bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dermis‐derived stem cells: a source of epidermal melanocytes and melanoma?
Authors: Zabierowski Susan E. , Fukunaga‐Kalabis Mizuho , Li Ling , Herlyn Meenhard 
Published: March 2011

SummaryHuman multipotent dermal stem cells (DSCs) have been isolated and propagated from the dermal region of neonatal foreskin. DSCs can self‐renew, express the neural crest stem cell markers NGFRp75 and nestin, and are capable of differentiating into a wide variety of cell types including mesenchymal and neuronal lineages and melanocytes, indicative of their neural crest origin. When placed in the context of reconstructed skin, DSCs migrate to the basement membrane zone and differentiate into melanocytes. These findings, combined with the identification of NGFRp75‐positive cells in the dermis of human foreskin, which are devoid of hair, suggest that DSCs may be a self‐renewing source of extrafollicular epidermal melanocytes. In this review, we discuss the properties of DSCs, the pathways required for melanocyte differentiation, and the value of 3D reconstructed skin to assess the behavior and contribution of DSCs in the naturalized environment of human skin. Potentially, DSCs provide a link to malignant melanoma by being a target of UVA‐induced transformation.
Arthroscopic treatment of meniscal cysts in the horse
Authors: SPARKS H. D. , NIXON A. J. , BOENING K. J. , POOL R. R. 
Published: March 2011

SummaryReasons for performing study:To describe the clinical symptoms, treatment, and outcome of meniscal cysts in horses. These structures have not been previously described in the literature as a potential cause of lameness in the horse.Hypothesis:Meniscal cysts are an uncommon condition of the femorotibial joint but can be a significant cause of lameness. Symptoms can be resolved by arthroscopic excision.Methods:Records of horses diagnosed with meniscal cysts and treated by cyst excision and meniscal debridement at 2 surgical practices were reviewed. Clinical outcome was determined by repeat veterinary examination and contact with owner.Results:Seven cases of meniscal cyst were treated with arthroscopic cyst excision and meniscal debridement. Five of 7 horses had lameness attributable to femorotibial joint pathology, while the remaining 2 horses had meniscal cysts found incidentally during diagnostic arthroscopy for the treatment of osteochondritis dissecans of the lateral trochlear ridge of the femur. Five of 6 horses with long‐term follow‐up were sound and a 7th horse was improved 11 months after surgery.Conclusions and potential relevance:Meniscal cysts, while uncommon, can be associated with progressive lameness in the horse. Surgical excision of the cysts results in resolution or improvement of symptoms, without evidence of recurrence on follow‐up examination.
Amelioration of cerebral infarction and improvement of neurological deficit by a Korean herbal medicine, modified Bo-Yang-Hwan-O-Tang
Authors: Choi Yookeum , Kim Seul-Ki , Choi In-Young , Ju Chung , Nam Kung-Woo , Hwang Sunyoung , Kim Byung-Woo , Yoon Min Ji , Won Moo-Ho , Park Yong-Ki , Kim Won-Ki 
Published: March 2011

Abstract

Objectives
Modified Bo-Yang-Hwan-O-Tang (mBHT) is an improved herbal formula of BHT, which has been widely used to treat ischaemic stroke in East Asia, by the addition of five herbs having anti-ischaemic properties. In this study, we investigated whether mBHT would reduce cerebral ischaemic injury in rats.

Methods
Sprague–Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) and subsequent 22-h reperfusion. mBHT was administered either intraperitoneally twice 15 min before and 15 min after, or orally once 30 min or 120 min after the onset of MCAO (50 or 200 mg/kg each).

Key findings
Intraperitoneal administration of mBHT markedly reduced the cerebral infarct size and neurological deficit caused by MCAO/reperfusion. mBHT treatment also significantly improved long-term survival rate after cerebral ischaemic injury. Oral administration of mBHT 30 min after ischaemia also markedly reduced the infarct size after cerebral ischaemia. The anti-ischaemic effect of mBHT was significantly, but not fully, reduced when mBHT-induced hypothermia was abolished. In cultured cortical neurons, we further found that mBHT decreased oxygen-glucose deprivation/re-oxygenation-evoked neuronal injury by inhibiting production of reactive oxygen species, decrease in mitochondrial transmembrane potential, and activation of caspase-3. However, mBHT did not inhibit N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity.

