bluuebunny/crossref_metadata_2025 huggingface dataset:
Intramuscular and Periosteal Acupuncture for Anxiety and Sleep Quality in Patients with Chronic Musculoskeletal Pain – An Evaluator Blind, Controlled Study
Authors: Hansson Ylva , Carlsson Christer , Olsson Elisabeth
Published: April 2009

Objectives

Periosteal acupuncture seems clinically to have a stronger effect on pain than standard intramuscular acupuncture. The aim of the present study was to compare their relative effectiveness on promoting psychological functioning and quality of sleep.

Methods

Consecutive patients (n=144) referred to a physiotherapist for treatment of chronic nociceptive pain in the neck or low back for more than three months, aged 18–70, were alternately allocated to an intramuscular acupuncture group (n=59), to a periosteal acupuncture group (n=55), and, for the latter part of the study, to an information control group (n=30). Eight treatments were administered during a five week period with two optional treatments after one month. All patients were encouraged to stay active. Psychological functioning was estimated with the Hospital Anxiety and Depression Scale (HAD) and quality of sleep with a visual analogue scale. All estimations were performed prior to treatment, one week after the end of treatment, and one, three and six months after end of treatment. Non-parametric statistics were used.

Results

There were no significant differences between the acupuncture groups, nor between the acupuncture and control groups during the treatment period. One month after treatment, the level of anxiety was lower in both acupuncture groups compared with the control group. The proportions of non-cases (HAD score 0–7) increased in the intramuscular acupuncture group from 39 to 47 (not significant), in the periosteal acupuncture group from 37 to 49 (P<0.001), and in the control group from 15 to 16.

Conclusion

No differences between periosteal and intramuscular acupuncture were found. One month after treatment both acupuncture interventions reduced anxiety in patients suffering from chronic nociceptive musculoskeletal pain in the neck or low back when compared with a control intervention.
Is it All about Sex? Acupuncture for the Treatment of Pain from a Biological and Gender Perspective
Authors: Lund Iréne , Lundeberg Thomas
Published: April 2009

Pain is a unique personal experience showing variability where gender and sex related effects might contribute. The mechanisms underlying the differences between women and men are currently unknown but are likely to be complex and involving interactions between biological, sociocultural and psychological aspects.

In women, painful experimental stimuli are generally reported to produce a greater intensity of pain than in men. Clinical pain is often reported with higher severity and frequency, longer duration, and present in a greater number of body regions in women than in men. Women are also more likely to experience a number of painful conditions such as fibromyalgia, temporomandibular dysfunction, migraine, rheumatoid arthritis and irritable bowel syndrome. With regard to biological factors, quantitative as well as qualitative differences in the endogenous pain inhibitory systems have been implicated, as well as an influence of gonadal hormones. Psychosocial factors like sex role beliefs, pain coping strategies, and pain related expectancies may also contribute to the differences. Being exposed to repeated painful visceral events (eg menses, labour) during life may contribute to an increased sensitivity to, and greater prevalence of, pain among women.

When assessing the outcome of pharmacological and non-pharmacological therapies in pain treatment, the factors of gender and sex should be taken into account as the response to an intervention may differ. Preferably, treatment recommendations should be based on studies using both women and men as the norm. Due to variability in results, findings from animal studies and experiments in healthy subjects should be interpreted with care.
Acupuncture for Irritable Bowel Syndrome – An Exploratory Randomised Controlled Trial
Authors: Reynolds Julie A , Bland J Martin , MacPherson Hugh
Published: April 2009

Background

The evidence on the effectiveness of acupuncture for irritable bowel syndrome (IBS) is inconclusive. However, many patients with IBS are self referring for acupuncture, therefore it is of interest to know whether acupuncture is effective or not. The aim of this study was to establish variability in the primary outcome measure to enable a sample size to be calculated for a full scale trial, and to explore feasibility and design criteria.

Methods

A pragmatic randomised controlled trial compared 10 sessions of acupuncture plus usual GP care with usual GP care alone. Thirty patients were recruited from four GP databases in Birmingham, UK, and randomised one-to-two to acupuncture or usual care alone. The primary outcome was the IBS Symptom Severity Score (SSS) at three months (maximum score 500). Analysis was by intention-to-treat, and multiple imputation was used for missing data.

Results

From the databases, 189 patients with IBS were identified, of whom 30 were eligible and consented to randomisation. At three months, a statistically and clinically significant difference between groups of 138 points (SD 90) in favour of acupuncture was observed on the IBS SSS (95% CI: 66 to 210; P=0.001) using multiple imputation. For a full scale trial, we estimate that a sample size of 108 patients per arm is required, based on a minimum clinically significant change of 50 points, drawn from a primary care population of 140 000.

