bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylation of RASSF1A, RASSF2A, and HIN-1 Is Associated with Poor Outcome after Radiotherapy, but not Surgery, in Oral Squamous Cell Carcinoma
Authors: Huang Kuo-Hao , Huang Shiang-Fu , Chen I-How , Liao Chun-Ta , Wang Hung-Ming , Hsieh Ling-Ling
Published: June 2009

Purpose: Radiotherapy is the standard adjuvant treatment for oral squamous cell carcinoma (OSCC). The Ras/PI3K/AKT pathway is the major mechanism associated with radioresistance. To evaluate the potential significance on the outcome of radiotherapy in OSCC of the Ras/PI3K/AKT pathway with respect to methylation of negative regulators, we examined the methylation status of genes known to be involved in Ras/PI3K/AKT pathway and aberrantly methylated in human cancers together with the mutation status of K-ras/H-ras.

Experimental Design: PCR–denaturing high-performance liquid chromatography was used to examine the methylation status of the RASSF1A, RASSF2A, PTEN, and HIN-1 genes, and PCR-RFLP was used to determine the mutation status of K-ras/H-ras in 482 OSCCs. Associations between mutation, methylation, clinicopathologic parameters, and outcome were evaluated.

Results: The frequencies of K-ras/H-ras mutation and promoter methylation of the RASSF1A, RASSF2A, PTEN, and HIN-1 genes were 6.6%, 22.4%, 27.8%, 1.2%, and 7.3%, respectively. A combination of RASSF1A and RASSF2A methylation was found to be significantly associated with poor disease-free survival (DFS). Furthermore, a gene dosage effect of the activated Ras/PI3K/AKT signal on DFS was observed in patients treated with radiotherapy after surgery but not in patients treated with surgery alone. The Ras/PI3K/AKT pathway was activated in 140 primary OSCCs among 286 patients treated with radiotherapy after surgery and methylation of RASSF1A/RASSF2A (75.7%) was the most common mechanism.

Conclusion: Our study indicates that epigenetic silencing of tumor suppressor genes involved in the Ras/PI3K/AKT pathway plays an important role in OSCC radioresistance and this provides a rationale for exploring novel treatment strategies.
Restoration of p53 Pathway by Nutlin-3 Induces Cell Cycle Arrest and Apoptosis in Human Rhabdomyosarcoma Cells
Authors: Miyachi Mitsuru , Kakazu Naoki , Yagyu Shigeki , Katsumi Yoshiki , Tsubai-Shimizu Satoko , Kikuchi Ken , Tsuchiya Kunihiko , Iehara Tomoko , Hosoi Hajime
Published: June 2009

Purpose: Seventy to eighty percent of rhabdomyosarcoma (RMS) tumors retain wild-type p53. The tumor suppressor p53 plays a central role in inducing cell cycle arrest or apoptosis in response to various stresses. p53 protein levels are regulated by MDM2 through ubiquitin-dependent degradation. In this study, we evaluated whether nutlin-3, a recently developed small-molecule antagonist of MDM2, has an effect on p53-dependent cell cycle arrest and apoptosis in cultured human RMS cell lines.

Experimental Design: Five RMS cell lines with different p53 statuses and MDM2 expression levels were treated with nutlin-3. Gene expression patterns, cell viability, cell cycle, and apoptosis after nutlin-3 treatment, and antitumor activity of combination treatment with vincristine or actinomycin D were assessed.

Results: Significant p53 activation was observed in wild-type p53 cell lines after nutlin-3 treatment. p53 activation led to cell cycle arrest in parallel with increased p21 expression. Furthermore, these cell lines underwent p53-dependent apoptosis, concomitant with elevation of proapoptotic genes and activation of caspase-3. The effect of nutlin-3 was almost the same in terms of half maximal inhibitory concentration and apoptosis whether or not MDM2 was overexpressed. Nutlin-3 did not induce either cell cycle arrest or apoptosis in p53 mutant cell lines. A combination of vincristine or actinomycin D with nutlin-3 enhanced the antitumor activity in RMS cell lines with wild-type p53.

Conclusions: Nutlin-3 effectively restored p53 function in both normal MDM2 expression and MDM2 overexpression RMS cell lines with wild-type p53. p53 restoration therapy is a potential therapeutic strategy for refractory RMS with wild-type p53.
Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer
Authors: Rajeshkumar N.V. , Tan Aik Choon , De Oliveira Elizabeth , Womack Chris , Wombwell Helen , Morgan Shethah , Warren Madhuri V. , Walker Jill , Green Tim P. , Jimeno Antonio , Messersmith Wells A. , Hidalgo Manuel
Published: June 2009

Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity.

Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using the K-Top Scoring Pairs (K-TSP) method.

Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors (100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair (LRRC19 and IGFBP2) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity in an independent test set that consists of eight xenograft cases.

Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair (LRRC19 and IGFBP2) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for pancreatic tumor sensitivity to AZD0530.
Identifying the Safety Profile of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Anticipation of a Phase I Clinical Trial in Patients with Recurrent Ovarian Cancer
Authors: Matthews Kellie , Noker Patricia E. , Tian Baohong , Grimes Sheila D. , Fulton Ronna , Schweikart Karen , Harris Raymond , Aurigemma Rose , Wang Minghui , Barnes Mack N. , Siegal Gene P. , Hemminki Akseli , Zinn Kurt , Curiel David T. , Alvarez Ronald D.
Published: June 2009

Purpose: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma.

Experimental Design: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects.

Results: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD ± GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time.

Conclusions: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
GATA4 and GATA5 are Potential Tumor Suppressors and Biomarkers in Colorectal Cancer
Authors: Hellebrekers Debby M.E.I. , Lentjes Marjolein H.F.M. , van den Bosch Sandra M. , Melotte Veerle , Wouters Kim A.D. , Daenen Kathleen L.J. , Smits Kim M. , Akiyama Yoshimitsu , Yuasa Yasuhito , Sanduleanu Silvia , Khalid-de Bakker Carolina A.J. , Jonkers Daisy , Weijenberg Matty P. , Louwagie Joost , van Criekinge Wim , Carvalho Beatriz , Meijer Gerrit A. , Baylin Stephen B. , Herman James G. , de Bruïne Adriaan P. , van Engeland Manon
Published: June 2009

Purpose: The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer.

Experimental Design: Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines.

Results: GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% CI), 55-88%] and specificity of 84% (95% CI, 74–95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% CI, 37–65%) and specificity of 93% (95% CI, 84-100%) in the validation set.

Conclusions: Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.
High Expression of Mammalian Target of Rapamycin Is Associated with Better Outcome for Patients with Early Stage Lung Adenocarcinoma
Authors: Anagnostou Valsamo K. , Bepler Gerold , Syrigos Konstantinos N. , Tanoue Lynn , Gettinger Scott , Homer Robert J. , Boffa Daniel , Detterbeck Frank , Rimm David L.
Published: June 2009

Purpose: Mammalian target of rapamycin (mTOR) is a key kinase downstream of phosphoinositide 3-kinase (PI3K)/AKT predominantly involved in translational control in the presence of nutrients and energy. Despite the well known role of mTOR in carcinogenesis, its prognostic potential in lung cancer has not been investigated. Here, we quantitatively assessed mTOR protein expression in two large data sets to investigate the impact of mTOR expression on patient survival.

Experimental Design: Automated quantitative analysis (AQUA), a fluorescent-based method for analysis of in situ protein expression, was used to assess mTOR expression in a training cohort of 167 lung cancer patients. An independent cohort of 235 lung cancer patients (from a second institution) was used for validation.

Results: Tumors expressed mTOR in the cytoplasm in 56% and 50% of the cases in training and validation cohorts, respectively; mTOR expression was not associated with standard clinical or pathologic characteristics. Patients with high mTOR expression had a longer median overall survival compared with the low expressers (52.7 versus 38.5 months; log rank P = 0.06), which was more prominent in the adenocarcinoma group (55.7 versus 38.88 months; log rank P = 0.018). Multivariate analysis revealed an independent lower risk of death for adenocarcinoma and adenocarcinoma stage IA patients with mTOR-expressing tumors (hazard ratio, 0.48; 95% confidence interval, 0.24-0.98; P = 0.04, and hazard ratio, 0.12; 95% confidence interval, 0.03-0.72; P = 0.019, respectively).

Conclusions: mTOR expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of lung adenocarcinoma patients as well as incorporation of mTOR into clinical decisions.
A Mitochondrial Target Sequence Polymorphism in Manganese Superoxide Dismutase Predicts Inferior Survival in Breast Cancer Patients Treated with Cyclophosphamide
Authors: Glynn Sharon A. , Boersma Brenda J. , Howe Tiffany M. , Edvardsen Hege , Geisler Stephanie B. , Goodman Julie E. , Ridnour Lisa A. , Lønning Per E. , Børresen-Dale Anne-Lise , Naume Bjorn , Kristensen Vessela N. , Chanock Stephen J. , Wink David A. , Ambs Stefan
Published: June 2009

Purpose: Manganese superoxide dismutase protects against oxidative damage and modulates the efficacy of chemotherapeutic drugs. A functional single-nucleotide polymorphism in codon 16 of SOD2 (rs4880), which encodes manganese superoxide dismutase, results in a substitution of valine by alanine (Val16Ala). We hypothesized that this single-nucleotide polymorphism affects breast cancer survival of patients receiving chemotherapy.

Experimental Design: Two patient populations from the United States (n = 248) and Norway (n = 340) were genotyped for Val16Ala. Kaplan-Meier survival and Cox proportional hazards regression analyses were used to examine the relationship between Val16Ala and disease-specific survival.

Results: Val16Ala was significantly associated with breast cancer outcome in both patient populations. Carriers of the Ala allele had inferior survival rates in the multivariate analysis [hazard ratio (HR), 2.44 and 95% confidence interval (95% CI), 1.11-5.37 in U.S. cohort; HR, 1.91 and 95% CI, 1.06-3.45 in Norway cohort for Ala/Ala versus Val/Val]. In an analysis of the combined cohorts, this association was significant for patients receiving adjuvant therapy (HR, 2.47; 95% CI, 1.46-4.19), but not for patients without it (HR, 1.47; 95% CI, 0.57-3.74). After further stratification by type of chemotherapy, the effect of the Ala allele was mostly restricted to cyclophosphamide-containing chemotherapy regimens (HR, 22.0; 95% CI, 5.22-92.9; Ala/Ala versus Val/Val).

Conclusion: The Val16Ala polymorphism affects survival of patients receiving cyclophosphamide-containing chemotherapy. The findings provide the first evidence pointing toward a mechanism for cyclophosphamide resistance in breast cancer patients.
Eribulin: Rediscovering Tubulin as an Anticancer Target
Authors: Jimeno Antonio
Published: June 2009

Eribulin mesylate (E7389) is a synthetic analog of the marine macrolide halichondrin B, which acts as a novel microtubule modulator with a distinct mechanism of action. Two eribulin mesylate phase 1 studies exploring weekly and 3-weekly schedules are reported in this issue. These trials show linear pharmacokinetics, a toxicity profile consisting in neutropenia and fatigue, and early hints of antitumor activity. In this commentary we give a brief historical perspective of the halichondrins and put into context eribulin mesylate as a novel tubulin modulator.
Effect of Hemodialysis on Acid Leukocyte-Type Ribonuclease, Alkaline Ribonuclease and Polymorphonuclear Elastase Serum Levels in Patients with End-Stage Renal Disease
Authors: Naskalski Jerzy W. , Kapusta Maria , Fedak Danuta , Dumnicka Paulina , Kuśnierz-Cabala Beata , Kuźniewski Marek , Sułowicz Władysław
Published: June 2009

Background: Low-molecular-weight proteins (LMWPs) are substances of molecular weights 10–35 kDa, which accumulate in plasma of patients with end-stage renal disease (ESRD) due to the abolishment of plasma renal filtration. LMWPs are considered as a separate group of uremic toxins. Aim: The influence of hemodialysis (HD) on the release of some LMWPs from leukocytes was assessed by comparing levels of serum pancreatic-type alkaline RNase and leukocyte-type acid RNase as well aspolymorphonuclear (PMN) elastase. Methods: The mentioned proteins were assayed in 58 ESRD patients on HD prior and after the dialysis session and compared with the results obtained from 36 healthy subjects. The levels of elastase and acid and alkaline RNase were correlated with HD parameters, residual diuresis, predialysis concentrations of serum creatinine, urea and albumin as well as pre- and postdialysis granulocyte count. Results: Changes in PMN elastase produced by the dialysis session positively correlate with changes in acid RNase levels (r = 0.3650; p = 0.0061), while there is no such correlation for alkaline RNase. There is a negative correlation between pre- and postdialysis differences in levels of acid and alkaline RNases (r = –0.3542; p = 0.008), indicating that HD induces liberation of a factor suppressing alkaline RNase. Levels of acid and alkaline RNase negatively correlate with residual diuresis, indicating its significance in control of LMWP accumulation (r = –0.3970; p = 0.0025; r = –0.2596; p = 0.0533, respectively). Conclusions: Dialysis treatment causes an increase in both acid leukocyte-type and alkaline pancreatic-type RNase activity in plasma. Dialysis-related increases in acid RNase activity correlate with the respective changes in PMN elastase, which suggests that leukocyte activation during dialysis contributes to an increase in plasma LMWPs.
Impact of Residual Renal Function on Plasma Levels of Advanced Oxidation Protein Products and Pentosidine in Peritoneal Dialysis Patients
Authors: Furuya Ryuichi , Kumagai Hiromichi , Odamaki Mari , Takahashi Masaaki , Miyaki Asumi , Hishida Akira
Published: June 2009

Background: Residual renal function (RRF) affects the survival rate and the development of cardiovascular disease in peritoneal dialysis (PD) patients. We evaluated the impact of RRF on oxidative and carbonyl stress in PD patients. Methods: Plasma advanced oxidation protein products (AOPP) and pentosidine were measured in PD patients with a urine volume of ≥300 ml/day (group A, n = 17) and <300 ml/day (group B, n = 14). AOPP and pentosidine were reevaluated after 12 months of follow-up in group A. Results: Plasma levels of AOPP and pentosidine in group A were significantly lower than those in group B. Renal creatinine clearance was inversely correlated with AOPP (p < 0.05) and pentosidine (p < 0.01). After 12 months of follow-up, no significant change was observed in AOPP and pentosidine in groups who maintained a urine volume of ≥300 ml/day, but significantly increased in groups whose urine volume decreased to less than 300 ml/day. There were significant inverse relationships between the changes in renal creatinine clearance and AOPP (p < 0.01) and pentosidine (p < 0.05). Conclusion: Loss of RRF is associated with increased plasma AOPP and pentosidine, indicating that preservation of RRF has a beneficial effect in reducing the oxidative and carbonyl stress in PD patients.
Truncating Mutations in the Chloride/Proton ClC-5 Antiporter Gene in Seven Jewish Israeli Families with Dent’s 1 Disease
Authors: Dinour Dganit , Davidovitz Miriam , Levin-Iaina Nomy , Lotan Danny , Cleper Roxana , Weissman Irith , Knecht Aaron , Holtzman Eli J.
Published: June 2009

