Unlike other malignant bone tumors including osteosarcomas and Ewing sarcomas with a peak incidence in adolescents and young adults, conventional and dedifferentiated chondrosarcomas mainly affect ...people in the 4th to 7th decade of life. To date, the cell type of chondrosarcoma origin is not clearly defined. However, it seems that mesenchymal stem and progenitor cells (MSPC) in the bone marrow facing a pro-proliferative as well as predominantly chondrogenic differentiation milieu, as is implicated in early stage osteoarthritis (OA) at that age, are the source of chondrosarcoma genesis. But how can MSPC become malignant? Indeed, only one person in 1,000,000 will develop a chondrosarcoma, whereas the incidence of OA is a thousandfold higher. This means a rare coincidence of factors allowing escape from senescence and apoptosis together with induction of angiogenesis and migration is needed to generate a chondrosarcoma. At early stages, chondrosarcomas are still assumed to be an intermediate type of tumor which rarely metastasizes. Unfortunately, advanced stages show a pronounced resistance both against chemo- and radiation-therapy and frequently metastasize. In this review, we elucidate signaling pathways involved in the genesis and therapeutic resistance of chondrosarcomas with a focus on MSPC compared to signaling in articular cartilage (AC).
Context.
The origin of the
γ
-ray emission of the blazar
Mrk 421
is still a matter of debate.
Aims.
We used 5.5 years of unbiased observing campaign data, obtained using the FACT telescope and the
...Fermi
-LAT detector at TeV and GeV energies, the longest and densest so far, together with contemporaneous multi-wavelength observations, to characterise the variability of
Mrk 421
and to constrain the underlying physical mechanisms.
Methods.
We studied and correlated light curves obtained by ten different instruments and found two significant results.
Results.
The TeV and X-ray light curves are very well correlated with a lag of < 0.6 days. The GeV and radio (15 Ghz band) light curves are widely and strongly correlated. Variations of the GeV light curve lead those in the radio.
Conclusions.
Lepto-hadronic and purely hadronic models in the frame of shock acceleration predict proton acceleration or cooling timescales that are ruled out by the short variability timescales and delays observed in Mrk 421. Instead the observations match the predictions of leptonic models.
Rhabdomyosarcomas (RMS) are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients ...diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO) specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl), which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3β (GSK-3β) serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1) protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS.
ABSTRACT
By studying the variability of blazars across the electromagnetic spectrum, it is possible to resolve the underlying processes responsible for rapid flux increases, so-called flares. We ...report on an extremely bright X-ray flare in the high-peaked BL Lacertae object Markarian 421 (Mrk 421) that occurred simultaneously with enhanced γ-ray activity detected at very high energies by First G-APD Cherenkov Telescope on 2019 June 9. We triggered an observation with XMM–Newton, which observed the source quasi-continuously for 25 h. We find that the source was in the brightest state ever observed using XMM–Newton, reaching a flux of 2.8 × 10−9 $\mathrm{erg\, cm^{-2}\, s^{-1}}$ over an energy range of 0.3–10 keV. We perform a spectral and timing analysis to reveal the mechanisms of particle acceleration and to search for the shortest source-intrinsic time-scales. Mrk 421 exhibits the typical harder-when-brighter behaviour throughout the observation and shows a clock-wise hysteresis pattern, which indicates that the cooling dominates over the acceleration process. While the X-ray emission in different sub-bands is highly correlated, we can exclude large time lags as the computed z-transformed discrete correlation functions are consistent with a zero lag. We find rapid variability on time-scales of 1 ks for the 0.3–10 keV band and down to 300 s in the hard X-ray band (4–10 keV). Taking these time-scales into account, we discuss different models to explain the observed X-ray flare, and find that a plasmoid-dominated magnetic reconnection process is able to describe our observation best.
We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19.
Randomised, double-blind, placebo-controlled, fully remote, phase 2 ...clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory).
Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms.
Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.
Air-Oxidation of Nb Nano-Films Lubenchenko, A. V.; Batrakov, A. A.; Ivanov, D. A. ...