Conclusions

We established the feasibility of a full scale trial, successfully recruiting patients and calculating the sample size required. The results of our pilot analysis suggest that more definitive research into acupuncture for IBS is merited. A pragmatic trial design will not be able to distinguish between acupuncture specific effects and placebo effects; however, it is the design of choice to determine cost effectiveness.
Magnets Applied to Acupuncture Points as Therapy – a Literature Review
Authors: Colbert Agatha P , Cleaver James , Brown Kimberly Ann , Harling Noelle , Hwang Yuting , Schiffke Heather C , Brons John , Qin Youping
Published: April 2009

Objectives

To summarise the acu-magnet therapy literature and determine if the evidence justifies further investigation of acu-magnet therapy for specific clinical indications.

Methods

Using various search strategies, a professional librarian searched six electronic databases (PubMed, AMED, Science Direct College Edition, China Academic Journals, Acubriefs, and the in-house Journal Article Index maintained by the Oregon College of Oriental Medicine Library). English and Chinese language human studies with all study designs and for all clinical indications were included. Excluded were experimental and animal studies, electroacupuncture and transcranial magnetic stimulation. Data were extracted on clinical indication, study design, number, age and gender of subjects, magnetic devices used, acu-magnet dosing regimens (acu-point site of magnet application and frequency and duration of treatment), control devices and control groups, outcomes, and adverse events.

Results

Three hundred and eight citations were retrieved and 50 studies met our inclusion criteria. We were able to obtain and translate (when necessary) 42 studies. The language of 31 studies was English and 11 studies were in Chinese. The 42 studies reported on 32 different clinical conditions in 6453 patients from 1986–2007. A variety of magnetic devices, dosing regimens and control devices were used. Thirty seven of 42 studies (88%) reported therapeutic benefit. The only adverse events reported were exacerbation of hot flushes and skin irritation from adhesives.

Conclusions

Based on this literature review we believe further investigation of acu-magnet therapy is warranted particularly for the management of diabetes and insomnia. The overall poor quality of the controlled trials precludes any evidence based treatment recommendations at this time.
Setting up An Acupuncture Knee Clinic under Practice Based Commissioning
Authors: Freedman Jonathan , Richardson Marion
Published: April 2009

This paper outlines the setting up of a new service in primary care offering acupuncture to patients with severe osteoarthritis of the knee. The high volume clinic is funded under the Practice Based Commissioning initiative and is the first of its type in the UK. It appears to offer a model for similar services elsewhere.
Acupuncture Induced Pneumothorax – a Case Report
Authors: Juss Jatinder K , Speed Catherine A , Warrington Jayne , Mahadeva Ravi
Published: April 2009

We report a significant complication of acupuncture in a 50 year old woman who developed a pneumothorax shortly after receiving acupuncture needling to her scapulothoracic region in a lateral oblique direction. As acupuncture is increasingly being used in pain management, physicians need to be aware of its potential adverse effects. We discuss issues relating to appropriate counselling of patients receiving this form of therapy. The inner Bladder line should be needled obliquely towards the spine.
Do General Practices Which Provide An Acupuncture Service Have Low Referral Rates and Prescription Costs? A Pilot Survey
Authors: Johnson Gina , White Adrian , Livingstone Ruth
Published: April 2009

Background

Studies by individual acupuncture practitioners have given an indication that offering acupuncture in primary care may reduce the need for referral to secondary care and reduce the costs of prescriptions. It would be informative to find out whether these findings can be supported by data from other practices. The aim of this study was to test the feasibility of surveying national data on referrals and prescribing.

Methods

Three primary care trusts (PCTs) were selected, and all practices within each trust were sent an email asking whether any member of the primary care team offered acupuncture, and if so how many appointments per week. Data on rates of referral to orthopaedic, physiotherapy, pain and rheumatology clinics were then sought from the PCT, both for the practices offering acupuncture and for the PCT as a whole. Similarly, data on costs of prescriptions for non-steroidal (NSAID) and non-opioid analgesic drugs were obtained from the Prescription Pricing Authority.

Results

Out of the 109 practices surveyed, a total of 14 (13%) offered acupuncture services to some extent. There was wide variation in provision between the different PCTs. The eight practices which offered at least one appointment per week for every 2000 registered patients were included in the analysis. The mean values (and SDs) for the three PCTs and for the eight acupuncture practices, respectively, were as follows: for referral to various clinics: orthopaedic 32.3 (16.2) and 27.4 (10.87); pain clinic 1.6 (1.3) and 2.8 (1.6); physiotherapy 13.4 (14.5) and 29.5 (10.0); and rheumatology 4.7 (2.3) and 6.4 (3.0). The mean values for costs of non-opioid analgesics were £1820 (£442) and £2008 (£762); and for NSAIDs were £4148 (£269) and £4476 (£1366), respectively. There were no trends towards a reduction of clinic referral or prescription costs.

