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mp3 file (7.8 MB). In the January edition of the Cancer Discovery podcast, Executive Editor Mark Landis talks with David Weinstock about his paper, in which analysis of a donor-recipient pair of sisters with follicular lymphoma reveals the time-course of somatic mutations acquired during lymphomagenesis.

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Introduction One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid‐β (Aβ) protein in the brain. Evidence suggests that the low‐density lipoprotein receptor‐associated protein (RAP) binds strongly to Aβ and enhances its cellular uptake and that decreased RAP expression correlates with increased Aβ production in animal models of AD. Methods The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP and NeuN levels were determined by Western blot, while low‐density lipoprotein receptor‐related protein 1 (LRP1), tau and Aβ levels were determined by ELISA in the temporal cortex of 17 AD and 16 control cases. Results An increase in total Aβ and insoluble and soluble tau protein was observed in AD brain tissue. In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls. Correlation analysis revealed that levels of RAP correlated with both total Aβ and soluble and insoluble tau levels. Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aβ or tau protein levels. Conclusion Reduction in RAP may contribute to the accumulation and aggregation of Aβ in the AD brain., Low‐density lipoprotein receptor‐associated protein (RAP) binds strongly to Aβ and enhances its cellular uptake and that decreased RAP expression correlates with increased Aβ production in animal models of AD. The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP levels were significantly decreased in AD brain tissue compared to controls and correlated with both total Aβ and soluble and insoluble tau levels.

Inflammation is likely a key contributor to the pathogenesis of Parkinson’s disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem brain tissue from PD patients and matched controls. We confirm that TLR2 is increased in PD brain, and find that levels of TLR2 correlate with the accumulation of pathological α-synuclein. TLR2 was expressed on neurons as well as microglia; however, the neuronal rather than glial expression of TLR2 was significantly increased in PD brain in accordance with disease staging, and TLR2 was strongly localized to α-synuclein positive Lewy bodies. In cell culture, activation of neuronal TLR2 induced an inflammatory response, including the secretion of inflammatory cytokines and microglial-activating chemokines, as well as the production of reactive oxygen species. Moreover, activation of neuronal TLR2 increased levels of endogenous α-synuclein protein, which was in turn associated with increased levels of the autophagy/lysosomal pathway marker p62. Finally, promoting autophagy with rapamycin or pharmacological inhibition of the TLR2 signaling pathway prevented the TLR2-mediated increase in α-synuclein in neuronal cell cultures. These results implicate neuronal TLR2 expression in human PD pathogenesis. In particular, the increased expression of TLR2 on neurons may provide new insight into disease pathogenesis and/or options for therapeutic intervention. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1648-8) contains supplementary material, which is available to authorized users.

The aim of this study is to evaluate the efficacy of intermittent pneumatic compression (IPC) as a substitute for manual lymphatic drainage (MLD) in complete decongestive therapy (CDT) for treatment of advanced stages of breast cancer-related lymphedema. In this randomized, single-blind, controlled study, 46 patients with breast cancer-related lymphedema were divided into 2 groups. Both MLD with compression bandage (CB) group (n=24) and IPC with CB group (n=22) received treatment 3 days a week for 5 weeks. Home exercise program was also given to all patients. At the end of the 5th week, patients were treated with a daily 23-hour compression garment and home exercise routines. Assessments were taken at baseline, the fifth week, and the third month. Arm circumference was measured at 5 different areas, shoulder range of motion (ROM) was evaluated with a goniometer, pain, and tightness, and heaviness sensations were assessed with visual analog scale. Both groups had similar demographic and clinical characteristics (p0.05). There were no significant differences between groups and both groups showed significant improvement (p0.05) in the five measurement levels of the arm circumference at the fifth week and third month. Similarly, shoulder ROM, pain, tightness, and heaviness sensations improved in both groups (p0.05). Both MLD and IPC as a component of CDT were found successful at 5 weeks and 3 months without superiority to each other.