Dent’s disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent‘s disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent’s disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.
An Architectonic Study of the Neocortex of the Short-Tailed Opossum (Monodelphis domestica)
Authors: Wong Peiyan , Kaas Jon H.
Published: June 2009

Short-tailed opossums (Monodelphis domestica) belong to the branch of marsupial mammals that diverged from eutherian mammals approximately 180 million years ago. They are small in size, lack a marsupial pouch, and may have retained more morphological characteristics of early marsupial neocortex than most other marsupials. In the present study, we used several different histochemical and immunochemical procedures to reveal the architectonic characteristics of cortical areas in short-tailed opossums. Subdivisions of cortex were identified in brain sections cut in the coronal, sagittal, horizontal or tangential planes and processed for a calcium-binding protein, parvalbumin (PV), neurofilament protein epitopes recognized by SMI-32, the vesicle glutamate transporter 2 (VGluT2), myelin, cytochrome oxidase (CO), and Nissl substance. These different procedures revealed similar boundaries among areas, suggesting that functionally relevant borders were detected. The results allowed a fuller description and more precise demarcation of previously identified sensory areas, and the delineation of additional subdivisions of cortex. Area 17 (V1) was especially prominent, with a densely populated layer 4, high myelination levels, and dark staining of PV and VGluT2 immunopositive terminations. These architectonic features were present, albeit less pronounced, in somatosensory and auditory cortex. The major findings support the conclusion that short-tailed opossums have fewer cortical areas and their neocortex is less distinctly laminated than most other mammals.
Effects of New Peritoneal Dialysis Solutions, Pyridoxamine and AT1 Receptor Blocker, on TGF-β1 and VEGF Expression in Rat Peritoneal Mesothelial Cells
Authors: Mizuiri Sonoo , Ohashi Yasushi , Hemmi Hiromichi , Arita Michitsune , Yamada Kanae , Aoki Toshiyuki , Miyagi Moriatsu , Sakai Ken , Aikawa Atsushi
Published: June 2009

Background: Transforming growth factor β1 (TGF-β1) and vascular endothelial growth factor (VEGF) are involved in peritoneal deterioration in continuous ambulatory peritoneal dialysis. The present study was designed to determine whether new peritoneal dialysis solutions (PDS), pyridoxamine (advanced glycation end products (AGE) inhibitor) or AT1 receptor blocker (ARB), affect the expression of VEGF and TGF-β1 in rat peritoneal mesothelial cells (RPMC). Methods: RPMC were stimulated by phosphate-buffered saline (PBS) as control, Dianeal 1.5% (D 1.5%), Dianeal 2.5% (D 2.5%), Dianeal 4.25% (D 4.25%), Dianeal N 1.5% (N 1.5%), Dianeal N 2.5% (N 2.5%) or Extraneal (Ex). In co-incubation experiments, RPMC were stimulated with N 2.5% including pyridoxamine or olmesartan (ARB). VEGF and TGF-β1 protein and mRNA expression in RPMC were analyzed by ELISA and RT-PCR. Results: Glucose-containing PDS, even N 2.5% diluted twofold with M199 (which contains 1.25% glucose), increased VEGF and TGF-β1 expression in RPMC (p < 0.05). Ex did not inhibit VEGF expression and did not inhibit TGF- β1 expression after 24 h in RPMC. Pyridoxamine and ARB significantly reduced N 2.5%-induced VEGF and TGF-β1 protein and mRNA expression in RPMC (p < 0.01). Conclusions: Neither new pH-neutral, lactate-buffered, low-GDP, two-chamber bag PDS, nor 7.5% icodextrin PDS alone satisfactorily inhibited VEGF and TGF-β1 overproduction in RPMC, but ARB or pyridoxamine effectively inhibited glucose-containing PDS (N 2.5%)-induced overproduction.
Moderate Exercise Training Improves Survival and Ventricular Remodeling in an Animal Model of Left Ventricular Volume Overload
Authors: Lachance Dominic , Plante Éric , Bouchard-Thomassin Andrée-Anne , Champetier Serge , Roussel Élise , Drolet Marie-Claude , Arsenault Marie , Couet Jacques
Published: June 2009

Background—

Exercise training has beneficial effects in patients with heart failure, although there is still no clear evidence that it may impact on their survival. There are no data regarding the effects of exercise in subjects with chronic left ventricular (LV) volume overload. Using a rat model of severe aortic valve regurgitation (AR), we studied the effects of long-term exercise training on survival, development of heart failure, and LV myocardial remodeling.

Methods and Results—

One hundred sixty male adult rats were divided in 3 groups: sham sedentary (n=40), AR sedentary (n=80), and AR trained (n=40). Training consisted in treadmill running for up to 30 minutes, 5 times per week for 9 months, at a maximal speed of 20 m/minute. All sham-operated animals survived the entire course of the protocol. After 9 months, 65% of trained animals were alive compared with 46% of sedentary ones (
P
=0.05). Ejection fractions remained in the normal range (all above 60%) and LV masses between AR groups were similar. There was significantly less LV fibrosis in the trained group and lower LV filling pressures and improved echocardiographic diastolic parameters. Heart rate variability was also improved by exercise.

Conclusion—

Our data show that moderate endurance training is safe, does not increase the rate of developing heart failure, and most importantly, improves survival in this animal model of chronic LV volume overload. Exercise improved LV diastolic function, heart rate variability, and reduced myocardial fibrosis.
Cardiovascular Evaluation and Management of Severely Obese Patients Undergoing Surgery
Authors: Poirier Paul , Alpert Martin A. , Fleisher Lee A. , Thompson Paul D. , Sugerman Harvey J. , Burke Lora E. , Marceau Picard , Franklin Barry A.
Published: June 2009

Obesity is associated with comorbidities that may lead to disability and death. During the past 20 years, the number of individuals with a body mass index >30, 40, and 50 kg/m
2
, respectively, has doubled, quadrupled, and quintupled in the United States. The risk of developing comorbid conditions rises with increasing body mass index. Possible cardiac symptoms such as exertional dyspnea and lower-extremity edema occur commonly and are nonspecific in obesity. The physical examination and electrocardiogram often underestimate cardiac dysfunction in obese patients. The risk of an adverse perioperative cardiac event in obese patients is related to the nature and severity of their underlying heart disease, associated comorbidities, and the type of surgery. Severe obesity has not been associated with increased mortality in patients undergoing cardiac surgery but has been associated with an increased length of hospital stay and with a greater likelihood of renal failure and prolonged assisted ventilation. Comorbidities that influence the preoperative cardiac risk assessment of severely obese patients include the presence of atherosclerotic cardiovascular disease, heart failure, systemic hypertension, pulmonary hypertension related to sleep apnea and hypoventilation, cardiac arrhythmias (primarily atrial fibrillation), and deep vein thrombosis. When preoperatively evaluating risk for surgery, the clinician should consider age, gender, cardiorespiratory fitness, electrolyte disorders, and heart failure as independent predictors for surgical morbidity and mortality. An obesity surgery mortality score for gastric bypass has also been proposed. Given the high prevalence of severely obese patients, this scientific advisory was developed to provide cardiologists, surgeons, anesthesiologists, and other healthcare professionals with recommendations for the preoperative cardiovascular evaluation, intraoperative and perioperative management, and postoperative cardiovascular care of this increasingly prevalent patient population.
The Role of Redaction Criticism in the Evaluation of a Textual Variant: Another Look at 1QIsaª XXXII 14 (38:21–22)
Authors: Stromberg Jacob
Published: June 2009

With the discovery of the Dead Sea Scrolls, new emphasis has been placed on the extent to which the last stages of the formation of the Hebrew Bible have been preserved in early manuscripts. It is very widely held that such manuscript evidence comes in 1QIsaª XXXII 14. Here, Isa 38:21–22, which commentators suspected were secondary long before the discovery of the scrolls, are written in a secondary hand partly down the margin. This has led to the conclusion that 1QIsaª preserves an earlier unexpanded form of this passage. In this study, I argue that, despite the validity of this approach and attractiveness of this specific case, 1QIsaª XXXII 14 more likely reflects an omission. It will be seen that a redactional analysis of Isa 38, informed by the parallel in 2 Kgs 20, illuminates the text-critical evaluation of 1QIsaª XXXII 14.
Economic Crisis, Henryk Grossman and the Responsibility of Socialists
Authors: Kuhn Rick
Published: June 2009

Henryk Grossman's discussion of economic crises was designed to complement his Leninist understanding of politics. For Grossman, as for Marx, the fundamental contradiction of capitalist production is between the unlimited scope for expanding the output of use-values and restrictions imposed by the framework of producing profits. The increasing weight of capitalists' outlays on dead compared to living labour, which is the only source of new value, gives rise to the system's tendency to break down and, hence, to economic crises. Deep financial crises can only be understood in the context of developments in production and particularly movements in the rate of profit. The initial widespread hostility to Grossman's development of Marxist economics can mainly be explained in terms of the logics of Social-Democratic and Stalinist politics. In contrast to dominant views on the Left today, the Marxist tradition in which Grossman stood places the construction of organisations capable of assisting the working class' conquest of political power at the heart of the responsibility of socialists. Grossman's political practice expressed his understanding of the close relationship between capitalism's breakdown tendency and the importance of building a revolutionary party.
Apocalyptic Sublime: On the Brighton Photo-Biennial
Authors: Edwards Steve
Published: June 2009

