bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies
Authors: Costa Luciano J. , Drabkin Harry A. 
Published: December 2007

Learning ObjectivesAfter completing this course, the reader will be able to: List the most frequent genetic abnormalities involved in RCC and explain how they lead to abnormal response to hypoxia, cell survival, and angiogenesis.Interpret the current literature concerning the treatment of RCC, and correlate therapeutic agents with their targets and underlying biological processes that drive the disease.Identify the limitations of current agents used in the treatment of RCC and the challenges that need to be overcome in developing therapies to improve the outcome of patients with advanced disease.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Review: Side Effects of Approved Molecular Targeted Therapies in Solid Cancers
Authors: Widakowich Christian , de Castro Gilberto , de Azambuja Evandro , Dinh Phuong , Awada Ahmad 
Published: December 2007

Learning Objectives
After completing this course, the reader will be able to: List the molecular targeted agents that are considered standard practice in solid tumors.Differentiate among the side effects of commonly used molecular targeted agents.Better characterize the side effects of molecular targeted agents.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Does Marital Status Impact Survival and Quality of Life in Patients with Non-Small Cell Lung Cancer? Observations from the Mayo Clinic Lung Cancer Cohort
Authors: Jatoi Aminah , Novotny Paul , Cassivi Stephen , Clark Matthew M. , Midthun David , Patten Christi A. , Sloan Jeff , Yang Ping 
Published: December 2007

Abstract

Purpose.
Previous studies have found that marriage is associated with longer survival and better quality of life among lung cancer patients. The present study used the Mayo Clinic Lung Cancer Cohort to re-examine this issue.

Methods.
In total, 5,898 non-small cell lung cancer (NSCLC) patients, who had available information on marital status and who had been enrolled in the Mayo Clinic Lung Cancer Cohort (MCLCC), were the focus of this study. Patients had extensive baseline and follow-up data on cancer stage, cancer treatment, and prognostic factors. All patients had been followed within the MCLCC with at least annual confirmation of vital status and patient-reported quality of life (the Lung Cancer Symptom Scale and the Linear Analogue Scales of Assessment).

Results.
The numbers of patients who were married, single, divorced, and widowed at the time of cancer diagnosis were 4,457 (76%), 265 (4%), 440 (7%), and 736 (12%), respectively. No statistically significant difference in survival was observed among these four groups, even after adjusting for a variety of prognostic factors, such as age, gender, and tumor stage. However, exploratory analyses suggested that widowed and divorced patients received less aggressive cancer therapy, and certain patient subgroups, such as stage IA widowed patients, had a shorter survival. Divorced patients reported greater financial concerns, and married and widowed patients reported greater spirituality and better social support.

Conclusion.
This study did not observe differences in survival or quality of life based on marital status at the time of diagnosis of NSCLC, but subgroup analyses appear to suggest findings worthy of further exploration.
Forkhead Transcription Factor FoxO1 in Adipose Tissue Regulates Energy Storage and Expenditure
Authors: Nakae Jun , Cao Yongheng , Oki Miyo , Orba Yasuko , Sawa Hirofumi , Kiyonari Hiroshi , Iskandar Kristy , Suga Koji , Lombes Marc , Hayashi Yoshitake 
Published: December 2007

OBJECTIVE—Adipose tissue serves as an integrator of various physiological pathways, energy balance, and glucose homeostasis. Forkhead box–containing protein O subfamily (FoxO) 1 mediates insulin action at the transcriptional level. However, physiological roles of FoxO1 in adipose tissue remain unclear.RESEARCH DESIGN AND METHODS—In the present study, we generated adipose tissue–specific FoxO1 transgenic mice (adipocyte protein 2 [aP2]-FLAG-Δ256) using an aP2 promoter/enhancer and a mutant FoxO1 (FLAGΔ256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed the effects of the overexpression of FLAGΔ256 on glucose metabolism and energy homeostasis.RESULTS—The aP2-FLAG-Δ256 mice showed improved glucose tolerance and insulin sensitivity accompanied with smaller-sized adipocytes and increased adiponectin (adipoq) and Glut 4 (Slc2a4) and decreased tumor necrosis factor α (Tnf) and chemokine (C-C motif) receptor 2 (Ccr2) gene expression levels in white adipose tissue (WAT) under a high-fat diet. Furthermore, the aP2-FLAG-Δ256 mice had increased oxygen consumption accompanied with increased expression of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α protein and uncoupling protein (UCP)-1 (Ucp1), UCP-2 (Ucp2), and β3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of FLAGΔ256 in T37i cells, which are derived from the hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1α protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1α (Ppargc1a), Pgc1β (Ppargc1b), Ucp1, and Adrb3 gene expression.CONCLUSIONS—These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue–specific gene expression in response to excessive calorie intake.
Insulin Mutation Screening in 1,044 Patients With Diabetes
Authors: Edghill Emma L. , Flanagan Sarah E. , Patch Ann-Marie , Boustred Chris , Parrish Andrew , Shields Beverley , Shepherd Maggie H. , Hussain Khalid , Kapoor Ritika R. , Malecki Maciej , MacDonald Michael J. , Støy Julie , Steiner Donald F. , Philipson Louis H. , Bell Graeme I. ,   the Neonatal Diabetes International Collaborative Group, Hattersley Andrew T. , Ellard Sian 
Published: December 2007

OBJECTIVE— Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.
RESEARCH DESIGN AND METHODS— The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed &lt;45 years). None had a molecular genetic diagnosis of monogenic diabetes.
RESULTS— We identified heterozygous INS mutations in 33 of 141 probands diagnosed at &lt;6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K+ channel mutation carriers (11 vs. 8 weeks, P &lt; 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant.
CONCLUSIONS— We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.
Homocysteine and Diabetic Retinopathy
Authors: Brazionis Laima , Rowley Kevin , Itsiopoulos Catherine , Harper Colin Alexander , O’Dea Kerin 
Published: December 2007

OBJECTIVE—Homocysteine is an emerging risk factor for cardiovascular and nondiabetic ocular vaso-occlusive diseases. However, studies of the relationship between homocysteine and diabetic retinopathy have reported inconsistent results. The purpose of this study was to evaluate the relationship between plasma total homocysteine concentration and diabetic retinopathy.
RESEARCH DESIGN AND METHODS—We assessed the homocysteine-retinopathy relationship in 168 men and women with type 2 diabetes in a community-based, cross-sectional study. We photodocumented diabetic retinopathy status and measured plasma total homocysteine concentration using a commercial fluorescence polarization immunoassay enzymatic kit. Data for selected clinical/demographic variables and established risk factors for diabetic retinopathy were obtained from fasting blood samples and an interviewer-assisted lifestyle questionnaire.
RESULTS—A higher mean plasma total homocysteine concentration was observed in diabetic individuals with retinopathy than in those without retinopathy (11.5 μmol/l [95% CI 10.4–12.5] vs. 9.6 μmol/l [9.1–10.2], P = 0.001). Furthermore, the relationship between homocysteine and diabetic retinopathy was not explained by renal dysfunction and was independent of the other major risk factors for diabetic retinopathy (duration of diabetes, A1C, and systolic blood pressure) and determinants of higher homocysteine concentrations (age, sex, and red cell folate) (odds ratio 1.20 [95% CI 1.023–1.41], P = 0.024).
CONCLUSIONS—Plasma total homocysteine concentration may be a useful biomarker and/or a novel risk factor for increased risk of diabetic retinopathy in people with type 2 diabetes.
Addition of Pioglitazone and Ramipril to Intensive Insulin Therapy in Type 2 Diabetic Patients Improves Vascular Dysfunction by Different Mechanisms
Authors: Fernandez Marianella , Triplitt Curtis , Wajcberg Estela , Sriwijilkamol Apiradee A. , Musi Nicholas , Cusi Kenneth , DeFronzo Ralph , Cersosimo Eugenio 
Published: December 2007

