Acute skin GVHD following syngeneic BMT for CLL

A 41-year-old woman received a syngeneic BMT for CLL and subsequently developed acute skin GVHD. Transfusion-related allogeneic GVHD was excluded on the basis of an unchanged HLA type in circulating lymphocytes. Short tandem repeat PCR was used to confirm syngeneicity between donor and recipient. The patient had a personal and family history of autoimmune disease which may have made her particularly susceptible to development of syngeneic GVHD. The distinction between allogeneic and syngeneic or autologous GVHD is important because of therapeutic implications.

Mechanisms of apoptosis in chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by the accumulation of terminally differentiated, mature B cells that do not progress beyond the G1 stage of cell cycle, suggesting that these cells possess intrinsic defects in apoptosis. Treatment relies heavily on chemotherapy (primarily nucleoside analogs and glucocorticoids) that may initially be effective in patients, but ultimately give rise to refractory, untreatable disease. The purpose of this study was to determine whether key components of the apoptotic machinery were intact in CLL lymphocytes, especially in patients refractory to therapy. ^ Activation of proteases has been shown to be at the core of the apoptotic pathway and this work demonstrates that protease activation is required for glucocorticoid and nucleoside analog-induced apoptosis in CLL cells. Inhibitors of serine proteases as well as caspase inhibitors blocked induced DNA fragmentation, and a peptide inhibitor of the nuclear scaffold (NS) protease completely suppressed both induced and spontaneous apoptosis. However, the NS protease inhibitor actually promoted several pro-apoptotic events, such as caspase activation, exposure of surface phosphatidylserine, and loss of mitochondrial membrane potential. These results suggested that the NS protease may interact with the apoptotic program in CLL cells at two separate points. ^ In order to further investigate the role of the NS protease in CLL, patient isolates were treated with proteasome inhibitors because of previous results suggesting that the ISIS protease might be a β subunit of the proteasome. Proteasome inhibitors induced massive DNA fragmentation in every patient tested, even in those resistant to the effects of glucocorticoid and nucleoside analogs in vitro. Several other features of apoptosis were also promoted by the proteasome inhibitor, including mitochondrial alterations such as release of cytochrome c and drops in mitochondrial membrane potential. Proteasome inhibitor-induced apoptosis was associated with inhibition of NFκB, a proteasome-regulated transcription factor that has been implicated in the suppression of apoptosis in a number of systems. The NS protease inhibitor also caused a decrease in active NFκB, suggesting that the proapoptotic effects of this agent might be due to depletion of NFκB. ^ Given these findings, the role of NFκB, in conferring survival in CLL was investigated. Glucocorticoid hormone treatment was shown to cause decreases in the activity of the transcription factor, while phorbol dibutyrate, which blocks glucocorticoid-induced DNA fragmentation, was capable of upregulating NFκB. Compellingly, introduction of an undegradable form of the constitutive NFκB inhibitor, IκB, caused DNA fragmentation in several patient isolates, some of which were resistant to glucocorticoid in vitro. Transcription of anti-apoptotic proteins by NFκB was postulated to be responsible for its effects on survival, but Bcl-2 levels did not fluctuate with glucocorticoid or proteasome inhibitor treatment. ^ The in vitro values generated from these studies were organized into a database containing numbers for over 250 patients. Correlation of relevant clinical parameters revealed that levels of spontaneous apoptosis in vitro differ significantly between Rai stages. Importantly, in vitro resistance to nucleoside analogs or glucocorticoids predicted resistance to chemotherapy in vivo, and inability to achieve remission. ^

Tercer rahonament del Rull de Payporta y Albudeca, y Còll de Barrat, Llauradors, que habent vengut éste de Barcelona, ahon ha vist la venguda dels Príncips de Nápols, y Reys de Etruria, conta als altres lo sosuit en aquells dies, y les Festes que han fet els Catalans : [Texto impreso] y algunes particularitats de esta Ciutat de Valencia en les previsions que es fan pera la venguda dels Reys

Hay un ejemplar encuadernado con: Romans, y coloqui nou, pera divertir el humor y desterrar la melancolia, yà que no tenim dinès ... (NP849.91/3085).

Combinations of ZAP-70, CD38 and IGHV mutational status as predictors of time to first treatment in CLL.

