Divergent roles of lysyl oxidase family members in ornithine decarboxylase-and RAS-transformed mouse fibroblasts and human melanoma cells

We have previously shown that proto-oncoprotein c-Jun is activated in ornithine decarboxylase (ODC)- and RAS-transformed mouse fibroblasts, and that the transformed morphology of these cells can be reversed by expressing the transactivation domain deletion mutant of c-Jun (TAM67). Here, we found that lysyl oxidase (Lox), encoding an extracellular matrix-modifying enzyme, is downregulated in a c-Jun-dependent manner in ODC-transformed fibroblasts (Odc cells). In addition to Lox, the Lox family members Lox-like 1 and 3 (Loxl1 and Loxl3) were found to be downregulated in Odc as well as in RAS-transformed fibroblasts (E4), whereas Lox-like 4 (Loxl4) was upregulated in Odc and downregulated in E4 cells compared to normal N1 fibroblasts. Tetracycline-regulatable LOX re-expression in Odc cells led to inhibition of cell growth and invasion in three-dimensional Matrigel in an activity-independent manner. On the contrary, LOX and especially LOXL2, LOXL3, and LOXL4 were found to be upregulated in several human melanoma cell lines, and LOX inhibitor B-aminopropionitrile inhibited the invasive growth of these cells particularly when co-cultured with fibroblasts in Matrigel. Knocking down the expression of LOX and especially LOXL2 in melanoma cells almost completely abrogated the invasive growth capability. Further, LOXL2 was significantly upregulated in clinical human primary melanomas compared to benign nevi, and high expression of LOXL2 in primary melanomas was associated with formation of metastases and shorter survival of patients. Thus, our studies reveal that inactive pro-LOX (together with Lox propeptide) functions as a tumor suppressor in ODC- and RAS-transformed murine fibroblasts by inhibiting cell growth and invasion, and active LOX and LOXL2 as tumor promoters in human melanoma cells by promoting their invasive growth. Copyright: Kielosto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Peer reviewe

Novel Data Acquisition System for Silicon Tracking Detectors

We have developed a novel data acquisition system for measuring tracking parameters of a silicon detector in a particle beam. The system is based on a commercial Analog-to-Digital VME module and a PC Linux based Data Acquisition System. This DAQ is realized with C++ code using object-oriented techniques. Track parameters for the beam particles were reconstructed using off-line analysis code and automatic detector position alignment algorithm. The new DAQ was used to test novel Czochralski type silicon detectors. The important silicon detector parameters, including signal size distributions and signal to noise distributions, were successfully extracted from the detector under study. The efficiency of the detector was measured to be 95 %, the resolution about 10 micrometers, and the signal to noise ratio about 10.Comment: Talk from the 2003 Computing in High Energy and Nuclear Physics (CHEP03), La Jolla, Ca, USA, March 2003, 6 pages, LaTeX, 5 eps figures. PSN TUGP00

Magnetic dipole probes of the sd and pf shell crossing in the A=36,38 argon isotopes

We have calculated the M1 strength distributions in the A=36,38 argon isotopes within large-scale shell model studies which consider valence nucleons in the sd and pf shells. While the M1 strength in 36Ar is well reproduced within the sd shell, the experimentally observed strong fragmentation of the M1 strength in 38Ar requires configuration mixing between the sd and the pf shells adding to our understanding of correlations across the N=20 shell gap.Comment: 14 pages, 8 figure

Spectroscopy of 34,35Si^{34,35}Si by β\beta decay: sd-fp shell gap and single-particle states

The $^{34,35}Al\beta$ decays were studied at the CERN on-line mass separator ISOLDE by $\beta-\gamma, \beta-\gamma-\gamma$ and $\beta-n-\gamma$ measurements, in order to corroborate thelow-level description of $^{34}Si$ and to obtain the first information on the level structure of the N=21 isotope $^{35}Si$. Earlier observed $\gamma$ lines in $^{34} Al$ decay were confirmed and new gamma transitions following both beta decay and $\beta$-delayed neutron emission were established. The first level scheme in $^{35}Si$, including three excited states at 910, 974 and 2168 keV, is consistent with $J^{\pi} =3/2^{-}$ and $3/2^{+}$ for the first two states respectively. Beta-decay half-life of $T_{1/2} = 38.6 (4)$ ms and beta-delayed neutron branching $P_{n}$ value $(P_{n} =41(13)$ were measured unambiguously. The significance of the single-particle energy determination at N=21, Z=14, for assessing the effective interaction in sd-fp shell-model calculations, is discussed and illustrated by predictions for different n-rich isotopes

[Formula Presented] decay of neutron-rich [Formula Presented] and [Formula Presented] isotopes

[Formula Presented] decays of on-line mass-separated neutron-rich [Formula Presented] and [Formula Presented] isotopes have been studied by using [Formula Presented] and [Formula Presented] coincidence spectroscopy. Extended decay schemes to the [Formula Presented] daughter nuclei have been constructed. The three-phonon quintuplet in [Formula Presented] is completed by including a new level at 2023.0 keV, which is tentatively assigned the spin and parity of [Formula Presented] The intruder band in [Formula Presented] is proposed up to the [Formula Presented] level at 2322.4 keV. The measured [Formula Presented]-decay half-life for the high-spin isomer of [Formula Presented] is [Formula Presented] Candidates for the three-phonon states, as well as the lowest members of the intruder band in [Formula Presented] are also presented. These data support the coexistence of quadrupole anharmonic vibration and proton particle-hole intruder excitations in [Formula Presented].</p

