Showing papers by "Hebron University published in 2006"

Decompressive craniectomy for the treatment of refractory high intracranial pressure in traumatic brain injury

Abstract: Background High intracranial pressure (ICP) is the most frequent cause of death and disability after a severe traumatic brain injury (TBI) High ICP is usually treated with general maneuvers (normothermia, sedation, etc) and a set of first-line therapeutic measures (moderate hypocapnia, mannitol, etc) When these measures fail to control high ICP, second-line therapies are initiated Of these, barbiturates, hyperventilation, moderate hypothermia, or removal of a variable amount of skull bone (decompressive craniectomy) are used Objectives To assess the effects of secondary decompressive craniectomy on outcomes and quality of life for patients with severe TBI in whom conventional medical therapeutic measures have failed to control a raised ICP Search methods We searched the following electronic databases: Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE, PubMed, EMBASE, ZETOC, CINAHL, and Controlled Trials metaRegister (wwwcontrolled-trialscom/mrct/search) We searched the Internet using Google Scholar (http://scholargooglecom) and handsearched relevant conference proceedings We also contacted experts in the field and authors of included studies The searches were last conducted in May 2008 Selection criteria Randomized or quasi-randomized studies assessing patients over the age of 12 months with severe TBI who underwent decompressive craniectomy to control ICP refractory to conventional medical treatments Data collection and analysis The electronic search and handsearching results were examined for reports of potentially relevant trials, which were then retrieved in full The selection criteria were applied, data extraction performed, and studies assessed for methodological quality Main results We found only one trial with 27 participants, conducted in a pediatric population Decompressive craniectomy was associated with a risk ratio (RR) for death of 054 (95% CI 017 to 172) and a RR of 054 (95% CI 029 to 101) for an unfavorable outcome (death, vegetative status, or severe disability 6 to 12 months after injury) To date, no results are available to confirm or refute the effectiveness of decompressive craniectomy in adults Authors' conclusions There is no evidence from randomized controlled trials that supports the routine use of secondary decompressive craniectomy to reduce unfavorable outcomes in adults with severe TBI and refractory high ICP In the study with a pediatric population, decompressive craniectomy reduced the risk of death and unfavorable outcomes Despite the wide CI for death and the small sample size of this one identified study, the treatment may be justified in patients below the age of 18 years when maximal medical treatment has failed to control ICP There are two ongoing randomized controlled trials of decompressive craniectomy (RescueICP and DECRA) that will allow further conclusions on the efficacy of this procedure in adults

Biosynthesis of tumorigenic HER2 C‐terminal fragments by alternative initiation of translation

Abstract: The overactivation of the HERs, a family of tyrosine kinase receptors, leads to the development of cancer. Although the canonical view contemplates HER receptors restricted to the secretory and endocytic pathways, full-length HER1, HER2 and HER3 have been detected in the nucleoplasm. Furthermore, limited proteolysis of HER4 generates nuclear C-terminal fragments (CTFs). Using cells expressing a panel of deletion and point mutants, here we show that HER2 CTFs are generated by alternative initiation of translation from methionines located near the transmembrane domain of the full-length molecule. In vitro and in vivo, HER2 CTFs are found in the cytoplasm and nucleus. Expression of HER2 CTFs to levels similar to those found in human tumors induces the growth of breast cancer xenografts in nude mice. Tumors dependent on CTFs are sensitive to inhibitors of the kinase activity but do not respond to therapeutic antibodies against HER2. Thus, the kinase domain seems necessary for the activity of HER2 CTFs and the presence of these HER2 fragments could account for the resistance to treatment with antibodies.

