bluuebunny/crossref_metadata_2025_split huggingface dataset:
The calcium‐sensing receptor: one of a kind
Authors: Lopez‐Fernandez Irene , Schepelmann Martin , Brennan Sarah C. , Yarova Polina L. , Riccardi Daniela 
Published: June 2015

New Findings

What is the topic of this review?
The extracellular calcium‐sensing receptor, CaSR, ensures whole‐body Ca2+ homeostasis. Recent developments highlight the importance of the CaSR beyond mineral ion metabolism. This review focuses on novel roles and the use of CaSR‐based therapeutics within the vasculature, the gut and the lung.

What advances does it highlight?
The ability of the CaSR to act as a multimodal chemosensor has led to the identification of signalling pathways that are ligand and cellular context dependent. Development of cell‐specific CaSR modulators is now being harnessed to rescue aberrant CaSR function outside the extracellular Ca2+ homeostatic system.

The extracellular calcium‐sensing receptor, CaSR, is the first G protein‐coupled receptor found to have an inorganic ion, calcium (Ca2+), as its physiological agonist. It is highly expressed in all organs involved in the regulation of mineral ion metabolism, namely the parathyroid gland, the kidney and bone. The CaSR is the master controller of extracellular Ca2+ concentration, as highlighted by the evidence that both inherited and acquired mutations in the CASR gene cause disturbances in mineral ion metabolism. CaSR positive allosteric modulators have been successfully employed in the clinic for over a decade to restore CaSR function, which is reduced in hyperparathyroidism secondary to kidney failure, while negative allosteric modulators are currently being tested in patients with hypocalcaemia with hypercalciuria due to gain‐of‐function CASR mutations. In addition to its expression within the bone–kidney–parathyroid axis, the CaSR can be found in other tissues, including but not limited to the gut, the vasculature and the lung. Here, the CaSR acts as a chemosensor, integrating signals deriving from nutrient availability, salinity, acidification and the presence of ubiquitous polyamines. Knowledge of what these stimuli are and of the cell‐specific signalling responses they evoke is crucial to our understanding of the non‐calciotropic roles of the CaSR in physiology and how these are affected in disease states.
Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise
Authors: Broxterman R. M. , Craig J. C. , Smith J. R. , Wilcox S. L. , Jia C. , Warren S. , Barstow T. J. 
Published: June 2015

Key pointsCritical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued.Peripheral fatigue appears to be constant across O2delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise.We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development andW ′.Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2delivery conditions for small muscle mass exercise.W ′ appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe‐intensity exercise.AbstractThe influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ′) have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post‐exercise blood flow occlusion (Con + Occ), and Occ with 5 min post‐exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements andW ′ were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central (65.5 ± 14.6% vs. 18.6 ± 4.1%) fatigue occurred for Occ + Occ than for Con + Occ.W ′ was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post‐exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest thatW ′ may be determined by the magnitude of fatigue accrued during exercise.
Increased excitability of medium‐sized dorsal root ganglion neurons by prolonged interleukin‐1β exposure is K+ channel dependent and reversible
Authors: Stemkowski Patrick L. , Noh Myung‐chul , Chen Yishen , Smith Peter A. 
Published: June 2015