A New Acoustic Portal into the Odontocete Ear and Vibrational Analysis of the Tympanoperiotic Complex

Global concern over the possible deleterious effects of noise on marine organisms was catalyzed when toothed whales stranded and died in the presence of high intensity sound. The lack of knowledge about mechanisms of hearing in toothed whales prompted our group to study the anatomy and build a finite element model to simulate sound reception in odontocetes. The primary auditory pathway in toothed whales is an evolutionary novelty, compensating for the impedance mismatch experienced by whale ancestors as they moved from hearing in air to hearing in water. The mechanism by which high-frequency vibrations pass from the low density fats of the lower jaw into the dense bones of the auditory apparatus is a key to understanding odontocete hearing. Here we identify a new acoustic portal into the ear complex, the tympanoperiotic complex (TPC) and a plausible mechanism by which sound is transduced into the bony components. We reveal the intact anatomic geometry using CT scanning, and test functional preconceptions using finite element modeling and vibrational analysis. We show that the mandibular fat bodies bifurcate posteriorly, attaching to the TPC in two distinct locations. The smaller branch is an inconspicuous, previously undescribed channel, a cone-shaped fat body that fits into a thin-walled bony funnel just anterior to the sigmoid process of the TPC. The TPC also contains regions of thin translucent bone that define zones of differential flexibility, enabling the TPC to bend in response to sound pressure, thus providing a mechanism for vibrations to pass through the ossicular chain. The techniques used to discover the new acoustic portal in toothed whales, provide a means to decipher auditory filtering, beam formation, impedance matching, and transduction. These tools can also be used to address concerns about the potential deleterious effects of high-intensity sound in a broad spectrum of marine organisms, from whales to fish

Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

Gene fusions can act as oncogenic drivers and offer targets for cancer therapy. Since fusions are rare in colorectal cancer (CRC), their universal screening seems impractical. Our aim was to investigate gene fusions in 62 CRC cases with deficient MLH1 (dMLH1) and BRAFV600E wild-type (wt) status from a consecutive real-life series of 2079 CRCs. First, gene fusions were analysed using a novel FusionPlex Lung v2 RNA-based next-generation sequencing (NGS) panel, and these results were compared to a novel Idylla GeneFusion assay and pan-TRK immunohistochemistry (IHC). NGS detected seven (7/62, 11%) NTRK1 fusions (TPM3::NTRK1, PLEKHA6::NTRK1 and LMNA::NTRK1, each in two cases, and IRF2BP2::NTRK1 in one case). In addition, two ALK, four RET and seven BRAF fusions were identified. Idylla detected seven NTRK1 expression imbalances, in line with the NGS results (overall agreement 100%). Furthermore, Idylla detected the two NGS-identified ALK rearrangements as one specific ALK fusion and one ALK expression imbalance, whilst only two of the four RET fusions were discovered. However, Idylla detected several expression imbalances of ALK (n = 7) and RET (n = 1) that were found to be fusion negative with the NGS. Pan-TRK IHC showed clearly detectable, fusion partner-dependent staining patterns in the seven NTRK1 fusion cases. Overall agreement for pan-TRK antibody clone EPR17341 was 98% and for A7H6R 100% when compared to the NGS. Of the 62 CRCs, 43 were MLH1 promoter hypermethylated (MLH1ph) and 39 were RASwt. All fusion cases were both MLH1ph and RASwt. Our results show that kinase fusions (20/30, 67%) and most importantly targetable NTRK1 fusions (7/30, 23%) are frequent in CRCs with dMLH1/BRAFV600Ewt/MLH1ph/RASwt. NGS was the most comprehensive method in finding the fusions, of which a subset can be screened by Idylla or IHC, provided that the result is confirmed by NGS

Weight gain in infancy and markers of cardiometabolic health in young adulthood

Aim We studied whether repeatedly measured weight gain from birth up to age 2 years associated with cardiometabolic health in young adulthood. Methods Using the data collected in the longitudinal Special Turku Coronary Risk Factor Intervention Project, we investigated in 454 healthy subjects how early weight gain in six age intervals (birth to 7 months, 7-13 months, 13-18 months, 18-24 months, and birth to 13 and 24 months) associated with measures of cardiometabolic health at age 20 years. Linear regression analyses were controlled for (1) child's sex, intervention/control group, gestational age, baseline weight and change in length for each interval, and (2) parents' education, mother's weight before pregnancy, height and weight gain during pregnancy, and father's body mass index at the 7-month visit. Results Weight gain after the first year of life associated directly, when adjusted for traits of the child and parents, with systolic blood pressure, waist circumference and body mass index at age 20 years. In the fully adjusted analyses, weight gain from birth to 1 year and to 2 years of age associated inversely with insulin and insulin resistance. We found no association between early growth and diastolic blood pressure or serum lipids. Conclusion Early weight gain during first 2 years of life may predict later markers of cardiometabolic health

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer