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1.  Development of criteria for evaluating clinical response in thyroid eye disease (CRI-TED) using a modified Delphi technique 
Archives of ophthalmology  2009;127(9):1155-1160.
To identify components of a provisional clinical response index for thyroid eye disease (CRI-TED) using a modified Delphi technique.
The International Thyroid Eye Disease Society (ITEDS) conducted a structured, 3-round Delphi exercise establishing consensus for a core set of measures for clinical trials in TED. The steering committee discussed the results in a face-to-face meeting (nominal group technique) and evaluated each criterion with respect to its feasibility, reliability, redundancy, and validity. Redundant measures were consolidated or excluded.
Criteria were parsed into 11 domains for the Delphi surveys. Eighty four respondents participated in the Delphi-1 survey, providing 220 unique items. Ninety- two members (100% of the respondents from Delphi 1 plus eight new participants) responded in Delphi-2 and rated the same 220 items. Sixty-four members (76% of participants) rated 153 criteria in Delphi-3 (67 criteria were excluded due to redundancy). Criteria with a mean greater than 6 (1 least appropriate to 9 most appropriate) were further evaluated by the nominal group technique and provisional core measures were chosen.
Using a Delphi exercise, we developed provisional core measures for assessing disease activity and severity in clinical trials of therapies for TED. These measures will be iteratively refined for use in multicenter clinical trials.
doi:10.1001/archophthalmol.2009.232
PMCID: PMC4005726  PMID: 19752424
provisional core set; thyroid eye disease; response measure; clinical trials; Delphi technique
2.  Evaluation of the Sustaining Effects of Tai Chi Qigong in the Sixth Month in Promoting Psychosocial Health in COPD Patients: A Single-Blind, Randomized Controlled Trial 
The Scientific World Journal  2013;2013:425082.
Objectives. To evaluate the sustaining effects of Tai Chi Qigong (TCQ) in improving the psychosocial health in chronic obstructive pulmonary disease (COPD) patients in the sixth month. Background. COPD affects both physical and emotional aspects of life. Measures to minimize patients' suffering need to be implemented. Methods. 206 COPD patients were randomly assigned into three groups: TCQ group, exercise group, and control group. The TCQ group completed a three-month TCQ program, the exercise group practiced breathing and walking exercise, and the control group received usual care. Results. Significant group-by-time interactions in quality of life (QOL) using St. George's respiratory questionnaire (P = 0.002) and the perceived social support from friends using multidimensional scale of perceived social support (P = 0.04) were noted. Improvements were observed in the TCQ group only. Conclusions. TCQ has sustaining effects in improving psychosocial health; it is also a useful and appropriate exercise for COPD patients.
doi:10.1155/2013/425082
PMCID: PMC3824309  PMID: 24282383
3.  The impact on patient health and service outcomes of introducing nurse consultants: a historically matched controlled study 
Background
The position of nurse consultant (NC) was introduced in Hong Kong by the Hospital Authority in January 2009. Seven NCs were appointed in five clinical specialties: diabetes, renal, wound and stoma care, psychiatrics, and continence. This was a pilot to explore the impact of the introduction of NCs on patient health and service outcomes.
Methods
The present paper describes a historically matched controlled study. A total of 280 patients, 140 in each cohort under NC or non-NC care, participated in the study. The patient health and service outcomes of both cohorts were evaluated and compared: accident and emergency visits, hospital admissions, length of hospital stays, number of acute complications, number of times of treatment or regimen altered by nurses according to patient’s condition, glycated haemoglobin A1c (HbA1c) levels, urea and urea-to-creatinine ratios, and number of wound dressings for patients in corresponding specialty units. A patient satisfaction instrument was also used to assess the NC cohort.
Results
The study showed that patients under NC care had favourable patient health and service outcomes compared with those under non-NC care. The NC cohort also reported a high level of patient satisfaction.
Conclusions
The study demonstrates that the introduction of NCs in specialty units may have a positive impact on patients’ health and service outcomes. The high level of patient satisfaction scores indicates that patients appreciate the care they are receiving with the introduction of NCs.
doi:10.1186/1472-6963-13-431
PMCID: PMC4016548  PMID: 24152979
Nurse consultant; Patient outcomes; Patient satisfaction; Hong Kong
4.  The Hong Kong Early Child Development Scale: A Validation Study 
Child Indicators Research  2012;6(1):115-135.
