Homeless health care: meeting the challenges of providing primary care.

People experiencing homelessness have multiple complex health conditions yet are typically disengaged from primary health care services and place a significant burden on the acute health system. Barriers preventing people who are homeless from accessing primary care can be both personal and practical and include competing needs and priorities, illness and poor health, physical access to health services, difficulty in contacting services, medication security, and the affordability of health care. Differences in social status and perceptions of being judged can lead to relationship barriers to accessing primary care. Key solutions include prioritising access to stable housing, continuity of health care, specialised homeless general practice, hospital inreach, discharge planning and coordinated care, general practice outreach, and medical recovery centres.

Increased Th17/Treg Ratio in Poststroke Fatigue.

Fatigue is a major debilitating symptom after stroke. The biological mechanisms underlying poststroke fatigue (PFS) are unknown. We hypothesized that PSF is associated with an alteration in the balance between Th17 and Treg cells. To test this hypothesis we assessed fatigue in 30 stroke survivors using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Peripheral blood was collected for assessment of Th17 and Treg cell populations and measurement of interleukin-10 (IL-10). Participants were dichotomized into severe fatigue (n = 14) and low-moderate fatigue (n = 16) groups by K-mean cluster analysis of FSMC scores. There were no group differences in age, gender, stroke type, stroke severity, or time since stroke. Stroke survivors in the severe fatigue group reported greater anxiety (p = 0.004) and depression (p = 0.001) than in the low-moderate fatigue group. The ratio of Th17 to Treg cells was significantly increased in the severe fatigue group relative to the mild-moderate fatigue group (p = 0.035). Serum levels of IL-10 negatively correlated withTh17/Treg ratio (r = -0.408, p = 0.025). Our preliminary findings suggest that an imbalance in the Th17/Treg ratio is associated with the severity of PSF.

The role of IL-1ß and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): a study using cytokine receptor-deficient mice.

Cytotoxic chemotherapeutic agents often induce a cluster of cancer treatment related symptoms (CTRS). The purpose of this study was to develop a mouse model of CTRS to examine the role of IL-1ß and TNF-α signaling in the genesis of these symptoms. CTRS (change in wheel running activity, food intake, and body weight from baseline) were examined in wild type (WT) mice or mice lacking the TNF-α p55 (type 1) receptor (TNFR1-/-) and/or IL-1ß type 1 receptor (IL-1R1-/-) injected with four doses of cyclophosphamide/Adriamycin/5-fluorouracil (CAF) at 20-day intervals. Inflammatory cytokines in blood and tissues were measured using multiplex immunoassays and quantitative RT-PCR. ANOVA was used to examine differences between genotype and/or treatment group. Kaplan-Meier analysis was used to estimate survival rate. CAF rapidly increased IL-1ß and TNF-α signaling in WT mice. CAF induced acute CTRS immediately following drug injection which returned to baseline prior to the next CAF dose. Persistent CTRS were evident 3weeks after the 4th CAF dose. Acute but not persistent CTRS were associated with increased levels of IL-7, IL-9, KC, MCP-1, GCSF, and IP-10. This CAF induced inflammatory response was blunted in IL-1R1 deficient mice and absent in IL-1R1/TNFR1-deficient mice. IL-1R1-/- mice showed an identical pattern of CTRS to their WT counterparts. The assessment of CTRS in IL-1R1/TNF-R1-deficient mice was precluded by severe toxicity. Our data suggest that an important function of the IL-1ß and TNF-α driven inflammatory cascade is to promote recovery following exposure to cytotoxic agents.

Socioeconomic area disparities in tobacco retail outlet density: a Western Australian analysis.

