Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

Ultracold atomic gases in optical lattices: mimicking condensed matter physics and beyond

We review recent developments in the physics of ultracold atomic and molecular gases in optical lattices. Such systems are nearly perfect realisations of various kinds of Hubbard models, and as such may very well serve to mimic condensed matter phenomena. We show how these systems may be employed as quantum simulators to answer some challenging open questions of condensed matter, and even high energy physics. After a short presentation of the models and the methods of treatment of such systems, we discuss in detail, which challenges of condensed matter physics can be addressed with (i) disordered ultracold lattice gases, (ii) frustrated ultracold gases, (iii) spinor lattice gases, (iv) lattice gases in "artificial" magnetic fields, and, last but not least, (v) quantum information processing in lattice gases. For completeness, also some recent progress related to the above topics with trapped cold gases will be discussed.Comment: Review article. v2: published version, 135 pages, 34 figure

Telomerase activity and telomere length in primary and metastatic tumors from pediatric bone cancer patients

The presence of telomerase activity has been analyzed in almost all tumor types and tumor-derived cell lines. However, there are very few studies that focus on the presence of telomerase activity in bone tumors, and most of them report analysis on very few samples or bone-derived cell lines. The objective of this study was to analyze the telomere length and telomerase activity in primary tumors and metastatic lesions from pediatric osteosarcoma and Ewing's sarcoma patients. The presence of telomerase activity was analyzed by the telomeric repeat amplification protocol assay, and the telomere length was measured by Southern blot. Results were related to survival and clinical outcome. Telomerase activity was detected in 85% of the bone tumor metastases (100% Ewing's sarcomas and 75% osteosarcomas) but only in 12% of the primary tumors (11.1% osteosarcomas and 12.5% Ewing's sarcomas). Bone tumor tissues with telomerase activity had mean telomere lengths 3 kb shorter than those with no detectable telomerase activity (p = 0.041). The presence of telomerase activity was associated with survival (p = 0.009), and longer event-free survival periods were found in patients who lacked telomerase activity compared with those who had detectable telomerase activity levels in their tumor tissues (p = 0.037). The presence of longer telomeres in primary pediatric bone tumors than in metastases could be indicative of alternative mechanisms of lengthening of telomeres for their telomere maintenance rather than telomerase activity. Nevertheless, the activation of telomerase seems to be a crucial step in the malignant progression and acquisition of invasive capability of bone tumors

Fundamental limits of repeaterless quantum communications

Quantum communications promises reliable transmission of quantum information, efficient distribution of entanglement and generation of completely secure keys. For all these tasks, we need to determine the optimal point-to-point rates that are achievable by two remote parties at the ends of a quantum channel, without restrictions on their local operations and classical communication, which can be unlimited and two-way. These two-way assisted capacities represent the ultimate rates that are reachable without quantum repeaters. Here, by constructing an upper bound based on the relative entropy of entanglement and devising a dimension-independent technique dubbed ‘teleportation stretching’, we establish these capacities for many fundamental channels, namely bosonic lossy channels, quantum-limited amplifiers, dephasing and erasure channels in arbitrary dimension. In particular, we exactly determine the fundamental rate-loss tradeoff affecting any protocol of quantum key distribution. Our findings set the limits of point-to-point quantum communications and provide precise and general benchmarks for quantum repeaters

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Long-term disability in neuromyelitis optica spectrum disorder with a history of myelitis is associated with age at onset, delay in diagnosis/preventive treatment, MRI lesion length and presence of symptomatic brain lesions

BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS) that preferentially targets the spinal cord and optic nerves. Increasing disability is accrued with each inflammatory attack. Disability has been shown to be an independent predictor of poor quality of life in those with NMOSD. Factors associated with increasing disability need further systematic investigation. METHODS:We performed a multi-center retrospective chart analysis of aquaporin-4 (AQP4) seropositive NMOSD patients with a history of myelitis seen at five large referral centers for patients with NMOSD worldwide for whom thorough records including relapse history and corresponding imaging were available. Potential contributors to long-term disability were extracted including demographics, radiographic findings, and clinical characteristics. Multivariable regression modeling was conducted to determine correlates of disability in patients with NMOSD, as measured by the Expanded Disability Status Scale (EDSS). RESULTS:One hundred eighty-two AQP4 seropositive patients (88% female) were included in this analysis. Multiple regression modeling revealed that older age at disease onset, delay in diagnosis/preventive treatment, length of longest acute myelitis lesion and presence of symptomatic brain/brainstem lesions were associated with increased disability when holding other variables constant. CONCLUSION:While age at onset is a factor that cannot be controlled in NMOSD, we can reduce the delay in diagnosis/preventive treatment and reduce future relapses in the brain/brainstem and spinal cord. Delay in diagnosis/preventive treatment and imaging variables that contributed to increased disability support the need for improved measures for early, accurate diagnosis and management of NMOSD, and aggressive treatment of acute relapses

