Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Adaptive metering algorithm for electronic commercial vehicle preclearance systems

This paper presents an adaptive metering algorithm for enhancing the electronic screening (e-screening) operation at truck weight stations. This algorithm uses a feedback control mechanism to control the level of truck vehicles entering the weight station. The basic operation of the algorithm allows more trucks to be inspected when the weight station is underutilized by adjusting the weight threshold lower. Alternatively, the algorithm restricts the number of trucks to inspect when the station is overutilized to prevent queue spillover. The proposed control concept is demonstrated and evaluated in a simulation environment. The simulation results demonstrate the considerable benefits of the proposed algorithm in improving overweight enforcement with minimal negative impacts on nonoverweighed trucks. The test results also reveal that the effectiveness of the algorithm improves with higher truck participation rates in the e-screening program.

Denaturing high performance liquid chromatography for the detection of microsatellite instability using Bethesda and pentaplex marker panels

Microsatellite instability (MSI) is a characteristic molecular phenotype of tumors from the hereditary nonpolyposis colorectal cancer (Lynch) syndrome. Routine MSI screening of tumors in patients is an efficient prescreening tool for the population-based detection of Lynch syndrome in the absence of family cancer history. We describe here the optimization of a denaturing high performance liquid chromatography (DHPLC) assay for MSI analysis with the

Training general practitioners in flexible sigmoidoscopy to screen for colorectal cancer

Background: A screening programme to detect polyps or early carcinoma would significantly reduce the mortality and morbidity of colorectal cancer (CRC). The aims of the present study were to evaluate: (i) the feasibility of training general practitioners in flexible sigmoidoscopy (FS) for CRC screening; (ii) the acceptability of screening by faecal occult blood testing (FOBT) and FS in asymptomatic standard risk Australians aged over 50 years; and (iii) the yield of such screening. Methods: Subjects were recruited by general practitioner (GP) referral, newspaper advertisement or by a direct approach to retirement villages. Participants were mailed a FOBT kit and a prescreening questionnaire. Flexible sigmoidoscopy was performed by a GP supervised by an experienced endoscopist. Subjects then completed a second questionnaire. General practitioners were assessed after 50 unassisted procedures. Results: A total of 264 individuals contacted the study coordinator; 169 were screened. Screening was accepted well by the participants. Fifteen per cent of subjects had polyps and 4% had a positive FOBT. Training in FS was adversely affected by the availability of resources. Three GPs completed 50 unassisted procedures over a 15-month period, but none were able to reliably assess the distal bowel. Conclusions: Although the three trainees and their supervisors did not consider that the GPs were adequately trained after 50 unassisted procedures, training was adversely affected by limited resources within the Victorian public hospital system. Screening by FOBT and FS was considered to be acceptable by the patients undergoing these procedures. Existing facilities are not adequate if GPs are to be trained in FS as part of a national CRC screening program.

Experimental study of abattoir wastewater treatment from an economic perspective

The most cost effective treatment scheme for effluent from Midfield Meats, an abattoir in Warrnambool, Australia, was evaluated via a series of laboratory and commercial scale experiments. Effectiveness was measured in terms of suspended solids (SS) and biological oxygen demand (BOD) reduction. Economic assessment was based on predicted reduction in trade waste charges versus infrastructure and running costs. From the range of potential treatment technologies, those deemed most appropriate for trialling included pre-screening, sedimentation, coagulation and flocculation treatment and dissolved air floatation (DAF). Prior to evaluation of treatment types, flow, loads and contaminant characterisation of the waste streams was conducted to aid in selection of treatment type and capacity. Prescreening was found to be the most cost effective, followed by sedimentation, coagulation and flocculation treatment and finally DAF. The most economical treatment scheme that satisfied the requirements of Midfield Meats included a combination of prescreening and sedimentation. DAF and coagulation and flocculation treatment satisfactorily treated the wastewater, however were not cost effective under the current trade waste agreement.

Health and fitness benefits of a resistance training intervention performed in the workplace

Zavanela, PM, Crewther, BT, Lodo, L, Florindo, AA, Miyabara, EH, and Aoki, MS. Health and fitness benefits of a resistance training intervention performed in the workplace. J Strength Cond Res 26(3): 811-817, 2012-This study examined the effects of a workplace-based resistance training intervention on different health-, fitness-, and work-related measures in untrained men (bus drivers). The subjects were recruited from a bus company and divided into a training (n = 48) and control (n = 48) groups after initial prescreening. The training group performed a 24-week resistance training program, whereas the control group maintained their normal daily activities. Each group was assessed for body composition, blood pressure (BP), pain incidence, muscular endurance, and flexibility before and after the 24-week period. Work absenteeism was also recorded during this period and after a 12-week follow-up phase. In general, no body composition changes were identified in either group. In the training group, a significant reduction in BP and pain incidence, along with improvements in muscle endurance and flexibility were seen after 24 weeks (p < 0.05). There were no changes in these parameters in the control group, and the between-group differences were all significant (p < 0.05). A reduction in worker absenteeism rate was also noted in the training (vs. control) group during both the interventional and follow-up periods (p < 0.05). In conclusion, it was found that a periodized resistance training intervention performed within the workplace improved different aspects of health and fitness in untrained men, thereby potentially providing other work-related benefits. Thus, both employers and employees may benefit from the setup, promotion, and support of a work-based physical activity program involving resistance training.

