205 research outputs found
Nanoinformatics: developing new computing applications for nanomedicine
Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others
Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma
Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrackÂź), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09-0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06-0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment
Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer
Introduction: We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC xenografts hosted by immunodeficient mice. Methods: To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures. Results: PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells. Conclusions: These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC
The Energy Spectrum of TeV Gamma-Rays from the Crab Nebula as measured by the HEGRA system of imaging air Cherenkov telescopes
The Crab Nebula has been observed by the HEGRA (High-Energy Gamma-Ray
Astronomy) stereoscopic system of imaging air Cherenkov telescopes (IACTs) for
a total of about 200 hrs during two observational campaigns: from September
1997 to March 1998 and from August 1998 to April 1999. The recent detailed
studies of system performance give an energy threshold and an energy resolution
for gamma-rays of 500 GeV and ~ 18%, respectively. The Crab energy spectrum was
measured with the HEGRA IACT system in a very broad energy range up to 20 TeV,
using observations at zenith angles up to 65 degrees. The Crab data can be
fitted in the energy range from 1 to 20 TeV by a simple power-law, which yields
dJg/dE = (2.79+/-0.02 +/- 0.5) 10^{-7} E^{-2.59 +/- 0.03 +/- 0.05}, ph m^{-2}
s^{-1} TeV^{-1} The Crab Nebula energy spectrum, as measured with the HEGRA
IACT system, agrees within 15% in the absolute scale and within 0.1 units in
the power law index with the latest measurements by the Whipple, CANGAROO and
CAT groups, consistent within the statistical and systematic errors quoted by
the experiments. The pure power-law spectrum of TeV gamma-rays from the Crab
Nebula constrains the physics parameters of the nebula environment as well as
the models of photon emission.Comment: to appear in ApJ, 29 pages, 6 figure
Wideband 67-116 GHz cryogenic receiver development for ALMA Band 2
The Atacama Large Millimeter/sub-millimeter Array (ALMA) is already
revolutionising our understanding of the Universe. However, ALMA is not yet
equipped with all of its originally planned receiver bands, which will allow it
to observe over the full range of frequencies from 35-950 GHz accessible
through the Earth's atmosphere. In particular Band 2 (67-90 GHz) has not yet
been approved for construction. Recent technological developments in cryogenic
monolithic microwave integrated circuit (MMIC) high electron mobility
transistor (HEMT) amplifier and orthomode transducer (OMT) design provide an
opportunity to extend the originally planned on-sky bandwidth, combining ALMA
Bands 2 and 3 into one receiver cartridge covering 67-116 GHz.
The IF band definition for the ALMA project took place two decades ago, when
8 GHz of on-sky bandwidth per polarisation channel was an ambitious goal. The
new receiver design we present here allows the opportunity to expand ALMA's
wideband capabilities, anticipating future upgrades across the entire
observatory. Expanding ALMA's instantaneous bandwidth is a high priority, and
provides a number of observational advantages, including lower noise in
continuum observations, the ability to probe larger portions of an astronomical
spectrum for, e.g., widely spaced molecular transitions, and the ability to
scan efficiently in frequency space to perform surveys where the redshift or
chemical complexity of the object is not known a priori. Wider IF bandwidth
also reduces uncertainties in calibration and continuum subtraction that might
otherwise compromise science objectives.
Here we provide an overview of the component development and overall design
for this wideband 67-116 GHz cryogenic receiver cartridge, designed to operate
from the Band 2 receiver cartridge slot in the current ALMA front end receiver
cryostat.Comment: 8 pages, proceedings from the 8th ESA Workshop on Millimetre-Wave
Technology and Applications
(https://atpi.eventsair.com/QuickEventWebsitePortal/millimetre-wave/mm-wave
Correlated intense X-ray and TeV activity of Mrk~501 in 1998 June
We present exactly simultaneous X-ray and TeV monitoring with {\it RXTE} and
HEGRA of the TeV blazar Mrk 501 during 15 days in 1998 June. After an initial
period of very low flux at both wavelengths, the source underwent a remarkable
flare in the TeV and X-ray energy bands, lasting for about six days and with a
larger amplitude at TeV energies than in the X-ray band. At the peak of the TeV
flare, rapid TeV flux variability on sub-hour timescales is found. Large
spectral variations are observed at X-rays, with the 3--20 keV photon index of
a pure power law continuum flattening from to on a
timescale of 2--3 days. This implies that during the maximum of the TeV
activity, the synchrotron peak shifted to energies keV, a behavior
similar to that observed during the longer-lasting, more intense flare in 1997
April. The TeV spectrum during the flare is described by a power law with
photon index and an exponential cutoff at 4 TeV; an
indication for spectral softening during the flare decay is observed in the TeV
hardness ratios. Our results generally support a scenario where the TeV photons
are emitted via inverse Compton scattering of ambient seed photons by the same
electron population responsible for the synchrotron X-rays. The simultaneous
spectral energy distributions (SEDs) can be fit with a one-zone
synchrotron-self Compton model assuming a substantial increase of the magnetic
field and the electron energy by a factor of 3 and 10, respectively.Comment: Accepted for publication in ApJ, Part
Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors
Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0â121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25â0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of â„VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04â115.96; p < 0.0001), one-fourth of patients with â„VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS
Network metaâanalysis of postâexposure prophylaxis randomized clinical trials
Objectives: We performed a network metaâanalysis of PEP randomized clinical trials to evaluate the best regimen. /
Methods: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP threeâdrug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavirâboosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistatâboosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP nonâcompletion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to followâup and adverse events. /
Results: Participants were mostly men who have sex with men (n = 832, 75%) with nonâoccupational exposure to HIV (89.86%). Fourâhundred fiftyâfour (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP nonâcompletion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58â1.56; EVG/c: OR 0.65 95% CI 0.30â1.37; RAL: OR 0.68 95% CI 0.41â1.13; and MVC: OR 0.69 95% CI 0.47â1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP nonâcompletion at day 28, switching, lost to followâup or adverse events and MVC for PEP discontinuations due to adverse events. /
Conclusions: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a SingleâTablet Regimen
Pembrolizumab as consolidation strategy in patients with multiple myeloma: Results of the GEM-Pembresid clinical trial
PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma
patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of
pembrolizumab as consolidation in patients achieving at least very good partial response but with
persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the
immune system were investigated to identify potential biomarkers of response to pembrolizumab.
One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a
potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were
considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted
treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced
a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive
subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly
lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed.
In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity
profile but did not improve responses in this MM patient population. The trial was registered at
clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23
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