bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of flexible-heteroarotinoids for kidney cancer
Authors: Liu Tongzu , Masamha Chioniso Patience , Chengedza Shylet , Berlin K. Darrell , Lightfoot Stan , He Feng , Benbrook Doris Mangiaracina
Published: May 2009

Potential chemopreventive and therapeutic value of the lead Flexible Heteroarotinoid (Flex-Het), SHetA2, was indicated by growth inhibition of multiple cancer cell lines. The objective of this study was to evaluate the SHetA2 mechanism and in vivo activity in kidney cancer. SHetA2 induced apoptosis in the Caki-1 kidney cancer cell line through reduction of Bcl-2 protein and induction of PARP-1 and caspase 3 cleavages, whereas normal kidney epithelial cells exhibited resistance. Both normal and cancerous cells underwent G1 arrest and loss of Cyclin D1. Tubule differentiation was induced in organotypic cultures and xenograft tumors in association with increases in E-Cadherin mRNA and protein expression. SHetA2 repressed activity of nuclear factor-κB, a transcription factor that regulates apoptosis, Bcl-2, growth, Cyclin D1, differentiation, and E-Cadherin in the opposite manner as SHetA2. Glutathione binding and generation of reactive oxygen species were not required for these activities. Oral SHetA2 inhibited growth in one of two renal cancer xenograft models without causing mortality or weight loss. Structure function analysis of related Flex-Hets for potential improvement of SHetA2 pharmaceutical properties showed that compounds with increased hydrophilicity slightly reduced the growth inhibition efficacy, but retained the differential effect on cancer over normal cells. Flex-Hets and metabolites were not mutagenic in the Ames test. In conclusion, SHetA2 regulates growth, differentiation, and apoptosis in kidney cancer cells through multiple molecular events downstream of nuclear factor-κB repression. Increasing the hydrophilicity of Flex-Hets does not attenuate the differential effect on cancer cells over normal cells, thus offering alternatives for improvement of therapeutic value.[Mol Cancer Ther 2009;8(5):OF1–12]
Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor–induced apoptosis
Authors: Baumeister Peter , Dong Dezheng , Fu Yong , Lee Amy S.
Published: May 2009

Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with antiapoptotic properties. We present here the mechanism for repression of the Grp78 promoter by HDAC1. Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before, but not after, ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor–induced apoptosis in cancer cells, and conversely, suppression of GRP78 sensitizes them to HDAC inhibitors. These results define HDAC inhibitors as new agents that up-regulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anticancer therapies that use these compounds. [Mol Cancer Ther 2009;8(5):1086–94]
Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin
Authors: LeBeau Aaron M. , Brennen W. Nathaniel , Aggarwal Saurabh , Denmeade Samuel R.
Published: May 2009

Fibroblast-Activation Protein-α (FAP) is a membrane-bound serine protease that is expressed on the surface of reactive stromal fibroblasts present within the majority of human epithelial tumors but is not expressed by normal tissues. FAP is a postprolyl peptidase that differs from other dipeptidyl prolyl peptidases such as diprolylpeptidase 4 in that it also has gelatinase and collagenase endopeptidase activity. Therefore, FAP represents a potential pan-tumor target whose enzymatic activity can be exploited for the intratumoral activation of prodrugs and protoxins. To evaluate FAP as a tumor-specific target, putative FAP-selective peptide protoxins were constructed through modification of the prodomain of melittin, a 26 amino acid amphipathic cytolytic peptide that is the main toxic component in the venom of the common European honeybee Apis milefera. Melittin is synthesized as promelittin, containing a 22 amino acid NH2-terminal prodomain rich in the amino acids proline and alanine. In this study, peptides containing truncated melittin prodomain sequences were tested on erythrocytes to determine the optimal prodomain length for inhibiting cytolytic activity. Once optimized, modified promelittin peptides were generated in which previously identified FAP substrate sequences were introduced into the prodomain. Peptide protoxins were identified that were efficiently activated by FAP and selectively toxic to FAP-expressing cell lines with an IC50 value in the low micromolar range that is similar to melittin. Intratumoral injection of an FAP-activated protoxin produced significant lysis and growth inhibition of human breast and prostate cancer xenografts with minimal toxicity to the host animal. [Mol Cancer Ther 2009;8(5):1378–86]
Knowledge of Heart Disease Risk Among SHIELD Respondents With Dyslipidemia
Authors: Lewis Sandra J. , Fox Kathleen M. , Bullano Michael F. , Grandy Susan
Published: May 2009

Background—

Respondents in the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) reported whether they had a diagnosis of dyslipidemia, were taking prescription dyslipidemia medication, and knew their heart disease risk (low, moderate, high, or do not know). We assessed whether respondents who reported a diagnosis of dyslipidemia with or without lipid-modifying treatment knew their heart disease risk and whether it correlated with National Cholesterol Education Program Adult Treatment Panel (ATP) III risk.