Adjuvant Trastuzumab: A Milestone in the Treatment of HER-2-Positive Early Breast Cancer

Abstract: Up to one fourth of women diagnosed with early breast cancer (EBC) have tumors that are human epidermal growth factor receptor 2 (HER-2) positive. This is associated with a high risk of relapse and death from meta-static disease. Trastuzumab, a monoclonal antibody directed against the extracellular domain of HER-2, improves survival and quality of life in women with HER-2-positive metastatic breast cancer receiving chemotherapy. Four major adjuvant trials-Herceptin Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006-including between them >13,000 women with HER-2-positive EBC, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this population. The benefit was similar across the trials despite differences in patient populations, chemotherapy regimens, and sequencing of treatment. At a 2-year follow-up, interim results from the combined analysis of the NSABP B-31 and NCCTG N9831 trials showed a one third lower mortality for trastuzumab, and there was a trend toward an overall survival benefit in the HERA and BCIRG trials. A small Finnish trial, FinHer, investigating another regimen of trastuzumab, has also shown similarly positive results. Further follow-up of the major adjuvant trials will clarify the survival benefit for women receiving trastuzumab, as well as the optimal treatment duration (1 or 2 years). Notably, cardiac events in the trastuzumab-containing arms of these trials have remained within acceptable levels, with a slightly higher (0.6%-3.3%) incidence of congestive heart failure that mostly responded to treatment. Further follow-up will provide information on long-term cardiac safety. Overall, results from clinical trials are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER-2-positive EBC based on the risk:benefit ratio demonstrated in these studies.

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Abstract: BACKGROUND. Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream. METHODS. One hundred twenty-nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c-erb-B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK. RESULTS. Among 129 ovarian neoplasms, 17.8% were positive for c-erb-B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p-AKT), 58.9% were positive for p-ERK, 41.1% were positive for p-4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p-S6. Although EGFR, p-AKT, and p-ERK expression did not differ between benign, borderline, or malignant tumors, c-erb-B2, p-4EBP1, p-p70S6K, and p-S6 were expressed significantly more often in malignant tumors. Only p-4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p-4EBP1 expression had statistical significance in the multivariate analysis. CONCLUSIONS. In patients with ovarian carcinoma, significant expression of p-4EBP1 was associated with high-grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. Cancer 2006. © 2006 American Cancer Society.

Multilocular cystic renal cell carcinoma : a report of 45 cases of a kidney tumor of low malignant potential.

Abstract: The 2004 World Health Organization (WHO) classification of kidney tumors recognizes multilocular cystic renal cell carcinoma (MCRCC) as a rare variant of clear cell renal cell carcinoma with a good prognosis. Available information on its clinical significance is limited. The study cohort included 45 MCRCC cases classified according to 2004 WHO criteria obtained through a multi-institutional international search. Most patients had unilateral MCRCC with no side predominance that was found incidentally; 62% were men, but women had tumors at an earlier age (P = .385). MCRCC occurred slightly more often in men than in women (1.7:1). At diagnosis, 82% of patients had stage T1 and 16%, stage T2; 1 patient had stage T3. The Fuhrman grade was 1 (62%) or 2 (38%), with smaller tumors (

Pharmacodynamic Studies of Gefitinib in Tumor Biopsy Specimens From Patients With Advanced Gastric Carcinoma

Abstract: Purpose Epidermal growth factor receptor (EGFR) is highly expressed in some gastric cancers and is implicated in cancer cell growth and proliferation. The objective of this study was to assess the in situ biologic activity of the EGFR tyrosine kinase inhibitor gefitinib in gastric tumor samples in a phase II study. Methods Patients with previously treated stage IV adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive gefitinib (250 or 500 mg/d). Tumor biopsies, obtained at screening and on day 28 of treatment, were assessed for biomarker expression using immunohistochemistry and analysis of apoptosis. Results One hundred sixteen tumor samples from 70 patients were available, 70 were baseline and 46 were on-therapy biopsies. At baseline, levels of EGFR expression significantly correlated with levels of phosphorylated EGFR (pEGFR; P < .001) and Ki67 expression (P = .011), but not with phosphorylated mitogen-activated protein kinase (pMAPK). After gefitinib treatment, l...

Islam and management: What can be learned?