Key points
Neuropathic pain resulting from peripheral nerve injury is initiated and maintained by persistent ectopic activity in primary afferent neurons.
Sciatic nerve injury increases the excitability of medium‐sized dorsal root ganglion (DRG) neurons. Levels of the inflammatory cytokine interleukin 1β (IL‐1β) increase and peak after 7 days.
Five to six days of exposure of medium sized DRG neurons to 100 pm IL‐1β promotes persistent increases in excitability which abate within 3–4 days of cytokine removal. This is associated with a profound attenuation of K+ channel currents but only modest increases in function of cyclic nucleotide‐sensitive hyperpolarization‐activated channels (HCNs) and of voltage‐gated Na+ and Ca2+ channel currents.
It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons is capable of initiating an enduring phenotypic shift in their electrophysiological properties that follows sciatic nerve injury.
The findings also underline the importance of K+ channel modulation in the actions of inflammatory mediators on peripheral neurons.
AbstractChronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the level of interleukin 1β (IL‐1β) in primary afferents that peaks at 7 days. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper‐excitability in sensory nerves, which initiates and maintains chronic neuropathic pain. We have shown previously that 5–6 days of exposure of rat dorsal root ganglia (DRGs) to 100 pm IL‐1β increases the excitability of medium‐sized neurons. We have now found using whole‐cell recording that this increased excitability reverts to control levels within 3–4 days of cytokine removal. The effects of IL‐1β were dominated by changes in K+ currents. Thus, the amplitudes of A‐current, delayed rectifier and Ca2+‐sensitive K+ currents were reduced by ∼68%, ∼64% and ∼36%, respectively. Effects of IL‐1β on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage‐activated Ca2+ channel current, a small increase in rates of activation of hyperpolarization‐activated cyclic nucleotide‐gated channel current (IH), and a shift in the voltage dependence of activation of tetrodotoxin‐sensitive sodium current (TTX‐S INa) to more negative potentials. It is unlikely, therefore, that direct interaction of IL‐1β with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K+ channel function and on the continued presence of slightly elevated levels IL‐1β and other cytokines.
A data‐mining framework for large scale analysis of dose‐outcome relationships in a database of irradiated head and neck cancer patients
Authors: Robertson Scott P. , Quon Harry , Kiess Ana P. , Moore Joseph A. , Yang Wuyang , Cheng Zhi , Afonso Sarah , Allen Mysha , Richardson Marian , Choflet Amanda , Sharabi Andrew , McNutt Todd R. 
Published: June 2015

Purpose:To develop a hypothesis‐generating framework for automatic extraction of dose‐outcome relationships from an in‐house, analytic oncology database.Methods:Dose–volume histograms (DVH) and clinical outcomes have been routinely stored to the authors’ database for 684 head and neck cancer patients treated from 2007 to 2014. Database queries were developed to extract outcomes that had been assessed for at least 100 patients, as well as DVH curves for organs‐at‐risk (OAR) that were contoured for at least 100 patients. DVH curves for paired OAR (e.g., left and right parotids) were automatically combined and included as additional structures for analysis. For each OAR‐outcome combination, only patients with both OAR and outcome records were analyzed. DVH dose points, , at a given normalized volume threshold Vt were stratified into two groups based on severity of toxicity outcomes after treatment completion. The probability of an outcome was modeled at each Vt = [0%, 1%, …, 100%] by logistic regression. Notable OAR‐outcome combinations were defined as having statistically significant regression parameters (p < 0.05) and an odds ratio of at least 1.05 (5% increase in odds per Gy).Results:A total of 57 individual and combined structures and 97 outcomes were queried from the database. Of all possible OAR‐outcome combinations, 17% resulted in significant logistic regression fits (p < 0.05) having an odds ratio of at least 1.05. Further manual inspection revealed a number of reasonable models based on either reported literature or proximity between neighboring OARs. The data‐mining algorithm confirmed the following well‐known OAR‐dose/outcome relationships: dysphagia/larynx, voice changes/larynx, esophagitis/esophagus, xerostomia/parotid glands, and mucositis/oral mucosa. Several surrogate relationships, defined as OAR not directly attributed to an outcome, were also observed, including esophagitis/larynx, mucositis/mandible, and xerostomia/mandible.Conclusions:Prospective collection of clinical data has enabled large‐scale analysis of dose‐outcome relationships. The current data‐mining framework revealed both known and novel dosimetric and clinical relationships, underscoring the potential utility of this analytic approach in hypothesis generation. Multivariate models and advanced, 3D dosimetric features may be necessary to further evaluate the complex relationship between neighboring OAR and observed outcomes.
Correlation between GyrA Substitutions and Ofloxacin, Levofloxacin, and Moxifloxacin Cross-Resistance in Mycobacterium tuberculosis
Authors: Willby Melisa , Sikes R. David , Malik Seidu , Metchock Beverly , Posey James E. 
Published: June 2015

