Cohesin biology meets the loop extrusion model

Extensive research has revealed that cohesin acts as a topological device, trapping chromosomal DNA within a large tripartite ring. In so doing, cohesin contributes to the formation of compact and organized genomes. How exactly the cohesin subunits interact, how it opens, closes, and translocates on chromatin, and how it actually tethers DNA strands together are still being elucidated. A comprehensive understanding of these questions will shed light on how cohesin performs its many functions, including its recently proposed role as a chromatid loop extruder. Here, we discuss this possibility in light of our understanding of the molecular properties of cohesin complexes

Use of positron emission tomography in evaluation of brachial plexopathy in breast cancer patients

18-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) has previously been used successfully to image primary and metastatic breast cancer. In this pilot study, 19 breast cancer patients with symptoms/signs referrable to the brachial plexus were evaluated with 18FDG-PET. In 11 cases computerized tomography (CT) scanning was also performed. Of the 19 patients referred for PET study, 14 had abnormal uptake of 18FDG in the region of the symptomatic plexus. Four patients had normal PET studies and one had increased FDG uptake in the chest wall that accounted for her axillary pain. CT scans were performed in 9 of the 14 patients who had positive brachial plexus PET studies; six of these were either normal or showed no clear evidence of recurrent disease, while three CTs demonstrated clear brachial plexus involvement. Of two of the four patients with normal PET studies, one has had complete resolution of symptoms untreated while the other was found to have cervical disc herniation on magnetic resonance imaging (MRI) scan. The remaining two patients almost certainly had radiation-induced plexopathy and had normal CT, MRI and PET study. These data suggest that 18FDG-PET scanning is a useful tool in evaluation of patients with suspected metastatic plexopathy, particularly if other imaging studies are normal. It may also be useful in distinguishing between radiation-induced and metastatic plexopathy. © 1999 Cancer Research Campaig

Interpretations of Presburger Arithmetic in Itself

Presburger arithmetic PrA is the true theory of natural numbers with addition. We study interpretations of PrA in itself. We prove that all one-dimensional self-interpretations are definably isomorphic to the identity self-interpretation. In order to prove the results we show that all linear orders that are interpretable in (N,+) are scattered orders with the finite Hausdorff rank and that the ranks are bounded in terms of the dimension of the respective interpretations. From our result about self-interpretations of PrA it follows that PrA isn't one-dimensionally interpretable in any of its finite subtheories. We note that the latter was conjectured by A. Visser.Comment: Published in proceedings of LFCS 201

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

Characterizing Polytobacco Use Trajectories and Their Associations With Substance Use and Mental Health Across Mid-Adolescence.

Background:Polytobacco product use is suspected to be common, dynamic across time, and increase risk for adverse behavioral outcomes. We statistically modeled characteristic types of polytobacco use trajectories during mid-adolescence and tested their prospective association with substance use and mental health problems. Methods:Adolescents (N = 3393) in Los Angeles, CA, were surveyed semiannually from 9th to 11th grade. Past 6-month combustible cigarette, e-cigarette, or hookah use (yes/no) over four assessments were analyzed using parallel growth mixture modeling to identify a parsimonious set of polytobacco use trajectories. A tobacco product use trajectory group was used to predict substance use and mental health at the fifth assessment. Results:Three profiles were identified: (1) tobacco nonusers (N = 2291, 67.5%) with the lowest use prevalence (<3%) of all products across all timepoints; (2) polyproduct users (N = 920, 27.1%) with moderate use prevalence of each product (8-35%) that escalated for combustible cigarettes but decreased for e-cigarettes and hookah across time; and (3) chronic polyproduct users (N = 182, 5.4%) with high prevalence of each product use (38-86%) that escalated for combustible cigarettes and e-cigarettes. Nonusers, polyproduct users, and chronic polyproduct users reported successively higher alcohol, marijuana, and illicit drug use and ADHD at the final follow-up, respectively. Both tobacco using groups (vs. nonusers) reported greater odds of depression and anxiety at the final follow-up but did not differ from each other. Conclusions:Adolescent polytobacco use may involve a common moderate risk trajectory and a less common high-risk chronic trajectory. Both trajectories predict substance use and mental health symptomology. Implications:Variation in use and co-use of combustible cigarette, e-cigarette, and hookah use in mid-adolescence can be parsimoniously characterized by a small set common trajectory profiles in which polyproduct use are predominant patterns of tobacco product use, which predict adverse behavioral outcomes. Prevention and policy addressing polytobacco use (relative to single product use) may be optimal tobacco control strategies for youth, which may in turn prevent other forms of substance use and mental health problems

Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants

Conserved noncoding sequences (CNSs) in DNA are reliable pointers to regulatory elements controlling gene expression. Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes. Distinct positioning, length, and enrichment for transcription factor binding sites suggest these CNSs play a functional role in transcriptional regulation. The enrichment of transcription factors within the set of genes associated with CNS is consistent with the hypothesis that together they form part of a conserved transcriptional network whose function is to regulate other transcription factors and control development. We identified a set of promoters where regulatory mechanisms are likely to be shared between the model organism Arabidopsis and other dicots, providing areas of focus for further research

Descriptive Complexity of Deterministic Polylogarithmic Time and Space

We propose logical characterizations of problems solvable in deterministic polylogarithmic time (PolylogTime) and polylogarithmic space (PolylogSpace). We introduce a novel two-sorted logic that separates the elements of the input domain from the bit positions needed to address these elements. We prove that the inflationary and partial fixed point vartiants of this logic capture PolylogTime and PolylogSpace, respectively. In the course of proving that our logic indeed captures PolylogTime on finite ordered structures, we introduce a variant of random-access Turing machines that can access the relations and functions of a structure directly. We investigate whether an explicit predicate for the ordering of the domain is needed in our PolylogTime logic. Finally, we present the open problem of finding an exact characterization of order-invariant queries in PolylogTime.Comment: Submitted to the Journal of Computer and System Science

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL

Sustainable positive psychology interventions enhance primary teachers’ wellbeing and beyond – a qualitative case study in England

Positive psychology interventions (PPIs) have become an influential approach to foster teacher wellbeing; however, little research addresses the critiques and sustainability of PPIs. This study investigated teacher experiences of PPIs and the impact on their wellbeing in professional and personal contexts. Qualitative data were collected using multi-methods in a primary school in two settings: staff-meetings with 21 teachers and a self-interest group with 9 teachers. Results showed practising PPIs enhanced teachers' wellbeing multidimensionally and produced positive impacts on others. The challenges experienced and plans for sustainable actions were identified. Insights into sustainable teacher wellbeing programmes and professional development are offered

B Lymphocyte Memory: Role of Stromal Cell Complement and FcγRIIB Receptors

To dissect the influence of CD21/CD35 and FcγRIIB in antigen retention and humoral memory, we used an adoptive transfer model in which antigen-primed B and T lymphocytes were given to sublethally irradiated wild-type mice or mice deficient in CD21/CD35 (Cr2−/−) or FcγRIIB receptors (FcγRIIB−/−). Cr2−/− chimeras showed impaired memory as characterized by a decrease in antibody titer, reduced frequency of antibody secreting cells, an absence of affinity maturation, and significantly reduced recall response. The impaired memory in Cr2−/− chimeras corresponded with the reduced frequency of antigen-specific memory B cells. Interestingly, FcγRIIB−/− chimeras showed a differential phenotype with impaired splenic but normal bone marrow responses. These data suggest that CD21/CD35 on stroma, including follicular dendritic cells, is critical to the maintenance of long-term B lymphocyte memory