bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metformin, an Antidiabetic Agent Reduces Growth of Cutaneous Squamous Cell Carcinoma by Targeting mTOR Signaling Pathway†
Authors: Chaudhary Sandeep C. , Kurundkar Deepali , Elmets Craig A. , Kopelovich Levy , Athar Mohammad 
Published: April 2012

AbstractThe biguanide metformin is widely used for the treatment of Type‐II diabetes. Its antiproliferative and pro‐apoptotic effects in various tumor cells suggest its potential candidacy for cancer chemoprevention. Herein, we report that metformin significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which was associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. This tumor growth reduction was accompanied by the enhanced apoptotic cell death and an increase in Bax:Bcl2 ratio. The mechanism by which metformin manifests antitumor effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Decreased phosphorylation of NFkB inhibitory protein IKBα together with reduced enhancement of NFkB transcriptional target proteins, iNOS/COX‐2 were observed. In addition, a decrease in the activation of ERK/p38‐driven MAP kinase signaling was seen. Similarly, AKT signaling activation as assessed by the diminished phosphorylation at Ser473 with a concomitant decrease in mTOR signaling pathway was also noted as phosphorylation of mTOR regulatory proteins p70S6K and 4E‐BP‐1 was significantly reduced. Consistently, decreased phosphorylation of GSK3β, which is carried out by AKT kinases was also observed. These results suggest that metformin blocks SCC growth by dampening NFkB and mTOR signaling pathways.
Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen
Authors: EL DIN M. S. , AMIN D. G. , RAGAB S. B. , ASHOUR E. E. , MOHAMED M. H. , MOHAMED A. M. 
Published: April 2012

SummaryIntroduction:  Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or stroke complicate its use. We aimed to determine the allele and genotype frequency of VKORC1 1173 C>T, CYP2C9*2 and CYP2C9*3 variant polymorphisms in the Egyptian population and to evaluate their influence on the interindividual differences in warfarin dosage.Methods:  A total of 154 unrelated healthy adult patients and 46 warfarin‐treated patients were included. SYBR Green‐based real‐time polymerase chain reaction (PCR) assay was used for studying VKORC1 (C1173T) and CYP2C9*3 polymorphisms. Mutagenically separated PCR assay was used to detect the CYP2C9*2 allele.Results:  VKORC1 genotype frequencies were 11%, 24% and 65% for CC, CT and TT, respectively. The prevalence of CYP2C9 haplotypes was 81% (*1\*1), 3.3% (*1\*2), 9.7% (*1\*3), 4.5% (*2\*2) and 0.65% (2\*3 and *3\*3). VKORC1 TT and CYP2C9*2\*2 were associated with a significantly lower warfarin dose. VKORC1 and CYP2C9 accounted for 31.7% and 15.6% of warfarin dose variability, respectively, and together with clinical factors explained 61.3% of total variability.Conclusion:  VKORC1‐TT and CYP2C9 *1/*1 are the most prevalent genotypes among Egyptians. Patients with VKORC1‐TT genotype required a lower warfarin dose.
Exercise Training in Heart Failure With Preserved Systolic Function: A Randomized Controlled Trial of the Effects on Cardiac Function and Functional Capacity
Authors: Smart Neil A. , Haluska Brian , Jeffriess Leanne , Leung Dominic 
Published: April 2012

©2012 Wiley Periodicals Inc.Exercise training improves functional capacity in patients with exercise limitation attributed to systolic dysfunction (SD), but exercise training effects in patients with diastolic dysfunction is unclear. The authors determined the functional capacity, quality of life, and echocardiography responses of heart failure with preserved ejection fraction (HFpEF) patients to 16 weeks exercise training. Thirty patients with HFpEF were randomized to an exercise training or non‐exercising control group. The patients had a baseline mean age of 64±8 years, left ventricular ejection fraction 57%±10%, and peak oxygen consumption (peak VO2) of 13.3±3.8 mL O2/kg/min. Minnesota Living With Heart Failure and Hare‐Davis scores and echocardiographic measures (ejection fraction, systolic and diastolic tissue velocity and filling pressure [E/E′]) were performed at baseline and after 16 weeks of exercise training. The exercise training and non‐exercising control groups showed similar baseline VO2 (12.2±3.6 mL/kg/min vs 14.1±4.1 mL/kg/min), ejection fraction (58%±13% vs 57%±8%), and systolic and diastolic function. After exercise training the increment in peak VO2 in the exercise training group was (24.6%, P=.02), and the non‐exercising control group (5.1%, P=.19). VE/VCO2 slope was reduced by 12.7% in the exercise training group (P=.02) but was unchanged in the non‐exercising control group (P=.03). No significant changes in diastolic or systolic function were noted in either group. Quality‐of‐life and depression scores were unchanged with exercise training. Changes in peak VO2 and VE/VCO2 slope were unrelated to measures of diastolic and systolic function. In patients with exercise limitation attributed to HFpEF, the improvement in peak VO2 with exercise training was not clearly related to changes in cardiac function. Congest Heart Fail.
Clinical Picture and Social Characteristics of Super‐Elderly Patients With Heart Failure in Japan
Authors: Kawai Yu , Inoue Nobutaka , Onishi Kazuo 
Published: April 2012