Based on an account of the Brighton Photo-Biennial Memory of Fire: The War of Images and Images of War, curated by Julian Stallabrass in late 2008, this essay considers the photographic coverage of the recent imperialist interventions in the Middle East. Taking its cue from Stallabrass's event, it reflects on the decline of documentary and photojournalism since the Vietnam War and the current attenuated politics of the media. It argues that the problem of the sublime extends beyond the current genre of 'aftermath'-photography and asks what might constitute a more cognitively adequate politics of the image.
Financialised Capitalism: Crisis and Financial Expropriation
Authors: Lapavitsas Costas
Published: June 2009

The current crisis is one outcome of the financialisation of contemporary capitalism. It arose in the USA because of the enormous expansion of mortgage-lending, including to the poorest layers of the working class. It became general because of the trading of debt by financial institutions. These phenomena are integral to financialisation. During the last three decades, large enterprises have turned to open markets to obtain finance, forcing banks to seek alternative sources of profit. One avenue has been provision of financial services to individual workers. This trend has been facilitated by the retreat of public provision from housing, pensions, education, and so on. A further avenue has been to adopt investment-banking practices in open financial markets. The extraction of financial profits directly out of personal income constitutes financial expropriation. Combined with investment-banking, it has catalysed the current gigantic crisis. More broadly, financialisation has sustained the emergence of new layers of rentiers, defined primarily through their relation to the financial system rather than ownership of loanable capital. Finally, financialisation has posed important questions regarding finance-capital and imperialism.
Firing Back: Against the Tyranny of the Market 2: Global Turbulence: Social Activists' and State Responses to Globalization: Globalization and Inequality: Neoliberalism's Downward Spiral: Anti-Capitalism: A Marxist Introduction
Authors: Westra Richard
Published: June 2009

This article reviews a cross-section of the globalisation-literature written prior to the unfolding economic crisis of 2007. It assesses the literature in terms of its apprehending of changes in capitalism and the prospects for social change that are envisioned.
Gramsci storico. Una lettura dei 'Quaderni del carcere'
Authors: Filippini Michele
Published: June 2009

The review article reconstructs the reception of Gramsci's writings in Italy from the postwar-period to the present. Compared to the Italian debate that has given little attention to Gramsci's writings, except for in some periods such as the 1970s, Gramsci's fortune has continued to grow internationally. Recent Italian contributions, such as the book of Alberto Bugio, Grasmci storico, criticised in this review, remain indebted to an historicist approach that does not allow a use of Gramscian categories as an optic for interpreting and enacting the transformation of the present. The analysis concentrates on concepts such as 'passive revolution', 'fascism', 'Taylorism' and 'bureaucracy'.
Why We Recommend Analytic Treatment for Some Patients and Not for Others
Authors: Caligor Eve , Stern Barry L . , Hamilton Margaret , MacCornack Verna , Wininger Lionel , Sneed Joel , Roose Steven P.
Published: June 2009

One hundred consecutive patients applying for analysis completed a comprehensive battery of structured interviews and self-report questionnaires assessing dimensions of psychopathology and psychological functions that analysts consider important when evaluating patients for analysis. Patients were evaluated for analysis by a candidate supervised by a training analyst. Fifty patients were accepted for analysis and fifty rejected. In both groups, psychiatric morbidity and psychosocial impairment were high, with a 50% current and 74% lifetime diagnosis of mood disorder, 56% current and 61% lifetime history of anxiety disorder. The mean Beck Depression Inventory score fell in the moderate range, 19.1 ( SD = 11.0), mean Hamilton Depression score in the mild range, 14.1 ( SD = 7.8), and the mean Hamilton Anxiety score in the moderate range, 14.6 ( SD = 8.1), with 57% meeting criteria for an Axis II diagnosis, and mean social adjustment in the moderate to high pathology range. Patients accepted and rejected for analysis did not differ with regard to any of these dimensions. Accepted patients scored lower on measures of impulsivity, aggression, and sociopathy, and on scores of personality rigidity, primitive defenses, and outward aggression. The major finding was the striking similarity between patients accepted and rejected for psychoanalytic treatment.
“After A Long Pause”: How to Read Dora as History
Authors: Ahbel-Rappe Karin
Published: June 2009