OBJECTIVE—We examined the relationship between glycemic control, vascular reactivity, and inflammation in type 2 diabetic subjects.RESEARCH DESIGN AND METHODS—Thirty subjects with type 2 diabetes were initiated on intensive insulin therapy (continuous subcutaneous insulin infusion [n = 12] or multiple daily injections [n = 18]) and then randomized to either pioglitazone (PIO group;45 mg/day), ramipril (RAM group; 10 mg/day), or placebo (PLC group) for 36 weeks. Euglycemic-hyperinsulinemic clamp was used to quantify insulin resistance, and plethysmography was used to assess changes in forearm blood flow (FBF) after 1) 5 min of reactive hyperemia and 2) brachial artery infusion of acetylcholine (7.5, 15, and 30 μg/min) and sodium nitroprusside (3 and 10 μg/min).RESULTS—The decreases in A1C (∼9.0–7.0%) and fasting plasma glucose (∼190–128 mg/dl) were equal in all groups. In the PIO group, glucose disposal increased from 3.1 to 4.7 mg · kg−1 · min−1, and there was a greater decrease in plasma triglycerides (∼148 vs. 123 mg/dl) and free fatty acids (∼838 vs. 595 mEq/l) compared with the RAM or PLC groups (P &lt; 0.05). Plasma adiponectin doubled with pioglitazone treatment (6.2 ± 0.7 to 13.1 ± 1.8 μg/ml), while endothelin-1 decreased only with ramipril treatment (2.5 ± 0.2 to 1.1 ± 0.2 pg/ml) (P &lt; 001). The increase in FBF during reactive hyperemia (215%) and acetylcholine (from 132 to 205%, 216 to 262%, and 222 to 323%) was greater in the PIO versus RAM or PLC groups. In contrast, FBF during sodium nitroprusside treatment was greater in the RAM group (141–221% and 218–336%) compared with the PIO or PLC groups (all P &lt; 0.05).CONCLUSIONS—Addition of pioglitazone or ramipril to intensive insulin therapy in type 2 diabetes further improves vascular dysfunction. Pioglitazone enhances endothelial-mediated vasodilation, whereas ACE inhibition enhances endothelial-independent vasodilation. These different vascular effects, combined with the observation that pioglitazone decreases free fatty acids and triglycerides and increases adiponectin, while ramipril reduces endothelin-1, suggest that different mechanisms underlie the vascular responses.
Prevalence of Diabetes and Impaired Fasting Glucose in the Adult Population of Iran
Authors: Esteghamati Alireza , Gouya Mohamad M. , Abbasi Mehrshad , Delavari Alireza , Alikhani Siamak , Alaedini Farishid , Safaie Afshin , Forouzanfar Mehrdad , Gregg Edward W. 
Published: December 2007

OBJECTIVE—Despite concerns regarding a diabetes epidemic in the Middle East, internationally published data on national estimates of prevalent type 2 diabetes in Iran do not exist. With this article, we document a dramatically high prevalence of diabetes in Iran.
RESEARCH DESIGN AND METHODS—Our data are based on the results of the first Survey of Risk Factors of Non-Communicable Diseases of Iran, 2005. In this national cross-sectional survey, 70,981 Iranian citizens aged 25–64 years were recruited.
RESULTS—We found that 7.7% of adults aged 25–64 years, or 2 million adults, have diabetes, among whom one-half are undiagnosed. An additional 16.8%, or 4.4 million, of Iranian adults have impaired fasting glucose.
CONCLUSIONS—The high prevalence of diabetes in working-age adults is an ominous sign for this developing nation. As the relatively young Iranian population ages in the future and urbanization continues or accelerates, the prevalence of diabetes will likely escalate.
Prevalence of Depression Among U.S. Adults With Diabetes
Authors: Li Chaoyang , Ford Earl S. , Strine Tara W. , Mokdad Ali H. 
Published: December 2007

OBJECTIVE—To estimate the prevalence rate of depression among adults with diabetes using a large population-based sample in the U.S.
RESEARCH DESIGN AND METHODS—Data from the 2006 Behavioral Risk Factor Surveillance System, a standardized telephone survey among U.S. adults aged ≥18 years, were analyzed (n = 18,814). The Patient Health Questionnaire diagnostic algorithm was used to identify major depression.
RESULTS—The age-adjusted prevalence rate of major depression was 8.3% (95% CI 7.3–9.3), ranging from a low of 2.0% in Connecticut to a high of 28.8% in Alaska. There were 25-fold differences in the rate among racial/ethnic subgroups (lowest, 1.1% among Asians; highest, 27.8% among American Indians/Alaska Natives). People with type 2 diabetes who were currently using insulin had a higher rate than people with type 1 diabetes (P = 0.0009) and those with type 2 diabetes who were currently not using insulin (P = 0.01).
CONCLUSIONS—Major depression was highly prevalent among people with diabetes; the prevalence rate varied greatly by demographic characteristics and diabetes types.
Prediction of Healing for Postoperative Diabetic Foot Wounds Based on Early Wound Area Progression
Authors: Lavery Lawrence A. , Barnes Sunni A. , Keith Michael S. , Seaman John W. , Armstrong David G. 
Published: December 2007