©2012 Wiley Periodicals Inc.The number of super‐elderly patients older than 80 years with chronic heart failure (HF) is dramatically increased in Japan; however, therapeutic strategies for patients 80 years or older remains to be established. The present investigation was undertaken to clarify the clinical picture and socioeconomic characteristics of super‐elderly HF patients. A total of 380 consecutive patients with acute HF or acutely worsening chronic HF were divided into three groups according to age: patients younger than 60 years, those 60 to 80 years, and those 80 years or older (super‐elderly group). HF patients in the super‐elderly group initially presented with more atypical symptoms at admission compared with those in the younger age group. The prevalence of HF with preserved ejection fraction was more pronounced compared with the patients in the younger age group. Furthermore, the social background was quite different for the 3 groups in several respects: recurrent hospitalization, the prevalence of dementia, and the number of patients living alone all increased with age. The lack of social support in patients with HF is a problem that needs to be resolved in the “super‐graying” societies such as Japan.
A prognostic signature of defective p53‐dependent G1 checkpoint function in melanoma cell lines
Authors: Carson Craig , Omolo Bernard , Chu Haitao , Zhou Yingchun , Sambade Maria J. , Peters Eldon C. , Tompkins Patrick , Simpson Dennis A. , Thomas Nancy E. , Fan Cheng , Sarasin Alain , Dessen Philippe , Shields Janiel M. , Ibrahim Joseph G. , Kaufmann William K. 
Published: April 2012

SummaryMelanoma cell lines and normal human melanocytes (NHM) were assayed for p53‐dependent G1 checkpoint response to ionizing radiation (IR)‐induced DNA damage. Sixty‐six percent of melanoma cell lines displayed a defective G1 checkpoint. Checkpoint function was correlated with sensitivity to IR with checkpoint‐defective lines being radio‐resistant. Microarray analysis identified 316 probes whose expression was correlated with G1 checkpoint function in melanoma lines (P ≤ 0.007) including p53 transactivation targets CDKN1A, DDB2, and RRM2B. The 316 probe list predicted G1 checkpoint function of the melanoma lines with 86% accuracy using a binary analysis and 91% accuracy using a continuous analysis. When applied to microarray data from primary melanomas, the 316 probe list was prognostic of 4‐yr distant metastasis‐free survival. Thus, p53 function, radio‐sensitivity, and metastatic spread may be estimated in melanomas from a signature of gene expression.
How the Bladder Senses? A Five‐Grade Measure
Authors: TSUNOYAMA Kuniko , SAKAKIBARA Ryuji , TAKAHASHI Osamu , SUGIYAMA Megumi , UCHIYAMA Tomoyuki , TATENO Fuyuki , KISHI Masahiko , TSUYUSAKI Yohei , YAMAMOTO Tatsuya , TANABE Kazunari 
Published: April 2012