Clusterin (CLU) is a pleiotropic glycoprotein that exists as a secreted, neuroprotective or intracellular, neurotoxic form, both of which increase in Alzheimer's disease (AD) causing increased Aβ42 deposition. No studies have assessed the association between functionally distinct alloforms of CLU and tau protein or neuronal loss, despite its intracellular toxicity. We confirm previous reports of significant increases in both intracellular CLU and secreted CLU in the brain tissue of individuals with AD (p0.01) and show no association with neuronal loss. The increase in CLU alloforms was most closely associated with increases in both insoluble Aβ42 and tau protein (p = 0.001), supporting its role in AD pathogenesis. Further research should investigate whether altering human CLU levels may have viability as a therapeutic option for AD.

Introduction/Background After stroke, standing balance is usually described as a predictor of functional recovery. Regarding literature, various type of physical therapy (PT) is used to improve balance. The aim of this meta-analysis is to evaluate the effects of PT directly focused on balance training (DFBT) and theses of PT indirectly focused on balance training (IFBT) on balance after stroke. Material and method Randomised controlled trials (RCT), without language restriction, until October 2015, assessing the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke, the posturographic parameters in static condition and measures of independence in activities of daily living were included. Two independent authors (AH and JDM) led this selection following the Cochrane recommendations (Hugues et al., 2017). Results One hundred and ninety-three parallel and crossover RCT from 9337 records were included, involving 8018 subjects [study sample: mean 41.5 (SD 49.7) subjects, age: pooled mean 61.7 (pooled SD 12.78) years]. A significant difference in favor of PT compared to no treatment was immediately found after the intervention for the BBS (DFBT: 7 studies, mean difference [MD] 1.38; 95% confidence interval [CI] [0.71; 2.05]. IFBT: 18 studies, MD 1.88; 95% CI [1.31; 2.45]). Only IFBT PT is more effective than sham treatment or usual care immediately after the intervention for the BBS (DFBT: 1 study, MD 5.33; 95% CI [−4.68; 15.34]. IFBT: 26 studies, MD 1.85; 95% CI [0.67; 3.03]). Conclusion These results show immediately after the intervention: –that balance can be improved by PT aiming directly or indirectly at the recovery of balance compared to no treatment; –an improvement of balance by PT indirectly focused on the recovery of balance compared to sham treatment or usual care.

Introduction/Background Several studies highlight that the physical therapy (PT) timing is important in rehabilitation process from physical disability after stroke. The purpose of this meta-analysis was to investigate the effect of all PT on balance after stroke and to evaluate whether changes are related to stroke stage of recovering [acute and subacute (ASS) or chronic stage (CS)]. Material and method Randomised controlled trials (RCT), without language restriction, until October 2015, assessing the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke, the posturographic parameters in static condition and measures of independence in activities of daily living were included. Two independent authors (AH and JDM) led this selection following the Cochrane recommendations (Hugues et al., 2017). Results One hundred and ninety-three parallel and crossover RCT from 9337 records were included, involving 8018 subjects [study sample: mean 41.5 (SD 49.7) subjects, age: pooled mean 61.7 (pooled SD 12.78) years]. A significant difference in favor of PT compared to no treatment was immediately found after the intervention for the BBS at ASS and CS (ASS: 11 studies, mean difference (MD) 3.14; 95% confidence interval (CI) [2.21; 4.06]. CS: 12 studies, MD 1.31; 95% CI [0.79; 1.82]. Mixed: 2 studies, MD 0.89; 95% CI [−0.63; 2.40]). Only at CS, PT is more effective than sham treatment or usual care immediately after the intervention for the BBS (ASS: 12 studies, MD 2.21; 95% CI [−0.37; 4.78]. CS: 13 studies, MD 2.50; 95% CI [1.00; 3.99]. Mixed: 2 studies, MD −1.17; 95% CI [−2.94; 0.60]). Conclusion These results show immediately after the intervention: –that balance can be improved by PT compared to no treatment whatever the stage of stroke; –an improvement of balance by PT compared to sham treatment or usual care at chronic stage.

The following books are reviewed in this issue: 1) Analytical Mechanics: A Comprehensive Treatise on the Dynamics of Constrained Systems; For Engineers, Physicists and Mathematicians (Papastavridis, J.G.; 2002); 2) Mechanics of Micromechanical Systems (Lobontiu, N. and Garcia, E.; 2004); 3) Plasma Physics and Controlled Nuclear Fusion (Miyamoto, K.; 2005); and 4) Feedback Control of Computing Systems (Hellerstein, J.L. et al.; 2004).

Background and objective: In 1989, a therapeutic drug monitoring service was established in Assir Central Hospital, Abha, Saudi Arabia, by the Department of Clinical Pharmacology and Therapeutics of the College of Medicine, King Saud University Abha Branch (now King Khalid University). We report a 10-year follow-up of the results of monitoring the commonly used aminoglycosides (amikacin, gentamycin and tobramycin) obtained from our adult patients on first monitoring. Method: Two educational seminars for doctors and nurses were conducted 6 months before the initiation of this study. Drug assay requests were made on specially designed forms. Drug dosages were determined by the attending physicians. Samples for peak and trough drug level determinations were drawn after the fourth dose. The results of first time monitoring were sent to the wards with appropriate comments for dosage modifications where indicated. Results: The results for 2022 patients were analysed. Of these, 929, 899 and 194 were for amikacin, gentamycin and tobramycin, respectively. Therapeutic trough concentrations were 71·2%, 28·3% and 28·3% of patients on amikacin, gentamycin and tobramycin, respectively. A total of 8·8%, 17·6% and 11·9% had trough concentrations considered toxic for amikacin, gentamycin and tobramycin, respectively. Peak therapeutic concentrations were achieved in 31·6%, 42·3% and 39·7% of patients on amikacin, gentamycin and tobramycin. A total of 53·3% of patients on amikacin, 50·3% on gentamycin and 57·2% on tobramycin had peak serum drug concentrations in the subtherapeutic range. Toxic concentrations were noticed mainly in patients aged over 60 years and in the critically ill in the intensive care, coronary care and bums units of the hospital. Conclusions: To be cost-effective, intensive therapeutic monitoring of aminoglycosides in adults should continue to be monitored mainly for the old and sick patients in critical care units to optimize patient management.

Dynamical problems subject to non-linear non-holonomic constraints are analyzed using the differential variational principles of Jourdain (JVP) and Gauss (GVP). In contrast with linear non-holonomic constraints which arise from passive contact or rolling constraints, non-linear non-holonomic constraints (NNHC) arise in problems where the constraints are actively imposed, such as control or servo-constraints, consideration of some first integrals as kinetic side conditions, or mathematical constraints without regard to their physical realizability. To date, such problems have been treated by various ad hoc and unrelated methods in a fragmented manner, without a unifying idea running through the various methods of approach. In the present paper, it is shown that by applying the JVP to velocity constraints, and the GVP to acceleration constraints, dynamical problems subject to NNHC can be handled in a uniform way. Both the method of constraint embedding (elimination of variations) and constraint adjoining (use of Lagrange multipliers) are used in analyzing the behavior of the dynamical system subject to NNHC.

Improving minimal residual disease detection in precursor B-ALL based on immunoglobulin-κ and heavy-chain gene rearrangements

The Appell-Hamel non-holonomic problem which is intrinsically linear, has been formulated by the same authors as a non-linear problem by means of a limiting procedure. This limiting process has been shown to be incorrect, in addition to being unnecessary in problems with rolling-type contact, where the constraint relations are known to be linear. It is well established however, that there exist non-linear non-holonomic constraints that arise from sources other than rolling-type contact. In order to be able to study the effect of constraints that arise from sources other than rolling, the Appell-Hamel problem is reformulated in terms of non-linear non-holonomic constraints, leading to the same results as the linear formulation, thus validating the non-linear analysis. A complete set of constants of the motion are derived, and limiting motions are investigated. The paper concludes with a description of the general method of solution to determine the time-history of the generalized coordinates. It ends with a detailed discussion of the numerical integration of the equations of motion.