ZAP-70, CD38 and IGHV mutations have all been reported to have prognostic impact in chronic lymphocytic leukemia (CLL), both individually and in paired combinations. We aimed to determine whether the combination of all three factors provided more refined prognostic information concerning the treatment-free interval (TFI) from diagnosis. ZAP-70, CD38 and IGHV mutations were evaluated in 142 patients. Combining all three factors, the ZAP-70-/CD38-/Mutated group showed the longest median TFI (62 months, n = 37), ZAP-70+/CD38+/Unmutated cases the shortest (11 months, n = 37) and cases discordant for > or = 1 factor, an intermediate TFI (27 months, n = 68) (p = 0.006). Analysis of discordant cases revealed values that were otherwise masked when measuring single prognostic factors. The presence or absence of cytogenetic abnormalities did not explain the variability among discordant cases. Simultaneous analysis of ZAP-70, CD38 and IGHV mutations in CLL provides more discriminatory prediction of TFI than any factor alone.

Severe viral hepatitis in a patient with chronic lymphocytic leukemia (CLL) complicated with autoimmune hemolytic anemia (AIHA), treated with steroids.

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A new method to detect loss of heterozygosity using cohort heterozygosity comparisons

Background Loss of heterozygosity (LOH) is an important marker for one of the 'two-hits' required for tumor suppressor gene inactivation. Traditional methods for mapping LOH regions require the comparison of both tumor and patient-matched normal DNA samples. However, for many archival samples, patient-matched normal DNA is not available leading to the under-utilization of this important resource in LOH studies. Here we describe a new method for LOH analysis that relies on the genome-wide comparison of heterozygosity of single nucleotide polymorphisms (SNPs) between cohorts of cases and un-matched healthy control samples. Regions of LOH are defined by consistent decreases in heterozygosity across a genetic region in the case cohort compared to the control cohort. Methods DNA was collected from 20 Follicular Lymphoma (FL) tumor samples, 20 Diffuse Large B-cell Lymphoma (DLBCL) tumor samples, neoplastic B-cells of 10 B-cell Chronic Lymphocytic Leukemia (B-CLL) patients and Buccal cell samples matched to 4 of these B-CLL patients. The cohort heterozygosity comparison method was developed and validated using LOH derived in a small cohort of B-CLL by traditional comparisons of tumor and normal DNA samples, and compared to the only alternative method for LOH analysis without patient matched controls. LOH candidate regions were then generated for enlarged cohorts of B-CLL, FL and DLBCL samples using our cohort heterozygosity comparison method in order to evaluate potential LOH candidate regions in these non-Hodgkin's lymphoma tumor subtypes. Results Using a small cohort of B-CLL samples with patient-matched normal DNA we have validated the utility of this method and shown that it displays more accuracy and sensitivity in detecting LOH candidate regions compared to the only alternative method, the Hidden Markov Model (HMM) method. Subsequently, using B-CLL, FL and DLBCL tumor samples we have utilised cohort heterozygosity comparisons to localise LOH candidate regions in these subtypes of non-Hodgkin's lymphoma. Detected LOH regions included both previously described regions of LOH as well as novel genomic candidate regions. Conclusions We have proven the efficacy of the use of cohort heterozygosity comparisons for genome-wide mapping of LOH and shown it to be in many ways superior to the HMM method. Additionally, the use of this method to analyse SNP microarray data from 3 common forms of non-Hodgkin's lymphoma yielded interesting tumor suppressor gene candidates, including the ETV3 gene that was highlighted in both B-CLL and FL.

University students and their working pathways

This paper examines the working pathways of young full-time university students in Australia. It draws on some of the data from a three year research project funded by the Australian Research Council. The project was called ‘Changing the way that Australian enter the workforce: Part-time working careers of young full-time school and tertiary students’. The project had three industry partners: Service Skills Australia (the Industry Skills Council for the service industries), McDonalds Australia (a fast food company) and The Reject Shop (a discount chain). Much of the research took place inside companies, in schools and with national stakeholders (eg Smith & Patton, 2011; Smith & Patton, 2013), but this paper reports on the research that took place with students in universities. In the project we were keen to explore the notion of part-time working while studying as a medium-term career, especially in the context of the need for career flexibility and adaptability (Poehnell & Amundson, 2002).