Conclusions
Taken together, our data suggest that mBHT has multiple anti-ischaemic properties and would be a good therapeutic herbal prescription for the treatment of cerebral ischaemic stroke.
CMX001 (1-
O
-Hexadecyloxypropyl-Cidofovir) Inhibits Polyomavirus JC Replication in Human Brain Progenitor-Derived Astrocytes
Authors: Gosert Rainer , Rinaldo Christine Hanssen , Wernli Marion , Major Eugene O. , Hirsch Hans H. 
Published: March 2011

ABSTRACT

Polyomavirus JC (JCV) replication causes progressive multifocal leukoencephalopathy (PML), a frequently fatal brain disease in immunodeficient patients, yet antiviral drugs are lacking. We characterized the lipid conjugate 1-
O
-hexadecyloxypropyl-cidofovir (CMX001) regarding JCV (Mad-4) replication in human brain progenitor-derived astrocytes (PDA) and the simian virus 40 (SV40) large-T-antigen-expressing COS-7 cells up to 7 days postinfection (dpi). We examined JCV loads by PCR, the infection rate by immunofluorescence, and host cell toxicity by WST-1 and BrdU incorporation assays. Supernatants from CMX001-treated PDA demonstrated a drug concentration-dependent decrease in JCV loads and infectivity. CMX001 had only a modest effect on host cell metabolism but reduced overall BrdU incorporation. In PDA at 7 dpi, the CMX001 50% effective concentration (EC
50
) was 5.55 nM, the 50% cytotoxic concentration (CC
50
) was 184.6 nM, and the 50% selectivity index (SI
50
) was 33.3. The EC
90
was 19.7 nM, the CC
90
was 5,054 nM, and the SI
90
was 256.1. In COS-7 cells, JCV replication was faster and the EC
50
and EC
90
were 18- and 37-fold higher than those in PDA, i.e., 0.1 μM and 0.74 μM (CC
50
, 0.67 μM; SI
50
, 6.7; CC
90
, 12.2 μM; SI
90
, 16.5) at 5 dpi. We conclude that CMX001 inhibits JCV replication at concentrations
in vitro
that can be attained by oral administration without significant side effects in clinical studies.
Changes in Antibiotic Distribution Due to Pancreatitis
Authors: Fanning Kent J. , Robertson Thomas A. , Prins Johannes B. , Roberts Michael S. 
Published: March 2011

ABSTRACT
This work sought to define how pancreatitis affected antibiotic distribution in a perfused rat pancreas model. The distribution kinetics of four antibiotics were examined in control animals and animals with pancreatitis. Meropenem and piperacillin distributed into the extracellular space, and their distribution kinetics were unaffected by pancreatitis. In contrast, in pancreatic cells from animals with pancreatitis, ciprofloxacin showed a reduced uptake and clindamycin showed a reduced distribution.
Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers
Authors: Bulitta J. B. , Kinzig M. , Landersdorfer C. B. , Holzgrabe U. , Stephan U. , Sörgel F. 
Published: March 2011

ABSTRACT

Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (
P
≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.
Trypanocidal Furamidine Analogues: Influence of Pyridine Nitrogens on Trypanocidal Activity, Transport Kinetics, and Resistance Patterns
Authors: Ward Christopher P. , Wong Pui Ee , Burchmore Richard J. , de Koning Harry P. , Barrett Michael P. 
Published: March 2011

ABSTRACTCurrent therapies for human African trypanosomiasis (HAT) are unsatisfactory and under threat from emerging drug resistance linked to the loss of transporters, e.g., the P2 aminopurine transporter (TbAT1). Here we compare the uptake and trypanocidal properties of furamidine (DB75), recently evaluated in clinical trials against stage 1 (haemolymphatic) HAT, and two aza analogues, DB820 and CPD0801 (DB829), which are candidate compounds for treatment of stage 2 (neurological) disease. Values of 50% inhibitory concentrations (IC50s) determinedin vitroagainst both wild-type and transporter mutant parasites were submicromolar, with DB75 trypanotoxicity shown to be better than and DB820 trypanotoxicity similar to that of the widely used veterinary trypanocide diminazene, while CPD0801 was less active. Activity correlated with uptake and with the minimum drug exposure time necessary to kill trypanosomes: DB75 accumulated at double and 10-fold the rates of DB820 and CPD0801, respectively. All three compounds inhibited P2-mediated adenosine transport with similarKivalues, indicating affinity values for this permease in the low to submicromolar range. Uptake of DB75, DB820, and CPD0801 was significantly reduced intbat1−/−parasites and was sensitive to inhibition by adenine, showing that all three compounds are substrates for the P2 transporter. Uptakein vitrowas significantly less than that seen with parasites freshly isolated from infected rats, correlating with a downregulation of P2 activityin vitro. We conclude that DB75, DB820, and CPD0801 are actively accumulated byTrypanosoma brucei brucei, with P2 as the main transport route. The aza analogues of DB75 accumulate more slowly than furamidine itself and reveal less trypanocidal activity in standardin vitrodrug sensitivity assays.
Insertion Sequence IS
Aba11
Is Involved in Colistin Resistance and Loss of Lipopolysaccharide in Acinetobacter baumannii
Authors: Moffatt Jennifer H. , Harper Marina , Adler Ben , Nation Roger L. , Li Jian , Boyce John D. 
Published: March 2011