Conclusions

We have conducted the first survey of the effects of provision of acupuncture in UK general practice, using data provided by the NHS, and uncovered a wide variation in the availability of the service in different areas. We have been unable to demonstrate any consistent differences in the prescribing or referral rates that could be due to the use of acupuncture in these practices. The wide variation in the data means that if such a trend exists, a very large survey would be needed to identify it. However, we discovered inaccuracies and variations in presentation of data by the PCTs which have made the numerical input, and hence our results, unreliable. Thus the practicalities of access to data and the problems with data accuracy would preclude a nationwide survey.
Perforation of the Median Nerve with An Acupuncture Needle Guided by Ultrasound
Authors: Kessler Jens , Streitberger Konrad
Published: April 2009

In an experiment on one of the authors, we used ultrasound to visualise an acupuncture needle completely perforating the median nerve at the acupuncture point PC6. During this procedure only a slight sensation occurred, and no pain. We conclude that, in individual cases, the median nerve might be perforated without causing pain or neurological problems.
The Methodology of Controlled Trials of Acupuncture
Authors: Vincent C A
Published: April 2009

The double-blind controlled trial methodology cannot be straightforwardly applied to trials of acupuncture. The double-blind condition, where the clinician is ignorant of the treatment allocation, cannot be sensibly maintained in trials of acupuncture or other physical treatments. The definition of an appropriate control group is also a difficult matter. The great majority of controlled trials of acupuncture so far conducted are seriously flawed by the use of a placebo control that itself has therapeutic effects. Recently more appropriate control groups have been developed, notably mock TENS, which is inert, and minimal acupuncture, which has only a very slight specific effect. As trials can only be single blind, if is especially important to monitor the adequacy of the control procedure, to ensure that it is perceived as being as effective as the true treatment. It is suggested that this can be achieved by assessing the: credibility of the two treatment procedures.

Controlled trials of acupuncture should therefore be single blind, and employ a control condition that has no more than minimal specific effects, but is nevertheless seen as a credible, bona fide treatment by patients.
UTILITY INDIFFERENCE PRICING OF INTEREST-RATE GUARANTEES
Authors: BENTH FRED ESPEN , PROSKE FRANK
Published: April 2009

We consider the problem of utility indifference pricing of a put option written on a non-tradeable asset, where we can hedge in a correlated asset. The dynamics are assumed to be a two-dimensional geometric Brownian motion, and we suppose that the issuer of the option have exponential risk preferences. We prove that the indifference price dynamics is a martingale with respect to an equivalent martingale measure (EMM) Q after discounting, implying that it is arbitrage-free. Moreover, we provide a representation of the residual risk remaining after using the optimal utility-based trading strategy as the hedge.

Our motivation for this study comes from pricing interest-rate guarantees, which are products usually offered by companies managing pension funds. In certain market situations the life company cannot hedge perfectly the guarantee, and needs to resort to sub-optimal replication strategies. We argue that utility indifference pricing is a suitable method for analysing such cases.

We provide some numerical examples giving insight into how the prices depend on the correlation between the tradeable and non-tradeable asset, and we demonstrate that negative correlation is advantageous, in the sense that the hedging costs become less than with positive correlation, and that the residual risk has lower volatility. Thus, if the insurance company can hedge in assets negatively correlated with the pension fund, they may offer cheaper prices with lower Value-at-Risk measures on the residual risk.
PRICING DOUBLE BARRIER PARISIAN OPTIONS USING LAPLACE TRANSFORMS
Authors: LABART CÉLINE , LELONG JÉRÔME
Published: April 2009

In this article, we study a double barrier version of the standard Parisian options. We give closed formulas for the Laplace transforms of their prices with respect to the maturity time. We explain how to invert them numerically and prove a result on the accuracy of the numerical inversion when the function to be recovered is sufficiently smooth. Henceforth, we study the regularity of the Parisian option prices with respect to maturity time and prove that except for particular values of the barriers, the prices are of class [Formula: see text] (see Theorem 5.1). This study heavily relies on the existence of a density for the Parisian times, so we have deeply investigated the existence and the regularity of the density for the Parisian times (see Theorem 5.3).
ENABLING OPEN INNOVATION PROCESS THROUGH INTERACTIVE METHODS: SCENARIOS AND GROUP DECISION SUPPORT SYSTEMS
Authors: BERGMAN JUKKA , JANTUNEN ARI , SAKSA JUHA-MATTI
Published: April 2009

