Comparison of select cancer biomarkers in human circulating and bulk tumor cells using magnetic nanoparticles and a miniaturized micro-NMR system

Circulating tumor cells (CTC) harvested from peripheral blood have received significant interest as sources for serial sampling to gauge treatment efficacy. Nanotechnology and microfluidic based approaches are emerging to facilitate such analyses. While of considerable clinical importance, there is little information on how similar or different CTCs are from their shedding bulk tumors. In this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from cancer patients during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, we compared selected biomarkers (EpCAM, EGFR, HER-2 and vimentin) in both CTC and fine needle biopsies of solid epithelial cancers. We show a weak correlation between each paired sample, suggesting that use of CTC as “liquid biopsies” and proxies to metastatic solid lesions could be misleading.From the Clinical EditorIn this clinical study, paired tumor fine needle aspirate and peripheral blood samples were obtained from patients with solid epithelial cancers during image-guided biopsy. Using targeted magnetic nanoparticles and a point-of-care micro-NMR system, the authors compared selected biomarkers in both circulating tumor cells (CTC) and fine needle biopsies, demonstrating a weak correlation between each paired sample, suggesting that use of CTC could be misleading in this context.     

Relationship of chemical structure and anti-inflammatory activity of dihydrocorynantheol and its analogues

BackgroundDihydrocorynantheol (DHC) is an alkaloid compound isolated from Esenbeckia leiocarpa Engl. that has demonstrated anti-inflammatory properties in experimental models. The aim of this study was to investigate whether the modification of the chemical structure of DHC could alter its anti-inflammatory effect in a mouse model of pleurisy induced by carrageenan.MethodsDHC was isolated from Esenbeckia leiocarpa Engl. Capillary electrophoresis, physical characteristics, spectral data produced by infrared analysis and nuclearmagnetic resonance (¹H and ¹³C), andmass spectrometry analysiswere used to identify and elucidate DHC structure. The DHC compound was subjected to chemical structural modifications by nucleophilic substitution reactions, yielding five analogous compounds: acetyl (1), p-methylbenzoyl (2), benzoyl (3), p-methoxybenzoyl (4) and p-chlorobenzoyl (5). Swiss mice were used throughout the experiments. Pro-inflammatory parameters leukocyte migration, exudate concentrations and myeloperoxidase (MPO) activity were quantified in the fluid leakage from the mouse pleural cavities at 4 h after pleurisy induction.ResultsDHC and its analogues acetyl, p-methylbenzoyl, benzoyl, p-methoxybenzoyl and p-chlorobenzoyl inhibited total and differential leukocyte migration andMPOactivity (p < 0.05). OnlyDHCsignificantly decreased the exudate concentrations (p < 0.01).ConclusionsDHC was more effective than its analogues as an anti-inflammatory agent in the mouse model of pleurisy induced by carrageenan.We did not determine what physicochemical modifications altered the anti-inflammatory effect of DHC, but this effect may be due to the modifications on the hydroxyl group at carbon 17 of the DHC.     

The human gene connectome as a map of short cuts for morbid allele discovery

High-throughput genomic data reveal thousands of gene variants per patient, and it is often difficult to determine which of these variants underlies disease in a given individual. However, at the population level, there may be some degree of phenotypic homogeneity, with alterations of specific physiological pathways underlying the pathogenesis of a particular disease. We describe here the human gene connectome (HGC) as a unique approach for human Mendelian genetic research, facilitating the interpretation of abundant genetic data from patients with the same disease, and guiding subsequent experimental investigations. We first defined the set of the shortest plausible biological distances, routes, and degrees of separation between all pairs of human genes by applying a shortest distance algorithm to the full human gene network. We then designed a hypothesis-driven application of the HGC, in which we generated a Toll-like receptor 3-specific connectome useful for the genetic dissection of inborn errors of Toll-like receptor 3 immunity. In addition, we developed a functional genomic alignment approach from the HGC. In functional genomic alignment, the genes are clustered according to biological distance (rather than the traditional molecular evolutionary genetic distance), as estimated from the HGC. Finally, we compared the HGC with three state-of-the-art methods: String, FunCoup, and HumanNet. We demonstrated that the existing methods are more suitable for polygenic studies, whereas HGC approaches are more suitable for monogenic studies. The HGC and functional genomic alignment data and computer programs are freely available to noncommercial users from http://lab.rockefeller.edu/casanova/HGC and should facilitate the genome-wide selection of disease-causing candidate alleles for experimental validation.     