Methods and Results—

Based on self-report of risk factors, ATP III high risk was defined as diagnosis of heart disease/heart attack, narrow/blocked arteries, stroke, or diabetes; moderate risk included ≥2 risk factors (ie, men aged >45 years, women aged >55 years, hypertension, low high-density lipoprotein cholesterol, current smoking, and family history of CHD); and low risk included <2 risk factors. Of 7629 respondents with dyslipidemia, 35% reported not taking cholesterol medication, and 29% reported not knowing their heart disease risk. For respondents treated for dyslipidemia, 27% reported not knowing their risk, and of the 73% who reported knowing, 24% to 35% reported the same risk level as ATP III risk. For respondents with untreated dyslipidemia, 33% reported not knowing their risk, and of the 67% who reported knowing, 20% to 37% reported the same risk as ATP III risk.

Conclusions—

A large proportion of respondents with dyslipidemia did not know their heart disease risk. Among those who reported knowing their risk level, >60% of respondents did not classify themselves at the same ATP III-defined risk level. There is a gap in understanding and awareness of heart disease risk among respondents with dyslipidemia regardless of treatment status.
Is Environmental Tobacco Smoke Exposure a Risk Factor for Acute Gastroenteritis in Young Children?
Authors: Kum-Nji Philip , Mangrem Carole L. , Wells Peggy J. , Herrod Henry G.
Published: May 2009

Because passive smoke exposure has not been previously linked to diarrhea diseases in children, it was hypothesized that very young children exposed to environmental tobacco smoke (ETS) exposure at home would also be more likely to develop infectious gastroenteritis (GE) than their unexposed counterparts. During 1-year period, 260 children 36 months and younger were prospectively followed up in a private pediatric practice in a southern community in the United States. Multiple logistic regression analysis showed that ETS was strongly predictive of acute GE in the univariate analysis ( P = .003). Even after controlling for the various confounders, ETS exposure was still significantly associated with acute GE (relative risk = 2.55; 95% CI = 1.26-5.18). It is speculated that, similar to acute respiratory infections, the same mechanisms may explain why ETS may also be associated with acute infectious GE.
Optimizing Fiber Direction in Perforated Orthotropic Media to Reduce Stress Concentration
Authors: Cho H.K. , Rowlands R.E.
Published: May 2009

Structures often consist of composite members containing holes or notches. Since stress concentrations associated with such geometric discontinuities can decrease strength, there is desire to minimize stress concentrations. This article demonstrates ability to reduce tensile stress concentrations in perforated composites by synergizing a finite-element program with a feasible-direction method to optimize fiber directions locally, i.e., form a functionally graded material. Optimization is conducted under constraints on the maximum stress in the structure. In addition to reducing the tensile stress concentration beyond that achieved by previous methods, the current approach is compatible with contemporary processing techniques.
Victim-Offender Racial Dyads and Clearance of Lethal and Nonlethal Assault
Authors: Roberts Aki , Lyons Christopher J.
Published: May 2009

Previous clearance research provides an incomplete test of theories emphasizing the role of both victim and offender status in police discretion. Using National Incident Based Reporting System (NIBRS) data, we investigate the impact of both victim's and offender's race, and, in particular, victim— offender racial dyads on homicide clearance by arrest, using event history (survival) analysis, so that time to clearance and censoring are considered. We also compare models for homicide clearance with those for aggravated assault. For homicides, results indicate that incidents with non-white offenders are more likely to be cleared by arrest than those with white offenders, regardless of victim's race. In contrast, for aggravated assault, dyads are important: incidents involving white victims and offenders are most likely to be cleared, with incidents involving non-white parties least likely to be cleared. Furthermore, the impact of victim—offender racial dyads on clearance is smaller for homicide than for aggravated assault.
A Spatial Statistical Approach to Identifying Areas with Poor Access to Grocery Foods in the City of Buffalo, New York
Authors: Lee Gyoungju , Lim Hyunwoo
Published: May 2009