Toxic effects of lipid-mediated gene transfer in ventral mesencephalic explant cultures

Adverse effects of cDNA and oligonucleotide delivery methods have not yet been systematically analyzed. We introduce a protocol to monitor toxic effects of two non-viral lipid-based gene delivery protocols using CNS primary tissue. Cell membrane damage was monitored by quantifying cellular uptake of propidium iodide and release of cytosolic lactate dehydrogenase to the culture medium. Using a liposomal transfection reagent, cell membrane damage was already seen 24 hr after transfection. Nestin-positive target cells, which were used as morphological correlate, were severely diminished in some areas of the cultures after liposomal transfection. In contrast, the non-liposomal transfection reagent revealed no signs of toxicity. This approach provides easily accessible information of transfection-associated toxicity and appears suitable for prescreening of transfection reagents.

Metabolomics and its potential in drug development

Metabolomics is the global and unbiased survey of the complement of small molecules (say, <1 kDa) in a biofluid, tissue, organ or organism and measures the end-products of the cellular metabolism of both endogenous and exogenous substrates. Many drug candidates fail during Phase II and III clinical trials at an enormous cost to the pharmaceutical industry in terms of both time lost and of financial resources. The constantly evolving model of drug development now dictates that biomarkers should be employed in preclinical development for the early detection of likely-to-fail candidates. Biomarkers may also be useful in the preselection of patients and through the subclassification of diseases in clinical drug development. Here we show with examples how metabolomics can assist in the preclinical development phases of discovery, pharmacology, toxicology, and ADME. Although not yet established as a clinical trial patient prescreening procedure, metabolomics shows considerable promise in this regard. We can be certain that metabolomics will join genomics and transcriptomics in lubricating the wheels of clinical drug development in the near future.

Winter Survival of Transgenic Alfalfa Overexpressing Superoxide Dismutase1

To test the hypothesis that enhanced tolerance of oxidative stress would improve winter survival, two clones of alfalfa (Medicago sativa) were transformed with a Mn-superoxide dismutase (Mn-SOD) targeted to the mitochondria or to the chloroplast. Although Mn-SOD activity increased in most primary transgenic plants, both cytosolic and chloroplastic forms of Cu/Zn-SOD had lower activity in the chloroplast SOD transgenic plants than in the nontransgenic plants. In a field trial at Elora, Ontario, Canada, the survival and yield of 33 primary transgenic and control plants were compared. After one winter most transgenic plants had higher survival rates than control plants, with some at 100%. Similarly, some independent transgenic plants had twice the herbage yield of the control plants. Prescreening the transgenic plants for SOD activity, vigor, or freezing tolerance in the greenhouse was not effective in identifying individual transgenic plants with improved field performance. Freezing injury to leaf blades and fibrous roots, measured by electrolyte leakage from greenhouse-grown acclimated plants, indicated that the most tolerant were only 1°C more freezing-tolerant than alfalfa clone N4. There were no differences among transgenic and control plants for tetrazolium staining of field-grown plants at any freezing temperature. Therefore, although many of the transgenic plants had higher winter survival rates and herbage yield, there was no apparent difference in primary freezing injury, and therefore, the trait is not associated with a change in the primary site of freezing injury.

Survey of habits and attitudes to retinoscopy by optometrists in the UK

This research suggests that although retinoscopy is considered to be an important part of the eye examination by the majority, it is being carried out less by optometrists working in multiple practices. This less frequent use of retinoscopy may be due to the greater use of non-optometric staff in prescreening and that the more 'difficult' patients (young children or adults with poor communication) may be more likely to attend independent practices or an eye clinic.

Aplicación del modelo Discovering Hands en Argentina

Discovering Hands (DH) es un proyecto que nace en Alemania en el 2006, liderado por el doctor Frank Hoffmann. El programa se desarrolla pensando en el importante problema de salud pública en el cual se ha convertido en el cáncer de mama, pues según la Organización Mundial de la Salud es el mayor causal de muerte en mujeres, tanto en países desarrollados como en vía de desarrollo, y en Alemania esta enfermedad acaba con la vida de aproximadamente 18.000 mujeres cada año. (The Global Journal, 2014) DH entrena y capacita mujeres visualmente impedidas para detectar de manera temprana los signos de cáncer de mama, dado que estas poseen un sentido del tacto más desarrollado que el de una persona que no se encuentre limitada visualmente. Esto les permite localizar el cáncer de forma más rápida que un médico general ya que son capaces de identificar los tumores más pequeños, logrando así reducir notablemente los costos totales del tratamiento de esta enfermedad. Adicional a esto, el capacitar y preparar a mujeres con discapacidad visual para la detección temprana de cáncer de mama, incrementa la fuerza laboral del país, pues estas mujeres pasarían a ser parte de la población económicamente activa del mismo (PEA) y lograrían que las personas dejen de percibir esta condición como una discapacidad y por el contrario la vean como una ventaja. Después de unos años de prueba, el programa ha sido mejorado y extendido tanto en Alemania como en otros países (Austria), razón por la cual se realizó el estudio de factibilidad del proyecto en países como Colombia - donde se quiere llevar a cabo un proyecto piloto en la ciudad de Cali - México y Argentina. El presente trabajo se enfoca en Argentina, por medio del cual se busca proponer aportes para disminuir las causas de muertes originadas por esta enfermedad y los altos costos que estas le generan al sector de la salud de este país. Con el estudio se logró identificar la factibilidad de la implementación del modelo de negocio, evidenciando que Argentina cuenta con unas particularidades en su sistema de gobierno que pueden hacer que la puesta en práctica del proyecto sea más compleja que en otros países.