Lesiones cutáneas y terapia biológica con antagonistas del factor de necrosis tumoral

The efficacy shown by biological therapy with tumor necrosis factor (TNF) antagonists has led in the recent years to its increased and extended use in different inflammatory arthopathies. Initially, safety studies of these drugs were mainly focused on the risk of infection and the development of malignancies. Recently, several cases of skin lesions induced by anti-TNF drugs have been reported with an increased incidence, highlighting the importance of the skin as a major target of the side effects of these drugs. In addition to skin lesions directly related to drug administration there is a wide spectrum of skin lesions of different morphology and etiology, especially the development of cutaneous immune-mediated conditions, an emergent phenomenon associated with this treatment. We describe the main skin lesions associated with treatment with anti-TNF drugs according to an extensive review of the literature.     

Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis

Objective

Impaired endothelium‐dependent vasodilator function may contribute to vascular damage in patients with systemic sclerosis (SSc). This study was undertaken to investigate whether increased activity of the endothelin 1 (ET‐1) system plays a role in the occurrence of endothelial dysfunction in patients with SSc.

Methods

In 12 patients with SSc (6 with diffuse cutaneous SSc [dcSSc] and 6 with limited cutaneous SSc [lcSSc]), forearm blood flow responses to graded doses of acetylcholine (ACh) and sodium nitroprusside (SNP) given intraarterially were assessed by plethysmography, during infusion of saline and following selective blockade of ET_A receptors with BQ‐123 (10 nmoles/minute).

Results

During saline infusion, the vasodilator response to ACh was blunted in patients with SSc as compared with that in healthy controls (P < 0.001), whereas the response to SNP was not different between groups (P = 0.27). The vasodilator effect of ET_A receptor antagonism was higher in patients than in controls (P < 0.001), indicating enhanced ET‐1–mediated vasoconstriction in SSc. In patients, ET_A receptor blockade resulted in a potentiation of the vasodilator response to ACh (P < 0.001 versus saline), but did not affect the response to SNP (P = 0.31). Notably, both the vasodilator effect of ET_A receptor antagonism and the improvement in the responsiveness to ACh following BQ‐123 infusion were higher in patients with dcSSc than in those with lcSSc (P < 0.01).

Conclusion

ET‐1–dependent vasoconstrictor tone is increased predominantly in the subgroup of SSc patients with dcSSc, in whom acute blockade of ET_A receptors was able to improve impaired endothelium‐dependent vasodilator function. Our results suggest novel vasculoprotective effects of ET_A receptor antagonism and support further exploration of strategies that target the ET‐1 pathway in SSc.

     

Relationship between anxiety disorders and opiate dependence— A systematic review of the literature : Implications for diagnosis and treatment

Our objective was to evaluate the prevalence and temporal sequence of co-occurrence of anxiety disorders with opiate dependence in order to better define the relationship between these two disorders and to improve diagnosis and treatment. The search used Medline and Toxibase up to January 1, 2009, and was based on a systematic review method. Eighteen studies were found. Prevalence of anxiety disorders assessed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria was high in opiate-dependent treated persons (lifetime prevalence ranged from 26% to 35%). Among anxiety disorders, phobic disorders have been shown to often precede the onset of opiate dependence. The identification of substance-induced versus independent anxiety disorder has important treatment implication. The monitoring of anxiety symptoms after several weeks of abstinence may allow physicians to determine the relationship between dependence and anxiety and make a reliable diagnosis of any initial anxious disorder. Specific management of anxiety disorder may then be used.     