This paper reports on the development and validation of the Hong Kong Early Child Development Scale (HKECDS), a holistic measure of child development designed specifically for preschool children in Hong Kong. Scale development was an iterative process and the first version of the scale contained 190 items whereas the final version includes only 95. Children ranging in age from three to six years were administered trial versions of the HKECDS in Studies 1 (n = 60) and 2 (n = 240). Item analyses indicated that it is a developmental scale and that it has an appropriate level of difficulty for preschool children. It also discriminates between three- to six-year-olds from different social backgrounds in Hong Kong. The final version of the HKECDS includes items from the following eight subscales: Personal, Social and Self-Care (7 items), Language Development (13 items), Pre-academic Learning (27 items), Cognitive Development (10 items), Gross Motor (12 items), Fine Motor (9 items), Physical Fitness, Health and Safety (7 items), and Self and Society (10 items). The HKECDS is the first early child development scale which considers both the holistic development of preschool children and incorporates current expectations of early child development in Hong Kong. In this era of evidence-based decision making, it can be used to evaluate both the efficacy of targeted interventions and broader child-related public policies on early child development in Hong Kong.
doi:10.1007/s12187-012-9161-7
PMCID: PMC3568467  PMID: 23420045
Early child development scale; Holistic development; Validation; Chinese
5.  A benefit-finding intervention for family caregivers of persons with Alzheimer disease: study protocol of a randomized controlled trial 
Trials  2012;13:98.
Background
Caregivers of relatives with Alzheimer’s disease are highly stressed and at risk for physical and psychiatric conditions. Interventions are usually focused on providing caregivers with knowledge of dementia, skills, and/or support, to help them cope with the stress. This model, though true to a certain extent, ignores how caregiver stress is construed in the first place. Besides burden, caregivers also report rewards, uplifts, and gains, such as a sense of purpose and personal growth. Finding benefits through positive reappraisal may offset the effect of caregiving on caregiver outcomes.
Design
Two randomized controlled trials are planned. They are essentially the same except that Trial 1 is a cluster trial (that is, randomization based on groups of participants) whereas in Trial 2, randomization is based on individuals. Participants are randomized into three groups - benefit finding, psychoeducation, and simplified psychoeducation. Participants in each group receive a total of approximately 12 hours of training either in group or individually at home. Booster sessions are provided at around 14 months after the initial treatment. The primary outcomes are caregiver stress (subjective burden, role overload, and cortisol), perceived benefits, subjective health, psychological well-being, and depression. The secondary outcomes are caregiver coping, and behavioral problems and functional impairment of the care-recipient. Outcome measures are obtained at baseline, post-treatment (2 months), and 6, 12, 18 and 30 months.
Discussion
The emphasis on benefits, rather than losses and difficulties, provides a new dimension to the way interventions for caregivers can be conceptualized and delivered. By focusing on the positive, caregivers may be empowered to sustain caregiving efforts in the long term despite the day-to-day challenges. The two parallel trials will provide an assessment of whether the effectiveness of the intervention depends on the mode of delivery.
Trial registration
Chinese Clinical Trial Registry (http://www.chictr.org/en/) identifier number ChiCTR-TRC-10000881.
doi:10.1186/1745-6215-13-98
PMCID: PMC3413525  PMID: 22747914
Alzheimer’s disease; Burden; Depression; Positive aspects of caregiving; Positive reappraisal
6.  Immunomodulation by imiquimod in patients with high-risk primary melanoma 
Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80–100% cure rate of lentigo maligna, but studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLN), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A*0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.
doi:10.1038/jid.2011.247
PMCID: PMC3229834  PMID: 21850019
7.  A chromatin-mediated reversible drug tolerant state in cancer cell subpopulations 
Cell  2010;141(1):69-80.
SUMMARY
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various anti-cancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly “drug-tolerant” cells. These cells demonstrate >100-fold reduced drug sensitivity, and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.
doi:10.1016/j.cell.2010.02.027
PMCID: PMC2851638  PMID: 20371346
cancer; KDM5A; IGF-1R; chromatin; drug resistance; bacterial persisters
8.  Rituximab treatment of patients with severe, corticosteroid-resistant thyroid-associated ophthalmopathy 
Ophthalmology  2009;117(1):133.
Purpose
To study the effectiveness of anti-CD20 (Rituximab, RTX, Rituxan®, Genentech Inc. USA) therapy in patients with severe, corticosteroid (CS)-resistant thyroid-associated ophthalmopathy (TAO).