Objectives: During bladder filling, the bladder starts to sense it and the sensation steadily increases. However, little is known concerning volume‐sensory correlation in normal bladder and pressure‐sensory correlation during detrusor overactivity (DO). We aimed to real‐time assess bladder sensation in normal bladder and DO using a five‐grade measure.Methods: We enrolled 74 normal individuals and 87 patients with DO (51 terminal, 36 phasic). During slow bladder filling, we instructed individuals to indicate sensation in five grades: 1, first sensation; 2, obviously greater than 1 but less than 3; 3, first desire to void when he or she usually goes to toilet; 4, obviously greater than 3 but less than 5; and 5, strong desire to void. We also instructed individuals to report other sensations, such as pain.Results: The five‐grade measure is feasible in all participants, showing a volume and pressure‐ sensory correlation. Among the five grades, grade 0 to 1 was the longest, followed by grade 4 to 5, in all participants. Grade 0 to 1 in phasic DO and grade 4 to 5 in terminal and phasic DO were shorter than those in normal bladder (P < 0.05). Eighty‐six percent of patients with DO reported that the rapidly increased sensory grade is akin to urinary urgency in daily life.Conclusion: The five‐grade measure is feasible to assess a volume and pressure‐sensory correlation. Using this measure the sensory grade rapidly increased during DO compared with normal bladder, and 86% of the patients with DO reported that it is akin to urinary urgency in daily life.
Efficacy of rosuvastatin for the treatment of non‐alcoholic steatohepatitis with dyslipidemia: An open‐label, pilot study
Authors: Nakahara Takashi , Hyogo Hideyuki , Kimura Yuki , Ishitobi Tomokazu , Arihiro Koji , Aikata Hiroshi , Takahashi Shoichi , Chayama Kazuaki 
Published: April 2012

Aim:  Statins, an inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase, are reported to be useful for the treatment of non‐alcoholic steatohepatitis (NASH). Currently, there is no proven therapy for NASH. In this study, we assessed the efficacy of rosuvastatin in NASH patients with dyslipidemia.Methods:  Nineteen patients with biopsy‐proven NASH with dyslipidemia who agreed to participate in this prospective study were enrolled. The patients were treated for 24 months with 2.5 mg/day rosuvastatin. Clinical and histological alterations were comparatively evaluated before and after treatment. Standard weight‐loss counseling was continued during the treatment period. Follow‐up liver biopsy was performed in nine patients.Results:  Twenty‐six percent of patients had hyperlipoproteinemia type IIa and 74% had hyperlipoproteinemia type IIb at baseline. Body mass indices were not significantly changed during the treatment. The levels of transaminases were relatively low at the beginning, and were not significantly changed during the treatment. Lipid profiles were significantly improved by the treatment with rosuvastatin for 24 months. While non‐alcoholic fatty liver disease activity score and fibrotic stage did not change significantly in all patients, they were improved in 33.3% and 33.3% individual patients, and stayed stable in 33.3% and 55.6%, respectively.Conclusion:  NASH‐related metabolic parameters improved with therapy including histology in some patients. However, one of nine patients had progression of fibrosis during the treatment. Our pilot study demonstrated the efficacy of rosuvastatin for the treatment of NASH with dyslipidemia, even if transaminases are not so elevated and controlled trials are needed in the future.
Effect of Tolfenamic Acid on Canine Cancer Cell Proliferation, Specificity Protein (Sp) Transcription Factors, and Sp‐Regulated Proteins in Canine Osteosarcoma, Mammary Carcinoma, and Melanoma Cells
Authors: Wilson H. , Chadalapaka G. , Jutooru I. , Sheppard S. , Pfent C. , Safe S. 
Published: April 2012

BackgroundTolfenamic acid (TA) is an NSAID currently under investigation as an anticancer agent in humans. TA induces proteosome‐dependent degradation of transcription factors Sp 1, 3, and 4. These proteins are known to be overexpressed in many human cancers.HypothesisTo evaluate the protein expression of Sps in canine tissue, and efficacy of TA against several canine tumor cell lines.MethodsSix canine cell lines (2 osteosarcoma, 2 mammary carcinoma, 2 melanoma) were evaluated. Protein levels of Sp 1–4 and their downstream targets were evaluated using Western Blots. Cell survival and TUNEL assays were performed on cell lines, and Sp1 expression was evaluated on histologic samples from archived canine cases.AnimalsSix immortalized canine cancer cell lines derived from dogs were used. Archived tissue samples were also used.ResultsSps were highly expressed in all 6 cell lines and variably expressed in histologic tissues. TA decreased expression of Sps 1–4 in all cell lines. All of the downstream targets of Sps were inhibited in the cell lines. Variable Sp1 expression was identified in all histologic samples examined. TA significantly inhibited cell survival in all cell lines in a dose dependant fashion. The number of cells undergoing apoptosis was significantly increased (P < .05) in all cell lines after exposure to TA in a dose‐dependent fashion.Conclusions, and Clinical ImportanceTolfenamic acid is a potential anticancer NSAID and further investigation is needed to determine its usefulness in a clinical setting.
Anti-tumour effects of elatol, a marine derivative compound obtained from red algae Laurencia microcladia
Authors: Campos Andreza , Souza Christiane Borges , Lhullier Cintia , Falkenberg Miriam , Schenkel Eloir Paulo , Ribeiro-do-Valle Rosa Maria , Siqueira Jarbas Mota 
Published: April 2012

Abstract

Objectives
This paper aims to evaluate the anti-tumour properties of elatol, a compound (sesquiterpene) isolated from algae Laurencia microcladia.

