascular variables other than BP. Selective expression of ChR2-mCherry by RVLM-CA neurons was achieved by injecting Cre-dependent vector AAV2-EF1α-DIO-ChR2-mCherry unilaterally into the brainstem of dopamine-β-hydroxylaseCre/0mice. Photostimulation of RVLM-CA neurons increased breathing in anesthetized and conscious mice. In conscious mice, photostimulation primarily increased breathing frequency and this effect was fully occluded by hypoxia (10% O2). In contrast, the effects of photostimulation were largely unaffected by hypercapnia (3 and 6% CO2). The associated cardiovascular effects were complex (slight bradycardia and hypotension) and, using selective autonomic blockers, could be explained by coactivation of the sympathetic and cardiovagal outflows. ChR2-positive RVLM-CA neurons expressed VGLUT2 and their projections were mapped. Their complex cardiorespiratory effects are presumably mediated by their extensive projections to supraspinal sites such as the ventrolateral medulla, the dorsal vagal complex, the dorsolateral pons, and selected hypothalamic nuclei (dorsomedial, lateral, and paraventricular nuclei).In sum, selective optogenetic activation of RVLM-CA neurons in conscious mice revealed two important novel functions of these neurons, namely breathing stimulation and cardiovagal outflow control, effects that are attenuated or absent under anesthesia and are presumably mediated by the numerous supraspinal projections of these neurons. The results also suggest that RVLM-CA neurons may underlie some of the acute respiratory response elicited by carotid body stimulation but contribute little to the central respiratory chemoreflex.
Axons Giving Rise to the Palisade Endings of Feline Extraocular Muscles Display Motor Features
Authors: Zimmermann Lars , Morado-Díaz Camilo J. , Davis-López de Carrizosa María A. , de la Cruz Rosa R. , May Paul J. , Streicher Johannes , Pastor Ángel M. , Blumer Roland 
Published: February 2013

Palisade endings are nerve specializations found in the extraocular muscles (EOMs) of mammals, including primates. They have long been postulated to be proprioceptors. It was recently demonstrated that palisade endings are cholinergic and that in monkeys they originate from the EOM motor nuclei. Nevertheless, there is considerable difference of opinion concerning the nature of palisade ending function.Palisade endings in EOMs were examined in cats to test whether they display motor or sensory characteristics. We injected an anterograde tracer into the oculomotor or abducens nuclei and combined tracer visualization with immunohistochemistry and α-bungarotoxin staining. Employing immunohistochemistry, we performed molecular analyses of palisade endings and trigeminal ganglia to determine whether cat palisade endings are a cholinergic trigeminal projection.We confirmed that palisade endings are cholinergic and showed, for the first time, that they, like extraocular motoneurons, are also immunoreactive for calcitonin gene-related peptide. Following tracer injection into the EOM nuclei, we observed tracer-positive palisade endings that exhibited choline acetyl transferase immunoreactivity. The tracer-positive nerve fibers supplying palisade endings also established motor terminals along the muscle fibers, as demonstrated by α-bungarotoxin. Neither the trigeminal ganglion nor the ophthalmic branch of the trigeminal nerve contained cholinergic elements.This study confirms that palisade endings originate in the EOM motor nuclei and further indicates that they are extensions of the axons supplying the muscle fiber related to the palisade. The present work excludes the possibility that they receive cholinergic trigeminal projections. These findings call into doubt the proposed proprioceptive function of palisade endings.
Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Valachis Antonis , Polyzos Nikolaos P. , Coleman Robert E. , Gnant Michael , Eidtmann Holger , Brufsky Adam M. , Aft Rebecca , Tevaarwerk Amye J. , Swenson Karen , Lind Pehr , Mauri Davide 
Published: February 2013

AbstractBackground.The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I–III) breast cancer.Materials and Methods.We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes.Results.Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70–0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70–1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64–1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63–0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%.Conclusion.Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment.
Factors Associated With Fatigue After Surgery in Women With Early-Stage Invasive Breast Cancer
Authors: Rotonda Christine , Guillemin Francis , Bonnetain Franck , Velten Michel , Conroy Thierry 
Published: February 2013

Abstract

Learning Objectives
Describe the effect of worsening fatigue after breast cancer surgery on physical functioning and psychological distress. Better identify women at risk for developing cancer-related fatigue. Direct target interventions to patients most in need.

Purpose.
Fatigue is one of the most frequent symptoms in patients with cancer. However, the precise determinants of fatigue are still unknown. This study was conducted to investigate factors correlated with cancer-related fatigue before surgery and just before subsequent adjuvant therapy.

Methods.
Patients completed the Multidimensional Fatigue Inventory (MFI-20), the European Organization for Research and Treatment of Cancer 30-item quality-of-life questionnaire before and after surgery, the Trait Anxiety Inventory and the Life Orientation Test before surgery, and the State Anxiety Inventory before the start of adjuvant therapy. Multiple regression analysis of determinants of change in MFI-20 total score after surgery was conducted.

Results.
A series of 466 eligible patients with stage I–III breast cancer with planned surgery were recruited. An increase in MFI-20 total score after surgery was significantly correlated with higher preoperative fatigue and lower role functioning before surgery; a decrease in role functioning, physical functioning, and cognitive functioning after surgery; an increase in insomnia after surgery; and a higher state anxiety after surgery. Disease stage, lymph node metastases, surgical procedure, and demographic characteristics (e.g., age, marital status, having children, educational level) were not correlated with fatigue in multivariate analysis.

Conclusion.
These results suggest that worsening fatigue after surgery for breast cancer is associated with a decrease in physical functioning and an increase in psychological distress rather than with the cancer characteristics. Therefore, screening measures should be implemented at the time of diagnosis—before starting treatment—to identify psychologically vulnerable patients and to offer them professional support.