Conjugated linoleic acid and the control of cancer and obesity

The effects of conjugated linoleic acid (CLA) in animals are reviewed. In most of the CLA preparations that have been investigated to date for biological activity, two CLA isomers are present in about equal concentrations: cis-9,trans-11 CLA, and trans-10,cis-12 CLA. The occurrence of these isomers in foods and their production by rumen microorganisms are discussed. Potential mechanisms of action as regards the effects of CLA on cancer and body composition are reviewed, including recent evidence that body composition changes are produced by the trans-10,cis-12 CLA isomer. Evidence is presented indicating that CLA may modulate cellular response to tumor necrosis factor-alpha (TNF- alpha). The mechanistic implications of this finding are considered.      

Atopy in parents of children dying with sudden infant death syndrome

36 parents of infants who had died suddenly did not differ in frequency of atopic symptoms, immediate skin tests, IgE, IgE antibody, immunoglobulin G, A, and M, or yeast opsonisation, from 36 matched controls, although atopy was common (about half had atopy in both groups.     

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis

Mutations in three different genes of phosphorylase kinase (Phk) subunits, PHKA2, PHKB and PHKG2, can give rise to glycogen storage disease of the liver. The autosomal-recessive, liver-specific variant of Phk deficiency is caused by mutations in the gene encoding the testis/liver isoform of the catalytic gamma subunit, PHKG2. To facilitate mutation detection and to improve our understanding of the molecular evolution of Phk subunit isoforms, we have determined the structure of the human PHKG2 gene. The gene extends over 9.5 kilonucleotides and is divided into 10 exons; positions of introns are highly conserved between PHKG2 and the gene of the muscle isoform of the gamma subunit, PHKG1. The beginning of intron 2 harbors a highly informative GGT/GT microsatellite repeat, the first polymorphic marker in the PHKG2 gene at human chromosome 16p11.2-p12.1. Employing the gene sequence, we have identified homozygous translation-terminating mutations, 277delC and Arg44ter, in the two published cases of liver Phk deficiency who developed cirrhosis in childhood. As liver Phk deficiency is generally a benign condition and progression to cirrhosis is very rare, this finding suggests that PHKG2 mutations are associated with an increased cirrhosis risk.      

Phenomenological comparisons of major depression following stroke, myocardial infarction or spinal cord lesions

Patients with major depression admitted to hospital with acute stroke (n = 44), acute myocardial infarction (n = 25), or acute spinal cord injury (n = 12) were examined for differences in their phenomenological presentation of major depression. Depressed stroke patients were found to have significantly higher scores on the syndrome clusters for generalized anxiety and ideas of reference than depressed cardiac or spinal cord injury patients. In addition, significantly more stroke patients met diagnostic criteria for generalized anxiety disorder compared with the other two groups. Although spinal cord injury patients were younger, more likely to be treated with benzodiazepines, and less likely to be treated with beta-blockers, none of these factors distinguished stroke patients with anxious depression from stroke patients with depression only. These findings are consistent with the hypothesis that the etiology of depression following stroke may be different from that associated with myocardial infarction or spinal cord injury.     

Paradigm shift in gastrointestinal surgery − combating sarcopenia with prehabilitation: Multimodal review of clinical and scientific data

A growing body of evidence has demonstrated the prognostic significance of sarcopenia in surgical patients as an independent predictor of postoperative complications and outcomes. These included an increased risk of total complications, major complications, re-admissions, infections, severe infections, 30 d mortality, longer hospital stay and increased hospitalization expenditures. A program to enhance recovery after surgery was meant to address these complications; however, compliance to the program since its introduction has been less than ideal. Over the last decade, the concept of prehabilitation, or “pre-surgery rehabilitation”, has been discussed. The presurgical period represents a window of opportunity to boost and optimize the health of an individual, providing a compensatory “buffer” for the imminent reduction in physiological reserve post-surgery. Initial results have been promising. We review the literature to critically review the utility of prehabilitation, not just in the clinical realm, but also in the scientific realm, with a resource management point-of-view.     

Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony- stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady- state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = - .86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = - .70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.