The stratification of patients with acute lymphoblastic leukemia (ALL) into treatment risk groups based on quantification of minimal residual disease (MRD) after induction therapy is now well accepted but the relapse rate of about 20% in intermediate risk patients remains a challenge. The purpose of this study was to further improve stratification by MRD measurement at an earlier stage. MRD was measured in stored day 15 bone marrow samples for pediatric patients enrolled on ANZCHOG ALL8 using Real-time Quantitative PCR to detect immunoglobulin and T-cell receptor gene rearrangements with the same assays used at day 33 and day 79 in the original MRD stratification. MRD levels in bone marrow at day 15 and 33 were highly predictive of outcome in 223 precursor B-ALL patients (log rank Mantel-Cox tests both P

It is known that a position which is accessible along a prescribed path, is also accessible in the presence of nonholonomic constraints, where the path is no longer prescribed, but is to be determined as part of the solution of the problem. To determine the precise trajectory, however, the kinematic constraint must be appended to the kinetic formulation of the problem for the object to reach its destination. In this paper, the initial conditions that are required in order to insure that a Caratheodory sled reach a preassigned final position are developed by considering the problem as an inverse dynamical problem. It is shown that the trajectory is not unique, but depends on the ratio of the initial linear and angular velocities, while the transit time depends only on one of the latter quantities.

The differential variational principle of Jourdain (JVP) is extended to cover the dynamics of impulsive motion, formulated in terms of quasi-velocities, instead of time rates of change of true or Lagrangian generalized coordinates. This enlarges the scope of the JVP, because the extension of its range to encompass the use of quasi-velocities (which includes true velocities as a special case), enables the analyst to solve a wider range of problems. It should be pointed out that the mathematical foundation of the JVP, which is based on the assumption that the variation of the position vectors as well as the time is zero (in true Lagrangian as well as quasi-coordinates), is ideally suited to the physics of impulsive motion, where finite changes in the velocity are accompanied by negligible changes in configuration and time.

The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor–recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo. Significance: For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation. Cancer Discovery; 2(1); 47–55. ©2011 AACR. This article is highlighted in the In This Issue feature, p. 1

The slate space approach to coupled thermoelasticity is revisited. The paper is concerned with a one-dimensional description of a semi-infinite body. The first pan of the article deals with issues concerning the formalisms of a methodology that has been extensively used. The second part illustrates that, in contrast to previous formulations, the solutions to the thermoelastic fields can be found in an exact manner by means of an entirely different approach.

A non-holonomic problem proposed by Greenwood is solved by reducing it to a Caratheodory problem. The resulting equations of motion are formulated in terms of natural physical variables corresponding to quasi-velocities. A connection between the two available methods of integration of the equations of motion is established that closes an existing gap in the literature. The explicit analytical results obtained for the particular set of initial conditions are confirmed by the numerical integration of the equations of motion performed on a computer. Thus, the procedure developed can be easily extended to a different set of input data. The time histories and trajectories obtained on the computer also suggest the development of asymptotic solutions for short and long times. Such results are obtained analytically and displayed in closed form.

The transition between the Airy stress function and the state space approach to elasticity is established. It is shown that a formulation based on a state vector that consists of the Fourier transforms of the Airy stress function and its spatial derivatives has advantages due to the simpler nature of the matrix involved. The approach is used as an intermediate step in obtaining the transformed stresses and displacements. The Flamant problem is used as an application. In contrast to previous studies, it is shown that one of the displacement components contains an integral that diverges in the classical sense, but converges in the sense of generalized functions or distributions.