OBJECTIVE: To examine the association between tobacco outlet density and area socioeconomic status (SES) in Western Australia. DESIGN AND SETTING: Ecological cross-sectional study investigating the relationship between the area SES of, and the density of tobacco retail outlets in, WA suburbs and towns for the Perth metropolitan area, and at the regional and state level. SES was determined using the 2006 Australian Bureau of Statistics Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) and classified into quartiles (very low, low, high and very high); tobacco outlet data were sourced from the WA Department of Health register of retailers licensed to sell tobacco at May 2011. MAIN OUTCOME MEASURE: Tobacco outlet density rate (per 10 000 residents). RESULTS: In WA overall, suburbs and towns with a very low IRSAD had more than four times the number of tobacco outlets compared with those with a very high IRSAD (P> < 0.001). This trend was similar when analyses were restricted to the Perth metropolitan area and to regional areas. Suburbs and towns in regional WA with a very low IRSAD had more than five times the number of tobacco outlets than those with a very high IRSAD (P> < 0.001). CONCLUSIONS: This study provides the first Australian evidence of a strong relationship between area SES and tobacco outlet density. Findings are consistent with a number of United States studies that report higher tobacco outlet densities in lower SES or minority neighbourhoods. The results underscore the importance of policy approaches to limit the number of tobacco retail licences granted, and to reduce the geographic density of outlets in more disadvantaged suburbs and towns.

Multiplex array analysis of serum cytokines offers minimal predictive value for cognitive function in the subacute phase after stroke.

Objective: The effects of inflammation on post-stroke cognitive function are still unclear. This study investigated the correlation between the Th17-related cytokines in peripheral blood and post-stroke cognitive function after ischemic stroke in the subacute phase. Design: A retrospective cohort study. Setting: Academic acute inpatient rehabilitation facility. Participants: One hundred and fourteen patients with first ischemic stroke were categorized as the poor cognitive recovery group (n = 58) or good cognitive recovery group (n = 56) based on their cognitive MRFS efficiency. Interventions: All subjects received routine physical, occupational, and speech-language pathology therapy. Main outcome measures: Serum cytokines/chemokine (IL-1 ß, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-17E, IL-17F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, GM-CSF, IFN-γ, MIP-3 α, TNF-α, and TNF-ß) levels were measured in duplicate using Human Th17 magnetic bead panel and multiplex array analysis (Luminex-200 system). The primary functional outcome was a gain in functional independence measure (FIM) cognitive subscore at discharge. The secondary outcome measures were FIM total score at discharge, length of stay in the hospital, and discharge destination. Cognitive Montebello Rehabilitation Factor Score (MRFS) and cognitive MRFS efficiency were calculated. Demographic and clinical characteristics were obtained from the medical record. Results: The good cognitive recovery group had an interesting trend of higher IL-13 than the poor cognitive recovery group (good cognitive recovery group 257.82 ± 268.76 vs. poor cognitive recovery group 191.67 ± 201.82, p = 0.049, unit: pg/ml). However, Pearson's correlation analysis showed no significant correlation between cytokine levels and gain of cognition, cognitive MRFS, or cognitive MRFS efficiency. Receiver operating characteristic (ROC) analysis of cytokines also suggested a low accuracy of prediction as a predictor for post-stroke cognitive recovery improvement. Conclusion: Our preliminary findings suggested that the level of serum cytokines had minimal predictive value for the recovery of cognitive function during the subacute inpatient rehabilitation after stroke.

Application of Network Analysis to Uncover Variables Contributing to Functional Recovery after Stroke.

To estimate network structures to discover the interrelationships among variables and distinguish the difference between networks. Three hundred and forty-eight stroke patients were enrolled in this retrospective study. A network analysis was used to investigate the association between those variables. A Network Comparison Test was performed to compare the correlation of variables between networks. Three hundred and twenty-five connections were identified, and 22 of these differed significantly between the high- and low-Functional Independence Measurement (FIM) groups. In the high-FIM network structure, brain-derived neurotrophic factor (BDNF) and length of stay (LOS) had associations with other nodes. However, there was no association with BDNF and LOS in the low-FIM network. In addition, the use of amantadine was associated with shorter LOS and lower FIM motor subscores in the high-FIM network, but there was no such connection in the low-FIM network. Centrality indices revealed that amantadine use had high centrality with others in the high-FIM network but not the low-FIM network. Coronary artery disease (CAD) had high centrality in the low-FIM network structure but not the high-FIM network. Network analysis revealed a new correlation of variables associated with stroke recovery. This approach might be a promising method to facilitate the discovery of novel factors important for stroke recovery.