Subsoil constraints in Vertosols: Crop water use nutrient concentration, and grain yields of bread wheat, durum wheat, barley, chickpea and canola

Single or multiple factors implicated in subsoil constraints including salinity, sodicity, and phytotoxic concentrations of chloride (Cl) are present in many Vertosols including those occurring in Queensland, Australia. The variable distribution and the complex interactions that exist between these constraints limit the agronomic or management options available to manage the soil with these subsoil constraints. The identification of crops and cultivars adapted to these adverse subsoil conditions and/or able to exploit subsoil water may be an option to maintain productivity of these soils. We evaluated relative performance of 5 winter crop species, in terms of grain yields, nutrient concentration, and ability to extract soil water, grown on soils with various levels and combinations of subsoil constraints in 19 field experiments over 2 years. Subsoil constraints were measured by levels of soil Cl, electrical conductivity of the saturation extract (ECse), and exchangeable sodium percentage (ESP). Increasing levels of subsoil constraints significantly decreased maximum depth of water extraction, grain yield, and plant-available water capacity for all the 5 crops and more so for chickpea and durum wheat than bread wheat, barley, or canola. Increasing soil Cl levels had a greater restricting effect on water availability than did ECse and ESP. We developed empirical relationships between soil Cl, ECse, and ESP and crop lower limit (CLL) for estimating subsoil water extraction by 5 winter crops. However, the presence of gypsum influenced the ability to predict CLL based on the levels of ECse. Stronger relationships between apparent unused plant-available water (CLL - LL15; LL15 is lower limit at -1.5 MPa) and soil Cl concentrations than ESP or ECse suggested that the presence of high Cl in these soils most likely inhibited the subsoil water extraction by the crops. This was supported by increased sodium (Na) and Cl concentration with a corresponding decrease in calcium (Ca) and potassium (K) in young mature leaf of bread wheat, durum wheat, and chickpea with increasing levels of subsoil constraints. Of the 2 ions, Na and Cl, the latter appears to be more damaging than the former, resulting in plant dieback and reduced grain yields.

Simulating the effects of saline and sodic subsoils on wheat crops growing on Vertosols

Soils with high levels of chloride and/or sodium in their subsurface layers are often referred to as having subsoil constraints (SSCs). There is growing evidence that SSCs affect wheat yields by increasing the lower limit of a crop's available soil water (CLL) and thus reducing the soil's plant-available water capacity (PAWC). This proposal was tested by simulation of 33 farmers' paddocks in south-western Queensland and north-western New South Wales. The simulated results accounted for 79% of observed variation in grain yield, with a root mean squared deviation (RMSD) of 0.50 t/ha. This result was as close as any achieved from sites without SSCs, thus providing strong support for the proposed mechanism that SSCs affect wheat yields by increasing the CLL and thus reducing the soil's PAWC. In order to reduce the need to measure CLL of every paddock or management zone, two additional approaches to simulating the effects of SSCs were tested. In the first approach the CLL of soils was predicted from the 0.3-0.5 m soil layer, which was taken as the reference CLL of a soil regardless of its level of SSCs, while the CLL values of soil layers below 0.5 m depth were calculated as a function of these soils' 0.3-0.5 m CLL values as well as of soil depth plus one of the SSC indices EC, Cl, ESP, or Na. The best estimates of subsoil CLL values were obtained when the effects of SSCs were described by an ESP-dependent function. In the second approach, depth-dependent CLL values were also derived from the CLL values of the 0.3-0.5 m soil layer. However, instead of using SSC indices to further modify CLL, the default values of the water-extraction coefficient (kl) of each depth layer were modified as a function of the SSC indices. The strength of this approach was evaluated on the basis of correlation of observed and simulated grain yields. In this approach the best estimates were obtained when the default kl values were multiplied by a Cl-determined function. The kl approach was also evaluated with respect to simulated soil moisture at anthesis and at grain maturity. Results using this approach were highly correlated with soil moisture results obtained from simulations based on the measured CLL values. This research provides strong evidence that the effects of SSCs on wheat yields are accounted for by the effects of these constraints on wheat CLL values. The study also produced two satisfactory methods for simulating the effects of SSCs on CLL and on grain yield. While Cl and ESP proved to be effective indices of SSCs, EC was not effective due to the confounding effect of the presence of gypsum in some of these soils. This study provides the tools necessary for investigating the effects of SSCs on wheat crop yields and natural resource management (NRM) issues such as runoff, recharge, and nutrient loss through simulation studies. It also facilitates investigation of suggested agronomic adaptations to SSCs.