Explicit solutions for some gyroscopic linear dynamical systems are obtained by selecting a change of the dependent vector variable, which eliminates the velocity term in the transformed equation of motion. The transformation corresponds to the vector counterpart of the technique used for the reduction of order in ordinary scalar differential equations. The matrix coefficients of the equations considered obey a certain commutativity condition, which can be expressed in terms of the vanishing of their Lie product or commutator. For purely gyroscopic systems, the results obtained are compared to a generalization of a method originally proposed by Gantmacher.

Detection of minimal residual disease (MRD) after induction and consolidation therapy is highly predictive of outcome for childhood acute lymphoblastic leukaemia (ALL) and is used to identify patients at high risk of relapse in several current clinical trials. To evaluate the prognostic significance of MRD at other treatment phases, MRD was measured by real-time quantitative polymerase chain reaction on a selected group of 108 patients enrolled on the Australian and New Zealand Children's Cancer Study Group Study VII including 36 patients with a bone marrow or central nervous system relapse and 72 matched patients in first remission. MRD was prognostic of outcome at all five treatment phases tested: at day 15 (MRDor = 5 x 10(-2), log rank P0.0001), day 35 (or =1 x 10(-2), P = 0.0001), 4 months (or =5 x 10(-4), P0.0001), 12 months (MRDor = 1 x 10(-4), P = 0.006) and 24 months (MRDor = 1 x 10(-4), P0.0001). Day 15 was the best early MRD time-point to differentiate between patients with high, intermediate and low risk of relapse. MRD testing at 12 and particularly at 24 months, detected molecular relapses in some patients up to 6 months before clinical relapse. This raised the question of whether a strategy of late monitoring and salvage therapy will improve outcome.

Molecular markers for minimal residual disease in B-lineage acute lymphoblastic leukemia were identified by determining, at the time of diagnosis, the repertoire of rearrangements of the immunoglobulin heavy chain (IGH) gene using segment-specific variable (V), diversity (D), and junctional (J) primers in two different studies that involved a total study population of 75 children and 18 adults. This strategy, termed repertoire analysis, was compared with the conventional strategy of identifying markers using family-specific V, D, and J primers for a variety of antigen receptor genes. Repertoire analysis detected significantly more markers for the major leukemic clone than did the conventional strategy, and one or more IgH rearrangements that were suitable for monitoring the major clone were detected in 96% of children and 94% of adults. Repertoire analysis also detected significantly more IGH markers for minor clones. Some minor clones were quite large and a proportion of them would not be able to be detected by a minimal residual disease test directed to the marker for the major clone. IGH repertoire analysis at diagnosis has potential advantages for the identification of molecular markers for the quantification of minimal residual disease in acute lymphoblastic leukemia cases. An IGH marker enables very sensitive quantification of the major leukemic clone, and the detection of minor clones may enable early identification of additional patients who are prone to relapse.

Gantmacher formulas are generalized by including the effect of the centripetal and angular accelerations in addition to the usual Coriolis term. The integration is accomplished by using a method based on functions of matrices, which permits the summation of an infinite series in closed form through the use of the Cayley–Hamilton theorem. The problem is further extended by allowing arbitrary matrix coefficients in the vector equation of motion, provided they obey a certain commutativity condition. In addition to standard examples, the problem of a particle moving on a plane rotating with variable angular velocity is considered. This example differs from the ones considered in the literature because neither the centripetal nor the angular acceleration terms can be neglected. Solutions of various orders are developed by truncating the exact solution when appropriate.

The Finite Element-Transfer Matrix (FETM) method was developed for reducing the computational efforts involved in structural analysis. While being widely used by structural analysts, this method does, however, have certain limitations, particularly when used for the control design of large flexible structures. In this paper, a new formulation based on the FETM method is presented. The new method effectively overcomes the limitations in the original FETM method, and also allows an easy construction of reduced models that are tailored for the control design. Other advantages of this new method include the ability to extract open loop frequencies and mode shapes with less computation, and simplification of the design procedures for output feedback, constrained compensation, and decentralized control. The development of this new method and the procedures for generating reduced models using this method are described in detail and the role of the reduced models in control design is discussed through an illustrative example.

Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analyzed for clonal populations using polymerase chain reaction (PCR)–based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. More sensitive clone-specific PCR revealed that, in 8 cases, these “relapse clones” were present at diagnosis and a significant relationship existed between presence of the relapse clone at diagnosis and time to first relapse (P < .007). Furthermore, in cases where the relapse clone could be quantified, time to first relapse was dependent on the amount of the relapse clone at diagnosis (r = −0.84; P = .018). This observation, together with demonstrated differential chemosensitivity between subclones at diagnosis, argues against therapy-induced acquired resistance as the mechanism of relapse in the informative patients. Instead these data indicate that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant subclone that is undetectable by routine PCR-based methods. Relapse prediction may be improved with strategies to detect minor potentially resistant subclones early during treatment, hence allowing intensification of therapy.

Several studies have shown that Ashkenazi Jews in the United States and Israel have a high prevalence of the founder mutations BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT, and APC I1307K at frequencies of 1.0--1.1%, 0.2--0.3%, 0.6--1.4%, and 6.1--7.0%, respectively. The objective of this study was to compare the prevalence of these alleles in the Australian Jewish population with that of U.S. Jews. Australian Jews have a different history of migration, with less opportunity for changes in allele frequency due to conversion or intermarriage with non-Jewish Australians. The results obtained therefore can be used to assess whether U.S. data can be generalized to other Jewish populations. SUBJECTS AND METHODS. Subject samples were ascertained through a screening program for Tay-Sachs disease as part of a community-based screening program in New South Wales and Victoria. DNA extracted from 1200 deidentified blood samples was tested using amplification refractory mutation system polymerase chain reaction.The allele frequencies found were as follows: BRCA1 185delAG 1.25% (95% confidence interval [CI], 0.62--1.88%), BRCA1 5382insC 0.25% (95% CI, 0--0.53%), BRCA2 6174delT 1.08% (95% CI, 0.50--1.67%), and APC I1307K 8.67% (95% CI, 7.07--10.26%). The prevalence of breast carcinoma predisposition alleles therefore is greater than 2.5% in Australian Ashkenazim.There were no significant differences between the allele frequencies in Australian Ashkenazim and those identified in other studies with similar ascertainment strategies, despite the different migration patterns of Australian Jews. This suggests the broad applicability of the U.S. and Israeli data, not only to Australian Ashkenazim, but also to Ashkenazi communities throughout the world.

