A historical survey of the office of Kansas county superintendent of schools

Call number: LD2668 .R4 1964 F98

A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.

BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients

Driving under the influence of an intoxicant in Ireland.

The number of specimens analysed by the MBRS has been increasing for both alcohol and drugs. Blood and urine specimens are analysed for the concentration of alcohol using Headspace Gas Chromatography. Specimens testing positive were forwarded to the State Laboratory for confirmatory analysis by either GC/MS or LC/MS. In 2000, 93 per cent of blood specimens, 91 per cent of urine specimens and 82 per cent of breath specimens were over the limit. In the same year, 57 per cent of blood specimens, 66 per cent of urine specimens and 33 per cent of breath specimens were over twice the limit. Of the 78 specimens tested for the presence of a drug or drugs, 37 were blood specimens and 41 urine specimens. Of these, 34 blood specimens and 37 urine specimens were found to be positive, while seven specimens were negative for the drug or drug classes tested (three blood and four urine specimens). There were 23 specimens found positive for one drug class and 48 for more than one drug.The number of requests for the presence of drugs in RTA blood and urine specimens is increasing annually and the high percentage of positives found in the specimens tested indicates the need for such analyses. The results showed excellent agreement for drug detection in the blood specimens analysed by the different methods, except for the cannabinoids. The number of specimens in this study is small and care must be exercised in interpreting the results

Laboratory investigation of a load carriage task observed in forestry

The objective of the present study was to investigate and compare the human responses to two load carriage tasks performed with three different load masses and on three different gradients. The task of carrying hydrogel in one hand was observed in a silviculture industry and crude physiological and perceptual responses were measured. This task was simulated in a laboratory setting together with a suggested intervention of backpack carriage. Eighteen conditions were established which consisted of the two modes of carriage and a combination of three load masses (9kg, 12kg and 15kg) and three gradients (5%, 10% and 15%). Twenty eight Rhodes University female students comprised the sample and the experimental procedures were conducted on a Quinton treadmill. Each participant was required to complete nine of the eighteen conditions which were each four minutes in duration. Postural changes were assessed using lateral and posterior digital images taken at the second and fourth minute and compression and shearing forces were estimated with the ErgolmagerTM Physiological responses (heart rate, ventilation and metabolic responses) were measured continuously with the Quark b² and perceptual responses ('central' and 'local' RPE) were measured every minute during the experimentation and body discomfort was rated at the completion of each condition. Overall responses revealed that hand carriage (146 bt.min⁻¹ , 25.09 mIO₂. kg-l.min⁻¹) was generally found to be more physiologically stressful than backpack carriage (130 bt.min⁻¹, 22.15 mIO₂.kg⁻¹ .min⁻¹) independent of load mass and gradient. Physiological responses were higher (113 bt.min-1 to 174 bt.min⁻¹ ) in responses to increasing gradient as opposed to increasing load mass (104 bt.min-1 to 153 bt.min⁻¹ ) for both backpack and hand carriage. Categorisation using the guidelines of Sanders and McCormick (1993) allowed for classification of conditions, with respect to physiological responses, into 'moderate', 'heavy' and 'very heavy' stress. For almost all of the physiological responses the majority of conditions which were classified as 'moderate' were backpack carriage conditions and the conditions classified as 'very heavy' were mostly hand carriage conditions. In terms of postural responses hand carriage resulted in more strain and greater compression and shearing forces on the spine. In terms of the compression forces increasing gradient had a greater affect on backpack carriage (681 N to 935 N) compared to hand carriage (570N to 793N). In contrast, increasing load mass had a larger affect on hand carriage postures and compression forces (751 N to 935N) in comparison to backpack carriage (723N to 780N). Shearing forces were found to be worse in hand carriage conditions overall. Although participants generally underrated perceived exertion in relation to cardiorespiratory responses, these perceptions revealed that backpack carriage, with a mean 'central' RPE of 12 compared to 11 for hand carriage, was somewhat preferred to hand carriage and that increasing gradient was perceived to be marginally more straining than increasing load mass

Absence of a serum melatonin rhythm under acutely extended darkness in the horse

<p>Abstract</p> <p>Background</p> <p>In contrast to studies showing gradual adaptation of melatonin (MT) rhythms to an advanced photoperiod in humans and rodents, we previously demonstrated that equine MT rhythms complete a 6-h light/dark (LD) phase advance on the first post-shift day. This suggested the possibility that melatonin secretion in the horse may be more strongly light-driven as opposed to endogenously rhythmic and light entrained. The present study investigates whether equine melatonin is endogenously rhythmic in extended darkness (DD).</p> <p>Methods</p> <p>Six healthy, young mares were maintained in a lightproof barn under an LD cycle that mimicked the ambient natural photoperiod outside. Blood samples were collected at 2-h intervals for 48 consecutive h: 24-h in LD, followed by 24-h in extended dark (DD). Serum was harvested and stored at -20°C until melatonin and cortisol were measured by commercial RIA kits.</p> <p>Results</p> <p>Two-way repeated measures ANOVA (n = 6/time point) revealed a significant circadian time (CT) x lighting condition interaction (<it>p < .0001</it>) for melatonin with levels non-rhythmic and consistently high during DD (CT 0-24). In contrast, cortisol displayed significant clock-time variation throughout LD and DD (<it>p = .0009</it>) with no CT x light treatment interaction (<it>p </it>= .4018). Cosinor analysis confirmed a significant 24-h temporal variation for melatonin in LD <it>(p = .0002) </it>that was absent in DD <it>(p = .51)</it>, while there was an apparent circadian component in cortisol, which approached significance in LD <it>(p = .076)</it>, and was highly significant in DD <it>(p = .0059).</it></p> <p>Conclusions</p> <p>The present finding of no 24 h oscillation in melatonin in DD is the first evidence indicating that melatonin is not gated by a self-sustained circadian process in the horse. Melatonin is therefore not a suitable marker of circadian phase in this species. In conjunction with recent similar findings in reindeer, it appears that biosynthesis of melatonin in the pineal glands of some ungulates is strongly driven by the environmental light cycle with little input from the circadian oscillator known to reside in the SCN of the mammalian hypothalamus.</p

