Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations ...into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs.
MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro.
Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E-09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E-06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster.
The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.
Background
Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection.
99m
TcTilmanocept is a novel receptor-targeted ...radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.
Methods
A total of 13 centers contributed 148 patients with breast cancer. Each patient received
99m
Tctilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and
99m
Tctilmanocept.
Results
A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by
99m
Tctilmanocept for a concordance rate of 99.04 % (
p
< 0.0001).
99m
Tctilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD.
99m
TcTilmanocept detected at least 1 SLN in more patients (146) than did VBD (131,
p
< 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate),
99m
Tctilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (
p
= 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to
99m
Tctilmanocept.
Conclusion
99m
TcTilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly,
99m
Tctilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.
This work details the fabrication and performance of a sensor for ammonia gas analysis which has been constructed via the inkjet-printed deposition of polyaniline nanoparticle films. The conducting ...films were assembled on interdigitated electrode arrays and characterised with respect to their layer thickness and thermal properties. The sensor was further combined with heater foils for operation at a range of temperatures. When operated in a conductimetric mode, the sensor was shown to exhibit temperature-dependent analytical performance to ammonia detection. At room temperature, the sensor responded rapidly to ammonia (
t
50
=
15
s). Sensor recovery time, response linearity and sensitivity were all significantly improved by operating the sensor at temperatures up to 80
°C. The sensor was found to have a stable logarithmic response to ammonia in the range of interest (1–100
ppm). The sensor was also insensitive to moisture in the range from 35 to 98% relative humidity. The response of the sensor to a range of common potential interferents was also studied.
The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight ...laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.
This work describes a fully printable polyaniline-copper (II) chloride sensor for the detection of hydrogen sulfide gas. The sensing device is composed of screen printed silver interdigitated ...electrode (IDE) on a flexible PET substrate with inkjet printed layers of polyaniline and copper (II) chloride. The sensor is employed as a chemiresistor with changes in measured current being correlated with concentration. On exposure to hydrogen sulfide, 2.5 ppmv (parts per million by volume) is clearly detectable with a linear relationship between measured current and concentration over the 10-100 ppmv region. The detection mechanism is discussed with respect to the hydrogen sulfide response, the choice of electrode materials in addition to UV-vis and surface enhanced Raman spectroscopy (SERS) characterization.
Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect)
to ...be a notable factor in their evolution
. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum
is typical of bodies in this part of the main belt
. Here we report observations by the Lucy spacecraft
as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event.
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