To be able to utilise opportunities in a radically changing business environment, various organisations are transforming their practices towards open innovation processes. Openness does not, however, mean any kind of looseness in innovation management but calls for coordination and facilitation. The challenge for the management in the open innovation process is to find out the appropriate methods and practices for the utilisation of external knowledge resources. One of the first attempts, this study brings two widely utilised innovation management methods — scenarios and the group decision support system (GDSS) — to the open innovation context and suggests guidelines for the management of the open innovation process in an inter-organisational context.
PREPARATION OF CINOBUFAGIN-LOADED BOVINE SERUM ALBUMIN NANOPARTICLES FOR HEPATOCARCINOMA THERAPY
Authors: SU YONG-HUA , ZHANG JIAN-GUO , SHEN JIE , LI FENG-QIAN , SU HUA , LING CHANG-QUAN
Published: April 2009

Cinobufagin-loaded bovine serum albumin nanoparticles were prepared for treating hepatocellular carcinoma. In this report, cinobufagin-bovine serum albumin-nanoparticles (Cino-BSA-NP) were prepared by an aqueous desolvation process. The physicochemical properties, toxicity, and cancer-related applications of Cino-BSA-NP were investigated. Cino-BSA-NP had a uniform spherical morphology with a particle size in the range of 50–240 nm and an average size of 86.3 nm. The zeta potential of the nanoparticles was -49 mV. The overall embedding ratio was 79.5% and the drug loading was 24.1%. Cino-BSA-NP gave cinobufagin release of up to 53.5% within 3 h, followed by slower controlled release. Cino-BSA-NP inhibited growth of hepatocarcinoma cells in vitro to a similar extent as free cinobufagin, but with a much higher median lethal dose (LD50). Hepatic histomorphological changes indicated that hepatic damage was much less severe with Cino-BSA-NP than with free cinobufagin (2.19 mg/kg). The survival time of nude mice with orthotopic transplantation tumors treated with Cino-BSA-NP was prolonged significantly. The results confirm that Cino-BSA-NP renders cinobufagin completely dispersible in aqueous media, meeting the key requirements for intravenous injection, and show controlled release, thus significantly improving cinobufagin's antitumor activity while reducing its side effects.
TIME DOMAIN ANALYSIS OF CARBON NANOTUBE INTERCONNECTS BASED ON DISTRIBUTED RLC MODEL
Authors: FATHI DAVOOD , FOROUZANDEH BEHJAT
Published: April 2009

This paper introduces an accurate analysis of time domain response of carbon nanotube (CNT) interconnects based on distributed RLC model that takes the effect of both the series resistance and the output parasitic capacitance of the driver into account. Using rigorous principle calculations, accurate expressions for the transfer function of these lines and their time domain response have been presented. It has been shown that the second-order transfer function cannot represent the distributed behavior of the long CNT interconnects, and the fourth-order approximation offers a better result. Also, the time response of a driven long CNT interconnect versus length and diameter have been studied. The obtained results show that the overshoot increases and the time delay decreases with increasing the CNT diameter, such that with the diameter value of 10 nm for a 3.3 mm CNT interconnect, the maximum overshoot value reaches about 95% of the amplitude of the driver input. On the contrary, the overshoot increases and the time delay decreases with decreasing the length of the CNT, such that with the length value of 1 mm for a 5 nm diameter CNT interconnect, the maximum overshoot reaches about 90% of the amplitude of the driver input.
INCREASING OF THE SHARPNESS OF p–n-JUNCTIONS IN THYRISTOR STRUCTURES BY OPTIMIZATION OF INHOMOGENEITY OF DOPED STRUCTURE AND ANNEALING TIME
Authors: PANKRATOV E. L.
Published: April 2009

In the present paper the conditions to increase both the sharpness of the p–n-junctions, which produced as the elements of a system of rectifiers, and homogeneity of impurity concentrations in doped areas are determined. Moreover the development of a mathematical approach for analysis of dopant dynamics during annealing of dopant or radiation defects is presented. Annealing time has been optimized for increasing simultaneously the sharpness and the homogeneity.
PERFORMANCE EVALUATION OF ENSEMBLE EMPIRICAL MODE DECOMPOSITION
Authors: NIAZY R. K. , BECKMANN C. F. , BRADY J. M. , SMITH S. M.
Published: April 2009

Empirical mode decomposition (EMD) is an adaptive, data-driven algorithm that decomposes any time series into its intrinsic modes of oscillation, which can then be used in the calculation of the instantaneous phase and frequency. Ensemble EMD (EEMD), where the final EMD is estimated by averaging numerous EMD runs with the addition of noise, was an advancement introduced by Wu and Huang (2008) to try increasing the robustness of EMD and alleviate some of the common problems of EMD such as mode mixing. In this work, we test the performance of EEMD as opposed to normal EMD, with emphasis on the effect of selecting different stopping criteria and noise levels. Our results indicate that EEMD, in addition to slightly increasing the accuracy of the EMD output, substantially increases the robustness of the results and the confidence in the decomposition.
Delays in Grip Initiation and Termination in Persons With Stroke: Effects of Arm Support and Active Muscle Stretch Exercise
Authors: Seo Na Jin , Rymer William Z. , Kamper Derek G.
Published: April 2009