This paper proposes a spatial statistical approach to identifying the deprived areas where the access to grocery foods is restricted due to the destitute economic status of the target residents (the poor). For this purpose, the ratio of the expected population demand and observed food supply in each census block group is formulated as discrepancy index to denote the level of accessibility to grocery. Then, using the G-statistic, the regional spatial pattern of the indices is investigated to detect local hot-spots of disparity between population need and grocery provision at various spatial scales. The City of Buffalo is illustrated for this approach and planning implications for improving the accessibility are briefly discussed.
Culture-led Urban Regeneration and Community Mobilisation: The Case of the Taipei Bao-an Temple Area, Taiwan
Authors: Lin Cheng-Yi , Hsing Woan-Chiau
Published: May 2009

This article aims to explore the role of community mobilisation in Taipei's culture-led urban regeneration process by analysing the case of the Bao-an Temple area. Over recent years, capitalising on cultural resources as a motor driving urban regeneration has increasingly become a central issue of post-industrial urban governance. Although previous researchers have emphasised the contributions of cultural strategies to local economic regeneration, the means to integrate unique cultural resources of local communities into urban regeneration projects still remain poorly understood. Within the debates on urban cultural strategies, this article argues that the generation and use of cultural resources in urban regeneration lie in community mobilisation and institutional support, rather than in a state-led cultural flagship approach. After examining the Bao-an Temple area in Taipei, Taiwan, this article concludes that local government needs to move beyond the instrumentalism of urban cultural strategies and to rediscover the spaces where local cultural activities and mobilisation capacities are attached. Only through understanding the relationship between place and community mobilisation will a virtuous cycle for the revitalisation of a unique and historical urban area be generated.
Student Intercultural Proficiency From Study Abroad Programs
Authors: Clarke Irvine , Flaherty Theresa B. , Wright Newell D. , McMillen Robert M.
Published: May 2009

In the past decade, study abroad programs (SAPs) have more than doubled, where today, about 223,000 U.S. college students study abroad, immersing themselves in foreign language, culture, and business practices. It is customary to hear students describe these experiences as “life changing,” yet little empirical evidence exists to establish the specific areas of personal development achieved in a SAP. This study investigates several of the potential intercultural influences of a semester abroad for students from the United States. Findings reveal that students who study abroad may have greater intercultural proficiency, increased openness to cultural diversity, and become more globally minded than those students remaining in a traditional campus setting. Students who participate in SAPs perceive themselves as being more proficient, approachable, and open to intercultural communication.
Differences in Physician and Patient Ratings of Items Used to Assess Hip Disorders
Authors: Martin RobRoy L. , Mohtadi Nicholas G. , Safran Marc R. , Leunig Michael , Martin Hal D. , McCarthy Joseph , Guanche Carlos A. , Kelly Bryan T. , Byrd J. W. Thomas , Clohisy John C. , Philippon Marc J. , Sekiya Jon K.
Published: May 2009

Background

The purpose of this study was to determine what issues are important to active individuals with hip lesions and to assess whether these issues are different from those that surgeons think are important.

Hypothesis

A discrepancy will be noted between what patients and surgeons believe to be important.

Study Design

Cross-sectional study; Level of evidence, 3.

Methods

This study comprised 150 consecutive patients (73 men, 77 women) from the international practices of 9 orthopaedic surgeons specializing in the management of hip disorders. All participants were seeking treatment for musculoskeletal hip disease. Average patient age was 42 ± 11 years (range, 18-60). Patients and surgeons rated the importance of 146 potential hip outcome assessment items on a 6-point Likert-type scale.

Results

Of the 23 items identified as being important to patients, 16 were in the sports and recreation category. The top 11 items that the clinicians thought were most important were rated significantly lower by patients (P <. 0005). Specifically, surgeons rated several items as being important that fell into the symptoms, functional limitations, and occupational issues categories, whereas patients did not. That is, a difference was found between patients and clinicians in how they rated items related to symptoms, functional limitations, and occupation (P <. 01). A difference was not found between patients and surgeons in how they rated items related to sports and recreation and social-emotional lifestyle (P >. 01).

Conclusion

The hypothesis of this study was affirmed: a discrepancy was found between what issues patients believe are important and what surgeons perceive as being important to patients. This information may be particularly important when assessing treatment outcomes from a patient's perspective. Clinicians must be careful in presuming that the issues that they are attempting to improve with treatment are issues that are important to patients. These findings also emphasize the importance of discussing appropriate postoperative expectations for those considering surgery.
Flame Spread in Opposed Flow along the Ground Soaked with High-volatile Liquid Fuel
Authors: Ishida Hiroki , Kenmotsu Yusuke
Published: May 2009