Co-occurring Fatigue and Lymphatic Pain Incrementally Aggravate Their Negative Effects on Activities of Daily Living, Emotional Distress, and Overall Health of Breast Cancer Patients.

BACKGROUND: Fatigue and lymphatic pain are the most common and debilitating long-term adverse effects of breast cancer treatment. Fatigue and pain independently have negative effects on quality of life, physical functions, and cancer recurrence-free survival. The interactions between fatigue and pain may aggravate their negative effects. OBJECTIVES: Examine the effects of co-occurring fatigue and lymphatic pain on activities of daily living (ADLs), emotional distress, and overall health of breast cancer patients. METHODS: A cross-sectional and observational design was used to enroll 354 breast cancer patients. Valid and reliable instruments were used to assess fatigue, lymphatic pain, ADLs, emotional distress, and overall health. Descriptive statistics and multivariable regression models were used for data analysis. RESULTS: After controlling for demographic and clinical factors, patients with co-occurring fatigue and lymphatic pain had higher odds of having impaired ADLs (OR = 24.43, CI = [5.44-109.67], P < .001) and emotional distress (OR = 26.52, CI = [9.64-72.90], P < .001) compared to patients with only fatigue and only lymphatic pain. Patients with co-occurring fatigue and lymphatic pain had 179% increase in impaired ADL scores (B = 8.06, CI = [5.54-10.59]) and 211% increase in emotional distress scores (B = 9.17, CI = [5.52-12.83]) compared to those without co-occurring fatigue and lymphatic pain. Patients with co-occurring fatigue and lymphatic pain had a 34% decrease (B = -26.29, CI = [-31.90 to -20.69]) and patients with only fatigue had a 33% decrease in overall health scores (B = -25.74, 95% CI = [-34.14 to -17.33]), indicating poor overall health. CONCLUSIONS: Fatigue and lymphatic pain affected 66.4% of breast cancer patients. Findings from this study suggest that co-occurring fatigue and lymphatic pain have negative effects on breast cancer patients' ADLs, emotional distress, and overall health. The synergistic interactions between fatigue and lymphatic pain incrementally aggravated their negative effects on ADLs and emotional distress. Findings of the study highlight the need to evaluate the underlying mechanisms for co-occurring fatigue and lymphatic pain and develop interventions that target both fatigue and lymphatic pain to improve breast cancer patients' the quality of life.

Lymphatic Pain in Breast Cancer Survivors.

Background: Breast cancer survivors who report chronic pain in the affected ipsilateral upper limb or body are nearly twice as likely to develop lymphedema. Little is known about lymphatic pain, defined as co-occurring pain and swelling in the affected ipsilateral upper limb or body. The study aimed to examine the predictors and effects of lymphatic pain on breast cancer survivors' activities of daily living (ADLs). Materials and Methods: A sample of 568 patients was recruited in a metropolitan cancer center in the United States. Demographic and clinical data were collected. Body mass index (BMI) and limb volume were measured using infra-red perometer. Lymphatic pain and ADLs were measured by the Lymphedema and Breast Cancer Symptom Experience Index. Parametric and nonparametric tests and generalized linear models were used to analyze data. Results: Lymphatic pain affected 33% of survivors. Significant predictors of lymphatic pain included younger age, higher BMI, financial hardship, and a diagnosis of lymphedema. Patients with a diagnosis of lymphedema had 9.68 odds (confidence interval [CI]: 5.78-16.63; p < 0.001) and those with financial hardship had 4.64 odds (CI: 1.99-11.32; p = 0.001) of experiencing lymphatic pain. Patients with lymphatic pain had more impairments in ADLs (p < 0.001) compared to patients with only pain, only swelling, and no symptoms. Significantly more patients with lymphatic pain had a limb volume difference of >5% and >10% compared to patients with only pain and no symptom. Conclusion: This study is the first to report that in a large sample of patients, 33.1% experienced lymphatic pain and that lymphatic pain was associated with significant impairments in ADLs. Findings suggest that lymphatic pain may be due to abnormal accumulation of lymph fluid. Research is needed to ascertain the physiological mechanisms that underlie lymphatic pain and determine whether strategies to prevent and treat lymphedema can decrease lymphatic pain.