Design
Retrospective interventional case series
Participants
Six consecutive subjects with severe, progressive TAO unresponsive to CS.
Methods
Electronic medical record review of consecutive patients receiving RTX during the previous 18 months. Responses to therapy were graded using standard clinical assessment and flow-cytometric analysis of peripheral lymphocytes.
Main outcome measures
Clinical activity score (CAS), proptosis, strabismus, treatment side-effects, and quantification of regulatory T cells.
Results
Six patients were studied. Systemic CS failed to alter clinical activity in all patients (CAS= 5.3 + 1.0 (mean + standard deviation) before vs 5.5 + 0.8 during therapy for 7.5+ 6.4 months, p=1.0). However following RTX treatment, CAS improved from 5.5 + 0.8 to 1.3 + 0.5 at 2 months post treatment (p<0.03) and remained quiescent in all patients (CAS=0.7 + 0.8; p≤0.0001) at 6.2 + 4.5 month follow-up. Vision improved bilaterally in all 4 patients with dysthyroid optic neuropathy (DON). None of the six patients experienced disease relapse following RTX infusion and proptosis remained stable (Hertel measurement = 24 + 3.7mm before and 23.6 + 3.7mm after therapy, p=0.17). The abundance of T regulatory cells, assessed in one patient, increased within one week of RTX and remained elevated at 18 month follow-up.
Conclusions
In progressive, CS-resistant TAO, rapid and sustained resolution of orbital inflammation and DON followed treatment with RTX.
doi:10.1016/j.ophtha.2009.05.029
PMCID: PMC2814962  PMID: 19818507
thyroid eye disease; B cells; anti-CD20; Rituximab
9.  Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico 
PLoS Medicine  2010;7(12):e1000379.
Joshua Salomon and colleagues performed a cost-effectiveness analysis using health and economic outcomes following preterm birth in Mexico and showed that neonatal intensive care provided high value for the money in this setting.
Background
Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.
Methods and Findings
A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24–26, 27–29, and 30–33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.
Conclusions
Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last about 40 weeks but increasing numbers of babies are being born preterm, before they reach 37 weeks of gestation (the period during which a baby develops in its mother). In developed countries and some middle-income countries such as Mexico, improvements in the care of newborn babies (neonatal intensive care) mean that more preterm babies survive now than in the past. Nevertheless, preterm birth is still a major cause of infant death worldwide that challenges attainment of Target 5 of Millennium Development Goal 4—the reduction of the global under-five mortality rate by two-thirds of the 1990 rate by 2015 (the Millennium Development Goals, which were agreed by world leaders in 2000, aim to reduce world poverty). Furthermore, many preterm babies who survive have long-term health problems and disabilities such as cerebral palsy, deafness, or learning difficulties. The severity of these disabilities and their long-term costs to families and to society depend on the baby's degree of prematurity.
Why Was This Study Done?
Mexico recently reformed its health system in an effort to improve access to care, particularly for the poorest sections of its population, and to improve the quality of its health care. The central component of this health care reform is the System of Social Protection of Health (SSPH). The SSPH contains a family health insurance program—Seguro Popular—that aims to provide the 50 million uninsured people living in Mexico with free access to an explicit set of health care interventions. As with any insurance program, decisions have to be made about which interventions Seguro Poplar should cover. Should neonatal intensive care be covered, for example? Do the benefits of this intervention (increased survival of babies) outweigh the costs of neonatal care and of long-term care for survivors with disabilities? In other words, is neonatal intensive care cost-effective? In this study, the researchers investigate this question by estimating the clinical benefits, costs, and cost-effectiveness of neonatal intensive care in Mexico.
What Did the Researchers Do and Find?
The researchers built a decision analytic model, a mathematical model that combines evidence on the outcomes and costs of alternative treatments to help inform decisions about health care policy. They gathered data about the health outcomes of preterm births in Mexico from registers of births and deaths and from hospital discharge databases, and estimated the costs of neonatal intensive care and long-term care for disabled survivors using data from the Mexican Ministry of Health and the World Health Organization. They then applied their model, which estimates changes in parameters such as life expectancy, lifetime costs, disability-adjusted life years (DALYs; one DALY represents the loss of a year of healthy life), and incremental cost-effectiveness ratios (ICERs; the additional cost expended for each DALY averted) for neonatal intensive care compared to no intensive care, to a group of 2 million infants. Neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestation prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs at incremental costs of US$11,000, US$10,000, and US$3000, respectively, compared to no intensive care. The ICERs of neonatal intensive care for babies born at these times were US$1200, US$700, and US$300 per DALY averted, respectively.