The flame spread in opposed flow through the layered flammable gas mixture along the ground soaked with high-volatile liquid fuel was studied experimentally. The effects of opposed flow velocity on the aspect of flame spread, the velocity of flame spread, the thickness of flammable gas layer and the preheated distance ahead of the flame leading edge were investigated experimentally. If the velocity of opposed flow at about 1 mm above the ground surface is over the flame spread velocity with no surrounding airflow, no flame spread occurs even when the ground temperature is highly above the flash point of the spilled liquid fuel. The velocity of opposed flow has a large effect on the preheat distance ahead of the flame leading edge also. With increase in the velocity of opposed flow, the maximum preheat distance decreases to the local minimum, and increases to the local maximum thereafter. This is due to the balance between the convective cooling by the flow and the heat conduction through the ground beneath the inclined flame in downstream.
Sex Objects, Athletes, and Sexy Athletes
Authors: Daniels Elizabeth A.
Published: May 2009

In contrast to the large body of research examining the negative effects of idealized media images on girls' and women's body image, little research has investigated whether media images can positively impact body concept among females. Using a between-participants experimental design, this study examined how images of performance athletes, sexualized athletes, sexualized models, and nonsexualized models impacted adolescent girls' and college women's tendency to self-objectify. Participants were 350 adolescent girls and 225 college women who completed a measure of body objectification after viewing photographs. As expected, performance athlete images prompted less self-objectification, suggesting the need for more of this imagery in mainstream media.
Forging the Future Between Two Different Worlds
Authors: Jun Li
Published: May 2009

In order to understand the interplay of culture and mind in immigrant adolescent learning and psychological adjustment, this multiple-case qualitative study examined salient home and school experiences told by recent Chinese immigrant youth in semistructured interviews and narrative essays. Forging the future between two different worlds defined, respectively, by Chinese tradition and Canadian culture, these adolescents struggled with high parental expectations and intergenerational conflicts at home and suffered acculturative stresses and ethnic peer divides at school. Situating the voices of the immigrant adolescents in the personal, relational, and larger sociocultural contexts, the study suggests that their ongoing psychological adjustment and transformation at the crossroad of two different cultures must be understood in light of the emerging, interdependent individual and social processes.
Consistency of Clinical Diagnosis of Dementia in NEDICES: A Population-Based Longitudinal Study in Spain
Authors: Bermejo-Pareja F. , Benito-León J. , Vega S. , Olazarán J. , de Toledo M. , Díaz-Guzmán J. , Sánchez-Sánchez F. , Morales-González J.M. , Trincado R. , Portera-Sánchez A. , Román G.C.
Published: May 2009

Background: Few longitudinal studies have verified the clinical diagnosis of dementia based on clinical examinations. We evaluated the consistency of the clinical diagnosis of dementia over a period of 3 years of follow-up in a population-based, cohort study of older people in central Spain. Methods: Individuals (N = 5278) were evaluated at baseline (1994-1995) and at follow-up (1997-1998). The evaluation included a screening questionnaire for dementia and a neurological assessment. Results: Dementia screening consisted of a 37-item version of the Mini-Mental State Examination (MMSE) and the Pfeffer Functional Activities Questionnaire (FAQ). Study neurologists investigated those participants who screened positively (N = 713) as well as 843 who had screened negatively to test the sensitivity of the screening instruments or because they had a positive screening for other chronic neurological diseases. We detected 295 patients among those who screened positive and 13 among those who screened negatively. Three years follow-up evaluation demonstrated 14 diagnostic errors at baseline (4.5%) leading to a final number of 306 patients with dementia. The corrected prevalence of dementia was 5.8% (95% confidence interval [CI] 5.2-6.5). Conclusions: The diagnosis of dementia was highly accurate in this population-based, Spanish cohort study, and our prevalence figures agree with other European surveys. Given the high cost and difficulties of population rescreening and its relatively low yield, we conclude that a single 2-phase investigation (screening followed by clinical examination) provides accurate information for most population-based prevalence studies of dementia.
North Carolina Family Assessment Scale: Measurement Properties for Youth Mental Health Services
Authors: Lee Bethany R. , Lindsey Michael A.
Published: May 2009

Objective: The purpose of this study is to assess the reliability and validity of the North Carolina Family Assessment Scale (NCFAS) among families involved with youth mental health services. Methods: Using NCFAS data collected by child mental health intake workers with 158 families, factor analysis was conducted to assess factor structure, and thematic analysis of intake notes was used to test content validity. Results: This study found only three NCFAS subscales. The case notes included themes specific to youth with mental health needs that were not captured by current NCFAS items. Conclusions: This study suggests variation in the fit for the NCFAS in child mental health services compared to the measurement properties established in child welfare samples.
Using Feature Films as the Primary Instructional Medium to Teach Organizational Behavior
Authors: Smith Gerald W.
Published: May 2009