Stroke survivors' difficulty in releasing grasped objects may be attributable not only to impaired finger extension but also to delays in terminating activity in the gripping flexor muscles. This study was undertaken 1) to quantify the time needed to initiate and terminate grip muscular activity following stroke and 2) to examine effects of arm support, grip location, and active muscle stretch on the delays recorded in the paretic hand. Delays in initiation and termination of finger flexor muscle activity in response to an auditory stimulus were measured for both paretic and nonparetic hands of ten stroke survivors with chronic hemiparesis and the dominant hand of five neurologically intact subjects. Additionally, the delays for the paretic hand were recorded while an external arm support was used and after 30 min of active muscle stretch. We found that delays in grip initiation and termination were greatest for the paretic hand (1.9 and 5.0 s), followed by the nonparetic hand (0.5 and 1.6 s), and least for the control hand (0.2 and 0.4 s). Arm support reduced delay in grip termination 37% for the paretic hand. Repeated active muscle stretch resulted in 24% reduced delay in grip initiation and 32% increased delay in grip termination for the paretic hand. Therapies and interventions reducing these delays may improve the ability to grasp and release objects and thus increase functional independence for stroke survivors.
Tobacco Smoke Induces Polycomb-Mediated Repression of Dickkopf-1 in Lung Cancer Cells
Authors: Hussain Mustafa , Rao Mahadev , Humphries Ashley E. , Hong Julie A. , Liu Fang , Yang Maocheng , Caragacianu Diana , Schrump David S.
Published: April 2009

Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells. [Cancer Res 2009;69(8):3570–8]
Lineage-Specific T-Cell Responses to Cancer Mucosa Antigen Oppose Systemic Metastases without Mucosal Inflammatory Disease
Authors: Snook Adam E. , Li Peng , Stafford Benjamin J. , Faul Elizabeth J. , Huang Lan , Birbe Ruth C. , Bombonati Alessandro , Schulz Stephanie , Schnell Matthias J. , Eisenlohr Laurence C. , Waldman Scott A.
Published: April 2009

Cancer mucosa antigens are emerging as a new category of self-antigens expressed normally in immunologically privileged mucosal compartments and universally by their derivative tumors. These antigens leverage the established immunologic partitioning of systemic and mucosal compartments, limiting tolerance opposing systemic antitumor efficacy. An unresolved issue surrounding self-antigens as immunotherapeutic targets is autoimmunity following systemic immunization. In the context of cancer mucosa antigens, immune effectors to self-antigens risk amplifying mucosal inflammatory disease promoting carcinogenesis. Here, we examined the relationship between immunotherapy for systemic colon cancer metastases targeting the intestinal cancer mucosa antigen guanylyl cyclase C (GCC) and its effect on inflammatory bowel disease and carcinogenesis in mice. Immunization with GCC-expressing viral vectors opposed nascent tumor growth in mouse models of pulmonary metastasis, reflecting systemic lineage-specific tolerance characterized by CD8+, but not CD4+, T-cell or antibody responses. Responses protecting against systemic metastases spared intestinal epithelium from autoimmunity, and systemic GCC immunity did not amplify chemically induced inflammatory bowel disease. Moreover, GCC immunization failed to promote intestinal carcinogenesis induced by germ-line mutations or chronic inflammation. The established role of CD8+ T cells in antitumor efficacy, but CD4+ T cells in autoimmunity, suggests that lineage-specific responses to GCC are particularly advantageous to protect against systemic metastases without mucosal inflammation. These observations support the utility of GCC-targeted immunotherapy in patients at risk for systemic metastases, including those with inflammatory bowel disease, hereditary colorectal cancer syndromes, and sporadic colorectal cancer. [Cancer Res 2009;69(8):3537–44]
Lack of Muc1-Regulated β-Catenin Stability Results in Aberrant Expansion of CD11b+Gr1+ Myeloid-Derived Suppressor Cells from the Bone Marrow
Authors: Poh Tze Wei , Bradley Judy M. , Mukherjee Pinku , Gendler Sandra J.
Published: April 2009