Freud's “Fragment of an Analysis of a Case of Hysteria” (1905a,b) is well recognized for making psychoanalytic history. In the Dora paper Freud first publicized a new theory of the etiology of neurosis that made fantasy and repression central. And yet the paper also refers to trauma and seduction. What role do they play in the text? Part 1 shows that this is not a case of Freud broadening his etiological framework by adding a new focus to older ones. Rather, the references to trauma and seduction in Dora need to be understood in two ways. First, there is in the 1905 paper an implicit theoretical autobiography, of which Freud's references to the trauma and seduction theories early in the paper are part. Second, Freud's reference to seduction later in the paper constitutes Freud's first public critique of the seduction theory. The Dora paper is the actual site of the abandonment of the seduction theory. In Part 2 the focus shifts to the text's “theoretical unconscious.” Despite its rejection of the seduction theory in its avowed theorizing, the text is haunted by displaced signifiers of the theory. This suggests that Freud was unconsciously conflicted about not applying the insights of the seduction theory to Dora.
The Sense of Defect
Authors: Coen Stanley J.
Published: June 2009

The sense of defect, physical or psychological, is here regarded as a fantasy, a compromise formation, rather than an actual defect existing somewhere in the body, or in some psychological structure. It need not correlate with the reality to an external observer of physical or psychological disability. Psychoanalytic emphasis is directed to the motivations for the persistence of this sense of defect, rather than primarily to etiology (trauma) or genetic history. Accurate perception and evaluation, having been interdicted during childhood, is avoided with the magical hope that thereby one will be acceptable and what is wrong will disappear. The interaction between self and parents, real and fantasied, cannot be clearly known. The patient remains uncertain as to what is wrong, in whom it is located, and how it has come about. The sense of defect, physical or psychological, becomes the nidus around which much is crystallized. This is then offered up to a parent (and the superego) as an appeasement and seduction, aiming to help this parent feel better by agreeing that the child is indeed the cause of what is wrong. Dangerously destructive (and sexual) wishes are defended against and atoned for by emphasis on one's defectiveness.
A Theoretical Basis for the Concepts of Self and Authentic Self
Authors: Havens Leston
Published: June 2009

Concepts of self of Grossman, Kohut, and Kernberg are briefly summarized and some limitations suggested. The author proposes a theoretical basis of the concepts of self and authentic self parallel to superego development and the concept of ownership of impulses and values.
Bulimia: Psychoanalytic Perspectives
Authors: Schwartz Harvey J.
Published: June 2009

Bulimia, the syndrome of food binging often followed by purging has been reported to be increasing in recent years. This communication reviews the psychoanalytic understanding of eating disorders, focusing on the pathology of early object relation and later intrapsychic conflicts over incestuous impregnation fantasies. Ancillary symptoms of kleptomania, laxative abuse, and vegetarianism are discussed, and associations with masturbatory conflicts and early adolescent phallic activity, i.e., horseback riding, are elaborated.
Reconstruction and Perceptual Experience: Further Thoughts on Psychoanalytic Listening
Authors: Schwaber Evelyne Albrecht
Published: June 2009

Freud's monumental shift to the fantasy theory heralded the view that “it is psychical and not material reality” which is our sole domain of inquiry. Yet despite theoretical agreement and cogent technical admonitions against concerning ourselves with absolute or “external” truth, psychoanalytic listening betrays a stance in which the analyst attunes to a reality other than that of the patient's inner world, assuming the position of arbiter—even if a silent one—of what is or is not “distorted” in the patient's perceptual experience. The central impact of perception as a significant component of the patient's inner experience—past and present—goes unattended. Clinical examples from differing theoretical persuasions are reviewed to demonstrate this occurrence.

An alternative mode of listening is considered which assumes an underlying shift in outlook, suspending any notion that we can “know” what is “correct” in the patient's perception, while sharpening attunement to its clinical impact—as may be evidenced by a shift in affect or state, a turn of phrase, or the transient appearance of a symptom or old behavior. It is argued that such a stance will lead to a more singular focus on the patient's psychic reality, permitting the emergence of a deepening realm of psychic phenomena, enhancing the capacity of self-observation, and richly facilitating the reconstructive process.
Changes in the Level and Quality of Object Relations in Psychoanalysis: Followup of A Longitudinal, Prospective Study
Authors: Kantrowitz Judy L. , Katz Ann L. , Paolitto Frank , Sashin Jerome , Solomon Leonard
Published: June 2009

As part of a prospective, longitudinal study of suitability for and outcome of psychoanalysis, 22 patients were evaluated for changes in the level and quality of their object relations. These patients had been accepted for supervised analysis with candidates in training by senior analysis who had diagnosed them as neurotic. The majority of these patients reported difficulties in relationships as at least one of their reasons for originally seeking psychoanalytic treatment. Prior to beginning analysis, each patient was given a battery of psychological tests. One year after the termination of analysis, the test battery was readministered and a followup interview was conducted separately with each patient and analyst. Ratings of change based on patient and analyst interviews and comparisons of psychological tests before and after treatment all showed statistically significant improvement in the level and quality of object relations for this patient group. The results of this study support what is often observed in clinical practice, that psychoanalysis has a positive effect on the level and quality of a patient's object relations.
The Manifest Dream in Psychoanalysis: A Clarification
Authors: Pulver Sydney E.
Published: June 2009