The use of film to assist with teaching various theoretical concepts has been integrated into the classroom for many years. However, the use of films has been primarily as a supplementary material to the typical textbook instruction. This article bridges the gap in the literature and discusses one approach whereby feature films were incorporated into an organizational behavior class as the primary instructional medium. Student exam results, coupled with their in-class discussion and evaluation comments, reflected great success with this approach.
Suicide Risk Screening in an Emergency Department
Authors: Folse Victoria N. , Hahn Rebecca L.
Published: May 2009

A study was conducted to detect suicide risk in adolescents and adults seeking treatment in an emergency department (ED) in the Midwest as well as to continue testing reliability and validity of the 4-item Risk of Suicide Questionnaire (RSQ) developed by Horowitz et al. This study included ED staff nurses in a Level II Trauma Center who administered the RSQ to adolescent, adult, and geriatric patients, regardless of chief complaint or psychiatric history. Participants consisted of a convenience sample of 202 patients composed of 59 adolescents and 143 adults, including 36 geriatric patients. Psychometric analysis demonstrated a lower-than-expected degree of reliability and an adequate level of criterion-related validity for the RSQ in this sample. Interrater reliability was established. Approximately 42% of all patients who participated screened positive for suicide risk using the RSQ. Results support screening by nurses as part of the admission assessment to determine suicide risk in patients who present to the ED.
Metastatic Clear Cell Renal Cell Carcinoma Presenting as Multiple Colonic Polyps
Authors: Chetty Runjan , Syed Abdul , van der Kwast Theodorus
Published: May 2009

A 92-year-old male presented for routine endoscopic surveillance of his gastrointestinal (GI) tract. He did not have any GI symptoms currently, and the patient had undergone a right nephrectomy for renal cell carcinoma 17 years previously. A lower GI endoscopy revealed polyps in the ascending colon, hepatic flexure, and sigmoid colon (2 polyps). All the polyps were snared and removed in toto. Histological evaluation of all 4 polyps showed similar features. There was expansion of the lamina propria by sheets of clear cells arranged in a nested pattern with a rich vascular network. Immunohistochemistry showed the tumor to be positive for low-molecular-weight cytokeratin, CD10, and vimentin. The features were morphologically and immunophenotypically that of clear cell renal cell carcinoma. This case highlights an extremely unusual presentation of recurrent renal cell carcinoma as multiple, separate colonic polyps 17 years after resection of the primary tumor.
Autopsy Findings in 14 Patients With Penile Squamous Cell Carcinoma
Authors: Chaux Alcides , Reuter Victor , Lezcano Cecilia , Velazquez Elsa , Codas Ricardo , Cubilla Antonio L.
Published: May 2009

The aim of this study was to describe pathologic features found at autopsy of 14 patients with penile cancer. Nine patients died from disseminated disease; 5 of them presented local/regional recurrences. Five patients died from other causes, 2 of them postoperatively. Local recurrence sites were corpus cavernosum, Buck’s fascia and urethra, regional skin, and prostate. Metastatic sites were lymph nodes (9 cases), liver (7 cases), lungs (6 cases), heart (5 cases), adrenals, bone and skin (3 cases each), thyroid and brain (2 cases each), and pancreas, spleen, and pleura (1 case each). Patients with heart metastasis had arrhythmias. Patients who died and who did not die from penile cancer had different profiles: low-grade superficial tumors with usual and warty subtypes versus high-grade deeply invasive basaloid or hybrid verrucous/sarcomatoid carcinomas. A natural history model for penile cancer routes of spread is proposed: local intrapeneal, regional and systemic nodes, regional skin, liver, lungs, heart, and other multiple sites.
Immigration Effects on Homicide Offending For Total and Race/Ethnicity-Disaggregated Populations (White, Black, and Latino)
Authors: Feldmeyer Ben , Steffensmeier Darrell
Published: May 2009

Sociological studies of crime have rarely examined the effects of immigration on aggregate patterns of violent offending, and particularly few studies have examined this relationship across multiple racial/ethnic populations. The current study extends research on immigration and crime by examining this relationship across total and race/ ethnicity-disaggregated populations (i.e., White, Black, and Latino) and for homicide offending (rather than homicide victimization) using 1999-2001 arrest data drawn from 328 census places in California. Findings reveal that immigrant concentration has trivial (nonsignificant) effects on overall homicides and Latino homicides, but slightly reduces White and Black homicide offending, net of controls. Implications of these findings are as follows: (a) Immigration does not have violence-generating effects but instead appears to have violence-neutral or perhaps some violence-reducing effects on homicide offending, and (b) This small or null effect is fairly consistent across racial/ ethnic populations.
How to Make Switching Costly
Authors: Polo Yolanda , Sesé F. Javier
Published: May 2009

