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Background: The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC).
Methods: First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization.
Results: Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p = 0.002, p = 0.003, respectively) and miR-301 (p = 0.002, p = 0.001, respectively) best predicted pathological complete response (pCR).
Conclusion: Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.
In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.
In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).
The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).
Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylation
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Femtoscopic correlations with the particle pair combinations K0 SK0 S and K0 SK± are studied in pp collisions at √s = 5.02 and 13 TeV by the ALICE experiment. At both energies, boson source parameters are extracted for both pair combinations, by fitting models based on Gaussian size distributions of the sources, to the measured two-particle correlation functions. The interaction model used for the K0 SK0 S analysis includes quantum statistics and strong final-state interactions through the f0(980) and a0(980) resonances. The model used for the K0 SK± analysis includes only the final-state interaction through the a0 resonance. Source parameters extracted in the present work are compared with published values from pp collisions at √s = 7 TeV and the different pair combinations are found to be consistent. From the observation that the strength of the K0 SK0 S correlations is significantly greater than the strength of the K0 SK± correlations, the new results are compatible with the a0 resonance being a tetraquark state of the form (q1, q2, s, s), where q1 and q2 are u or d quarks.
First measurements of balance functions (BFs) of all combinations of identified charged hadron (π,K, p) pairs in Pb–Pb collisions at √sNN = 2.76 TeV recorded by the ALICE detector are presented. The BF measurements are carried out as two-dimensional differential correlators versus the relative rapidity (Δy) and azimuthal angle (Δφ) of hadron pairs, and studied as a function of collision centrality. The Δφ dependence of BFs is expected to be sensitive to the light quark diffusivity in the quark–gluon plasma. While the BF azimuthal widths of all pairs substantially decrease from peripheral to central collisions, the longitudinal widths exhibit mixed behaviors: BFs of ππ and cross-species pairs narrow significantly in more central collisions, whereas those of KK and pp are found to be independent of collision centrality. This dichotomy is qualitatively consistent with the presence of strong radial flow effects and the existence of two stages of quark production in relativistic heavy-ion collisions. Finally, the first measurements of the collision centrality evolution of BF integrals are presented, with the observation that charge balancing fractions are nearly independent of collision centrality in Pb–Pb collisions. Overall, the results presented provide new and challenging constraints for theoretical models of hadron production and transport in relativistic heavy-ion collisions.
Annihilation dynamics plays a fundamental role in the baryon–antibaryon interaction (B–B) at lowenergy and its strength and range are crucial in the assessment of possible baryonic bound states. Experimental data on annihilation cross sections are available for the p–p system but not in the low relative momentum region. Data regarding the B–B interaction with strange degrees of freedom are extremely scarce, hence the modeling of the annihilation contributions is mainly based on nucleon–antinucleon (N–N) results, when available. In this letter we present a measurement of the p–p, p–⊕p– and – interaction using correlation functions in the relative momentum space in high-multiplicity triggered pp collisions at √s = 13 TeV recorded by ALICE at the LHC. In the p–p system the couplings to the mesonic channels in different partial waves are extracted by adopting a coupled-channel approach with recent χEFT potentials. The inclusion of these inelastic channels provides good agreement with the data, showing a significant presence of the annihilation term down to zero momentum. Predictions obtained using the Lednický–Lyuboshits formula and scattering parameters obtained from heavy-ion collisions, hence mainly sensitive to elastic processes, are compared with the experimental p–⊕p– and – correlations. The model describes the – data and underestimates the p–⊕p– data in the region of momenta below 200 MeV/c. The observed deviation indicates a different contribution of annihilation channels to the two systems containing strange hadrons.
The first results on K∗(892)± resonance production in inelastic pp collisions at LHC energies of √s = 5.02, 8, and 13 TeV are presented. The K∗(892)± has been reconstructed via its hadronic decay channel K∗(892)± → K0 S + π± with the ALICE detector. Measurements of transverse momentum distributions, pT-integrated yields, and mean transverse momenta for charged K∗(892) are found to be consistent with previous ALICE measurements for neutral K∗(892) within uncertainties. For pT > 1 GeV/c the K∗(892)± transverse momentum spectra become harder with increasing centre-of-mass energy from 5.02 to 13 TeV, similar to what previously observed for charged kaons and pions. For pT < 1 GeV/c the K∗(892)± yield does not evolve significantly and the abundance of K∗(892)± relative to K is rather independent of the collision energy. The transverse momentum spectra, measured for K∗(892)± at midrapidity in the interval 0 < pT < 15 GeV/c, are not well described by predictions of different versions of PYTHIA 6, PYTHIA 8 and EPOS-LHC event generators. These generators reproduce the measured pTintegrated K∗±/K ratios and describe well the momentum dependence for pT < 2 GeV/c.
Neutral pion (π0) and η meson production cross sections were measured up to unprecedentedly high transverse momenta (pT) in p–Pb collisions at √sNN = 8.16 TeV. The mesons were reconstructed via their two-photon decay channel in the rapidity interval −1.3 < y < 0.3 in the ranges of 0.4 < pT < 200 GeV/c and 1.0 < pT < 50 GeV/c, respectively. The respective nuclear modification factor (RpPb) is presented for pT up to of 200 and 30 GeV/c, where the former was achieved by extending the π0 measurement in pp collisions at √s = 8 TeV using the merged cluster technique. The values of RpPb are below unity for pT < 10 GeV/c, while they are consistent with unity for pT > 10 GeV/c, leaving essentially no room for final state energy loss. The new data provide strong constraints for nuclear parton distribution and fragmentation functions over a broad kinematic range and are compared to model predictions as well as previous results at √sNN = 5.02 TeV.
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.