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that inhibit T-cell activity and contribute to the immune suppression characteristic of most tumors. We discovered that bone marrow (BM) progenitor cells from the Muc1 knockout (KO) mice differentiated into CD11b+Gr1+ MDSCs in vitro under granulocyte macrophage colony-stimulating factor and interleukin-4 signaling. MUC1 is a tumor-associated mucin and its cytoplasmic tail (MUC1-CT) can regulate β-catenin to promote oncogenesis. Given the importance of β-catenin in hematopoiesis, we hypothesized that the MUC1 regulation of β-catenin is important for MDSC development. Our current study shows that the aberrant development of BM progenitors into CD11b+Gr1+ MDSCs is dependent on the down-regulation of β-catenin levels that occurs in the absence of Muc1. In light of this, KO mice showed enhanced EL4 tumor growth and were able to better tolerate allogeneic BM185 tumor growth, with an accumulation of CD11b+Gr1+ cells in the blood and tumor-draining lymph nodes. WT mice were able to similarly tolerate allogeneic tumor growth when they were injected with CD11b+Gr1+ cells from tumor-bearing KO mice, suggesting that tolerance of allogeneic tumors is dependent on MDSC-mediated immune suppression. This further delineates the ability of Muc1 to control MDSC development, which could directly affect tumorigenesis. Knowledge of the biology by which Muc1 regulates the development of myeloid progenitors into MDSCs would also be very useful in enhancing the efficacy of cancer vaccines in the face of tumor immune suppression. [Cancer Res 2009;69(8):3554–62]
Natural Killer Cell IFN-γ Levels Predict Long-term Survival with Imatinib Mesylate Therapy in Gastrointestinal Stromal Tumor–Bearing Patients
Authors: Ménard Cédric , Blay Jean-Yves , Borg Christophe , Michiels Stefan , Ghiringhelli François , Robert Caroline , Nonn Céline , Chaput Nathalie , Taïeb Julien , Delahaye Nicolas F. , Flament Caroline , Emile Jean-François , Le Cesne Axel , Zitvogel Laurence
Published: April 2009

Clinical outcomes of gastrointestinal stromal tumor (GIST)–bearing patients treated with imatinib mesylate (IM) are variable. Other than the site of mutation within the c-kit gene, prognostic features of GIST remain undefined. IM can exhibit off-target effects such as triggering natural killer (NK) cell activity. We addressed whether NK cell functions could predict long term survival with IM. NK cell functions were followed up in 77 GIST patients enrolled onto two phase III trials. “Immunologic responders” were defined as patients whose NK cell IFN-γ values after 2 months of IM were higher than or equal to the baseline value at entry into the trial. The prognostic effect of IFN-γ on progression-free survival was assessed by a Wald test in a Cox regression analysis using the landmark method and stratified by trial and on the c-kit mutational status. Fifty-six patients were evaluable for the NK cell IFN-γ responses at baseline and 2 months. Their median follow-up for progression-free survival was 3.7 years. Thirty-four of 56 patients were immunologic responders to IM. In the Cox regression analysis, immunologic responders possessed a hazard ratio of progression or death equal to 0.29 (95% confidence interval, 0.12–0.70; P = 0.006) compared with nonresponders. Kaplan-Meier 2-year survival estimates were 85% for immunologic responders and 50% for nonresponders. Moreover, the immunologic response added prognostic value to the c-kit mutation. The NK cell IFN-γ production after 2 months of treatment could be considered an independent predictor of long term survival in advanced GISTs treated with IM. [Cancer Res 2009;69(8):3563–9]
Inhibition of Ataxia Telangiectasia Mutated Kinase Activity Enhances TRAIL-Mediated Apoptosis in Human Melanoma Cells
Authors: Ivanov Vladimir N. , Zhou Hongning , Partridge Michael A. , Hei Tom K.
Published: April 2009

The aim of the present study was to elucidate the effects of ataxia telangiectasia mutated (ATM) kinase on the regulation of the extrinsic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2/DR5-mediated death pathway in human melanoma cells. We revealed that total ATM protein levels were high in some human melanoma lines compared with normal cells. The basal levels of active form ATM phospho-Ser1981 were also detectable in many melanoma lines and could be further up-regulated by γ-irradiation. Pretreatment of several melanoma lines just before γ-irradiation with the inhibitor of ATM kinase KU-55933 suppressed p53 and nuclear factor-κB (NF-κB) activation but notably increased radiation-induced DR5 surface expression, down-regulated cFLIP (caspase-8 inhibitor) levels, and substantially enhanced exogenous TRAIL-induced apoptosis. Furthermore, γ-irradiation in the presence of KU-55933 rendered TRAIL-resistant HHMSX melanoma cells susceptible to TRAIL-mediated apoptosis. In addition, suppression of ATM expression by the specific short hairpin RNA also resulted in down-regulation of cFLIP levels, up-regulation of surface DR5 expression, and TRAIL-mediated apoptosis in melanoma cells. Besides p53 and NF-κB, crucial regulators of DR5 expression, transcription factor STAT3 is known to negatively regulate DR5 expression. Suppression of Ser727 and Tyr705 phosphorylation of STAT3 by KU-55933 reduced STAT3 transacting activity accompanied by elevation in DR5 expression. Dominant-negative STAT3β also efficiently up-regulated the DR5 surface expression and down-regulated cFLIP levels in melanoma cells in culture and in vivo. Taken together, our data show the existence of an ATM-dependent STAT3-mediated antiapoptotic pathway, which on suppression sensitizes human melanoma cells to TRAIL-mediated apoptosis. [Cancer Res 2009;69(8):3510–9]
IFR-9/STAT2 Functional Interaction Drives Retinoic Acid–Induced Gene G Expression Independently of STAT1
Authors: Lou Ye-Jiang , Pan Xiao-Rong , Jia Pei-Min , Li Dong , Xiao Shu , Zhang Zhang-Lin , Chen Sai-Juan , Chen Zhu , Tong Jian-Hua
Published: April 2009