Customer switching costs have emerged as one of the fundamental drivers of customer retention. Although the consequences of these costs have been well documented in the literature, research on the determinants of switching costs remains limited. The present study seeks to address this issue by investigating the extent to which switching costs are influenced by marketing variables—price and advertising—and relationship characteristics. The authors develop a conceptual framework about the drivers of switching costs and test the framework empirically in the mobile phone industry using a hierarchical Bayes approach. The empirical results show that by using price and advertising—both service and brand advertising—firms are able to make switching costly for customers. Moreover, relationship characteristics significantly contribute to explaining consumers’ differences in the cost of switching. Finally, this study illustrates the key role played by competitors’ marketing actions in affecting the cost of switching for customers of the focal firm. Implications for decision makers are discussed.
Impact of self-reported multiple chemical sensitivity on everyday life: A qualitative study
Authors: Skovbjerg Sine , Brorson Stig , Rasmussen Alice , Johansen Jeanne Duus , Elberling Jesper
Published: May 2009

Background: Multiple chemical sensitivity (MCS) is a descriptive term covering symptoms attributed to exposure to common airborne chemicals. There are no internationally accepted criteria, but it has been suggested that MCS is a chronic and disabling condition. However, details of the impact of MCS on everyday life are limited. Objective: To describe the impact of MCS on everyday life, strategies for managing the condition, and experiences with healthcare management. Methods: A focus group study was conducted, including two interviews with a sample of six women and six men between 27 and 78 years of age, a duration of MCS of at least 1 year, and with different occupational conditions. Results: MCS may severely influence different aspects of everyday life, including lifestyle, social relations, and occupational conditions. Avoiding common airborne chemicals was the most prevalent coping strategy, which implied creating a chemical-free living space and limiting social activities. Experiences with healthcare management were overall reported as negative in terms of not receiving acknowledgement of the reported symptoms. Conclusions: MCS may have serious implications for daily functioning. Further research on individual consequences and the social and psychological factors that may be associated with MCS is needed in order to add to our understanding of this condition and to the provision of more satisfactory healthcare.
Osteoporosis and Strength Training
Authors: Going Scott B. , Laudermilk Monica
Published: May 2009

Osteoporosis is a major public health problem. Mechanical strain, imparted by muscle action and ground reaction forces, regulates bone size, shape, mineral mass, and density and subsequently bone strength. Thus, physical activity is critical for bone development, bone health, and fracture risk reduction. Animal studies, in which strain can be manipulated and measured directly, consistently show bone responds to high-strain magnitudes and rates, and only a few repetitions are needed to elicit a response. Extrapolation to humans suggests resistance exercise may be effective for osteoporosis prevention. Indeed, strength-trained athletes have significantly higher bone mass and density than athletes and nonathletes who do not engage in similar training. Prospective studies also support the benefits of resistance exercise demonstrating slowed bone loss and often an increase of 1% to 3% in regional bone mineral density, especially in women. Although more work is needed to define the optimal dose and the effects of nonmechanical factors (eg, nutritional, endocrine, body composition) on the response, the effects of resistance exercise on muscle mass and strength, balance, and agility, in addition to direct skeletal benefits, underscore its importance for osteoporosis, falls, and fracture prevention.
Effect of fine dispersoids and anisotropic nature of β-Sn on thermal fatigue properties of flip chips connected by Sn–xAg–0·5Cu (x: 1, 3 and 4 mass-%) lead free solders
Authors: Terashima S. , Tanaka M.
Published: May 2009

A significance of two factors, fine dispersoids in a solder and the anisotropic nature of β-Sn, on thermal fatigue endurance is discussed using flip chips connected by Sn– xAg–0·5Cu ( x: 1, 3 and 4 mass-%) lead free solders, together with Sn and Sn–1·2Ag–0·5Cu–0·05Ni, for comparison. Both 3Ag and 4Ag showed better thermal fatigue properties than Sn and 1Ag, and a thermal fatigue life of 1·2Ag with Ni was close to that of 3Ag despite of its low silver content. Microstructures of the solders before thermal fatigue tests can be classified into a single crystal-like and a fine grain type. However, this classification, which affects the amount of thermal strain by the anisotropic nature of β-Sn, cannot accurately describe thermal fatigue lives observed. On the other hand, Vickers microhardness of the solders, which was resulted from fine dispersoids, showed good relationship with observed thermal fatigue endurance.
Mitochondrial clearance is regulated by Atg7-dependent and -independent mechanisms during reticulocyte maturation
Authors: Zhang Ji , Randall Mindy S. , Loyd Melanie R. , Dorsey Frank C. , Kundu Mondira , Cleveland John L. , Ney Paul A.
Published: May 2009