Methods
In-vitro and in-vivo anti-tumour properties of elatol were investigated using: MTT assays to assess the cytotoxic effects; flow cytometry analysis to examine the cell cycle and apoptosis; Western blot analysis for determination of the expression of cell cycle and apoptosis proteins; and study of in-vivo tumour growth in mice (C57Bl6 mice bearing B16F10 cells).

Key findings
Elatol exhibited a cytotoxic effect, at least in part, by inducing cell cycle arrest in the G1 and the sub-G1 phases, leading cells to apoptosis. Western blot analysis demonstrated that elatol reduced the expression of cyclin-D1, cyclin-E, cyclin-dependent kinase (cdk)2 and cdk4. A decrease in bcl-xl and an increase in bak, caspase-9 and p53 expression was also observed. In the in-vivo experiment, treatment with elatol was able to reduce tumour growth in C57Bl6 mice.

Conclusions
Elatol promotes a delay in the cell cycle, probably in the G1/S transition, activating the apoptotic process and this could be responsible, at least in part, for the in-vivo effects observed. Taken together, the in-vitro and in-vivo experiments suggested that elatol has anti-tumour properties. Further studies should be conducted to clarify the mechanism of action.
Investigation into the effect of varying l-leucine concentration on the product characteristics of spray-dried liposome powders
Authors: Chen Kun-Hung , Mueannoom Wunlapa , Gaisford Simon , Kett Vicky L 
Published: April 2012

Abstract

Objectives
Spray-dried formulations offer an attractive delivery system for administration of drug encapsulated into liposomes to the lung, but can suffer from low encapsulation efficiency and poor aerodynamic properties. In this paper the effect of the concentration of the anti-adherent l-leucine was investigated in tandem with the protectants sucrose and trehalose.

Methods
Two manufacturing methods were compared in terms of their ability to offer small liposomal size, low polydispersity and high encapsulation of the drug indometacin.

Key findings
Unexpectedly sucrose offered the best protection to the liposomes during the spray drying process, although formulations containing trehalose formed products with the best powder characteristics for pulmonary delivery; high glass transition values, fine powder fraction and yield. It was also found that l-leucine contributed positively to the characteristics of the powders, but that it should be used with care as above the optimum concentration of 0.5% (w/w) the size and polydispersity index increased significantly for both disaccharide formulations.

Conclusions
The method of liposome preparation had no effect on the stability or encapsulation efficiency of spray-dried powders containing optimal protectant and anti-adherent. Using l-leucine at concentrations higher than the optimum level caused instability in the reconstituted liposomes.
Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy
Authors: Tomek Mary , Akiyama Toru , Dass Crispin R 
Published: April 2012

Abstract

Objectives
Bcl-2 is a protein that inhibits apoptosis, leading to cell survival. The Bcl-2 family has six different anti-apoptotic proteins, three pro-apoptotic proteins that are similar in structure, and other integrating proteins that function as promotors or inhibitors in the progression of apoptosis. In this discussion paper, we provide an overview of apoptosis, the role of Bcl-2 in normal cellular and molecular processes, and the role of Bcl-2 in tumour cell survival. It focuses primarily on anti-apoptotic Bcl-2, its activation in cancer, the manner in which it regulates the intrinsic and extrinsic mechanisms of apoptosis, and its broad molecular interactions with other critical proteins in the cell. Certain cancer treatments are reviewed and related directions for the future are presented.

Key findings
Apoptosis is common to all organisms – for eukaryotes it is a normal process of development and regeneration. The rate at which apoptosis occurs is critical to the survival of the organism, as too much can lead to the onset of degenerative diseases such as dementia, and too little may lead to cancer. FKBP-38 is a binding protein that has been discovered to be upregulated in highly aggressive cancers and binds to Bcl-2 rather than the pro-apoptotics to induce a state of hyper-mitosis. A short binding protein (Nur-77) provides new insights into Bcl-2 ‘masking’. Nurr-77 binds to Bcl-2 and exposes the BH3 domain, transforming it from a cancer promoter to an unorthodox cancer inhibitor. This presents in itself an interesting and exciting opportunity – increasing the rate of apoptosis in neoplastic cells that are usually protected by Bcl-2 activity at the mitochondria.

