Model theory of operator algebras III: Elementary equivalence and II_1 factors

We use continuous model theory to obtain several results concerning isomorphisms and embeddings between II_1 factors and their ultrapowers. Among other things, we show that for any II_1 factor M, there are continuum many nonisomorphic separable II_1 factors that have an ultrapower isomorphic to an ultrapower of M. We also give a poor man's resolution of the Connes Embedding Problem: there exists a separable II_1 factor such that all II_1 factors embed into one of its ultrapowers.Comment: 16 page

Phosphorylation of HOX11/TLX1 on Threonine-247 during mitosis modulates expression of cyclin B1

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The HOX11/TLX1 (hereafter referred to as HOX11) homeobox gene was originally identified at a t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T cell acute lymphoblastic leukemias (T-ALLs). We previously reported a predisposition to aberrant spindle assembly checkpoint arrest and heightened incidences of chromosome missegregation in HOX11-overexpressing B lymphocytes following exposure to spindle poisons. The purpose of the current study was to evaluate cell cycle specific expression of HOX11. Results Cell cycle specific expression studies revealed a phosphorylated form of HOX11 detectable only in the mitotic fraction of cells after treatment with inhibitors to arrest cells at different stages of the cell cycle. Mutational analyses revealed phosphorylation on threonine-247 (Thr247), a conserved amino acid that defines the HOX11 gene family and is integral for the association with DNA binding elements. The effect of HOX11 phosphorylation on its ability to modulate expression of the downstream target, cyclin B1, was tested. A HOX11 mutant in which Thr247 was substituted with glutamic acid (HOX11 T247E), thereby mimicking a constitutively phosphorylated HOX11 isoform, was unable to bind the cyclin B1 promoter or enhance levels of the cyclin B1 protein. Expression of the wildtype HOX11 was associated with accelerated progression through the G2/M phase of the cell cycle, impaired synchronization in prometaphase and reduced apoptosis whereas expression of the HOX11 T247E mutant restored cell cycle kinetics, the spindle checkpoint and apoptosis. Conclusions Our results demonstrate that the transcriptional activity of HOX11 is regulated by phosphorylation of Thr247 in a cell cycle-specific manner and that this phosphorylation modulates the expression of the target gene, cyclin B1. Since it is likely that Thr247 phosphorylation regulates DNA binding activity to multiple HOX11 target sequences, it is conceivable that phosphorylation functions to regulate the expression of HOX11 target genes involved in the control of the mitotic spindle checkpoint.Published versio

A subgroup of microRNAs defines PTEN-deficient, triple-negative breast cancer patients with poorest prognosis and alterations in RB1, MYC, and Wnt signaling

Abstract Background Triple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs. Methods Publically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy. Results In TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway. Conclusions This analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy

Uterine Retiform Sertoli-Leydig Cell Tumor Report of a Case Providing Additional Evidence That Uterine Tumors Resembling Ovarian Sex Cord Tumors Have a Histologic and Immunohistochemical Phenotype of Genuine Sex Cord Tumors

Summary: We report a case of a retiform Sertoli-Leydig cell tumor of intermediate differentiation presenting as a uterine intracavity polypoid mass in a 63-year-old woman. In contrast to sertoliform endometrioid carcinoma and to hitherto reported uterine tumors resembling ovarian sex cord tumors (UTROSCTs), which are primarily characterized by tubular glands and solid tubules, this tumor, which most likely represents a UTROSCT, showed a large spectrum of histologic features typical of a genuine retiform Sertoli-Leydig cell tumor. The diagnosis was confirmed by a battery of immunohistochemical stains, which also served as a tool for differential diagnosis with other neoplasms. The tumor cells were positive for broad spectrum keratin (CK) CK18, vimentin, calretinin, and progesterone receptor. Only a few isolated cells stained for inhibin. The tumor cells were negative for CK7, CK5/6, epithelial membrance antigen (EMA), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), thrombomodulin, 013 (CD99), melan A, alpha-fetoprotein (AFP), placental alkaline phosphatase (PLAP), a-1-antitrypsin, estrogen receptor, S100, neusone specific enolase (NSE), chromogranin, synaptophysin, desmin, caldesmon, and CD10. Divergent differentiation of uterine cells seems to be the most likely pathogenetic mechanism. To the best of our knowledge, no UTROSCT showing such a variety of histologic features indicative of a true sex cord tumor has been reported before