Abstract: Religion has a major impact on human behavior, social interactions, and social relations. This research article discusses the impact of Islam on managers' behavior. The impact is exerted from the five pillars of Islam: faith, prayer, alms, fasting, and pilgrimage. From the article, it is evident that such pillars have a direct effect on Moslems' behavior. Besides that, the article shows the significant impact of Allah supreme names on managers' behavior and style. Allah names have a direct interrelationship with management functions like planning, organizing, and directing. A Moslem manager, in fact, can use Allah supreme names as a guide to his management style and action. Finally, the article sheds light on major Islamic management principles and their effect on managers' behavior and perception. © 2006 Wiley Periodicals, Inc.

ADAMs, cell migration and cancer

Abstract: The ADAMs are modular type I transmembrane proteins that contain a metalloprotease and a disintegrin-like domain. In fact, ADAM stands for “A Disintegrin And Metalloprotease” and has become the most widespread name to designate this group of proteins. Alternative terms such as metalloprotease disintegrins or MDC (metalloprotease/disintegrin/cysteinerich) are currently less used. Although ADAMs are frequently referred to as a family, they constitute a subfamily of the M10 family that, in turn, belongs to the metzincin clan of metalloproteases [4]. To date, 23 ADAMs have been identified in the human genome: ADAM1-3, 6–12, 15, 17–23, 28–30, 32 and 33 (for an up-to-date list of ADAMs in different organisms, see http://www.people.virginia.edu/%7Ejw7 g/Table of the ADAMs.html). ADAM9, 10, 12, 15, 17, 19, and 33 are widely expressed, the rest show a restricted tissue distribution. Analysis of their primary structure shows that, in addition to the disintegrin and metalloprotease, all ADAMs contain the following domains: signal peptide, prodomain, cysteine-rich, epidermal growth factor (EGF)-like, transmembrane and cytoplasmic (Fig. 1). The prodomain keeps the metalloprotease domain inactive until its removal by furin-like proprotein convertases or autocatalytic processing. The related group of ADAMTS are secreted soluble proteins that contain a variable number of thrombospondin-like repeats (Fig. 1). A particularly intriguing feature of the ADAMs is that they support both proteolytic activity and cell adhesion, making

Proteomic Identification of Desmoglein 2 and Activated Leukocyte Cell Adhesion Molecule as Substrates of ADAM17 and ADAM10 by Difference Gel Electrophoresis

Abstract: In contrast with the early view of metalloproteases as simple extracellular matrix-degrading entities, recent findings show that they are highly specific modulators of different signaling pathways involved, positively or negatively, in tumor development. Thus, before considering a given metalloprotease a therapeutic target, it seems advisable to characterize its function by identifying its repertoire of substrates. Here, we present a proteomic approach to identify ADAM17 substrates by difference gel electrophoresis. We found that the shedding of the extracellular domain of the transferrin receptor and those of two cell-cell adhesion molecules, activated leukocyte cell adhesion molecule (ALCAM) and desmoglein 2 (Dsg-2), is increased in cells overexpressing ADAM17. Genetic evidence shows that while ADAM17 is responsible for the shedding of ALCAM, both ADAM17 and ADAM10 can act on Dsg-2. Activation of the epidermal growth factor receptor leads to the upregulation of the shedding of Dsg-2 and to the concomitant upregulation of ADAM17, but not ADAM10, supporting the ability of overexpressed ADAM17 to shed Dsg-2. These results unveil a role of ADAM10 and ADAM17 in the shedding of cell-cell adhesion molecules. Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy.

Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer

Abstract: The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody matuzumab (formerly EMD 72000) is active against pancreatic cancer in preclinical studies. This phase I study assessed the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n=17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m–2 weekly in weeks 1–3 of each 4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters, and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe treatment-related toxicities were limited to grade 3 neutropenia (n=3), leucopenia (n=1), and decreased white blood cell count (n=1). Common study drug-related adverse events were skin toxicities (grade 2=6, grade 1=7) and fever (grade 1=4). Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction; effects were seen even in the lowest-dose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in the group receiving 800 mg weekly. Matuzumab in biologically effective doses with standard gemcitabine therapy appears well tolerated. The combination is feasible and may have enhanced activity.