OBJECTIVE—To evaluate the probability of wound healing based on percentage of wound area reduction (PWAR) at 1 and 4 weeks in individuals with large, chronic, nonischemic diabetic foot wounds following partial foot amputation.
METHODS—Data from a 16-week randomized clinical trial (RCT) of 162 patients were analyzed to compare outcomes associated with negative-pressure wound therapy (NPWT) delivered through the V.A.C. Therapy System (Kinetic Concepts, San Antonio, TX) (n = 77) versus standard moist wound therapy (MWT) (n = 85). The 1- and 4-week regression models included 153 and 129 of the RCT patients, respectively.
RESULTS—Early changes in PWAR were predictive of final healing at 16 weeks. Specifically, wounds that reached ≥15% PWAR at 1 week or ≥60% PWAR at 4 weeks had a 68 and 77% (respectively) probability of healing vs. a 31 and 30% probability if these wound area reductions were not achieved. Patients receiving NPWT were 2.5 times more likely to achieve both a 15% PWAR at 1 week and a 60% area reduction at 1 month (odds ratios 2.51 and 2.49, respectively) compared with those receiving MWT.
CONCLUSION—Results of this study suggest that clinicians can calculate the PWAR of a wound as early as 1 week into treatment to predict the likelihood of healing at 16 weeks. This might also assist in identifying a rationale to reevaluate the wound and change wound therapies.
Expression of Matrix Metalloproteinases, Cytokines, and Connexins in Diabetic and Nondiabetic Human Keratinocytes Before and After Transplantation Into an Ex Vivo Wound-Healing Model
Authors: Brandner Johanna M. , Zacheja Steffi , Houdek Pia , Moll Ingrid , Lobmann Ralf 
Published: December 2007

OBJECTIVE—Wound healing is known to require a well-organized balance of numerous factors, e.g., cytokines, matrix metalloproteinases (MMPs), and their inhibitors, as well as direct cell-cell communication (connexins). Disruption of this balance may lead to the formation of chronic wounds such as diabetic foot ulcers. The transplantation of autologous keratinocytes is a promising therapy for diabetic foot ulcers; however, little is known about their characteristics on a molecular level. Therefore, we intended to characterize transplanted keratinocytes from diabetic and nondiabetic origin before and after transplantation.
RESEARCH DESIGN AND METHODS—We isolated human keratinocytes from diabetic and nondiabetic origins and transplanted them into an ex vivo wound healing model. To characterize the keratinocytes, we investigated mRNA expression of MMP-1, MMP-2, and MMP-9; tissue inhibitor of MMP (TIMP)-1 and TIMP-2; interleukin (IL)-1β, tumor necrosis factor (TNF)-α; Cx26 (connexin 26) and Cx43; and, for connexins, immunolocalization.
RESULTS—We found no significantly increased expression of the molecules investigated in cultured keratinocytes from diabetic compared with nondiabetic origin, even though there were significant differences for MMP-2, IL-1β, and TNF-α in skin biopsies. Expression of IL-1β was significantly lower in keratinocytes from diabetic origin. In the course of wound healing, differences in the dynamics of expression of MMP-1, IL-1β, and Cx43 were observed.
CONCLUSIONS—Our results suggest that keratinocytes from diabetic origin are as capable for transplantation into chronic wounds as keratinocytes from healthy origin at the starting point of therapy. However, differences in expression dynamics later on might reflect the systemic influence of diabetes resulting in a memory of the transplanted keratinocytes.
Head-to-Head Comparison of Sirolimus- and Paclitaxel-Eluting Stent in the Same Diabetic Patient With Multiple Coronary Artery Lesions
Authors: Tomai Fabrizio , Reimers Bernhard , De Luca Leonardo , Galassi Alfredo R. , Gaspardone Achille , Ghini Anna S. , Ferrero Valeria , Favero Luca , Gioffrè Gaetano , Prati Francesco , Tamburino Corrado , Ribichini Flavio 
Published: December 2007

OBJECTIVE—It is still controversial whether sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) are equally effective in patients with diabetes. In these patients, multiple individual variables may be responsible for neointimal hyperplasia, thus making difficult the comparison of the two drug-eluting stents (DES).
RESEARCH DESIGN AND METHODS—We designed a prospective, randomized study to compare the efficacy in prevention of restenosis of SES and PES, both implanted in the same diabetic patient with multiple de novo coronary artery lesions undergoing elective percutaneous coronary intervention. We enrolled 60 patients with diabetes with at least two significant de novo angiographic stenoses in different coronary segments. The primary end point was in-stent late luminal loss (LLL) at 8-month angiographic follow-up.
RESULTS—A total of 120 lesions were successfully treated with the randomly assigned DES (SES, n = 60; PES, n = 60). In-stent LLL was lower in the SES than in the PES group (0.26 ± 0.4 vs. 0.50 ± 0.6 mm; P = 0.01). Coronary lesions treated with SES presented a reduced in-stent LLL in 40 (68%) patients, while PES resulted in a lower in-stent LLL in 19 (32%) patients (P = 0.0002). At multivariable analysis, the type of DES implanted was the only independent predictor of in-stent LLL (odds ratio 2.3 [95% CI 1.1–5.0]; P = 0.03).
CONCLUSIONS—SES directly compared with PES in the same diabetic patient is associated with a decrease in the extent of in-stent LLL at 8 months, suggesting a reduced risk of restenosis.
Liver Fat Is Increased in Type 2 Diabetic Patients and Underestimated by Serum Alanine Aminotransferase Compared With Equally Obese Nondiabetic Subjects
Authors: Kotronen Anna , Juurinen Leena , Hakkarainen Antti , Westerbacka Jukka , Cornér Anja , Bergholm Robert , Yki-Järvinen Hannele 
Published: December 2007