Summary
Development of drugs in the form of BH3-only and BH123 mimetic drugs provide a interesting avenue for cancer therapy for the future. Drugs that can either promote, or mimic anti-IAP activity such as Smac/Diablo would certainly be productive, thereby inducing apoptosis. Medicinal usage which can effectively suppress FKBP38 in Bcl-2-dependent cancers would provide further arsenal to combat apoptotic irregularities, particularly a treatment that is more dominant than kinetin riboside. WAVE-1 inhibitors may effectively suppress the phosphorylation of Bcl-2, thereby potentially reducing hyper-mitosis and increasing apoptosis. Recent findings shed molecular light on PDT, namely ER stress, and potential for anti-cancer therapy via either apoptosis or autophagy. A drug that can effectively upregulate Nurr-77, thereby masking the anti-apoptotic properties of Bcl-2, would indeed be life-saving for cancer patients.
The Model of Pathways to Treatment: Conceptualization and integration with existing theory
Authors: Scott S. E. , Walter F. M. , Webster A. , Sutton S. , Emery J. 
Published: April 2012

Background. Studying and understanding pathways to diagnosis and treatment is vital for the development of successful interventions to encourage early detection, presentation, and diagnosis. An existing framework posited to describe the decisional and behavioural processes that occur prior to treatment (Andersen et al.'s General Model of Total Patient Delay) does not appear to match the complex and dynamic nature of the pathways into and through the health care system or provide a clear framework for research. Therefore a revised descriptive framework, the Model of Pathways to Treatment, has been proposed.Purpose. This paper presents the concepts and definitions of the Model of Pathways to Treatment and specifies how the model can encompass existing psychological theory, with particular focus on the Appraisal and Help‐seeking intervals. The potential and direction for future work is also discussed.Statement of contributionWhat is already known on this subject?

The use of theory is often lacking in existing research into delays in presentation, diagnosis and treatment of illness.

What does this study add?

A detailed account of the concepts and definitions of a revised framework: the Model of Pathways to Treatment.

Specification of how the Model of Pathways to Treatment can encompass existing psychological theory such as the Common Sense Model of Illness Self‐regulation and Social Cognitive Theory.
Expression and Immunogenicity of Recombinant Immunoreactive Surface Protein 2 of Anaplasma phagocytophilum
Authors: Yu Qiang , Chen Chuang-fu , Chen Qiang , Zhang Li-juan 
Published: April 2012

ABSTRACT

Human granulocytic anaplasmosis (HGA), caused by
Anaplasma phagocytophilum
, is an emerging tick-borne zoonotic disease throughout the world. The first HGA cases in China were documented in 2008, and the greatest challenge posed by the disease is rapid and accurate diagnosis during the acute phage of illness. In this study, we successfully cloned and expressed an
A. phagocytophilum
immunoreactive surface protein (major surface protein 2 [MSP2]) and demonstrated that this recombinant protein has natural immunogenicity by Western blotting and enzyme-linked immunosorbent assay (ELISA) using human HGA-positive sera and reference rabbit HGA-positive sera. The rabbit antisera against the recombinant protein also reacted actively with the natural antigen of
A. phagocytophilum
by immunofluorescence assay (IFA). No cross-reaction was observed between the recombinant protein and rabbit antisera against 10 common members of the order
Rickettsiales
by ELISA when the sera were diluted more than 1:100. We concluded that the recombinant MSP2 protein exhibited excellent antigenicity and specificity, results that should lay the foundation for the development of a simple and rapid diagnostic reagent and a vaccination for anaplasmosis.
Sequencing of Cladosporium sphaerospermum, a Dematiaceous Fungus Isolated from Blood Culture
Authors: Ng Kee Peng , Yew Su Mei , Chan Chai Ling , Soo-Hoo Tuck Soon , Na Shiang Ling , Hassan Hamimah , Ngeow Yun Fong , Hoh Chee-Choong , Lee Kok-Wei , Yee Wai-Yan 
Published: April 2012

ABSTRACTCladosporium sphaerospermumis one of the most widely distributed allergens causing serious problems in patients with respiratory tract disease. We report the 26,644,473-bp draft genome sequence and gene annotation ofC. sphaerospermumUM843. Analysis of the genome sequence led to the finding of genes associated withC. sphaerospermum'smelanin biosynthesis, allergens, and antifungal drug resistance.