What Do These Findings Mean?
Interventions with ICERs of less than a country's per capita gross domestic product (GDP) are highly cost-effective; those with ICERs of 1–3 times the per capita GDP are potentially cost-effective. Mexico's per capita GDP in 2005 was approximately US$8,200. Thus, neonatal intensive care could provide exceptional value for money in Mexico (and maybe in other middle-income countries), even for very premature babies. The accuracy of these findings inevitably depends on the assumptions used to build the decision analytic model and on the accuracy of the data fed into it, but the findings were little changed by a wide range of alterations that the researchers made to the model. Importantly, however, this cost-effectiveness analysis focuses on health and economic consequences of different intervention choices, and does not capture all aspects of well-being. Decisions regarding neonatal intensive care will need to be based on a full consideration of all relevant factors, including ethical issues, and cost-effectiveness analyses should continue to be updated as new data emerge on health outcomes and costs associated with neonatal intensive care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000379.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies (in English and Spanish)
The United Nations Childrens Fund (UNICEF) works for children's rights, survival, development and protection around the world; it provides information on Millennium Development Goal 4 and its Childinfo website provides detailed statistics about child survival and health (some information in several languages)
A PLoS Medicine Policy Forum by Núria Homedes and Antonio Ugalde discusses health care reforms in Mexico
doi:10.1371/journal.pmed.1000379
PMCID: PMC3001895  PMID: 21179496
10.  Ligand-dependent PDGF receptor-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGF receptor kinase inhibitors 
Cancer research  2009;69(9):3937-3946.
Platelet-derived growth factor receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically-approved multi-targeted tyrosine kinase inhibitor which inhibits VEGFR, c-KIT, and PDGFR, and has demonstrated clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (GISTs) (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 out of 637 tested human tumor-derived cell lines demonstrate significant sensitivity to single-agent sunitinib exposure. These two cell lines (a NSCLC and a rhabdomyosarcoma) demonstrated expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adeno-squamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar co-dependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to GISTs, rare tumors that demonstrate PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
doi:10.1158/0008-5472.CAN-08-4327
PMCID: PMC2676215  PMID: 19366796
Platelet-derived growth factor receptor; PDGF-C; NSCLC; sarcoma; sunitinib
11.  Chylomicron-Bound LPS Selectively Inhibits the Hepatocellular Response to Proinflammatory Cytokines 
The Journal of surgical research  2007;146(1):96-103.
Background/Aims
Pretreatment of rodent hepatocytes with chylomicron-bound LPS (CM-LPS) renders these cells unresponsive to subsequent stimulation by proinflammatory cytokines. We sought to test the selectivity of this response.
Methods
Cellular responses to hypoxia, oxidative stress, apoptosis, and heat-shock response and thermotolerance induced in CM-LPS pretreated hepatocytes were compared with responses in unpretreated cells.
Results
CM-LPS inhibited the hepatocellular response to proinflammatory cytokines without affecting the response to the other cellular stressors. It did not affect the response to oxidative stress, as measured by mitochondrial activity after hydrogen peroxide was added, or protein induction before or after stimulation with cobalt chloride. Also, induction of heat shock proteins did not differ between the CM-LPS pretreated cells and unpretreated cells. CM-LPS did not interfere with the adoption of the thermotolerant phenotype, as shown by similar mitochondrial activity between pretreated and unpretreated cells. Although stimulation with TNF-α and actinomycin D increased activity of the apoptotic enzymes, there were no differences between cells pretreated with CM-LPS and unpretreated hepatocytes.
Conclusion
When the response to proinflammatory cytokines is inhibited, hepatocellular responses to hypoxia, oxidative stress, heat shock, and apoptosis remain intact after pretreatment with CM-LPS. CM-LPS may have a specific anti-inflammatory effect on hepatocytes.
doi:10.1016/j.jss.2007.06.013
PMCID: PMC2829601  PMID: 17707407
Hepatocyte; McArdle cell; sepsis; hypoxia; oxidative stress; heat shock; thermotolerance; apoptosis
12.  The Income Gradient in Children’s Health: A Comment on Currie, Shields and Wheatley Price 
Journal of health economics  2007;27(3):801-807.
doi:10.1016/j.jhealeco.2007.10.005
PMCID: PMC2700046  PMID: 18191487
13.  Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma 
Cancer research  2008;68(12):4853-4861.