Genomic microarrays in chromosomal analysis of leukemia

Chromosomal alterations in leukemia have been shown to have prognostic and predictive significance and are also important minimal residual disease (MRD) markers in the follow-up of leukemia patients. Although specific oncogenes and tumor suppressors have been discovered in some of the chromosomal alterations, the role and target genes of many alterations in leukemia remain unknown. In addition, a number of leukemia patients have a normal karyotype by standard cytogenetics, but have variability in clinical course and are often molecularly heterogeneous. Cytogenetic methods traditionally used in leukemia analysis and diagnostics; G-banding, various fluorescence in situ hybridization (FISH) techniques, and chromosomal comparative genomic hybridization (cCGH), have enormously increased knowledge about the leukemia genome, but have limitations in resolution or in genomic coverage. In the last decade, the development of microarray comparative genomic hybridization (array-CGH, aCGH) for DNA copy number analysis and the SNP microarray (SNP-array) method for simultaneous copy number and loss of heterozygosity (LOH) analysis has enabled investigation of chromosomal and gene alterations genome-wide with high resolution and high throughput. In these studies, genetic alterations were analyzed in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). The aim was to screen and characterize genomic alterations that could play role in leukemia pathogenesis by using aCGH and SNP-arrays. One of the most important goals was to screen cryptic alterations in karyotypically normal leukemia patients. In addition, chromosomal changes were evaluated to narrow the target regions, to find new markers, and to obtain tumor suppressor and oncogene candidates. The work presented here shows the capability of aCGH to detect submicroscopic copy number alterations in leukemia, with information about breakpoints and genes involved in the alterations, and that genome-wide microarray analyses with aCGH and SNP-array are advantageous methods in the research and diagnosis of leukemia. The most important findings were the cryptic changes detected with aCGH in karyotypically normal AML and CLL, characterization of amplified genes in 11q marker chromosomes, detection of deletion-based mechanisms of MLL-ARHGEF12 fusion gene formation, and detection of LOH without copy number alteration in karyotypically normal AML. These alterations harbor candidate oncogenes and tumor suppressors for further studies.

稀薄气体动力学

通常的气体动力学方法，当气体分子的平均自由程与流场特征长度相比不可忽略时，不再适用，要采用稀薄气体动力学的方法。这适用于航天飞行器在高空飞行时受的力和热，也适用于微机电系统和真空系统等离子体材料加工等21世纪技术前沿领域。本书系统、简明地阐述稀薄气体动力学方法，给出方法的基础并着重介绍直接模拟Monte Carlo(DSMC)方法以及与低速稀薄气体流动相关的前沿课题。全书共分7章。前两章是作为学科的基础引入的，第1章以空气为对象对于分子能态结构、能态分布以极小篇幅作了简要概括的叙述，以作为了解稀薄气流非平衡现象物理基础的初步。第2章对包括双体碰撞、Boltzmann方程以及气体的平衡态等分子动理论的基础做了必要的讨论，其中包括了对唯像论分子相互作用模型、变径硬球（VHS）、变径软球（VSS）和概括化硬球（GHS）等模型的介绍。第3章讨论了各种分子和表面的相互作用模型，包括反映细致平衡的互易原理和基于此原理的CLL模型的阐述。第4章讨论自由分子流。第5章讨论应用于滑流领域的各连续介质方程及滑流边界条件，一些简单解以及热泳问题。第6章则较全面、概括地介绍了求解过程领域中的各种解析和数值方法。第7章介绍了直接模拟Monte Carlo(DSMC)方法，讨论了非平衡流动及低速稀薄流动等前沿课题，包括处理内能松弛、化学反应的方法、用于复杂流场通用软件的方法、低速稀薄流动的信息保存（IP）方法等。　　本书适合高等学校力学一航空航天专业高年级学生、研究生及从事气动力学和航天研究的科研人员参考阅读。

通常的气体动力学方法，当气体分子的平均自由程与流场特征长度相比不可忽略时，不再适用，要采用稀薄气体动力学的方法。这适用于航天飞行器在高空飞行时受的力和热，也适用于微机电系统和真空系统等离子体材料加工等21世纪技术前沿领域。本书系统、简明地阐述稀薄气体动力学方法，给出方法的基础并着重介绍直接模拟Monte Carlo(DSMC)方法以及与低速稀薄气体流动相关的前沿课题。