A Complete Axiom System for Propositional Interval Temporal Logic with Infinite Time

Interval Temporal Logic (ITL) is an established temporal formalism for reasoning about time periods. For over 25 years, it has been applied in a number of ways and several ITL variants, axiom systems and tools have been investigated. We solve the longstanding open problem of finding a complete axiom system for basic quantifier-free propositional ITL (PITL) with infinite time for analysing nonterminating computational systems. Our completeness proof uses a reduction to completeness for PITL with finite time and conventional propositional linear-time temporal logic. Unlike completeness proofs of equally expressive logics with nonelementary computational complexity, our semantic approach does not use tableaux, subformula closures or explicit deductions involving encodings of omega automata and nontrivial techniques for complementing them. We believe that our result also provides evidence of the naturalness of interval-based reasoning

Comparative effectiveness of intensity modulated radiation therapy to 3-dimensional conformal radiation in locally advanced lung cancer: pathological and clinical outcomes.

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy. METHODS: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) and overall survival (OS) between 3DCRT and IMRT. RESULTS: Our cohort consisted of 74 patients with mean age 62.9 years, male in 51/74 (69%), adenocarcinoma in 46/74 (62.1%), stage 3 in 59/74 (79.7%) and chemotherapy in 72/74 (97.3%). Radiation mean dose: 59.2 Gy (SD ± 3.8). Radiation technique : 3DCRT in 51/74 (68.9%), IMRT in 23/74 (31%). Other variables were similar between groups.Major pathological response (including pathological complete response or less than 10% residual tumor cells) was similar: 32/51 (62.7%) in 3DCRT and 15/23 (65.2%) in IMRT, p=0.83. Pathological complete response (pCR) rates were similar: 17/51 (33.3%) in 3DCRT and 8/23 (34.8%) in IMRT, p=0.9. Surgical margins were negative in 46/51 (90.1%) in 3DCRT vs. 17/19 (89.4%) in IMRT (p=1.0).The 2-year LC rates were 81.6% (95% CI 69-89.4%); DFS 58.3% (95% CI 45.5-69%) and 3-year OS 70% (95% CI57-80%). Comparing radiation techniques, there were no significant differences in LC (p=0.94), DFS (p=0.33) and OS (p=0.72). CONCLUSION: When used to treat LANSCLC in the neoadjuvant setting, both IMRT and 3DCRT produce comparable pathological and clinical outcomes. ADVANCES IN KNOWLEDGE: This study validates the real-world effectiveness of IMRT compared to 3DCRT

