Joint co-clustering: co-clustering of genomic and clinical bioimaging data

AbstractFor better understanding the genetic mechanisms underlying clinical observations, and better defining a group of potential candidates for protein-family-inhibiting therapy, it is interesting to determine the correlations between genomic, clinical data and data coming from high resolution and fluorescent microscopy. We introduce a computational method, called joint co-clustering, that can find co-clusters or groups of genes, bioimaging parameters and clinical traits that are believed to be closely related to each other based on the given empirical information. As bioimaging parameters, we quantify the expression of growth factor receptor EGFR/erb-B family in non-small cell lung carcinoma (NSCLC) through a fully-automated computer-aided analysis approach. This immunohistochemical analysis is usually performed by pathologists via visual inspection of tissue samples images. Our fully-automated techniques streamlines this error-prone and time-consuming process, thereby facilitating analysis and diagnosis. Experimental results for several real-life datasets demonstrate the high quantitative precision of our approach. The joint co-clustering method was tested with the receptor EGFR/erb-B family data on non-small cell lung carcinoma (NSCLC) tissue and identified statistically significant co-clusters of genes, receptor protein expression and clinical traits. The validation of our results with the literature suggest that the proposed method can provide biologically meaningful co-clusters of genes and traits and that it is a very promising approach to analyse large-scale biological data and to study multi-factorial genetic pathologies through their genetic alterations

Bacterial faecal flora in healthy women of different ages.

The composition of the intestinal flora is the result of host physiology, microbial interaction and environmental influences. The possible relationship between faecal flora composition and hormonal modifications in healthy women of different ages was studied. Forty-four normal women were divided into the following groups according to age: group I, 27–41 yr; group II, 50–55 yr, 5 yr after menopause. The subjects received no pharmacological treatment. Samples were collected on the 8th and 23rd day of the cycle; two samples were obtained from each postmenopausal woman. Qualitative and quantitative determination of microorganisms was carried out using slightly modified standard methods. In fertile women (group I), the microflora composition was similar for samples collected on the 8th—10th day and during the premenstrual period (23rd day). In postmenopausal women (group III), an increase in fungi, clostridia and aerobic lactobacilli mean concentrations were observed. Escherichia coli mean levels increased and Enterobacteriaceae such as Enterobacter cloacae and Citrobacter freundii were present in 80 per cent of subjects studied. The length of menopause was found to have only a slight influence on flora: the behaviour of the microflora composition in menopausal women in group II may be considered intermediate between groups I and III. This preliminary study demonstrates that there are fluctuations in the composition of the faecal flora in healthy women. The differences observed between premenopausal and postmenopausal women may be a consequence of modifications of the steroid sex hormone pattern

Short course palliative radiotherapy in advanced solid tumors: a pooled analysis (the SHARON project)

Previous trials showed the tolerability and efficacy of a palliative radiotherapy (RT) regimen (SHARON) based on the 4 fractions delivered in 2 days in different oncological settings. In order to identify possible predictors of symptomatic response, the purpose of this study is to perform a pooled analysis of previous trials. We analyzed the impact on symptomatic response of the following parameters: tumor site, histological type, performance status (ECOG), dominant symptom, and RT dose using the Chi-square test and Fisher's exact test. One-hundred-eighty patients were analyzed. Median RT dose was 20 Gy (range: 14-20 Gy). The overall response rate was 88.8% (95% CI 83.3-92.7%) while pre- and post-treatment mean VAS was 5.3 (+/- 7.7) and 2.2 (+/- 2.2), respectively (p < 0.001). The overall response rate of pain, dyspnea, bleeding, dysphagia, and other symptoms was 86.2%, 90.9%, 100%, 87.5%, and 100%, respectively. Comparing the symptomatic effect based on the analyzed parameters no significant differences were recorded. However, patients with locally advanced disease showed a higher rate of symptomatic responses than metastatic ones (97.3% vs 83.0%; p = 0.021). Finally, the complete pain response rate was more than double in patients with mild to moderate (VAS: 4-7) compared to those with severe (VAS > 7) pain (36.0% vs 14.3%; p = 0.028). This pooled analysis showed high efficacy of the SHARON regimen in the relief of several cancer-related symptoms. The markedly and significantly higher complete pain response rate, in patients with mild-moderate pain, suggests early referral to palliative RT for patients with cancer-related pain

Variability in the release of antibiotics from PMMA bone cement spacers

Antibiotic-loaded PMMA spacers are used with increased frequency in two-stage revision arthroplasty. The release of aminoglycosides and vancomycin, the most commonly used antibiotics, is prompt, and concentrations are inhibitory. The release kinetic from PMMA bone cement shows a biphasic profile, consisting in an initially high and rapid drug release followed by a slower but sustained phase.However, this general profile of drug release kinetics from PMMA spacers in vitro may have great variability in terms of drug amount, modality, and duration of elution. Initial drug concentration, cement surface area and porosity are essential and well-known factors in determining the drug release. Moreover, viscosity, vacuum-preparation and the different technical characteristics of commercially available spacers are additional factors of variability. Industrial preformed spacers are considered superior to custom-made devices because of uniform mixing and standardized procedures.Spacers produced by different manufacturers vary in their mechanical properties and antibiotic elution characteristics. Small changes in the formulation of a bone cement can also affect these properties.Similar bone cements produced by various brands release different amount of drugs. Gentamicin diffuses from Palacos in a larger amount and for a longer period than from Simplex and CMV. Spacers produced in France (Synicem™) and in Argentina (Subiton™) elute less total amount of gentamicin than those produced in Italy (Spacer G™) and show a delayed peak drug release. The low initial release of antibiotic can contribute to unsatisfactory antimicrobial effect and to the risk of selection of resistant bacteria. Some spacers release gentamicin for longtime (months), while others release antibiotic for only two weeks.In the last years an evolution of PMMA spacers production occurred and modifications in the polimerization process of cement can increase cement porosity and antibiotic elution from spacers.The current commercial preformed spacers for 10 days elution (Spacer G™, prepared with Cemex HP) release more gentamicin (34.1 mg) than previous models, which were prepared with Cemex SP (16.4 mg). Furthermore, they maintain a high elution rate (1.4–1.6 mg/day after one month).The combination of Gentamicin and Vancomycin mantains an elution pharmacokinetic profile that is superimposable to that of Gentamicin and Vancomycin alone, with synergistic effects against multiresistant bacteria in prosthetic infection site.In conclusion, the antibiotic release from PMMA spacers of various brands is not equivalent. The old elution data are no longer valid for new preparations. Consequently, this additional factor of variability should be considered in clinical practice and literature data utilisation

DIFFUSION IN BONE OF THE COMBINATION GENTAMICIN AND VANCOMYCIN FOLLOWING IMPLANTATION OF A PMMA DEVICE IN EXPERIMENTAL OSTEOMYELITIS

Polymethylmetacrylate bone cement (PMMA), used to prepare joint prostheses and also for their fixation, is commonly used as a carrier to release antibiotics into the site of infection. The purpose of this research is to determine the antibiotic concentration in infection site of rabbits with experimental acute osteomyelitis induced by Methicillin-Resistant S. aureus (MRSA) and treated with 1- PMMA bone cements (intramedullary nails) loaded with gentamicin (G) and vancomycin (V) in combination and 2- systemic teicoplanin (T) administration. This research is part of the study made in collaboration with the Rizzoli Orthopaedic Institute, the results of which were presented separately. We studied the distribution of these two antibiotics in different bone fractions of the femur and determined the serum levels collected at removal of the intramedullary nails