Activating BRAF kinase mutations arise in about 7% of all human tumors, and pre-clinical studies have validated the RAF-MEK-ERK signaling cascade as a potentially important therapeutic target in this setting. Selective RAF kinase inhibitors are currently undergoing clinical development, and based on the experience with other kinase-targeted therapeutics, it is expected that clinical responses to these agents, if observed, will lead to the eventual emergence of drug resistance in most cases. Thus, it is important to establish molecular mechanisms underlying such resistance in order to develop effective therapeutic strategies to overcome or prevent drug resistance. To anticipate potential mechanisms of acquired resistance to RAF inhibitors during the course of treatment, we established drug-resistant clones from a human melanoma-derived cell line harboring the recurrent V600E activating BRAF mutation, which exhibits exquisite sensitivity to AZ628, a selective RAF kinase inhibitor. We determined that elevated CRAF protein levels account for the acquisition of resistance to AZ628 in these cells, associated with a switch from BRAF to CRAF dependency in tumor cells. We also found that elevated CRAF protein levels may similarly contribute to primary insensitivity to RAF inhibition in a subset of BRAF mutant tumor cells. Interestingly, AZ628-resistant cells demonstrating either primary drug insensitivity or acquired drug resistance exhibit exquisite sensitivity to the HSP90 inhibitor geldanamycin. Geldanamycin effectively promotes the degradation of CRAF, thereby revealing a potential therapeutic strategy to overcome resistance to RAF inhibition in a subset of BRAF-mutant tumors.
doi:10.1158/0008-5472.CAN-07-6787
PMCID: PMC2692356  PMID: 18559533
14.  A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes 
Cancer cell  2006;10(5):425-435.
SUMMARY
“Oncogene addiction” describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of pro-survival and pro-apoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and –STAT3/5, and a delayed accumulation of the pro-apoptotic effector, phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes, and suggest that “addiction” associated with apoptosis reflects an active, not a passive process.
SIGNIFICANCE
The phenomenon of “oncogene addiction” has now been well documented in multiple mouse tumor models and cancer cell lines. Moreover, oncogene addiction may account for the dramatic clinical responses reported in some cancer patients treated with targeted kinase inhibitors. However, a molecular mechanism to explain oncogene addiction has been elusive. Our findings suggest that differential decay rates of pro-survival and pro-apoptotic signals emanating from an oncoprotein, such as an activated kinase, can contribute to tumor cell death following acute inactivation of an oncogene upon which they have become dependent. Our findings represent the first experimental studies that attempt to provide a molecular mechanism for oncogene dependency, and they may have important implications for the therapeutic use of targeted kinase inhibitors.
doi:10.1016/j.ccr.2006.09.014
PMCID: PMC2673136  PMID: 17097564
15.  Dignity in the care of older people – a review of the theoretical and empirical literature 
BMC Nursing  2008;7:11.
Background
Dignity has become a central concern in UK health policy in relation to older and vulnerable people. The empirical and theoretical literature relating to dignity is extensive and as likely to confound and confuse as to clarify the meaning of dignity for nurses in practice. The aim of this paper is critically to examine the literature and to address the following questions: What does dignity mean? What promotes and diminishes dignity? And how might dignity be operationalised in the care of older people?
This paper critically reviews the theoretical and empirical literature relating to dignity and clarifies the meaning and implications of dignity in relation to the care of older people. If nurses are to provide dignified care clarification is an essential first step.
Methods
This is a review article, critically examining papers reporting theoretical perspectives and empirical studies relating to dignity. The following databases were searched: Assia, BHI, CINAHL, Social Services Abstracts, IBSS, Web of Knowledge Social Sciences Citation Index and Arts & Humanities Citation Index and location of books a chapters in philosophy literature. An analytical approach was adopted to the publications reviewed, focusing on the objectives of the review.
Results and discussion
We review a range of theoretical and empirical accounts of dignity and identify key dignity promoting factors evident in the literature, including staff attitudes and behaviour; environment; culture of care; and the performance of specific care activities. Although there is scope to learn more about cultural aspects of dignity we know a good deal about dignity in care in general terms.