OBJECTIVE—The purpose of this study was to determine whether type 2 diabetic patients have more liver fat than age-, sex-, and BMI-matched nondiabetic subjects and whether liver enzymes (serum alanine aminotransferase [S-ALT] and serum aspartate aminotransferase) are similarly related to liver fat in type 2 diabetic patients and normal subjects.
RESEARCH DESIGN AND METHODS—Seventy type 2 diabetic patients and 70 nondiabetic subjects matched for BMI, age, and sex were studied. Liver fat (1H-magnetic resonance spectroscopy), body composition (magnetic resonance imaging), and biochemical markers of insulin resistance were measured.
RESULTS—The type 2 diabetic patients had, on average, 80% more liver fat and 16% more intra-abdominal fat than the nondiabetic subjects. The difference in liver fat between the two groups remained statistically significant when adjusted for intra-abdominal fat (P &lt; 0.05). At any given BMI or waist circumference, the type 2 diabetic patients had more liver fat than the nondiabetic subjects. The difference in liver fat between the groups rose as a function of BMI and waist circumference. Fasting serum insulin (r = 0.55, P &lt; 0.0001), fasting plasma glucose (r = 0.29, P = 0.0006), A1C (r = 0.34, P &lt; 0.0001), fasting serum triglycerides (r = 0.36, P &lt; 0.0001), and fasting serum HDL cholesterol (r = −0.31, P = 0.0002) correlated with liver fat similarly in both groups. The slopes of the relationships between S-ALT and liver fat were significantly different (P = 0.004). Liver fat content did not differ between the groups at low S-ALT concentrations (10–20 units/l) but was 70–200% higher in type 2 diabetic patients compared with control subjects at S-ALT concentrations of 50–200 units/l.
CONCLUSIONS—Type 2 diabetic patients have 80% more liver fat than age-, weight-, and sex-matched nondiabetic subjects. S-ALT underestimates liver fat in type 2 diabetic patients.
Is Glycemic Control Improving in U.S. Adults?
Authors: Hoerger Thomas J. , Segel Joel E. , Gregg Edward W. , Saaddine Jinan B. 
Published: December 2007

OBJECTIVE—The purpose of this study was to examine whether glycemic control has improved in recent years among individuals with diagnosed diabetes.
RESEARCH DESIGN AND METHODS—We examined trends in A1C levels for adults with diagnosed diabetes using three consecutive waves of the National Health and Nutrition Examination Survey (NHANES): 1999–2000, 2001–2002, and 2003–2004. We estimated mean A1C levels and the proportion with A1C &lt;7.0, &lt;8.0, and &lt;9.0%. We used multivariate regression to test whether A1C levels differed by NHANES wave after controlling for other factors. Multivariate dichotomous logistic regression and predictive margins were used to test whether the percentages of individuals with diabetes in selected A1C intervals differed by NHANES wave.
RESULTS—Mean A1C levels among individuals with diagnosed diabetes declined from 7.82% in 1999–2000 to 7.47 and 7.18% in 2001–2002 and 2003–2004, respectively. After controlling for demographics and diabetes duration, A1C levels were 0.308 (P = 0.20) and 0.511 (P = 0.03) percentage points lower in 2001–2002 and 2003–2004, respectively, than in 1999–2000. The logistic results indicated corresponding improvements over time: the predictive margin for having A1C &lt;7.0% increased from 37.0% in 1999–2000 to 49.7% in 2001–2002 and to 55.7% in 2003–2004.
CONCLUSIONS—Glycemic control improved between 1999 and 2004. This trend may represent an important improvement in diabetes care and is encouraging for future reduction of diabetes-related complications.