Retinoic acid–induced gene G (RIG-G), a gene originally identified in all-trans retinoic acid–treated NB4 acute promyelocytic leukemia cells, is also induced by IFNα in various hematopoietic and solid tumor cells. Our previous work showed that RIG-G possessed a potent antiproliferative activity. However, the mechanism for the transcriptional regulation of RIG-G gene remains unknown. Here, we report that signal transducer and activator of transcription (STAT) 2 together with IFN regulatory factor (IRF)-9 can effectively drive the transcription of RIG-G gene by their functional interaction through a STAT1-independent manner, even without the tyrosine phosphorylation of STAT2. The complex IRF-9/STAT2 is both necessary and sufficient for RIG-G gene expression. In addition, IRF-1 is also able to induce RIG-G gene expression through an IRF-9/STAT2–dependent or IRF-9/STAT2–independent mechanism. Moreover, the induction of RIG-G by retinoic acid in NB4 cells resulted, to some extent, from an IFNα autocrine pathway, a finding that suggests a novel mechanism for the signal cross-talk between IFNα and retinoic acid. Taken together, our results provide for the first time the evidence of the biological significance of IRF-9/STAT2 complex, and furnish an alternative pathway modulating the expression of IFN-stimulated genes, contributing to the diversity of IFN signaling to mediate their multiple biological properties in normal and tumor cells. [Cancer Res 2009;69(8):3673–80]
Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer
Authors: Blackford Amanda , Parmigiani Giovanni , Kensler Thomas W. , Wolfgang Christopher , Jones Siân , Zhang Xiaosong , Parsons D. Willams , Lin Jimmy Cheng-Ho , Leary Rebecca J. , Eshleman James R. , Goggins Michael , Jaffee Elizabeth M. , Iacobuzio-Donahue Christine A. , Maitra Anirban , Klein Alison , Cameron John L. , Olino Kelly , Schulick Richard , Winter Jordan , Vogelstein Bert , Velculescu Victor E. , Kinzler Kenneth W. , Hruban Ralph H.
Published: April 2009

Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced >750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer. [Cancer Res 2009;69(8):3681–8]
Multiple-Type Human Papillomavirus Infection in Male Anogenital Sites: Prevalence and Associated Factors
Authors: Nielson Carrie M. , Harris Robin B. , Flores Roberto , Abrahamsen Martha , Papenfuss Mary R. , Dunne Eileen F. , Markowitz Lauri E. , Giuliano Anna R.
Published: April 2009

Human papillomavirus (HPV) causes cervical cancer and is strongly associated with other anogenital cancers. Multiple-type HPV infection has been associated with lengthier infection and precancerous lesions. Little is known about multiple-type HPV prevalence and associated factors in men. We examined the prevalence of and risk factors for multiple-type HPV in primarily asymptomatic men. Detection of 37 HPV types in male anogenital epithelium and semen was completed in 463 men in two U.S. cities. The proportions of men with multiple HPV of any type and with multiple oncogenic or nononcogenic types were calculated. Factors associated with multiple HPV were evaluated using multinomial logistic regression. Overall, 22.9% of men had multiple-HPV, 8.6% of men had multiple oncogenic types, and 13.4% had multiple nononcogenic types. Greater proportions of samples at the shaft, glans/corona, and scrotum had multiple HPV types (18.7%, 12.8%, and 7.3%, respectively) than did other anogenital sites (all ≤2.8%). Factors independently associated with multiple-type HPV were Hispanic ethnicity [adjusted odds ratio (AOR), 2.45; 95% confidence interval (95% CI), 1.05-5.67], concurrent detection of genital warts (AOR, 10.40; 95% CI, 1.12-96.6), smoking ≥10 cigarettes/d (AOR, 3.00; 95% CI, 1.07-8.43), greater lifetime number of female sexual partners (AOR, 13.73 for ≥21 versus 1-5; 95% CI, 5.34-35.3), and condom use less than half the time (AOR, 2.03; 95% CI, 1.07-3.84). Detection of multiple HPV types in this study of primarily asymptomatic men was common, particularly at external genital sites. Lifetime number of female sex partners, condom use, and smoking were modifiable factors associated with multiple HPV. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1077–83)
A Functional Genetic Variant in microRNA-196a2 Is Associated with Increased Susceptibility of Lung Cancer in Chinese
Authors: Tian Tian , Shu Yongqian , Chen Jiaping , Hu Zhibin , Xu Lin , Jin Guangfu , Liang Jie , Liu Ping , Zhou Xiaoyi , Miao Ruifen , Ma Hongxia , Chen Yijiang , Shen Hongbing
Published: April 2009