Conclusion
We argue that what is required is to provide sufficient support and education to help nurses understand dignity and adequate resources to operationalise dignity in their everyday practice. Using the themes identified from our review we offer proposals for the direction of future research.
doi:10.1186/1472-6955-7-11
PMCID: PMC2483981  PMID: 18620561
16.  Planar cell polarity signalling couples cell division and morphogenesis during neurulation 
Nature  2006;439(7073):220-224.
Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 in every 1000 births1. Mouse and frog models for these birth defects have suggested that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling control neurulation by promoting the convergence of neural progenitors to the midline2-8. Here we report a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anterior-posterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a role for PCP signalling in coupling cell division and morphogenesis at neurulation and suggest a novel mechanism underlying NTDs.
doi:10.1038/nature04375
PMCID: PMC1417047  PMID: 16407953
17.  Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas 
Background
Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity in vitro. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.
Methods
To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition in vitro using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m2/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).
Results
Doxycyline in vitro completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.
Conclusion
Doxycycline can block MMP-2 and MMP-9 activities from glioma cells in vitro. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.
doi:10.1186/1743-8454-5-1
PMCID: PMC2263020  PMID: 18186943
18.  Escape from serial stimuli leading to food 
If the functional relations governing the strength of a conditioned reinforcer correspond to those obtained with other Pavlovian procedures (e.g., Kaplan, 1984), the termination of stimuli appearing early in the interval between successive food deliveries should be reinforcing. During initial training we presented four key colors, followed by food, in a recurrent sequence to each of 6 pigeons. This established a baseline level of autoshaped pecking. In later sessions, we terminated each of these colors or only the first color for a brief period following each peck, replacing the original color with a standard substitute to avoid darkening the key. Pecking decreased in the presence of the last color in the sequence but increased in the presence of the first. In accord with contemporary models of Pavlovian conditioning, these and other data suggest that the behavioral effects of stimuli in a chain may be better understood in terms of what each stimulus predicts, as measured by relative time to the terminal reinforcer, than in the exclusively positive terms of the traditional formulation (Skinner, 1938). The same model may also account for the initial pause under fixed-interval and fixed-ratio schedules of reinforcement.
doi:10.1901/jeab.1986.46-259
PMCID: PMC1348266  PMID: 16812462
chaining model; sequence of stimuli; chain stimuli; relative time model; negative reinforcer; aversive stimulus; serial autoshaping; initial pause; key pecking; pigeons
19.  Intervention strategies to reduce the burden of non-communicable diseases in Mexico: cost effectiveness analysis 
Objective To inform decision making regarding intervention strategies against non-communicable diseases in Mexico, in the context of health reform.
Design Cost effectiveness analysis based on epidemiological modelling.
Interventions 101 intervention strategies relating to nine major clusters of non-communicable disease: depression, heavy alcohol use, tobacco use, cataracts, breast cancer, cervical cancer, chronic obstructive pulmonary disease, cardiovascular disease, and diabetes.
Data sources Mexican data sources were used for most key input parameters, including administrative registries; disease burden and population estimates; household surveys; and drug price databases. These sources were supplemented as needed with estimates for Mexico from the WHO-CHOICE unit cost database or with estimates extrapolated from the published literature.
Main outcome measures Population health outcomes, measured in disability adjusted life years (DALYs); costs in 2005 international dollars ($Int); and costs per DALY.
Results Across 101 intervention strategies examined in this study, average yearly costs at the population level would range from around ≤$Int1m (such as for cataract surgeries) to >$Int1bn for certain strategies for primary prevention in cardiovascular disease. Wide variation also appeared in total population health benefits, from <1000 DALYs averted a year (for some components of cancer treatments or aspirin for acute ischaemic stroke) to >300 000 averted DALYs (for aggressive combinations of interventions to deal with alcohol use or cardiovascular risks). Interventions in this study spanned a wide range of average cost effectiveness ratios, differing by more than three orders of magnitude between the lowest and highest ratios. Overall, community and public health interventions such as non-personal interventions for alcohol use, tobacco use, and cardiovascular risks tended to have lower cost effectiveness ratios than many clinical interventions (of varying complexity). Even within the community and public health interventions, however, there was a 200-fold difference between the most and least cost effective strategies examined. Likewise, several clinical interventions appeared among the strategies with the lowest average cost effectiveness ratios—for example, cataract surgeries.
Conclusions Wide variations in costs and effects exist within and across intervention categories. For every major disease area examined, at least some strategies provided excellent value for money, including both population based and personal interventions.
doi:10.1136/bmj.e355
PMCID: PMC3292518  PMID: 22389335

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