Eurythmy therapy in chronic disease: a four-year prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Many patients with chronic diseases use complementary therapies, often provided by their physicians. In Germany, several physician-provided complementary therapies have been reimbursed by health insurance companies as part of health benefit programs. In most of these therapies, the patient has a predominantly passive role. In eurythmy therapy, however, patients actively exercise specific movements with the hands, the feet or the whole body. The purpose of this study was to describe clinical outcomes in patients practising eurythmy therapy exercises for chronic diseases.</p> <p>Methods</p> <p>In conjunction with a health benefit program, 419 outpatients from 94 medical practices in Germany, referred to 118 eurythmy therapists, participated in a prospective cohort study. Main outcomes were disease severity (Disease and Symptom Scores, physicians' and patients' assessment on numerical rating scales 0–10) and quality of life (adults: SF-36, children aged 8–16: KINDL, children 1–7: KITA). Disease Score was documented after 0, 6 and 12 months, other outcomes after 0, 3, 6, 12, 18, 24, and (SF-36 and Symptom Score) 48 months.</p> <p>Results</p> <p>Most common indications were mental disorders (31.7% of patients; primarily depression, fatigue, and childhood emotional disorder) and musculoskeletal diseases (23.4%). Median disease duration at baseline was 3.0 years (interquartile range 1.0–8.5). Median number of eurythmy therapy sessions was 12 (interquartile range 10–19), median therapy duration was 119 days (84–188).</p> <p>All outcomes improved significantly between baseline and all subsequent follow-ups (exceptions: KITA Psychosoma in first three months and KINDL). Improvements from baseline to 12 months were: Disease Score from mean (standard deviation) 6.65 (1.81) to 3.19 (2.27) (p < 0.001), Symptom Score from 5.95 (1.75) to 3.49 (2.12) (p < 0.001), SF-36 Physical Component Summary from 43.13 (10.25) to 47.10 (9.78) (p < 0.001), SF-36 Mental Component Summary from 38.31 (11.67) to 45.01 (11.76) (p < 0.001), KITA Psychosoma from 69.53 (15.45) to 77.21 (13.60) (p = 0.001), and KITA Daily Life from 59.23 (21.78) to 68.14 (18.52) (p = 0.001). All these improvements were maintained until the last follow-up. Improvements were similar in patients not using diagnosis-related adjunctive therapies within the first six study months.</p> <p>Adverse reactions to eurythmy therapy occurred in 3.1% (13/419) of patients. No patient stopped eurythmy therapy due to adverse reactions.</p> <p>Conclusion</p> <p>Patients practising eurythmy therapy exercises had long-term improvement of chronic disease symptoms and quality of life. Although the pre-post design of the present study does not allow for conclusions about comparative effectiveness, study findings suggest that eurythmy therapy can be useful for patients motivated for this therapy.</p

Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the ankle region. A descriptive interventional study

BACKGROUND: The ankle region is frequently involved in juvenile idiopathic arthritis (JIA) but difficult to examine clinically due to its anatomical complexity. The aim of the study was to evaluate the role of ultrasonography (US) of the ankle and midfoot (ankle region) in JIA. Doppler-US detected synovial hypertrophy, effusion and hyperemia and US was used for guidance of steroid injection and to assess treatment efficacy. METHODS: Forty swollen ankles regions were studied in 30 patients (median age 6.5 years, range 1-16 years) with JIA. All patients were assessed clinically, by US (synovial hypertrophy, effusion) and by color Doppler (synovial hyperemia) before and 4 weeks after US-guided steroid injection. RESULTS: US detected 121 compartments with active disease (joints, tendon sheaths and 1 ganglion cyst). Multiple compartments were involved in 80% of the ankle regions. The talo-crural joint, posterior subtalar joint, midfoot joints and tendon sheaths were affected in 78%, 65%, 30% and 55% respectively. Fifty active tendon sheaths were detected, and multiple tendons were involved in 12 of the ankles. US-guidance allowed accurate placement of the corticosteroid in all 85 injected compartments, with a low rate of subcutaneous atrophy (4,7%). Normalization or regression of synovial hypertrophy was obtained in 89%, and normalization of synovial hyperemia in 89%. Clinical resolution of active arthritis was noted in 72% of the ankles. CONCLUSIONS: US enabled exact anatomical location of synovial inflammation in the ankle region of JIA patients. The talo-crural joint was not always involved. Disease was frequently found in compartments difficult to evaluate clinically. US enabled exact guidance of steroid injections, gave a low rate of subcutaneous atrophy and was proved valuable for follow-up examinations. Normalization or regression of synovial hypertrophy and hyperemia was achieved in most cases, which supports the notion that US is an important tool in the management of ankle involvement in JIA

Genetic variation exists for telomeric array organization within and among the genomes of normal, immortalized, and transformed chicken systems

This study investigated telomeric array organization of diverse chicken genotypes utilizing in vivo and in vitro cells having phenotypes with different proliferation potencies. Our experimental objective was to characterize the extent and nature of array variation present to explore the hypothesis that mega-telomeres are a universal and fixed feature of chicken genotypes. Four different genotypes were studied including normal (UCD 001, USDA-ADOL Line 0), immortalized (DF-1), and transformed (DT40) cells. Both cytogenetic and molecular approaches were utilized to develop an integrated view of telomeric array organization. It was determined that significant variation exists within and among chicken genotypes for chromosome-specific telomeric array organization and total genomic-telomeric sequence content. Although there was variation for mega-telomere number and distribution, two mega-telomere loci were in common among chicken genetic lines (GGA 9 and GGA W). The DF-1 cell line was discovered to maintain a complex derivative karyotype involving chromosome fusions in the homozygous and heterozygous condition. Also, the DF-1 cell line was found to contain the greatest amount of telomeric sequence per genome (17%) as compared to UCD 001 (5%) and DT40 (1.2%). The chicken is an excellent model for studying unique and universal features of vertebrate telomere biology, and characterization of the telomere length variation among genotypes will be useful in the exploration of mechanisms controlling telomere length maintenance in different cell types having unique phenotypes