Abstract 3671 Follicular lymphoma (FL) is characterized by the translocation t(14;18), which results in overexpression of the anti-apoptotic protein BCL2 through juxtaposition to the immunoglobulin heavy chain (IGH) locus. Additional genetic aberrations are required and recurrent mutations have been identified in FL, however their timing during lymphomagenesis remains unknown. We performed ultra-sensitive mutation detection to define in vivo clonal diversification in paired follicular lymphomas from a donor-recipient sibling pair that presented more than 9 years after hematopoietic cell transplantation. Briefly, a 41-year old woman with chronic myeloid leukemia (CML) underwent myeloablative bone marrow transplantation from her HLA-matched sister in 2000. She received three donor leukocyte infusions (DLI) for molecular relapse, with the last in June 2002. In November 2009, the donor was diagnosed with grade 2/3A FL. Six months later, the recipient was diagnosed with grade 2/3A FL. The FLs shared identical BCL2/IGH rearrangements, which was also recovered from the DLI at a frequency of 1-in-2000 cells. Both FLs also shared the same V(D)J rearrangement, with the exception of single base-pair mismatches and insertions/deletions (InDels) consistent with ongoing somatic hypermutation (SHM) during clonal divergence. Alignment with germline VH3-66 sequence indicated that the common ancestor had initiated SHM. Whole exome sequencing of both FLs identified 12 single nucleotide variants (SNVs) and 2 InDels in both lymphomas, 3 SNVs unique to the donor's FL, and 4 unique to the recipient's FL. All candidate mutations were validated and confirmed to be somatic by Sanger sequencing. Among the identical mutations identified in both FLs were two SNVs in BCL2, an in-frame deletion in EP300, and an in-frame insertion in KLHL6, which were recently found to be recurrently mutated in lymphoma. Among the SNVs unique to the recipient's FL was an ARID1A (adenine-thymine (AT)-rich interactive domain-containing protein 1A) R1276 premature stop. Loss-of-function mutations in ARID1A have been reported in solid cancers, but not yet in hematologic malignancies. On immunohistochemical staining both lymphomas had decreased ARID1A/BAF250 protein expression, suggesting that loss of ARID1A occurred through separate mechanisms in each FL (i.e. convergent evolution). In fact, the donor's lymphoma was found to have a copy number loss at this locus (1p35.3) by qPCR. To determine whether the somatic mutations that we identified were present at a low frequency within the DLI, we PCR amplified regions flanking each mutation site from the DLI and subjected the products to ultra-sensitive deep sequencing (average read coverage at mutation site, 361,723; range, 16,684–1,169,555). To correct for background frequencies of non-germline calls, we PCR amplified and deep sequenced the same positions from the donor's buccal swab (average read coverage at the mutation site, 418,499; range, 20,711–1,070,734). Eleven of the 12 SNVs and the 2 InDels that were identified in both lymphomas were ‘enriched' in the DLI, i.e., recovered at frequencies significantly above background, indicating that those mutations were present more than 7 years prior to presentation of either lymphoma. All 4 SNVs unique to the recipient's FL and a RAFTLIN V254M mutation identified only in the donor's FL were not enriched in the DLI, consistent with subsequent acquisition during clonal diversification. Of the final two mutations, one was detected only in the donor's FL and was enriched in the DLI. The other was initially detected only in the donor's FL, but deep sequencing recovered the mutation in 4.7% of reads from the recipient's FL and demonstrated enrichment in the DLI. The presence of a mutation in the donor's FL and DLI but not within the majority of recipient's FL cells is consistent with at least two scenarios: (i) the recipient's FL is derived from a clonally diversified population of ancestor cells transferred from the donor or (ii) the mutant allele was lost in a subset or in all cells of the recipient's FL during clonal evolution. In conclusion, we utilized ultra-sensitive mutation detection to elucidate the molecular ontogeny of follicular lymphoma during clonal evolution in separate hosts. This approach has broad applicability for identifying genetic variants within tumor populations that confer phenotypes like therapeutic resistance or metastatic potential. Disclosures: No relevant conflicts of interest to declare.

The authors summarize an approach to the static bifurcation analysis of electric power networks which combines bifurcation theory with proven computational methods and a graphical representation of information which has intuitive appeal. The relationship between contour maps and static bifurcation of power system equilibrium equations is examined. Preliminary results identify the limitations as well as possibilities for enhancement of the generalized circle diagrams introduced by G.B. Price (1984). By combining symbolic and numerical computations this approach appears to be moving toward making power system static bifurcation analysis an intuitive and practical tool for power system operations analysis. >