Current Issues in Adjuvant Treatment of Stage II Colon Cancer

Abstract: Background Adjuvant chemotherapy with 5-fluorouracil modulated by folinic acid, combined with oxaliplatin, has now become an accepted standard of care for patients with stage III colon cancer. In contrast, the use of adjuvant therapy for stage II patients remains controversial, and the identification of reliable prognostic factors to aid therapeutic decision making is crucial.

Community-based seroepidemiological survey of hepatitis E virus infection in Catalonia, Spain.

Abstract: The objective of the study was to investigate the prevalence of immunoglobulin G (IgG) antibodies to hepatitis E virus (HEV) infection in a population sample from Catalonia and to analyze the demographic and clinical variables associated with the presence of these antibodies. A total of 1,280 subjects between 15 and 74 years of age were selected randomly from urban and rural areas. Data for sociodemographic and clinical variables were collected by using a questionnaire. IgG antibodies to HEV were determined by an immunoenzymatic method. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for studied variables. Multiple logistic regression analysis was used to determine which variables were independently associated with the prevalence of HEV infection. Anti-HEV antibodies were detected in 96 (7.3%) of the 1,280 samples analyzed. The prevalence of antibodies was greater among males (7.8%) than among women (7%) and increased with age for both sexes, from 3% among subjects 15 to 24 years of age to 12% among subjects ≥65 years of age. Bivariate analysis of the sociodemographic and clinical variables showed an association between the prevalence of hepatitis E virus infection and minor surgery (OR, 1.96; 95% CI, 1.24 to 3.11), abdominal surgery (OR, 1.74; 95% CI, 1.12 to 2.73), and, for women, being uniparous or multiparous (OR, 2.84; 95% CI, 1.19 to 6.79). The multivariate analysis showed an association with minor surgery only (OR, 1.68; 95% CI, 1.03 to 2.70). In conclusion, anti-HEV antibodies were detected in 7.3% of the Catalan population. The seroprevalence of anti-HEV antibodies increased with age and was associated with previous minor surgery.

Multilocular Cystic Renal Cell Carcinoma

Abstract: The 2004 World Health Organization (WHO) classification of kidney tumors recognizes multilocular cystic renal cell carcinoma (MCRCC) as a rare variant of clear cell renal cell carcinoma with a good prognosis. Available information on its clinical significance is limited. The study cohort included 45 MCRCC cases classified according to 2004 WHO criteria obtained through a multi-institutional international search. Most patients had unilateral MCRCC with no side predominance that was found incidentally; 62% were men, but women had tumors at an earlier age ( P = .385). MCRCC occurred slightly more often in men than in women (1.7:1). At diagnosis, 82% of patients had stage T1 and 16%, stage T2; 1 patient had stage T3. The Fuhrman grade was 1 (62%) or 2 (38%), with smaller tumors (≤4 cm) most likely Fuhrman grade 1 ( P = .911). All 45 patients were alive with no evidence of disease at mean follow-up of 66.1 months, confirming an extremely good prognosis after surgery and a 5-year disease-specific survival rate of 100%. To rename this tumor as multilocular cystic renal cell neoplasm of low malignant potential might help urologists approach the patients conservatively.

Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer.

Abstract: Objectives: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer tre

Identification of substrates of the extracellular protease ADAMTS1 by DIGE proteomic analysis.

Abstract: Proteolytic modification of components of the extracellular milieu by metalloproteinases plays important roles in the regulation of multiple cellular and physiological processes and pathological conditions. ADAMTS1 is a secreted enzyme of the ADAMTS (adisintegrin and metalloproteinase with thrombospondin motifs) family of proteases, which is related to angiogenesis and inflammation processes. Here, we describe a proteomic screening for putative ADAMTS1 substrates by analyzing the protein profiles obtained from cultures of transfected cells overexpressing the protease as compared to parental cells. Conditioned medium proteins of cultures of the two cell lines have been quantitatively compared by DIGE. Proteins showing differential levels have been identified by MS techniques leading to the finding of five potential new substrates of ADAMTS1: the basement membrane proteins nidogen-1 and -2, the desmosomal protein desmocollin-3, and the extracellular glycoproteins dystroglycan 1 and Mac-2-binding protein. Nidogen-1 and -2 have been further validated as substrates by immunochemical analysis. Our results demonstrate the utility of the DIGE proteomic technique for the discovery of specific substrates of matrix proteases.