ABSTRACT

Infections caused by
Acinetobacter baumannii
are of increasing concern, largely due to the multidrug resistance of many strains. Here we show that insertion sequence IS
Aba11
movement can result in inactivation of the
A. baumannii
lipid A biosynthesis genes
lpxA
and
lpxC
, resulting in the complete loss of lipopolysaccharide production and high-level colistin resistance.
In Vitro Activity of Ceftaroline against Gram-Positive and Gram-Negative Pathogens Isolated from Patients in Canadian Hospitals in 2009
Authors: Karlowsky James A. , Adam Heather J. , DeCorby Melanie R. , Lagacé-Wiens Philippe R. S. , Hoban Daryl J. , Zhanel George G. 
Published: March 2011

ABSTRACT

The
in vitro
activities of ceftaroline and comparative agents were determined for a collection of the most frequently isolated bacterial pathogens from hospital-associated patients across Canada in 2009 as part of the ongoing CANWARD surveillance study. In total, 4,546 isolates from 15 sentinel Canadian hospital laboratories were tested using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. Compared with other cephalosporins, including ceftobiprole, cefepime, and ceftriaxone, ceftaroline exhibited the greatest potency against methicillin-susceptible
Staphylococcus aureus
(MSSA), with a MIC
90
of 0.25 μg/ml. Ceftaroline also demonstrated greater potency than ceftobiprole against community-associated methicillin-resistant
S. aureus
(MRSA) (MIC
90
, 0.5 μg/ml) and health care-associated MRSA (MIC
90
, 1 μg/ml) and was at least 4-fold more active than other cephalosporins against
Staphylococcus epidermidis
; all isolates of MSSA and MRSA tested were susceptible to ceftaroline (MIC, ≤1 μg/ml). Against streptococci, including
Streptococcus pneumoniae
, ceftaroline MICs (MIC
90
, ≤0.03 μg/ml) were comparable to those of ceftobiprole; however, against penicillin-nonsusceptible, macrolide-nonsusceptible, and multidrug-nonsusceptible isolates of
S. pneumoniae
, ceftaroline demonstrated 2- to 4-fold and 4- to 16-fold more potent activities than those of ceftobiprole and ceftriaxone, respectively. All isolates of
S. pneumoniae
tested were susceptible to ceftaroline (MIC, ≤0.25 μg/ml). Among Gram-negative isolates, ceftaroline demonstrated potent activity (MIC
90
, ≤0.5 μg/ml) against
Escherichia coli
(92.2% of isolates were susceptible),
Klebsiella pneumoniae
(94.1% of isolates were susceptible),
Proteus mirabilis
(97.7% of isolates were susceptible), and
Haemophilus influenzae
(100% of isolates were susceptible). Ceftaroline demonstrated less potent activity (MIC
90
, ≥4 μg/ml) against
Enterobacter
spp.,
Acinetobacter baumannii
,
Pseudomonas aeruginosa
,
Klebsiella oxytoca
,
Serratia marcescens
, and
Stenotrophomonas maltophilia
. Overall, ceftaroline demonstrated potent
in vitro
activity against a recent collection of the most frequently encountered Gram-positive and Gram-negative isolates from patients attending hospitals across Canada in 2009.
In Vitro and In Vivo Intracellular Killing Effects of Tigecycline against Clinical Nontyphoid Salmonella Isolates Using Ceftriaxone as a Comparator
Authors: Tang Hung-Jen , Ko Wen-Chien , Chen Chi-Chung , Chen Po-Lin , Toh Han Siong , Weng Tzu Chieh , Yu Wen-Liang , Chiang Shyh-Ren , Chuang Yin-Ching 
Published: March 2011