Semiconductors (Woodbury, N.Y.),
05/2018, Letnik:
52, Številka:
5
Journal Article
Recenzirano
X-ray photoelectron spectroscopy (XPS) depth chemical and phase profiling of air-oxidized niobium nanofilms has been performed. It is found that oxide layer thicknesses depend on the initial ...thickness of the niobium nanofilm. The increase in thickness of the initial Nb nano-layer is due to increase in thickness of an oxidized layer.
In this paper an impulse-radio ultra-wideband (IR-UWB) hardware demonstrator is presented, which can be used as a radar sensor for highly precise object tracking and breath-rate sensing. The hardware ...consists of an impulse generator integrated circuit (IC) in the transmitter and a correlator IC with an integrating baseband circuit as correlation receiver. The radiated impulse is close to a fifth Gaussian derivative impulse with σ = 51 ps, efficiently using the Federal Communications Commission indoor mask. A detailed evaluation of the hardware is given. For the tracking, an impulse train is radiated by the transmitter, and the reflections of objects in front of the sensor are collected by the receiver. With the reflected signals, a continuous hardware correlation is computed by a sweeping impulse correlation. The correlation is applied to avoid sampling of the RF impulse with picosecond precision. To localize objects precisely in front of the sensor, three impulse tracking methods are compared: Tracking of the maximum impulse peak, tracking of the impulse slope, and a slope-to-slope tracking of the object's reflection and the signal of the static direct coupling between transmit and receive antenna; the slope-to-slope tracking showing the best performance. The precision of the sensor is shown by a measurement with a metal plate of 1-mm sinusoidal deviation, which is clearly resolved. Further measurements verify the use of the demonstrated principle as a breathing sensor. The breathing signals of male humans and a seven-week-old infant are presented, qualifying the IR-UWB radar principle as a useful tool for breath-rate determination.
Tumour documentation is essential for quality assurance of oncological therapies and as a source of reliable information about the in- and outpatient care. The documentation effort and the associated ...resource consumption were analysed for the example of breast cancer.
The different steps in the care of patients with primary breast cancer in a standardised disease situation were defined from initial diagnosis to the end of the follow-up. After the pilot phase, a multicentre validation (n=7 centres) was performed with the support of the Federal Ministry of Health. The documentation time points were horizontally collected and analysed with regard to amount, duration and personnel expenses.
57% of the documentation costs are caused by the physicians. Regarding the different centres, documentation costs were calculated between € 352.82 and € 1 084.08 per patient from diagnosis to completion of aftercare. Non-certified centres had a reduced documentation effort and thus lower costs.
The results demonstrate the need for a reduction of the documentation effort - particularly for physicians - the most expensive profession in the health system. A quality improvement is expected from the certification with its special requirements. In this context, there is a justified demand for an adequate remuneration of the documentation effort for certified centres. Furthermore, it is necessary to reduce the number of variables for quality assurance and to define them centrally. A comprehensive multi-disciplinary documentation should be achieved. Investments in a single data set and interface enhancements of existing documentation systems should be realised.
Rhabdomyosarcomas (RMS) are soft tissue tumours treated with a combination of surgery and chemotherapy. However, mortality rates remain high in case of recurrences and metastatic disease due to drug ...resistance and failure to undergo apoptosis. Therefore, innovative approaches targeting specific signalling pathways are urgently needed. We analysed the impact of different hedgehog (Hh) pathway inhibitors on growth and survival of six RMS cell lines using MTS assay, colony formation assay, 3D spheroid cultures, flow cytometry and western blotting. Especially the glioma-associated oncogene family (GLI) inhibitor arsenic trioxide (ATO) effectively reduced viability as well as clonal growth and induced cell death in RMS cell lines of embryonal, alveolar and sclerosing, spindle cell subtype, whereas normal skeletal muscle cells were hardly compromised by ATO. Combination of ATO with itraconazole potentiated the reduction of colony formation and spheroid size. These results show that ATO is a promising substance for treatment of relapsed and refractory RMS by directly targeting GLI transcription factors. The combination with itraconazole or other chemotherapeutic drugs has the opportunity to enforce the treatment efficiency of resistant and recurrent RMS.
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