Expression of metallothionein-I, -II, and -III in Alzheimer disease and animal models of neuroinflammation.

Abstract: In recent years it has become increasingly clear that the metallothionein (MT) family of proteins is important in neurobiology. MT-I and MT-II are normally dramatically up-regulated by neuroinflammation. Results for MT-III are less clear. MTs could also be relevant in human neuropathology. In Alzheimer disease (AD), a major neurodegenerative disease, clear signs of inflammation and oxidative stress were detected associated with amyloid plaques. Furthermore, the number of cells expressing apoptotic markers was also significantly increased in these plaques. As expected, MT-I and MT-II immunostaining was dramatically increased in cells surrounding the plaques, consistent with astrocytosis and microgliosis, as well as the increased oxidative stress elicited by the amyloid deposits. MT-III, in contrast, remained essentially unaltered, which agrees with some but not all studies, of AD. In situ hybridization results in a transgenic mouse model of AD amyloid deposits, the Tg2576 mouse, which expresses human Abeta precursor protein harboring the Swedish K670N/M671L mutations, are in accordance with results in human brains. Overall, these and other studies strongly suggest specific roles for MT-I, MT-II, and MT-III in brain physiology.

Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors.

Abstract: A dualistic model, which has been established on a morphological basis and that differentiates type I endometrioid from type II non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type I endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. Genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, or altered genes associated with the initial steps of myometrial infiltration in endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer.

Novel targets in gastric and esophageal cancer

Abstract: Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant chemotherapy, radiotherapy or both have increased the survival of patients with loco-regional disease. However, most patients with GC or EC have advanced disease either at diagnosis or during the follow-up, and despite recent advances, these patients still do poorly. Understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC, including EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into clinical benefit for patients with these common malignancies.

Percutaneous implantation of cerebral microdialysis catheters by twist-drill craniostomy in neurocritical patients: description of the technique and results of a feasibility study in 97 patients.

Abstract: Cerebral microdialysis is increasingly used to monitor several types of neurocritical patients. This study presents the technique used in our unit for percutaneous implantation of cerebral microdialysis catheters using a small twist-drill craniostomy that can be performed in the intensive care unit (ICU). We also present the results of this technique in 89 head-injured patients and in eight patients with a malignant middle cerebral artery (MCA) infarction. One hundred and twenty-two cerebral microdialysis catheters were implanted in the 97 patients included in this study. One cerebral microdialysis catheter was implanted in the less damaged hemisphere of 67 head-injured patients with a diffuse brain injury. An additional microdialysis catheter was inserted in the pericontusional parenchyma of 22 patients with brain contusions. In five of the eight patients with a malignant MCA infarction, only one microdialysis probe was inserted in the penumbral zone. In the remaining three patients, two cerebral microdialysis catheters were implanted in the same hemisphere (one in the ischemic core and the other in the penumbra). Technical problems were detected in 18 (15%) of the 122 microdialysis catheters implanted and were more frequent during the initial period of using microdialysis in our unit. In four patients (3% of implanted catheters), follow-up computed tomography (CT) scans showed a small intracerebral blood collection (always

Biological Control of Sclerotium rolfsii by Using Indigenous Trichoderma spp. Isolates from Palestine