Controversies about the value of the manifest dream in psychoanalysis are usually a matter of semantics. The author concludes that two clinically meaningful questions about the manifest dream can be asked: (1) Is the patient's report of a dream useful in formulating an interpretation if no formal associations to the dream elements are given? Inasmuch as such reports always include some kind of associations, and the analyst always possesses considerable knowledge about the patient, the answer to this question would seem to be “Yes, at least at times.” (2) In what ways can the manifest dream contribute to our understanding of the dream and the dreamer? Both the literature and clinical experience indicate that there are many ways; these are summarized in an appendix. One approach, the direct decoding of manifest dream elements, is discussed in some detail. Several examples of the undisguised appearance of memories of childhood traumatic experiences in the manifest dream are presented.
Reconstruction of an Early Seduction and Its Aftereffects
Authors: Williams Miriam
Published: June 2009

This clinical presentation deals with the aftereffects, in a male patient, of a severely disturbed rapprochement phase, marked by many separations and a molestation before the age of three. The patient dreamed repeatedly of violence, often directed against himself, but the actual molestation was sealed off by formidable repression. A first analysis, with a male analyst, produced no relief from the patient's depression, crippling insomnia, and inability to form an intimate relationship. The second analysis progressed only when the repetitive dreams were understood to be repressed experiences of seduction and molestation.
Journal of the American Psychoanalytic Association: A Retrospective (1953–1972)
Authors: Frosch John
Published: June 2009

In this article, as Editor Emeritus, I review the early evolution of the Journal. It began with the Bulletin, of which I was Editor. It became necessary to give more attention and space to the publication of group discussions and panels.

The early days of the Journal were characterized at times by internecine strife of a personal, political, and scientific nature. My ability to deal with this situation was hampered by my lack of knowledge, and even an amateurish quality concerned with editing a journal, although I had had considerable experience in editing The Annual Survey of Psychoanalysis.

Out of the realization of the impact of this strife on the scientific activities of the Journal, grew the firm determination to emphasize the role of the Editor and the Journal as free from the political fluctuations that characterized the Association from time to time. This was essential in establishing freedom from pressure, and autonomy insofar as the scientific activities of the Journal were concerned. It was indicated especially in setting up the criteria for selection of papers, so as to create a climate of fairness and objectivity. These criteria are stated in the article.

How the various problems mentioned above were dealt with is described in this contribution.
Therapeutic Strategy and Psychoanalytic Technique
Authors: Levy Steven T.
Published: June 2009

The role of therapeutic strategy within psychoanalytic technique is described. An antistrategic bias inherent in certain aspects of the “classical” technique is explored in relation to the historical development of psychoanalysis. Clinical expertise, which includes the making of strategic or tactical choices, is relegated to the “unofficial,” due in part to this negative bias impeding the study of technical differences in favor of general agreement about a theory of technique that may differ considerably from actual clinical work. A case is presented that illustrates strategic choices in the management of a severe character resistance in a supervised analysis. Some consequences of a negative bias against therapeutic strategy as it relates to psychoanalytic training is described.
Drives, Affects, Behavior-And Learning: Approaches to A Psychobiology of Emotion and to An Integration of Psychoanalytic and Neurobiology Thought
Authors: Schwartz Andrew
Published: June 2009

Drawing on concepts and data from psychoanalysis, neuroscience, ethology, and experimental psychology, this paper suggests that affects are the prime movers of human motivation and, have, in addition, these properties:(1) they are neurophysiologically generated, sensationlike signals originating not in classical sensory systems, but in limbic structures; (2) activation of the neurobiologic affect generators reliably triggers motor stereotypes-like facial expression, posture, and tone of voice-which in turn transmit the physical data underlying empathy and emotional communication; and(3) appetitively sought pleasant emotions-sensations and aversive dysphoric feelings serve respectively as the ultimate, “brain-synthesized” positive and negative reinforcers of emotional learning.

The latter ideas point to derivative hypotheses: that parental nonverbal behavior and communication evoke in children the affects that guide character development and choice of defense, and that these processes are consistent with an affect-reinforced associative learning model comprising both operant and classical conditioning paradigms.

Psychoanalysis as therapy, then, may mechanistically rely for its clinical effectiveness on extinctionlike processes in which new experience in the analyst-patient relationship leads to the modulation or extinction of initially crippling signal affects associatively linked to various other affects, appetites, and behaviors.

Finally, the core hypotheses mesh both with recent findings from the cellular study of affect and learning mechanisms and wotj associative learning-unlearning assumptions variably exlplicit in psychoanalytic writings since the time of freud's (1895) Project.
Notes on Psychoanalysis by A Participant Observer: A Personal Chronicle
Authors: Brenner Charles
Published: June 2009

Experience has shown how difficult it may be to decide which ideas are of passing interest and relatively little value and which are more important and fruitful. Examples of each are given in the form of a personal memoir. Some thoughts are added about the present and the future from the same vantage point.