microRNAs (miRNA) are a new class of non-protein-coding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. Recently, we conducted a survey of common single nucleotide polymorphisms (SNP) in miRNA sequences and reported that, among four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs, rs11614913 in miR-196a2 might affect mature miR-196a expression and target mRNA-binding activity and was significantly associated with non-small cell lung cancer survival. However, it remains largely unknown whether miRNA SNPs may alter lung cancer susceptibility. In the current study, we evaluated associations between the above four SNPs in pre-miRNAs and lung cancer susceptibility in a case-control study of 1,058 incident lung cancer patients and 1,035 cancer-free controls in a Chinese population. We found that miR-196a2 rs11614913 variant homozygote CC was associated with ∼25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95% confidence interval, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1183–7)
Risk Factors for Triple-Negative Breast Cancer in Women Under the Age of 45 Years
Authors: Dolle Jessica M. , Daling Janet R. , White Emily , Brinton Louise A. , Doody David R. , Porter Peggy L. , Malone Kathleen E.
Published: April 2009

Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle–Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use ≥1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (Pheterogeneity = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (Pheterogeneity = 0.02 and 0.01, respectively). Among women ≤40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use ≥1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women ≤40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1157–66)
Sex Disparities in Cancer Incidence by Period and Age
Authors: Cook Michael B. , Dawsey Sanford M. , Freedman Neal D. , Inskip Peter D. , Wichner Sara M. , Quraishi Sabah M. , Devesa Susan S. , McGlynn Katherine A.
Published: April 2009

Background: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation.

Methods: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004.

Results: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gallbladder (0.57), and anus, anal canal, and anorectum (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages >70 years for esophageal squamous cell carcinoma, and ages >30 years for lung and bronchus cancer.

Conclusion: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1174–82)
Combining Milatuzumab with Bortezomib, Doxorubicin, or Dexamethasone Improves Responses in Multiple Myeloma Cell Lines
Authors: Stein Rhona , Smith Mitchell R. , Chen Susan , Zalath Maria , Goldenberg David M.
Published: April 2009

Purpose: The humanized anti-CD74 monoclonal antibody, milatuzumab, is in clinical evaluation for the therapy of multiple myeloma (MM). The ability of milatuzumab to increase the efficacy of bortezomib, doxorubicin, and dexamethasone was examined in three human CD74+ MM cell lines, CAG, KMS11, KMS12-PE, and one CD74-MM cell line, OPM-2.

Experimental Design: Activity of milatuzumab as a monotherapy and combined with the drugs was evaluated by studying in vitro cytotoxicity, signaling and apoptotic pathways, and in vivo therapeutic activity in severe combined immunodeficient (SCID) mouse models of MM.

Results: Given as a monotherapy, cross-linked milatuzumab, but not milatuzumab alone, yielded significant antiproliferative effects in CD74+ cells. The combination of cross-linked milatuzumab with bortezomib, doxorubicin, or dexamethasone caused more growth inhibition than either cross-linked milatuzumab or drug alone, producing significant reductions in the IC50 of the drugs when combined. Efficacy of combined treatments was accompanied by increased levels of apoptosis measured by increases of activated caspase-3 and hypodiploid DNA. Both milatuzumab and bortezomib affect the nuclear factor-κB pathway in CAG MM cells. In CAG- or KMS11-SCID xenograft models of disseminated MM, milatuzumab more than doubled median survival time, compared with up to a 33% increase in median survival with bortezomib but no significant benefit with doxorubicin. Moreover, combining milatuzumab and bortezomib increased survival significantly compared with either treatment alone.

Conclusions: The therapeutic efficacies of bortezomib, doxorubicin, and dexamethasone are enhanced in MM cell lines when given in combination with milatuzumab, suggesting testing these combinations clinically.