Pancreatic cancer outcome—local treatment with radiation using MRI-LINAC

IntroductionStereotactic MR-guided on-table adaptive radiotherapy (SMART) allows the precise delivery of high-dose radiation to tumors in great proximity to radiation-sensitive organs. The aim of this study is to evaluate the toxicity and clinical outcome in locally advanced or recurrent pancreatic tumors, with or without prior irradiation, treated with SMART.MethodsPatients were treated for pancreatic cancer (PC) using SMART technology to a prescribed dose of 50 Gy (BED10, 100 Gy) in five fractions, with daily on-table adaptation of treatment plan. Endpoints were acute and late toxicities, local control, local disease-free period, and overall survival.ResultsA total of 54 PC patients were treated between August 2019 and September 2022, with a median follow-up of 8.9 months from SMART. The median age was 70.4 (45.2–86.9) years. A total of 40 patients had upfront inoperable PC (55% were locally advanced and 45% metastatic), and 14 had local recurrence following prior pancreatectomy (six patients also had prior adjuvant RT). Of the patients, 87% received at least one chemotherapy regimen (Oxaliplatin based, 72.2%), and 25.9% received ≥2 regimens. Except from lower CA 19-9 serum level at the time of diagnosis and 6 weeks prior to SMART in previously operated patients, there were no significant differences in baseline parameters between prior pancreatectomy and the inoperable group. On-table adaptive replanning was performed for 100% of the fractions. No patient reported grade ≥2 acute GI toxicity. All previously irradiated patients reported only low-grade toxicities during RT. A total of 48 patients (88.9%) were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for a median of 9 months (2.8–28.8); three had later local progression. Eight patients had regional or marginal recurrence. Six- and 12-month OS were 75.0% and 52.1%, respectively. Apart from mild diarrhea 1–3 months after SMART and general fatigue, there were no significant differences in toxicity and outcomes between post-pancreatectomy and inoperable groups.ConclusionSMART allows safe delivery of an ablative dose of radiotherapy, with minimal treatment-related toxicity, even in previously resected or irradiated patients. In this real-world cohort, local control with complete response was achieved by 20% of the patients. Further studies are needed to evaluate long-term outcome and late toxicity

waviCGH: a web application for the analysis and visualization of genomic copy number alterations

waviCGH is a versatile web server for the analysis and comparison of genomic copy number alterations in multiple samples from any species. waviCGH processes data generated by high density SNP-arrays, array-CGH or copy-number calls generated by any technique. waviCGH includes methods for pre-processing of the data, segmentation, calling of gains and losses, and minimal common regions determination over a set of experiments. The server is a user-friendly interface to the analytical methods, with emphasis on results visualization in a genomic context. Analysis tools are introduced to the user as the different steps to follow in an experimental protocol. All the analysis steps generate high quality images and tables ready to be imported into spreadsheet programs. Additionally, for human, mouse and rat, altered regions are represented in a biological context by mapping them into chromosomes in an integrated cytogenetic browser. waviCGH is available at http://wavi.bioinfo.cnio.es

Coeliac plexus radiosurgery for pain management in patients with advanced cancer : study protocol for a phase II clinical trial

Introduction: Pancreatic cancer is characterised by severe mid-back and epigastric pain caused by tumour invasion of the coeliac nerve plexus. This pain is often poorly managed with standard treatments. This clinical trial investigates a novel approach in which high-dose radiation (radiosurgery) is targeted to the retroperitoneal coeliac plexus nerve bundle. Preliminary results from a single institution pilot trial are promising: pain relief is substantial and side effects minimal. The goals of this study are to validate these findings in an international multisetting, and investigate the impact on quality of life and functional status among patients with terminal cancer. Methods and analysis: A single-arm prospective phase II clinical trial. Eligible patients are required to have severe coeliac pain of at least five on the 11-point BPI average pain scale and Eastern Cooperative Oncology Group performance status of two or better. Non-pancreatic cancers invading the coeliac plexus are also eligible. The intervention involves irradiating the coeliac plexus using a single fraction of 25 Gy. The primary endpoint is the complete or partial pain response at 3 weeks. Secondary endpoints include pain at 6 weeks, analgesic use, hope, qualitative of life, caregiver burden and functional outcomes, all measured using validated instruments. The protocol is expected to open at a number of cancer centres across the globe, and a quality assurance programme is included. The protocol requires that 90 evaluable patients be accrued, based upon the assumption that a third of patients are non-evaluable (e.g. due to death prior to 3-weeks post-treatment assessment, or spontaneous improvement of pain pre-treatment), it is estimated that a total of 120 patients will need to be accrued. Supported by Gateway for Cancer Research and the Israel Cancer Association. Ethics and dissemination: Ethic approval for this study has been obtained at eight academic medical centres located across the Middle East, North America and Europe. Results will be disseminated through conference presentations and peer-reviewed publications. Trial registration number: NCT03323489