ABSTRACT

The newer fluoroquinolones moxifloxacin (MXF) and levofloxacin (LVX) are becoming more common components of tuberculosis (TB) treatment regimens. However, the critical concentrations for testing susceptibility of
Mycobacterium tuberculosis
to MXF and LVX are not yet well established. Additionally, the degree of cross-resistance between ofloxacin (OFX) and these newer fluoroquinolones has not been thoroughly investigated. In this study, the MICs for MXF and LVX and susceptibility to the critical concentration of OFX were determined using the agar proportion method for 133 isolates of
M. tuberculosis
. Most isolates resistant to OFX had LVX MICs of >1 μg/ml and MXF MICs of >0.5 μg/ml. The presence of mutations within the
gyrA
quinolone resistance-determining regions (QRDR) correlated well with increased MICs, and the level of LVX and MXF resistance was dependent on the specific
gyrA
mutation present. Substitutions Ala90Val, Asp94Ala, and Asp94Tyr resulted in low-level MXF resistance (MICs were >0.5 but ≤2 μg/ml), while other mutations led to MXF MICs of >2 μg/ml. Based on these results, a critical concentration of 1 μg/ml is suggested for LVX and 0.5 μg/ml for MXF drug susceptibility testing by agar proportion with reflex testing for MXF at 2 μg/ml.
Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an
In Vitro
Infection Model
Authors: VanScoy Brian D. , McCauley Jennifer , Ellis-Grosse Evelyn J. , Okusanya Olanrewaju O. , Bhavnani Sujata M. , Forrest Alan , Ambrose Paul G. 
Published: June 2015

ABSTRACT

Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment
in vitro
infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (
Escherichia coli
ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical
E. coli
isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant
E. coli
subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (
r
2
= 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2-log
10
CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study.
Catechol Siderophore Transport by Vibrio cholerae
Authors: Wyckoff Elizabeth E. , Allred Benjamin E. , Raymond Kenneth N. , Payne Shelley M. 
Published: June 2015

ABSTRACT

Siderophores, small iron-binding molecules secreted by many microbial species, capture environmental iron for transport back into the cell.
Vibrio cholerae
synthesizes and uses the catechol siderophore vibriobactin and also uses siderophores secreted by other species, including enterobactin produced by
Escherichia coli
.
E. coli
secretes both canonical cyclic enterobactin and linear enterobactin derivatives likely derived from its cleavage by the enterobactin esterase Fes. We show here that
V. cholerae
does not use cyclic enterobactin but instead uses its linear derivatives.
V. cholerae
lacked both a receptor for efficient transport of cyclic enterobactin and enterobactin esterase to promote removal of iron from the ferrisiderophore complex. To further characterize the transport of catechol siderophores, we show that the linear enterobactin derivatives were transported into
V. cholerae
by either of the catechol siderophore receptors IrgA and VctA, which also transported the synthetic siderophore MECAM [1,3,5-
N
,
N
′,
N
″-tris-(2,3-dihydroxybenzoyl)-triaminomethylbenzene]. Vibriobactin is transported via the additional catechol siderophore receptor ViuA, while the
Vibrio fluvialis
siderophore fluvibactin was transported by all three catechol receptors. ViuB, a putative
V. cholerae
siderophore-interacting protein (SIP), functionally substituted for the
E. coli
ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm. In
V. cholerae
, ViuB was required for the use of vibriobactin but was not required for the use of MECAM, fluvibactin, ferrichrome, or the linear derivatives of enterobactin. This suggests the presence of another protein in
V. cholerae
capable of promoting the release of iron from these siderophores.

IMPORTANCE
Vibrio cholerae
is a major human pathogen and also serves as a model for the
Vibrionaceae
, which include other serious human and fish pathogens. The ability of these species to persist and acquire essential nutrients, including iron, in the environment is epidemiologically important but not well understood. In this work, we characterize the ability of
V. cholerae
to acquire iron by using siderophores produced by other organisms. We resolve confusion in the literature regarding its ability to use the
Escherichia coli
siderophore enterobactin and identify the receptor and TonB system used for the transport of several siderophores. The use of some siderophores did not require the ferric reductase ViuB, suggesting that an uncharacterized ferric reductase is present in
V. cholerae
.
Intra-DIC (distal intracranial catheter) deployment of the Pipeline embolization device: a novel rescue strategy for failed device expansion
Authors: Lin Li-Mei , Colby Geoffrey P , Jiang Bowen , Nundkumar Neelesh , Huang Judy , Tamargo Rafael J , Coon Alexander L 
Published: June 2015