Abstract: The bioagent, Trichoderma species are known antagonists of other fungi, and have been shown to be very efficient biocontrol agents of several soil borne plant pathogenic fungi. Forty-seven local Trichoderma isolates were isolated from one hundred sixty nine soil samples from irrigated fields in the West Bank by using dilute plate techniques on Tri- choderma selective media (TSM).The antagonistic potential of the local isolates against the phytopathogenic Sclerotium rolfsii was investigated in dual culture and bioassay on bean plants. Application of testing isolates as a conidial suspension (3*10 6 ) greatly reduced the disease index of bean plants in different rates by a percentage of 67% .The results revealed that the variation of antagonistic potential between isolates was due to the variation in mycelium-coiling rate, sporulation, fungitoxic metabolites, induced growth response and temperature effect. The results showed that Jn14 and T36 were the most effective isolates at 25 °C and inhibited S. rolfsii mycelial growth at a percent- l age of 79% due to fungitoxic metabolites production. Sporulation of the isolates reached a peak at 30 °C and decreased at 35 °C. The maximum absolute conidia production was 1.5*10 9 conidia / ml by the isolate Jn14 at 30 °C. The Effect of Trichoderma on bean seedlings growth was obvious; height was nearly doubled (160% - 200%), while fresh and dry weight were increased in plant by 133% - 217% respectively. Germination of bean seeds treated with Trichoderma isolates occurred about four days earlier than those in untreated soil.

Is psychometric scoring of the McNew Quality of Life after Myocardial Infarction questionnaire superior to the clinimetric scoring? A comparison of the two approaches.

Abstract: Objective: ‘Clinimetric’ and ‘psychometric’ approaches are currently used to develop health related quality of life questionnaires. The Quality of Life after Myocardial Infarction questionnaire (QLMI) was originally developed using ‘clinimetric’ criteria; it was subsequently modified (McNew QLMI) and a new domain structure was defined using factor analysis. The objective of this study was to compare the measurement properties of the McNew QLMI scores when both approaches for scoring are used. Methods: The McNew QLMI and SF-36 were administered to patients 2 weeks and 2 months after myocardial infarction. Two sets of scores for the McNew QLMI were computed using the original ‘clinimetric’ and the subsequent ‘psychometrically’ derived scoring systems. Reliability statistics for the two sets of domains were compared and construct validity was assessed by establishing a priori hypotheses on the expected correlation between each score and the dimensions of the SF-36. Results: Both sets of scores had similar reliability (Cronbach’s α between 0.64 and 0.93) and responsiveness (SRMs between 0.17 and 0.87) while validity was better for the ‘clinimetric’ set of scores (concordance between observed and expected correlations was moderate for the ‘clinimetric’ scores and fair for the ‘psychometric’ scores). Conclusion: Since overall measurement properties of the ‘clinimetrically’ scored McNew QLMI are better than the ‘psychometrically’ scored version, we suggest that either the original ‘clinimetric’ system is used or that an improved ‘psychometric’ version is developed.

Differences in visual vs. verbal memory impairments as a result of focal temporal lobe damage in patients with traumatic brain injury.

Abstract: Primary objective: The aim of the present study was to determine whether the type of lesion in a sample of moderate and severe traumatic brain injury (TBI) was related to material-specific memory impairment.Methods and procedures: Fifty-nine patients with TBI were classified into three groups according to whether the site of the lesion was right temporal, left temporal or diffuse. Six-months post-injury, visual (Warrington's Facial Recognition Memory Test and Rey's Complex Figure Test) and verbal (Rey's Auditory Verbal Learning Test) memories were assessed.Main outcome and results: Visual memory deficits assessed by facial memory were associated with right temporal lobe lesion, whereas verbal memory performance assessed with a list of words was related to left temporal lobe lesion. The group with diffuse injury showed both verbal and visual memory impairment.Conclusions: These results suggest a material-specific memory impairment in moderate and severe TBI after focal temporal lesions and a non-specific m...

Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question

Abstract: In this issue of the Journal of Clinical Oncology, the results of the phase I study of EKB-569 in patients with solid tumors are presented. EKB-569 is a potent and irreversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. In this study, EKB569 was safe, exposure was dose proportional, and it had a prolonged mean terminal half-life, which allows for a daily administration schedule. The dose-limiting toxicity was grade 3 diarrhea, which is similar to other EGFR inhibitors. As with other anti-EGFR inhibitors, skin rash and asthenia were also observed. The maximum-tolerated dose was found to be 75 mg/d, both in the intermittent and in the continuous administration schedule, and a lower dose of 50 mg/d has been chosen for phase II studies because it is associated with fewer drug-related severe toxicities and there is a strong suggestion that this dose level results in biologically relevant concentrations in plasma and inhibits EGFR function in patients. On the basis of the results of this trial, EKB-569 clearly meets the early requirements for further clinical development; it is well tolerated, it has shown predictable pharmacokinetics, an optimal dose has been identified, it has the expected toxicities, and there is evidence of in vivo inhibition of the receptor. As usual with this class of agents, hints of clinical benefit were also observed. The critical question ahead for this and other anti-EGFR agents in early clinical development is whether they will be superior or complementary to the currently available anti-EGFR agents. The field of EGFR inhibitors is becoming increasingly crowded with the following two classes of agents: monoclonal antibodies against the extracellular domain of the receptor and low molecular weight tyrosine kinase inhibitors (for review, see Baselga and Arteaga). These two classes of agents have partially different mechanisms of action and nonoverlapping clinical indications. Anti-EGFR monoclonal antibodies are approved in the treatment of colon cancer and may be soon approved in other indications such as head and neck tumors. In the class of low molecular weight EGFR tyrosine kinase inhibitors, gefitinib and erlotinib are approved for the treatment of non–small-cell lung cancer (NSCLC), and erlotinib recently obtained approval for the treatment of advanced pancreas carcinoma. Do we have any suggestion that EKB-569 may be superior or complementary to gefitinib and erlotinib? Superiority may be achieved by different means, such as broader or greater efficacy, enhanced safety, or a more convenient administration schedule. None of these means seem to apply to EKB-569. Although a potential advantage of an irreversible EGFR inhibitor would be an easier dosing schedule, both gefitinib and erlotinib are already administered on a convenient daily basis. In terms of additional diseasebased indications, a phase II study of EKB-569 is underway in patients with advanced colorectal cancer (CRC). Although we need to wait for the outcome of this trial, one is tempted to speculate that EKB-569 will be inactive as a single agent in CRC based on the minimal activity of other EGFR tyrosine kinase inhibitors in CRC. It would also seem fair to wait for the results of currently ongoing studies of EKB-569 and chemotherapy in patients with pancreatic cancer and CRC. It seems more likely that the potential advantages of EKB-569 and other irreversible EGFR inhibitors in the treatment of cancer may be linked to the biology of EGFR itself. The EGFR is a transmembrane receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Ligand binding results in homoor heterodimerization and activation of the highly conserved intracellular tyrosine kinase domain, resulting in phosphorylation of specific tyrosine residues that serve as docking sites of proteins whose recruitment activates a multitude of downstream signaling pathways, which, in turn, engage mitogenic signaling and other tumor-promoting activities. Clinical responses to gefitinib and erlotinib are highly dependent on the presence of EGFR somatic mutations that affect critical amino acids in the adenosine triphosphate– binding cleft of the tyrosine kinase domain of the receptor. Responses have also been reported in patients with EGFR gene amplification. EGFR mutations arise in the following four exons of the gene: substitutions for G719 in the nucleotide binding loop of exon 18, in-frame deletions within exon 19, in-frame insertions within exon 20, and substitution for L858 or L861 in the activation loop in exon 21. Interestingly, not all EGFR mutations result in enhanced sensitivity to gefitinib and erlotinib. Patients who initially respond to gefitinib or erlotinib may acquire secondary EGFR mutations that render them resistant to these agents, specifically the T790M mutation. T790M primary mutations may also occur in previously untreated patients. Primary transforming mutations may also be resistant to gefitinib and erlotinib; this has been recently shown by the identification of an exon 20 insertion mutant that is completely resistant to these inhibitors. In addition, the T790M mutation is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 15 MAY 2

Clinical experience with erlotinib in non-small-cell lung cancer.