Mitochondrial clearance is a well recognized but poorly understood biologic process, and reticulocytes, which undergo programmed mitochondrial clearance, provide a useful model to study this phenomenon. At the ultrastructural level, mitochondrial clearance resembles an autophagy-related process; however, the role of autophagy in mitochondrial clearance has not been established. Here we provide genetic evidence that autophagy pathways, initially identified in yeast, are involved in mitochondrial clearance from reticulocytes. Atg7 is an autophagy protein and an E1-like enzyme, which is required for the activity of dual ubiquitin-like conjugation pathways. Atg7 is required for the conjugation of Atg12 to Atg5, and Atg8 to phosphatidylethanolamine (PE), and is essential for autophagosome formation. In the absence of Atg7, mitochondrial clearance from reticulocytes is diminished but not completely blocked. Mammalian homologs of Atg8 are unmodified in Atg7−/− erythroid cells, indicating that canonical autophagy pathways are inactive. Thus, mitochondrial clearance is regulated by both autophagy-dependent and -independent mechanisms. In addition, mitochondria, which depolarize in wild-type cells before elimination, remain polarized in Atg7−/− reticulocytes in culture. This suggests that mitochondrial depolarization is a consequence rather than a cause of autophagosome formation in reticulocytes.
Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3
Authors: Fukuda Seiji , Singh Pratibha , Moh Akira , Abe Mariko , Conway Edward M. , Boswell H. Scott , Yamaguchi Seiji , Fu Xin-Yuan , Pelus Louis M.
Published: May 2009

Internal tandem duplication mutations in the Flt3 tyrosine kinase gene (ITD-Flt3) and overexpression of Survivin are frequently found in patients with acute myeloid leukemia (AML). We investigated whether Survivin mediates the enhanced survival of primary hematopoietic progenitor cells (HPCs) resulting from ITD-Flt3 signaling. Ectopic ITD-Flt3 mutants increased Survivin expression in Ba/F3 cells downstream of PI3-kinase/Akt. Treatment of ITD-Flt3+ human MV4-11 leukemia cells with the ITD-Flt3 inhibitor SU5416 reduced Survivin expression and inhibited cell proliferation. ITD-Flt3 dramatically increased the number of primary mouse marrow c-kit+, Sca-1+, LinNeg cells and colony-forming unit granulocyte-macrophages (CFU-GMs) able to proliferate in the absence of growth factors, whereas Survivin deletion significantly reduced growth factor–independent proliferation and increased apoptosis, which was further accentuated by SU5416. Ectopic ITD-Flt3 reduced differentiation of LinNeg marrow cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus stem cell factor, which was partially blocked by Survivin deletion. In addition, Survivin deletion decreased secondary colony formation induced by ITD-Flt3. Dominant-negative (dn)–Survivin delayed development of acute leukemia in mice that received a transplant of Ba/F3 cells expressing ITD-Flt3. These results suggest that Survivin regulates expansion of ITD-Flt3–transformed HPCs with self-renewal capability and development of ITD-Flt3+ acute leukemia and that antagonizing Survivin may provide therapeutic benefit for patients with acute leukemia expressing ITD-Flt3.
Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins
Authors: Grassinger Jochen , Haylock David N. , Storan Melonie J. , Haines Gemma O. , Williams Brenda , Whitty Genevieve A. , Vinson Andrew R. , Be Cheang Ly , Li Songhui , Sørensen Esben S. , Tam Patrick P.L. , Denhardt David T. , Sheppard Dean , Choong Peter F. , Nilsson Susan K.
Published: May 2009

Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express α9β1 integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the α9β1 and α4β1 integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with α9β1 and α4β1 integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.
Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases
Authors: Xu Yibing , Li Jianwu , Ferguson Gregory D. , Mercurio Frank , Khambatta Gody , Morrison Lisa , Lopez-Girona Antonia , Corral Laura G. , Webb David R. , Bennett Brydon L. , Xie Weilin
Published: May 2009

IMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents.
The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios
Authors: Singhal Seema , Vickrey Eric , Krishnamurthy Jairam , Singh Veerpal , Allen Sharon , Mehta Jayesh
Published: May 2009