SAM: A Tool for Measurement of Moderate to Vigorous Physical Activity (MVPA) in School Physical Education

Int J Exerc Sci 5(2) : 127-135, 2012. Observational methods have been a primary methodology used by physical educators for assessing teacher and student behaviors in school physical education (PE) classes for over 30 years. Observational instruments traditionally used in PE are economical, but are time intensive and complicated. Recently national PE recommendations have been promoted to encourage practitioners to achieve ≥ 50% of PE class in moderate to vigorous physical activity (MVPA). The purpose of this preliminary study was to develop, validate, and test the reliability of the Simple Activity Measurement (SAM) instrument for assessing MVPA during school PE classes. Students (N=36, representing grades 3-10) from a convenient sample of schools in San Antonio, TX were randomly selected to wear SUUNTOTM heart rate (HR) monitors during PE classes as an MVPA intensity measure, and the SAM instrument was used to observe 6 classes (N=281 students) for MVPA each minute using the SAM 0-10 scale. The SAM instrument was found to be a significant predictor for HR (r=0.555, r2=0.308, p\u3c0.05) using linear regression, and the intra class correlation coefficient to test reliability was found to be R=0.803, p\u3c0.05. Students averaged 88.5 % of class time spent in MVPA at the elementary level and only 36.5 % of class time spent in MVPA at the high school level. The results of this preliminary study indicate that the SAM has promise to provide school PE evaluators with an effective economical observation tool to document minutes of student MVPA in PE classes, and to promote accountability with national MVPA recommendations

Prioritization of candidate cancer genes—an aid to oncogenomic studies

The development of techniques for oncogenomic analyses such as array comparative genomic hybridization, messenger RNA expression arrays and mutational screens have come to the fore in modern cancer research. Studies utilizing these techniques are able to highlight panels of genes that are altered in cancer. However, these candidate cancer genes must then be scrutinized to reveal whether they contribute to oncogenesis or are coincidental and non-causative. We present a computational method for the prioritization of candidate (i) proto-oncogenes and (ii) tumour suppressor genes from oncogenomic experiments. We constructed computational classifiers using different combinations of sequence and functional data including sequence conservation, protein domains and interactions, and regulatory data. We found that these classifiers are able to distinguish between known cancer genes and other human genes. Furthermore, the classifiers also discriminate candidate cancer genes from a recent mutational screen from other human genes. We provide a web-based facility through which cancer biologists may access our results and we propose computational cancer gene classification as a useful method of prioritizing candidate cancer genes identified in oncogenomic studies

Structural and functional properties of genes involved in human cancer

BACKGROUND: One of the main goals of cancer genetics is to identify the causative elements at the molecular level leading to cancer. RESULTS: We have conducted an analysis of a set of genes known to be involved in cancer in order to unveil their unique features that can assist towards the identification of new candidate cancer genes. CONCLUSION: We have detected key patterns in this group of genes in terms of the molecular function or the biological process in which they are involved as well as sequence properties. Based on these features we have developed an accurate Bayesian classification model with which human genes have been scored for their likelihood of involvement in cancer

Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

BACKGROUND: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. METHODS: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. RESULTS: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. CONCLUSION: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments

SANTET SEBAGAI SALAH SATU FAKTOR PENYEBAB PEMBUNUHAN MASAL (SUATU STUDI YURIDIS - KRIMINOLOGIS BERDASARKAN DATA DI KABUPATEN BANYUWANGI)

Isu santel seling kall menjadi faktor kriminogen terhadap timbulnya pembunuhan karena akibat yang ditimbulkan oleh santet dirasa sangat menakutkan dan mengancam jiwa masyarakat sekitarnya. tetapl karena tldak adanya buktl-buktl yang diperoleh untuk mengajukan seorang Dukun Santet kedepan pengadilan ma.ka reaksi masyarakat adalah main hakim sendin dengan cara membunuh orang-orang yang diduga sebagal Dukun Sante!. Hal tersebut juga dijadikan kedok untuk melakukan pembunuhan terhadap orang yang bukan dukun santel. Motlvasi pembunuhan itu blasanya karena adanya dendam prlbadl. memanfaatkan keadaan untuk mengambil keuntungan dan Juga hal yang sifatnya politis. Pandangan knminologi dalam mengkaJi permasalahan Itu dapat menggunakan pendekatan-pendekatan kriminologls yaltu tear! labeling, pendekatan sobural, pendekatan kontrol sosial dan pendekatan anomi. Pemberian cap atau label kepada orang yang dlduga sebaga! dukun santet member/kan alasan mengapa orang tersebut lebih diperhatikan tingkah lakunya. sehingga apablla terjadl sesuatu yang menyangkut santet maka dia yang akan dlduga sebagal tersangka utama. Faktor itu dapat Juga diketahul dengan tingkah laku sosialnya yang tldak sesuai dengan norma yang berlaku