符号表
绪论
第1节 稀薄气体动力学的提出
第2节 气体的分子模型
第3节 分子平均自由程
第4节 流动的领域划分
第5节 非平衡现象与稀薄气体动力学
第6节 相似准则
第1章 分子结构与能态
第1节 双原子分子
第2节 分子的能态分布
第3节 分子的内能、内自由度和内能分布函数
第2章 分子动理论基础
第1节 速度分布函数
第2节 宏观量的表达
第3节 分子的双体碰撞模型
第4节 碰撞截面与分子模型
第5节 Boltzmann方程
第6节 碰撞积分与气体分子的总碰撞数
第7节 碰撞积分的计算
第8节 Maxwell输运方程——矩方程
第9节 Maxwell分布
第10节 气体的平衡态
第11节 8速度气体模型
第12节 混合气体
第3章 分子表面相互作用
第1节 引言
第2节 镜面反射与漫反射，适应系数
第3节 互易性原理
第4节 CLL分子表面相互作用模型
第4章 自由分子流
第1节 气体中的分子数目通量和动量通量
第2节 作用于物体的气动力
第3节 表面元素的热传导
第4节 自由分子流出与热流逸
第5节 Couette流动与平板间的传热问题
第6节 无碰撞Boltzmann方程的通解，非定常流动
第5章 连续介质模型
第1节 引言
第2节 基本方程
第3节 滑流边界条件
第4节 一些简单问题的求解
第5节 热蠕动与热泳
第6章 过渡领域
第1节 概述
第2节 线化的BoltzmanN方程
第3节 矩方法
第4节 模型方程
第5节 有限差分法
第6节 间断纵坐标方法
第7节 积分方法
第8节 直接模拟方法
第7章 直接模拟Monte方法
第1节 引言
第2节 碰撞的取样
第3节 DSMC方法求解问题实例
第4节 内能的激发与松弛
第5节 化学反应的模拟
第6节 复杂流场的计算，位置元方法
第7节 微尺度低速气体流动，信息保存法
附录I 气体的性质和分子性质
附录II 分布函数求矩遇到的积分
附录III 具有给定分布的随机数的取样
附录IV Couette问题程序
参考文献
主题词索引

miRNA polymorphisms are associated with risk of developing chronic lymphocytic leukemia

Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia of adults in Western countries and shows a ~8.5-fold increased relative risk in first-degree relatives. Up to date several studies have identified low-penetrance susceptibility alleles in CLL. Nevertheless, these studies scarcely study regions that do not encode proteins such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Polymorphisms in these miRNAs may deregulate miRNAs expression levels and affect to the miRNA function. However, despite accumulating evidence that inherited genetic variation in miRNA genes can contribute to the predisposition for CLL, the role of these in the risk of CLL has not been extensively studied. Therefore, the aim of this study was to find new genetic markers of risk to CLL. To that end, we made a systematic search for SNPs in miRNAs and miRNAs deregulated in CLL and genotyped 213 polymorphisms in 401 samples of Spanish individuals. The literature search resulted in more than 100 miRNAs deregulated in CLL and 43 polymorphisms studied in the disease. Out of 213 genotyped SNPs, 13 showed to be significantly associated with CLL risk. rs2682818 in pre-mature miR618 was the most significant result, with 0.49 fold decreased risk to CLL. Interestingly, a previous study associated this SNP with an increased risk of developing follicular lymphoma. Secondly, rs10173558 SNP in mir- 1302-4 showed the highest risk association, with a 5.24 fold increased risk, but there were no previous works studying it. Finally, rs61992671 in miR412, previously associated with CLL risk, showed also association in our sample. In conclusion, we find 13 alleles which could contribute to the risk of CLL. However, new large-scale studies including functional analyses will be needed to validate our findings.

Genetic Variants in MiRNA Processing Genes and Pre-MiRNAs Are Associated with the Risk of Chronic Lymphocytic Leukemia

Genome wide association studies (GWAS) have identified several low-penetrance susceptibility alleles in chronic lymphocytic leukemia (CLL). Nevertheless, these studies scarcely study regions that are implicated in non-coding molecules such as microRNAs (miRNAs). Abnormalities in miRNAs, as altered expression patterns and mutations, have been described in CLL, suggesting their implication in the development of the disease. Genetic variations in miRNAs can affect levels of miRNA expression if present in pre-miRNAs and in miRNA biogenesis genes or alter miRNA function if present in both target mRNA and miRNA sequences. Therefore, the present study aimed to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA processing genes contribute to predisposition for CLL. A total of 91 SNPs in 107 CLL patients and 350 cancer-free controls were successfully analyzed using TaqMan Open Array technology. We found nine statistically significant associations with CLL risk after FDR correction, seven in miRNA processing genes (rs3805500 and rs6877842 in DROSHA, rs1057035 in DICER1, rs17676986 in SND1, rs9611280 in TNRC6B, rs784567 in TRBP and rs11866002 in CNOT1) and two in pre-miRNAs (rs11614913 in miR196a2 and rs2114358 in miR1206). These findings suggest that polymorphisms in genes involved in miRNAs biogenesis pathway as well as in pre-miRNAs contribute to the risk of CLL. Large-scale studies are needed to validate the current findings.