Proving the value of simulation in laparoscopic surgery

OBJECTIVE: To assess the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS) physical laparoscopic simulator for construct and predictive validity and for its educational utility. SUMMARY BACKGROUND DATA: MISTELS is the physical simulator incorporated by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) in their Fundamentals of Laparoscopic Surgery (FLS) program. MISTELS' metrics have been shown to have high interrater and test-retest reliability and to correlate with skill in animal surgery. METHODS: Over 200 surgeons and trainees from 5 countries were assessed using MISTELS in a series of experiments to assess the validity of the system and to evaluate whether practicing MISTELS basic skills (transferring) would result in skill acquisition transferable to complex laparoscopic tasks (suturing). RESULTS: Face validity was confirmed through questioning 44 experienced laparoscopic surgeons using global rating scales. MISTELS scores increased progressively with increasing laparoscopic experience (n = 215, P < 0.0001), and residents followed over time improved their scores (n = 24, P < 0.0001), evidence of construct validity. Results in the host institution did not differ from 5 beta sites (n = 215, external validity). MISTELS scores correlated with a highly reliable validated intraoperative rating of technical skill during laparoscopic cholecystectomy (n = 19, r = 0.81, P < 0.0004; concurrent validity). Novice laparoscopists were randomized to practice/no practice of the transfer drill for 4 weeks. Improvement in intracorporeal suturing skill was significantly related to practice but not to baseline ability, career goals, or gender (P < 0.001). CONCLUSION: MISTELS is a practical and inexpensive inanimate system developed to teach and measure technical skills in laparoscopy. This system is reliable, valid, and a useful educational tool.     

Palliative endoscopic treatment of pancreatic cancer

Pancreatic cancer has a very poor chance of being radically resected (20-25%) at the time of diagnosis. Palliation has thus proved to be the mode of treatment adopted in the majority of cases. When a radical surgical resection is not feasible, the endoscopic approach is one of the most common options among the therapeutic methods available. Endoscopic palliation for the treatment of jaundice is regarded as the best choice. It is associated with very low morbidity and no mortality. Hospitalization is short and the treatment is also inexpensive compared to other procedures. The authors report on their experience with endoscopic palliation for the treatment of inoperable pancreatic cancer.     

Risk factors for deep vein thrombosis in short-haul cockpit crews: a prospective study

BACKGROUND: Venous thrombosis is a concern receiving international attention, especially for passengers traveling on long distance flights. However, there are no data on the effect on cockpit crew of multiple short duration flights. METHODS: Cockpit crew flew two or more internal flights per day. At sign on, 15 ml of blood was venesected from the subjects; at sign off, 20 ml of blood was venesected. All flights originated and terminated at Johannesburg Airport. A full blood count, differential, and D-dimer levels were determined. All participants completed detailed questionnaires stating their ages, alcohol consumption 24 h prior to flight duty, the amount of liquid consumed during flying time, the number of times they went to the toilet, and the amount of time spent sitting during flights. RESULTS: Blood tests on 27 cockpit crew were performed. D-dimers were reduced from 163 ng x ml(-1) to 133 ng x ml(-1) (p = 0.03). Hemoglobin levels dropped from 16.0 g x dl(-1) to 15.8 g x dl(-1) (p = 0.004). Hematocrit levels decreased from 47.2 ml x 100 ml(-1) to 46.9 ml x 100 ml(-1) (p = 0.04). Platelets increased from 221 x 10(9) x L(-1) to 241 x 10(9) x L(-1) (p = 0.001). White cell counts increased from 6.4 x 10(9) x L(-1) to 7.01 x 10(9) x L(-1) (p = 0.0063). Correlation analysis was performed between blood test results and the parameters of the questionnaire. No correlation was found between any of the parameters and the blood results. CONCLUSION: There is no evidence of sub-clinical thrombotic events in this group of subjects. Cockpit crew who fly multiple short duration flights do not suffer sub-clinical thrombotic events as evidenced by an absence of increased D-dimers.