Fanconi anemia is a recessively inherited disease that is characterized by congenital abnormalities, bone marrow failure, and a predisposition to develop cancer, particularly squamous cell carcinomas ...(SCCs) in the head and neck and anogenital regions. Previous studies of Fanconi anemia SCCs, mainly from US patients, revealed the presence of high-risk human papillomavirus (HPV) DNA in 21 (84%) of 25 tumors analyzed. We examined a panel of 21 SCCs mainly from European Fanconi anemia patients (n = 19 FA patients; 16 head and neck squamous cell carcinomas HNSCCs, 2 esophageal SCCs, and 3 anogenital SCCs) for their clinical and molecular characteristics, including patterns of allelic loss, TP53 mutations, and the presence of HPV DNA by GP5+/6+ polymerase chain reaction. HPV DNA was detected in only two (10%) of 21 tumors (both anogenital SCCs) but in none of the 16 HNSCCs. Of the 18 tumors analyzed, 10 contained a TP53 mutation. The patterns of allelic loss were comparable to those generally found in sporadic SCCs. Our data show that HPV does not play a major role in squamous cell carcinogenesis in this cohort of Fanconi anemia patients and that the Fanconi anemia SCCs are genetically similar to sporadic SCCs despite having a different etiology.
We analyze two multi-chord stellar occultations by Pluto that were observed on 2012 July 18th and 2013 May 4th, and respectively monitored from five and six sites. They provide a total of fifteen ...light curves, 12 of which were used for a simultaneous fit that uses a unique temperature profile, assuming a clear (no haze) and pure N2 atmosphere, but allowing for a possible pressure variation between the two dates. We find a solution that satisfactorily fits (i.e., within the noise level) all of the 12 light curves, providing atmospheric constraints between ~1190 km (pressure ~11 mu bar) and ~1450 km (pressure -0.1 mu bar) from Pluto's center. Alternative explanations like zonal winds or vertical compositional variations of the atmosphere are unable to explain the observed mesospheric negative thermal gradient.
Patients with Fanconi anemia (FA) are prone to develop malignancies at an early age. Besides hematologic malignancies, squamous cell carcinomas in the anogenital region and head and neck are also ...frequently found in these patients. The aim of this study was to generate a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts of FA HNSCC, and to characterize these cell lines in comparison with a panel of seven cell lines from patients with sporadic HNSCC. Analyses have been done on sensitivity to DNA cross-linking agents, loss of heterozygosity profile, TP53 mutations, TP53 polymorphisms and the presence of human papillomavirus. Four FA HNSCC cell lines were established. Sensitivity to DNA cross-linking agents (cisplatin) in the FA HNSCC cell lines was on average 10 times higher as compared with the sporadic HNSCC cell lines. Human papillomavirus was not detected in any of the FA or sporadic cell lines. No differences were found in loss of heterozygosity pattern, TP53 mutation frequency and TP53 polymorphism between FA and sporadic HNSCC cell lines. This is the first report on the generation of squamous cell lines of FA patients. The FA HNSCC cell lines we have generated may be utilized for future studies and might aid in the development of new preventive therapies for FA patients. The genetic characteristics of these cell lines suggest that FA HNSCC are not very different from sporadic HNSCC, except for the sensitivity to cisplatin which is consistent with the known cellular FA phenotype.
A high-granularity timing detector for the ATLAS phase-II upgrade Casado, M.P.; Adam Bourdarios, C.; Belfkir, M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
2022, Letnik:
1032
Journal Article
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The large increase of pileup interactions is one of the main experimental challenges for the HL-LHC physics programme. A powerful new way to mitigate the effects of pileup is to use high-precision ...timing information to distinguish between collisions occurring close in space but well-separated in time. A High-Granularity Timing Detector, based on low gain avalanche detector technology, is therefore proposed for the ATLAS Phase-II upgrade. Covering the pseudorapidity region between 2.4 and 4.0, this device will improve the detector physics performance in the forward region. The typical number of hits per track in the detector was optimized so that the target average time resolution per track for a minimum-ionising particle is 30 ps at the start of lifetime, increasing to 50 ps at the end of HL-LHC operation. The high-precision timing information improves the pileup reduction to improve the forward object reconstruction, complementing the capabilities of the upgraded Inner Tracker (ITk) in the forward regions of ATLAS and leading to an improved performance for both jet and lepton reconstruction. These improvements in object reconstruction performance translate into sensitivity gains and enhance the reach of the ATLAS physics programme at the HL-LHC. In addition, the HGTD offers unique capabilities for the online and offline luminosity determination, an important requirement for precision physics measurements.
ABSTRACT We analyze two multi-chord stellar occultations by Pluto that were observed on 2012 July 18th and 2013 May 4th, and respectively monitored from five and six sites. They provide a total of ...fifteen light curves, 12 of which were used for a simultaneous fit that uses a unique temperature profile, assuming a clear (no haze) and pure N2 atmosphere, but allowing for a possible pressure variation between the two dates. We find a solution that satisfactorily fits (i.e., within the noise level) all of the 12 light curves, providing atmospheric constraints between ∼1190 km (pressure ∼11 bar) and ∼1450 km (pressure ∼0.1 bar) from Pluto's center. Our main results are: (1) the best-fitting temperature profile shows a stratosphere with a strong positive gradient between 1190 km (at 36 K, 11 bar) and r = 1215 km (6.0 bar), where a temperature maximum of 110 K is reached; above it is a mesosphere with a negative thermal gradient of −0.2 K km−1 up to ∼1390 km (0.25 bar), where the mesosphere connects itself to a more isothermal upper branch around 81 K; (2) the pressure shows a small (6%) but significant increase (6 level) between the two dates; (3) without a troposphere, Pluto's radius is found to be 5 km. Allowing for a troposphere, RP is constrained to lie between 1168 and 1195 km; and (4) the currently measured CO abundance is too small to explain the mesospheric negative thermal gradient. Cooling by HCN is possible, but only if this species is largely saturated. Alternative explanations like zonal winds or vertical compositional variations of the atmosphere are unable to explain the observed mesospheric negative thermal gradient.
Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been ...shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ ...hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.
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