Abstract: Lung cancer is the leading cause of cancer death worldwide. Despite the introduction of more- effective chemotherapeutic agents, it appears that a survival plateau has been reached, so new treatment strategies are clearly needed. One innovative therapeutic cancer strategy is the introduction of biological agents that target specific intracellular pathways related to the distinctive properties of cancer cells. Among these agents, epidermal growth factor receptor (EGFR)-targeting agents have received particular attention in lung cancer. Numerous EGFR blockers have been evaluated, including monoclonal antibodies to the receptor and small-molecule tyrosine kinase inhibitors. The present review focuses on the tyrosine kinase inhibitor erlotinib. Preclinical studies have shown that erlotinib blocks the growth of human non-small-cell lung cancer (NSCLC) cell lines in vitro by inhibiting the receptor and the downstream protein phosphorylation. In a randomized study conducted by the National Cancer Institute of Canada (BR.21) in second- and third-line NSCLC treatment, erlotinib significantly prolonged overall survival and decreased symptoms compared with placebo. A crucial aspect of the clinical development of molecular-targeted therapies is to understand which patients will obtain clinical benefit from their use. Sensitivity to erlotinib has been associated with EGFR mutations, most commonly deletions of four to six amino acids in exon 19 or a point mutation (L858R) in exon 21. Increased EGFR gene copy number has also been pointed out as a good predictive marker for erlotinib response. Intense research activity is ongoing to validate known predictive markers and to discover new tools which maximize clinical benefit using erlotinib. However, there is no conclusive evidence, as yet, linking response to survival.

ATM gene expression is associated with differentiation and angiogenesis in infiltrating breast carcinomas.

Abstract: Summary. The product of the ATM gene, mutated in the human genetic disorder ataxia-telangiectasia (A-T) plays a key role in the detection and repair of DNA doublestrand breaks. A-T is defined by progressive cerebellar ataxia, telangiectasia, sensitivity to ionising radiation and genomic instability with cancer predisposition. On the other hand, increased angiogenesis is essential for tumor growth and metastasis. The aim of this study was to investigate ATM expression in breast carcinomas and its relationship to neoangiogenesis. Methods and Results: Fifty-two breast tumors from 51 patients, 38 of them with concomitant in situ component (CIS), were analyzed by immunohistochemistry for the expression of A TM. CD34 expression was used for the morphometric evaluation of vasculature. ATM was positive in 1 to 10% of normal epithelial cells. ATM expression was reduced in 55.8% of infiltrating carcinomas, non-reduced in 34.6%, and increased in 9.6%. Expression of ATM in CIS was similar to the infiltrating component in 71% of cases and reduced in 23.7% of them. High-grade ductal infiltrating carcinomas showed lower ATM expression than lowgrade ones. Reduced ATM expression also correlated with increased microvascular area. Conclusions: Reduced ATM expression in breast carcinomas correlated with tumor differentiation and increased microvascular parameters, supporting its role in neoangiogenesis and tumor progression in breast carcinogenesis.

Corpus callosum functioning in patients with normal pressure hydrocephalus before and after surgery.

Abstract: Objectives: Our aim was to evaluate corpus callosum functioning in a group of patients with normal pressure hydrocephalus (NPH) before and after shunting. Methods: Left ear-extinction under a dichotic listening task was evaluated in twenty-three patients with NPH, 30 patients with Alzheimer's disease and 30 aged controls. Results: Patients with NPH had higher levels of left ear extinction than the control and Alzheimer's groups. Sixty-one percent of NPH patients exhibited left ear suppression, compared with 13% of Alzheimer's patients and 17% of controls. Following surgery, NPH patients showed a significant change in the degree of asymmetry in the dichotic listening task. Conclusions: Hydrocephalus was associated with leftear extinction,which diminished after surgery. Our results may indicate reversible functional damage in the corpus callosum.