BackgroundThe Pipeline embolization device (PED) is a braided flow diverter that requires a combination of meticulous maneuvers to assure proper device opening and expansion. Mechanical, anatomical, or technical challenges can result in a partially deployed PED with failed expansion.ObjectiveTo present a new alternative method of PED deployment using the Navien distal intracranial catheter (DIC) as a salvage maneuver for cases where PED opening fails with standard techniques.MethodsWe retrospectively reviewed a prospective, single-center aneurysm database to identify all patients who underwent endovascular treatment of intracranial aneurysms using the PED with the Navien distal intracranial catheter access platform. Cases requiring PED deployment within the Navien catheter were reviewed. Data was collected for patient demographics, aneurysm characteristics, and technical details of the interventional procedure.ResultsEleven PED neurointerventions requiring intra-Navien PED deployment to fully open the PED were identified. Mean patient age was 55.5±9.9 years (range 37–76 years). Mean aneurysm size was 12.5 mm±4.9 mm (range 2–42 mm). All aneurysms were located in the anterior circulation (anterior cerebral artery, n=1; supraclinoid, n=1; ophthalmic/paraophthalmic, n=6; cavernous, n=3; petrocervical, n=1). Mean fluoroscopy time was 67.1±20.5 min. The intra-Navien technique was used to open the proximal PED (n=7) and the mid-portion (n=4). Post-processing of the PED with a balloon was used in six cases.ConclusionsWhen a partially deployed PED remains constrained despite exhaustion of standard maneuvers to facilitate opening, the technique of intra-Navien PED deployment is a valuable rescue strategy. This new alternative method of PED deployment can be used to open a stretched device with successful completion of the PED implantation.
MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16
Authors: Qian Dong , Chen Kailin , Deng Haixia , Rao Huilan , Huang Huiqiang , Liao Yiji , Sun Xiaofei , Lu Suying , Yuan Zhiyong , Xie Dan , Cai Qingqing 
Published: June 2015

Abstract
Purpose: Deregulation of microRNA (miRNA) has been extensively investigated in both Hodgkin and non-Hodgkin lymphomas (NHL); however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). The aim of the present study was to investigate the potential roles of miR-374b in the development and treatment of T-LBL.
Experimental Design: MiRCURY LNA array was used to generate a miRNA-expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1, and Wnt16 in T-LBL samples. The dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor-suppressive effect of miR-374b was determined by both in vitro and in vivo studies.
Results: The expression of 380 miRNAs was evaluated in five human T-LBL tissues and five infantile thymus samples by microRNA microarrays. Downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence of the 58 patients enrolled in this study. miR-374b suppressed T-LBL cell proliferation in vitro and in vivo and sensitized cells to serum starvation- and chemotherapeutic agent-induced apoptosis. Furthermore, we characterized two AKT pathway–associated molecules, AKT1 and Wnt16, as direct targets of miR-374b. Consistently, in T-LBL patient tissues, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and was an independent predictor of recurrence and survival.
Conclusions: Our data highlight the molecular etiology and clinical significance of miR-374b in T-LBL. Targeting miR-374b may represent a new therapeutic strategy to improve therapy and survival for T-LBL patients. Clin Cancer Res; 21(21); 4881–91. ©2015 AACR.
Omega-3-Acid Ethyl Esters Block the Protumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-like and Claudin-Low Breast Cancer
Authors: Ford Nikki A. , Rossi Emily L. , Barnett Kelsey , Yang Peiying , Bowers Laura W. , Hidaka Brandon H. , Kimler Bruce F. , Carlson Susan E. , Shureiqi Imad , deGraffenried Linda A. , Fabian Carol J. , Hursting Stephen D. 
Published: June 2015

Abstract
Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable with women taking Lovaza 4 g/d) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly affect Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and proinflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of COX-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the protumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest that EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women. Cancer Prev Res; 8(9); 796–806. ©2015 AACR.