Background: Detection of molecular markers for monitoring MRD in B-ALL conventionally involves searching for a variety of immunoglobulin and T-cell receptor rearrangements. However preliminary studies have suggested that AIRR may have advantages. Aim :To directly compare AIRR to the conventional approach for detection of molecular markers. Materials and Methods Marrow samples from a consecutive series of 50 children with B-linage ALL were studied by the conventional approach in Sydney and by AIRR in Adelaide. AIRR involves use of primers specific for individual V and J segments of the IgH gene followed by sequencing of amplified products and calculation of the relative abundance of rearrangements from the quantitative PCR data. IgH rearrangements are regarded as suitable for detecting the major leukemic clone if they comprise > 10% of the rearrangements present. Incomplete D-J rearrangements are detected using primers directed towards genomic regions upstream of the D segments. Results Table 1 shows the number of patients with either 0, 1 or 2 rearrangements suitable for monitoring MRD of the major leukemic clone. The 2 approaches appeared to be equivalent in terms of the number of markers for the major clone, but, of the rearrangements detected conventionally, 49% were IgH rearrangements and 51% involved IgK or various T-cell receptor genes. All of the IgH rearrangements detected in the 50 patients, grouped by abundance, are shown in Table 2. Table 1 number of patients no marker 1 marker 2 markers conventional approach 2 9 39 AIRR 2 12 36 Table 2 relative abundance of rearrangement 100-10% 10-1% High and low abundance rearrangements mark major and minor clones repectively. AIRR detected significantly more rearrangements of both types. Clone sizes and lineage relationships could be inferred from rearrangement abundance and sequence relationships. 68 minor clones were detected at diagnosis in 31 patients. 26 of the 68 showed no sequence relationship to the major clone. Discussion Use of IgH gene rearrangements as markers enables MRD in B-ALL to be sensitively quantified, down to 10−6. The superior ability of AIRR to identify marker IgH rearrangements is therefore likely to enable more sensitive monitoring of the major leukemic clone. Relapse in B-ALL is sometimes due a minor chemoresistant leukemic clone which is already present at diagnosis but is only identified retrospectively. The ability of AIRR to identify IgH markers for minor clones at diagnosis, together with the ability to sensitively monitor clones marked by IgH rearrangements, may enable prospective identification of these minor clones. Conclusions AIRR and the conventional strategy are similar in terms of the number of patients with ALL in whom 1 or 2 molecular markers for the major leukemic clone can be detected. AIRR detects significantly more IgH markers for the major leukemic clone. This should enable more sensitive quantification of the major clone in many patients. AIRR is much superior at identification of markers for minor clones. This may enable chemoresistant minor clones to be detected prospectively. The clonal hierarchies of minor clones at diagnosis resemble those observed in patients who relapse.

A method to predict the dynamic response of a linear nonconservative system with nonsymmetric parameter matrices, due to a discretized forcing function is developed. The method is based on sampled-data techniques widely used in modern control theory. However, instead of appealing to the state space approach which recasts the equations of motion into a first order system, the numerical integration is attempted directly on the second order differential equations as given. Finally, a sample problem considered in a previous matrix exponential method is worked out by the method developed here. The results indicate that the approach is well-suited for problems where the input data is known in digitized form.

A topological mixed potential function, P*T, is defined and shown to be an exact differential. From P*T, the Brayton-Moser equations are obtained from topological relationships of the network and the constitutive relationships of the elements. A relationship between P*T and Brayton-Moser's mixed potential function, Q, is developed.

An ad hoc procedure is given for obtaining first integrals of second order differential equations in which the non-linear term is a power of the dependent variable, as in the Emden-Fowler equation. The main theorem is a considerable extension of previous results along these lines. A corollary implies several known examples.

This paper presents a study of time-varying linear systems of second order ordinary differential equations, which can be derived from a Lagrangian after multiplication by a suitable matrix. It concerns a generalization of previous studies on systems with constant coefficients. After a simplification of the Helmholtz conditions, it is shown that the problem is reduced to a purely algebraic one, provided one can solve a matrix differential equation which produces the transformation to canonical form of the given system. This further leads to a theoretical characterization of all systems admitting a multiplier. Various algebraic relations are derived, involving constant matrices only, which can help to detect, prior to any integration procedure, whether or not: a multiplier exists. They are referred to as the generalized commutativity conditions. The first of these, which is sufficient for the existence of a Lagrangian, is shown to allow also a simple construction of a quadratic first integral, and to have some other interesting features. The paper ends with an example.

The method of the matrix exponential, which constitutes the basis of the state space approach of modern control theory, is applied to the nondimensional equations of coupled thermoelasticity. The disadvantages of using the thermoelastic potential are thus avoided. The results obtained can be used to generate solutions in the Laplace-transform domain to a broad class of problems in thermoelasticity. Applications to problems pertaining to a half-space and a layer are presented.