The ATLAS Inner Detector consists of three sub-systems, the Pixel Detector at the innermost radius, the Semi-Conductor Tracker at intermediate radii, and the Transition Radiation Tracker (TRT) at the ...outermost radius in front of the electromagnetic calorimeter. The TRT provides a combination of continuous tracking with many projective measurements based on individual drift-tubes (or straws) and of electron identification based on radiator fibres or foils interleaved between the straws themselves. This paper describes the current status of design and construction of the various components of the TRT: the assembly of the barrel modules has recently been completed, that of the end-cap wheels is well underway, and the on-detector front-end electronics is in production. The detector modules and front-end electronics boards will be integrated together over the next year, the barrel and end-cap TRT parts will be assembled and tested with their SCT counterparts during 2005 and installation and commissioning in the ATLAS pit will take place at the end of 2005 and the beginning of 2006.
Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, ...persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo, its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications.
The Transition Radiation Tracker (TRT) sits at the outermost part of the ATLAS Inner Detector, encasing the Pixel Detector and the Semi-Conductor Tracker (SCT). The TRT combines charged particle ...track reconstruction with electron identification capability. This is achieved by layers of xenon-filled straw tubes with periodic radiator foils or fibers providing TR photon emission. The design and choice of materials have been optimized to cope with the harsh operating conditions at the LHC, which are expected to lead to an accumulated radiation dose of 10 Mrad and a neutron fluence of up to 2middot10 14 n/cm 2 after ten years of operation. The TRT comprises a barrel containing 52 000 axial straws and two end-cap parts with 320 000 radial straws. The total of 420 000 electronic channels (two channels per barrel straw) allows continuous tracking with many projective measurements (more than 30 straw hits per track). The assembly of the barrel modules in the US has recently been completed, while the end-cap wheel construction in Russia has reached the 50% mark. After testing at the production sites and shipment to CERN, all modules and wheels undergo a series of quality and conformity measurements. These acceptance tests survey dimensions, wire tension, gas-tightness, high-voltage stability and gas-gain uniformity along each individual straw. This paper gives details on the acceptance criteria and measurement methods. An overview of the most important results obtained to-date is also given
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk ...stratification are lacking.
To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions.
Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in
-related genes (
,
, and
) and identified novel SVs facilitating immune evasion (
and
). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg,
,
, and
) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact.
mutations (31%) showed the strongest association with worse PFS (hazard ratio HR, 2.52 95% CI, 1.50 to 4.21;
< .001) and overall survival (HR, 2.33 95% CI, 1.14 to 4.76;
= .02). IPI high-risk patients with mutated
demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the
mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast,
-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 95% CI, 0.07 to 0.55;
= .002) and prolonged OS (HR, 0.11 95% CI, 0.01 to 0.78;
= .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively.
This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification.
and
mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.
Although classical Hodgkin lymphoma (cHL) is usually curable, 20-30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem ...cell transplantation (autoSCT). However, 45-55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90-95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident.
TRPV4 channels are calcium channels, activated by mechanical stress, that have been implicated in the pathogenesis of pulmonary inflammation. During resistive breathing (RB), increased mechanical ...stress is imposed on the lung, inducing lung injury. The role of TRPV4 channels in RB-induced lung injury is unknown.
Spontaneously breathing adult male C57BL/6 mice were subjected to RB by tracheal banding. Following anaesthesia, mice were placed under a surgical microscope, the surface area of the trachea was measured and a nylon band was sutured around the trachea to reduce area to half. The specific TRPV4 inhibitor, HC-067047 (10 mg/kg ip), was administered either prior to RB and at 12 hrs following initiation of RB (preventive) or only at 12 hrs after the initiation of RB (therapeutic protocol). Lung injury was assessed at 24 hrs of RB, by measuring lung mechanics, total protein, BAL total and differential cell count, KC and IL-6 levels in BAL fluid, surfactant Protein (Sp)D in plasma and a lung injury score by histology.
RB decreased static compliance (Cst), increased total protein in BAL (p < 0.001), total cell count due to increased number of both macrophages and neutrophils, increased KC and IL-6 in BAL (p < 0.001 and p = 0.01, respectively) and plasma SpD (p < 0.0001). Increased lung injury score was detected. Both preventive and therapeutic HC-067047 administration restored Cst and inhibited the increase in total protein, KC and IL-6 levels in BAL fluid, compared to RB. Preventive TRPV4 inhibition ameliorated the increase in BAL cellularity, while therapeutic TRPV4 inhibition exerted a partial effect. TRPV4 inhibition blunted the increase in plasma SpD (p < 0.001) after RB and the increase in lung injury score was also inhibited.
TRPV4 inhibition exerts protective effects against RB-induced lung injury.
The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (rr-cHL) has improved considerably in recent years owing to the approval of highly active novel agents such as brentuximab ...vedotin and Programmed Death-1 (PD-1) inhibitors. Although no randomized trials have been conducted to provide formal proof, it is almost undisputable that the survival of these patients has been prolonged. As autologous stem-cell transplantation (SCT) remains the standard of care for second-line therapy of most patients with rr-cHL, optimization of second-line regimens with the use of brentuximab vedotin, or, in the future, checkpoint inhibitors, is promising to increase both the eligibility rate for transplant and the final outcome. The need for subsequent therapy, and especially allogeneic SCT, can be reduced with brentuximab vedotin consolidation for 1 year, while pembrolizumab is also being tested in this setting. Several other drug categories appear to be active in rr-cHL, but their development has been delayed by the appearance of brentuximab vedotin, nivolumab and pembrolizumab, which have dominated the field of rr-cHL treatment in the last 5 years. Combinations of active drugs in chemo-free approaches may further increase efficacy and hopefully reduce toxicity in rr-cHL, but are still under development.
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