“Stringent” complete remission in myeloma has been defined by a normal serum free light chain ratio (SFLCR) in addition to the standard criteria for CR. 2648 serial samples from 122 IgG or IgA myeloma patients were studied to explore the relationship between SFLCR and serum immunofixation electrophoresis (SIFE). SFLCR was normal in 34% of cases with positive SIFE and abnormal in 66%. SFLCR was normal in 69% of cases with negative SIFE and abnormal in 31%. When evaluated with SIFE as the benchmark, the sensitivity of SFLCR was 66% and specificity was 69%. These findings were unchanged when abnormal SFLCR values were classified as concordant (< 0.26 for λ disease and > 1.65 for κ) or discordant (< 0.26 for κ disease and > 1.65 for λ). Additional studies are required to determine the temporal relationship between SFLCR normalization and paraprotein clearance. Until then, the role of SFLCR in defining response remains controversial.
Cellular senescence of white blood cells in very long-term survivors after allogeneic hematopoietic stem cell transplantation: the role of chronic graft-versus-host disease and female donor sex
Authors: Baerlocher Gabriela M. , Rovó Alicia , Müller Astrid , Matthey Sybille , Stern Martin , Halter Jörg , Heim Dominik , Rischewski Johannes , Gratwohl Alois , Tichelli André
Published: May 2009

In this single-center, cross-sectional study, we evaluated 44 very long-term survivors with a median follow-up of 17.5 years (range, 11-26 years) after hematopoietic stem cell transplantation. We assessed the telomere length difference in human leukocyte antigen-identical donor and recipient sibling pairs and searched for its relationship with clinical factors. The telomere length (in kb, mean ± SD) was significantly shorter in all recipient blood cells compared with their donors' blood cells (P < .01): granulocytes (6.5 ± 0.9 vs 7.1 ± 0.9), naive/memory T cells (5.7 ± 1.2 vs 6.6 ± 1.2; 5.2 ± 1.0 vs 5.7 ± 0.9), B cells (7.1 ± 1.1 vs 7.8 ± 1.1), and natural killer/natural killer T cells (4.8 ± 1.0 vs 5.6 ± 1.3). Chronic graft-versus-host disease (P < .04) and a female donor (P < .04) were associated with a greater difference in telomere length between donor and recipient. Critically short telomeres have been described in degenerative diseases and secondary malignancies. If this hypothesis can be confirmed, identification of recipients at risk for cellular senescence could become part of monitoring long-term survivors after hematopoietic stem cell transplantation.
Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats
Authors: Hsu Hsao-Hsun , Ko Wen-Je , Hsu Jo-Yu , Chen Jin-Shing , Lee Yung-Chie , Lai I-Rue , Chen Chau-Fong
Published: May 2009

Background

Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway.

Methods

Simvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 μmol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1.

Results

Simvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 ± 2.2 mm Hg to 22.1 ± 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 ± 0.8 mm Hg to 17.5 ± 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression.

Conclusion

This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.
Puromycin-based vectors promote a ROS-dependent recruitment of PML to nuclear inclusions enriched with HSP70 and Proteasomes
Authors: Moran Diarmuid M , Shen Hong , Maki Carl G
Published: May 2009

Background

Promyelocytic Leukemia (PML) protein can interact with a multitude of cellular factors and has been implicated in the regulation of various processes, including protein sequestration, cell cycle regulation and DNA damage responses. Previous studies reported that misfolded proteins or proteins containing polyglutamine tracts form aggregates with PML, chaperones, and components of the proteasome, supporting a role for PML in misfolded protein degradation.

Results

In the current study, we have identified a reactive oxygen species (ROS) dependent aggregation of PML, small ubiquitin-like modifier 1 (SUMO-1), heat shock protein 70 (HSP70) and 20S proteasomes in human cell lines that have been transiently transfected with vectors expressing the puromycin resistance gene, puromycin n-acetyl transferase (pac). Immunofluorescent studies demonstrated that PML, SUMO-1, HSP70 and 20S proteasomes aggregated to form nuclear inclusions in multiple cell lines transfected with vectors expressing puromycin (puro) resistance in regions distinct from nucleoli. This effect does not occur in cells transfected with identical vectors expressing other antibiotic resistance genes or with vectors from which the pac sequence has been deleted. Furthermore, ROS scavengers were shown to ablate the effect of puro vectors on protein aggregation in transfected cells demonstrating a dependency of this effect on the redox state of transfected cells.

Conclusion

Taken together we propose that puromycin vectors may elicit an unexpected misfolded protein response, associated with the formation of nuclear aggresome like structures in human cell lines. This effect has broad implications for cellular behavior and experimental design.