ABSTRACT

Salmonella
is an important, worldwide food-borne pathogen. Resistance to fluoroquinolones and cephalosporins has been increasingly reported, and new therapeutic agents are desperately needed. In this study, we evaluated the
in vitro
antimicrobial susceptibility of clinical nontyphoidal
Salmonella
isolates to tigecycline. Antibacterial activity of tigecycline, ceftriaxone, and ciprofloxacin were investigated by time-kill studies and the murine peritonitis model. The MIC
50
/MIC
90
values of tigecycline, ceftriaxone, and ciprofloxacin against 76
Salmonella
isolates were 0.25/0.5, 1/8, and 0.125/0.5 μg/ml, respectively. The intracellular inhibitory activity of tigecycline at 0.5 μg/ml (1× MIC) against
Salmonella
isolates in human peripheral blood mononuclear cells was sustained for 24 h. In a mouse peritonitis model, tigecycline reduced the extracellular and intracellular bacterial counts from 10
7
CFU/ml and 10
5
CFU/ml, respectively, to an undetectable level within 96 h. The results were similar to those obtained with ceftriaxone. The survival rate of mice exposed to tigecycline after being infected by an inoculum of 1 × 10
5
CFU was 80%, and that of mice exposed to ceftriaxone was 100%. When the inoculum was increased to 1.3 × 10
6
CFU, the survival rate of mice treated by tigecycline was 20%, and that of mice exposed to ceftriaxone was 0% (
P
= 0.2). When a ceftriaxone- and ciprofloxacin-resistant but tigecycline-susceptible isolate was tested, mice treated by tigecycline had a higher survival rate than those treated by ceftriaxone (15/20 [75%] versus 6/20 [30%];
P
= 0.011). Our results suggest that tigecycline is at least as effective as ceftriaxone for murine
Salmonella
infections and warrants further clinical investigations to delineate its potential against human
Salmonella
infections.
A Weak Convergence Theorem for Total Asymptotically Pseudocontractive Mappings in Hilbert Spaces
Authors: Qin Xiaolong , Cho SunYoung , Kang ShinMin 
Published: March 2011

AbstractThe modified Ishikawa iterative process is investigated for the class of total asymptotically pseudocontractive mappings. A weak convergence theorem of fixed points is established in the framework of Hilbert spaces.
About Robust Stability of Caputo Linear Fractional Dynamic Systems with Time Delays through Fixed Point Theory
Authors: De la Sen M 
Published: March 2011

AbstractThis paper investigates the global stability and the global asymptotic stability independent of the sizes of the delays of linear time-varying Caputo fractional dynamic systems of real fractional order possessing internal point delays. The investigation is performed via fixed point theory in a complete metric space by defining appropriate nonexpansive or contractive self-mappings from initial conditions to points of the state-trajectory solution. The existence of a unique fixed point leading to a globally asymptotically stable equilibrium point is investigated, in particular, under easily testable sufficiency-type stability conditions. The study is performed for both the uncontrolled case and the controlled case under a wide class of state feedback laws.
Adjuvant Combination and Antigen Targeting as a Strategy to Induce Polyfunctional and High-Avidity T-Cell Responses against Poorly Immunogenic Tumors
Authors: Aranda Fernando , Llopiz Diana , Díaz-Valdés Nancy , Riezu-Boj José Ignacio , Bezunartea Jaione , Ruiz Marta , Martínez Marta , Durantez Maika , Mansilla Cristina , Prieto Jesús , Lasarte Juan José , Borrás-Cuesta Francisco , Sarobe Pablo 
Published: March 2011

AbstractLow antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8+ T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors. Cancer Res; 71(9); 3214–24. ©2011 AACR.
Calcineurin Signaling as a Negative Determinant of Keratinocyte Cancer Stem Cell Potential and Carcinogenesis
Authors: Dotto G. Paolo 
Published: March 2011

Abstract
Calcineurin is the only known serine-threonine phosphatase under calcium–calmodulin control and key regulator of the immune system. Treatment of patients with calcineurin-inhibitory drugs like cyclosporin A and FK506 to prevent graft rejection dramatically increases the risk of cutaneous squamous cell carcinoma, which is a major cause of death after organ transplants. Recent evidence indicates that suppression of calcineurin signaling, together with its impact on the immune system, exerts direct tumor-promoting effects in keratinocytes, enhancing cancer stem cell potential. The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin and nuclear factors of activated T-cell signaling inhibits expression of ATF3, a negative regulator of p53. The resulting suppression of keratinocyte cancer cell senescence is of likely clinical significance for the many patients under treatment with calcineurin inhibitors and may be of relevance for other cancer types in which altered calcium–calcineurin signaling plays a role. Cancer Res; 71(6); 2029–33. ©2011 AACR.
Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia
Authors: Amrein Philip C. , Attar Eyal C. , Takvorian Tak , Hochberg Ephraim P. , Ballen Karen K. , Leahy Kathleen M. , Fisher David C. , LaCasce Ann S. , Jacobsen Eric D. , Armand Philippe , Hasserjian Robert P. , Werner Lillian , Neuberg Donna , Brown Jennifer R. 
Published: March 2011

Abstract
Purpose: Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL.
Experimental Design: Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily.
Results: Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6–44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA.
Conclusions: Dasatinib as a single agent has activity in relapsed and refractory CLL. Clin Cancer Res; 17(9); 2977–86. ©2011 AACR.