An epidermotypic model of interface dermatitis reveals individual functions of fas ligand and gamma interferon in hypergranulosis, cytoid body formation, and gene expression.

Analysis of complex cutaneous reactions using animal models allows for the identification of essential or modulatory participants, that is, cyto- and chemokines or adhesion molecules. However, complex whole animal modeling is bound to obscure some specific contributions of individual players. Mouse models suggest that expression of Fas ligand (FasL) by donor T cells is essential for the cutaneous acute graft-versus-host reaction (aGvHR), a major complication after allogeneic hematopoietic stem cell transplantation. The role of FasL/Fas in human cutaneous GvHR is not known. To understand the mechanisms of cytotoxicity and inflammation in human cutaneous GvHR, we developed an organotypic model using reconstructed human epidermis (RHE) that was exposed to FasL, gamma-interferon (IFNγ), or both. The model recapitulated key histological hallmarks of cutaneous aGvHR, including interface dermatitis, appearance of cytoid bodies, hypergranulosis, and expression of ICAM-1. Cytoid body formation and expression of ICAM-1 were attributable entirely to IFNγ, whereas hypergranulosis was triggered by FasL. Both FasL and IFNγ triggered vacuolar degeneration of keratinocytes. The validity of the RHE model of GvHR was demonstrated by histological correlation with biopsied skin from patients with acute graft-versus-host disease. FasL and IFNγ each elicited potent and specific proinflammatory genomic responses in RHE. Inhibition of caspase activity dramatically augmented the FasL-induced proinflammatory responses, suggesting an "apoptosis-versus-inflammation" antagonism in cutaneous aGvHR and other lichenoid dermatoses.

Glyphosate-Based Herbicides Alter the Reproductive Morphology of Rosa acicularis (Prickly Rose).

Glyphosate is a broad-spectrum herbicide that is widely used in many different commercial formulations. Glyphosate-based herbicides (GBH) are used in forestry operations to reduce populations of plants that compete with merchantable conifers. Past research has found that low-dose GBH applications caused male sterility in agriculturally relevant plants, sparking a need to determine the potential impacts of forestry-related GBH applications on understory plants. We investigated the effects of GBH on the reproductive morphology of Rosa acicularis, a highly prevalent understory shrub within British Columbia, Canada, growing on three operational forestry cutblocks treated with 1.782 kg a.i./ha of glyphosate, in the Omineca Region, and also in a controlled experiment. We analyzed floral and pollen morphology from treated plants and compared these with untreated plants in both scenarios. Pollen viability of treated plants was reduced by an average of 66%, and >30% of anthers were non-dehiscent compared to controls across our three field sites and experimental plants. We also found alterations in pollen and petal morphology in flowers from treated sites and glyphosate residues present in floral tissues 2 years after GBH applications. It is important to fully understand how long GBH-induced change will impact forest vegetation, to preserve natural forest biodiversity and reduce anthropogenic influences on boreal forest ecosystems.

Topographical data analysis to identify high-density clusters in stroke patients undergoing post-acute rehabilitation.

BACKGROUND: During acute stroke rehabilitation, the recovery of motor and cognitive function is highly variable: while some patients regain function, others do not. OBJECTIVE: Our objective was to identify data-driven subgroups of stroke patients undergoing acute rehabilitation using topological data analysis (TDA), compare TDA with K-means clustering, and to assess inter-group demographic and clinical differences among the subgroups. METHODS: This is a secondary data analysis of clinical, functional outcomes, and demographic data collected from 339 stroke patients undergoing acute rehabilitation post-stroke. We identified stroke recovery sub-groups using TDA on the point cloud, persistent homology, and finally, density clustering. We assessed inter-group differences in demographic and clinical characteristics using one-way ANOVA, Kruskal-Wallis, or χ2 tests. RESULTS: TDA revealed three high-density clusters among 137 subjects in the point cloud- poor-recoverers (G1(n = 34)), intermediate-recoverers (G2 (n = 88)) and good-recoverers (G3(n = 15)).Significant differences across clusters were observed for amantadine use (p = .009), number of stroke risk factors (p = .047), creatinine (p = .015), length of stay (p < .001), discharge destination (p < .001), FIM motor, FIM cognition, and FIM total on admission and discharge (all p < .001), and motor, cognition, and total MRFS scores (all p < .001). CONCLUSION: This study revealed that in addition to functional status on admission, stroke risk factors are associated with recovery outcomes. Future studies using TDA to analyze omic data, including clinical, biological, and sociodemographic factors, will accelerate the development of personalized treatment plans in post-acute stroke rehabilitation patients.

Exploring Factors Associated With Long-Term Opioid Therapy in Cancer Survivors: An Integrative Review.

CONTEXT: The prevalence of chronic pain in cancer survivors is double that of the general U.S. POPULATION: Opioids have been the foundation of cancer pain management for decades; however, there is a paucity of literature on long-term opioid therapy (LTOT) in cancer survivors. An understanding of factors related to LTOT use in cancer survivors is needed to address chronic pain and balance opioid harms in the expanding population of cancer survivors. OBJECTIVES: To analyze the research of LTOT utilization and factors associated with persistent opioid use in cancer survivors. METHODS: A five-stage integrative review process was adapted from Whittemore and Knafl. Data sources searched included Web of Science, PubMed, Embase, Cochrane, and Google Scholar. Quantitative research studies from 2010 to present related to cancer survivors managed on LTOT were included. Editorials, reviews, or abstracts were excluded. RESULTS: After reviewing 315 articles, 21 articles were included. We found that there were several definitions of LTOT in the reviewed studies, but the duration of opioid use (i.e., more than three months after completion of curative treatment) was the most common. The reviewed literature describes a relationship between LTOT and important biopsychosocial factors (cancer type, socioeconomic factors, and comorbidities). CONCLUSION: The studies in this review shed light on the factors associated with LTOT in cancer survivors. LTOT was common in certain populations of cancer survivors and those with a collection of patient-specific characteristics. This review suggests that there is a critical need for specialized research on chronic cancer pain and opioid safety in cancer survivors.

Atypical depression is more common than melancholic in fibromyalgia: an observational cohort study.

BACKGROUND: It has been postulated that atypical and melancholic depression subtypes exist in depressed fibromyalgia (FM) patients, yet no study has empirically tested this hypothesis. The purpose of this study is to determine whether major depressive disorder (MDD) with atypical features and MDD with melancholic features occurs in a FM sample and to describe their demographic, clinical and diagnostic characteristics. METHODS: An observational cohort study using a descriptive cross-sectional design recruited a convenience sample of 76 outpatients with FM from an academic rheumatology clinic and a community mental health practice. Diagnoses of FM were confirmed using the 1990 ACR classification guidelines. Diagnoses of MDD and diagnostic subtypes were determined using the DSM-IV-TR criteria. Clinical characteristics were measured using the Fibromyalgia Impact Questionnaire, Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and other standardized instruments. Odds ratios were computed on subtype-specific diagnostic criteria. Correlations assessed associations between subtype diagnoses and diagnostic criteria. RESULTS: Of the 76 subjects with FM, 11.8% (n = 9) were euthymic, 52.6% (n = 40) met diagnostic criteria for MDD with atypical features and 35.6% (n = 27) for MDD with melancholic features. Groups did not differ on demographic characteristics except for gender (p = 0.01). The non-depressed and atypical groups trended toward having a longer duration of FM symptoms (18.05 yrs. +/- 12.83; 20.36 yrs. +/- 15.07) compared to the melancholic group (14.11 yrs. +/- 8.82; p = 0.09). The two depressed groups experienced greater severity on all clinical features compared to the non-depressed group. The atypical group did not differ clinically from the melancholic group except the latter experienced greater depression severity (p = 0.001). The atypical group demonstrated the highest prevalence and correlations with atypical-specific diagnostic criteria: (e.g., weight gain/ increased appetite: OR = 3.5, p = 0.02), as did the melancholic group for melancholic-specific criteria: (e.g., anhedonia: OR = 20, p < 0.001). CONCLUSION: Depressed fibromyalgia patients commonly experience both atypical and melancholic depressive features; however, in this study, atypical depression was 1.5 times more common than melancholic depression. This finding may have significant research and clinical implications.

Symptom Clusters and Functional Impairment in Individuals Treated for Lyme Borreliosis.

Context: Persistent fatigue, pain, and neurocognitive impairment are common in individuals following treatment for Lyme borreliosis (LB). Poor sleep, depression, visual disturbance, and sensory neuropathies have also been reported. The cause of these symptoms is unclear, and widely accepted effective treatment strategies are lacking. Objectives: To identify symptom clusters in people with persistent symptoms previously treated for LB and to examine the relationship between symptom severity and perceived disability. Methods: This was a retrospective chart review of individuals with a history of treatment of LB referred to The Dean Center for Tick-Borne Illness at Spaulding Rehabilitation Hospital between 2015 and 2018 (n = 270) because of persistent symptoms. Symptoms and functional impairment were collected using the General Symptom Questionnaire-30 (GSQ-30), and the Sheehan Disability Scale. Clinical tests were conducted to evaluate for tick-borne co-infections and to rule out medical disorders that could mimic LB symptomatology. Exploratory factor analysis was performed to identify symptom clusters. Results: Five symptom clusters were identified. Each cluster was assigned a name to reflect the possible underlying etiology and was based on the majority of the symptoms in the cluster: the neuropathy symptom cluster, sleep-fatigue symptom cluster, migraine symptom cluster, cognitive symptom cluster, and mood symptom cluster. Symptom severity for each symptom cluster was positively associated with global functional impairment (p < 0.001). Conclusion: Identifying the interrelationship between symptoms in post-treatment LB in a cluster can aid in the identification of the etiological basis of these symptoms and could lead to more effective symptom management strategies. Key Message: This article describes symptom clusters in individuals with a history of Lyme borreliosis. Five clusters were identified: sleep-fatigue, neuropathy, migraine-like, cognition, and mood clusters. Identifying the interrelationship between symptoms in each of the identified clusters could aid in more effective symptom management through identifying triggering symptoms or an underlying etiology.

Acceptability and feasibility of using actigraphy to assess habitual physical activity and sleep parameters in men and women living in rural communities in conflict-affected Eastern Democratic Republic of Congo.

BACKGROUND: The goals of this study were to (1) determine the feasibility and acceptability of using actigraphy to objectively measure sleep quality and habitual physical activity in rural Democratic Republic of Congo (DRC) and (2) examine the relationship between sleep parameters, self-report symptoms, daytime physical activity, and physical function, including the ability to work. METHOD: Thirty individuals were asked to wear a wrist-worn accelerometer for 5 nights and 4 days. Nighttime sleep parameters derived were average and intra-individual variability (IIV) in total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), and wake after sleep onset (WASO). Daytime habitual physical data derived were average and peak activity and daytime napping. RESULTS: Ninety-three percent (n = 28) of participants completed the study. All participants who wore the device marked sleep and wake cycles and periods of non-wear using the marker. Trauma-related symptoms were not associated with mean or IIV in TST, SE, SOL, or WASO (p > 0.01). Those with higher levels of bodily pain slept longer (ß = 0.633, p = 0.003, adjusted R 2 = 0.279), were more likely to report that their physical health limited their physical activities (ß = 0.71, p < 0.001, adjusted R 2 = 0.679) and had greater difficulty doing daily work (ß = 0.84, p = 0.001, adjusted R 2 = 0.665). CONCLUSION: The use of actigraphy to collect objective measures of activity and sleep quality in rural post-conflict settings is feasible and acceptable. Our preliminary findings suggest that bodily pain and not trauma-related symptoms have a significant impact on sleep and functional outcomes in men and women survivors of prolonged conflict in the DRC.

HMGA2 participates in transformation in human lung cancer.

Although previous studies have established a prominent role for HMGA1 (formerly HMG-I/Y) in aggressive human cancers, the role of HMGA2 (formerly HMGI-C) in malignant transformation has not been clearly defined. The HMGA gene family includes HMGA1, which encodes the HMGA1a and HMGA1b protein isoforms, and HMGA2, which encodes HMGA2. These chromatin-binding proteins function in transcriptional regulation and recent studies also suggest a role in cellular senescence. HMGA1 proteins also appear to participate in cell cycle regulation and malignant transformation, whereas HMGA2 has been implicated primarily in the pathogenesis of benign, mesenchymal tumors. Here, we show that overexpression of HMGA2 leads to a transformed phenotype in cultured lung cells derived from normal tissue. Conversely, inhibiting HMGA2 expression blocks the transformed phenotype in metastatic human non-small cell lung cancer cells. Moreover, we show that HMGA2 mRNA and protein are overexpressed in primary human lung cancers compared with normal tissue or indolent tumors. In addition, there is a statistically significant correlation between HMGA2 protein staining by immunohistochemical analysis and tumor grade (P < 0.001). Our results indicate that HMGA2 is an oncogene important in the pathogenesis of human lung cancer. Although additional studies with animal models are needed, these findings suggest that targeting HMGA2 could be therapeutically beneficial in lung cancer and other cancers characterized by increased HMGA2 expression.

Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib.

Kinase domain (KD) mutations of Bcr-Abl interfering with imatinib binding are the major mechanism of acquired imatinib resistance in patients with Philadelphia chromosome-positive leukemia. Mutations of the ATP binding loop (p-loop) have been associated with a poor prognosis. We compared the transformation potency of five common KD mutants in various biological assays. Relative to unmutated (native) Bcr-Abl, the ATP binding loop mutants Y253F and E255K exhibited increased transformation potency, M351T and H396P were less potent, and the performance of T315I was assay dependent. The transformation potency of Y253F and M351T correlated with intrinsic Bcr-Abl kinase activity, whereas the kinase activity of E255K, H396P, and T315I did not correlate with transforming capabilities, suggesting that additional factors influence transformation potency. Analysis of the phosphotyrosine proteome by mass spectroscopy showed differential phosphorylation among the mutants, a finding consistent with altered substrate specificity and pathway activation. Mutations in the KD of Bcr-Abl influence kinase activity and signaling in a complex fashion, leading to gain- or loss-of-function variants. The drug resistance and transformation potency of mutants may determine the outcome of patients on therapy with Abl kinase inhibitors.

Encouraging young Western Australians to be smarter than smoking.

PURPOSE: Smarter than Smoking is a multistrategy statewide youth smoking intervention. This article describes key strategies and results from its inception in 1995 to 2005. DESIGN: Comprehensive evaluation included formative research and baseline and follow-up surveys. Triennial national surveys provided independent monitoring of adolescent smoking prevalence. SETTING: Western Australia. SUBJECTS: 10- to 15-year-olds. INTERVENTION: A multipronged strategy mix, including mass media, the Internet, sponsorship, school initiatives, publications, and advocacy. MEASURES: Smoking prevalence, media awareness, and attitudes toward smoking and campaign messages. ANALYSIS: Trend comparisons across the first decade of the project, along with descriptive statistics. RESULTS: Significant attitudinal and behavioral shifts were observed following media waves and over time. There was a steady increase in the proportion who had never smoked (from 40% in 1996 to 61% in 2005). Results also showed a significant decrease in smoking prevalence from 1996 to 2005, down from 28% to 7% among 14-year-olds and from 43% to 14% among 15-year-olds. CONCLUSIONS: Smarter than Smoking was effective in achieving positive shifts in awareness, attitudes, intentions, and behavior. Effectiveness appeared to have been enhanced by sustained long-term funding, youth involvement in strategy development, and a strong research and evaluation base.