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Inhibitors of the mammalian target of rapamycin (mTOR) have improved the treatment of renal cell carcinoma (RCC). However, chronic drug exposure may trigger resistance, limiting the utility of these agents. The metastatic behavior of RCC cells, susceptible (RCC(par)) or resistant (RCC(res)) to the mTOR inhibitor temsirolimus, was investigated. Adhesion to vascular endothelium or immobilized collagen and fibronectin was quantified. Chemotactic motility was evaluated with a modified Boyden chamber assay. Integrin α and β subtype receptors were analyzed by flow cytometry and Western blot analysis. The physiological relevance of the integrins was then determined by blocking studies and small interfering RNA knockdown. Adhesion to endothelial cells and to fibronectin (not to collagen) and chemotaxis were enhanced in RCC(res) compared to RCC(par). RCC(res) detached from fibronectin and motile activity further increased under retreatment with low-dosed temsirolimus. α5 integrin was diminished inside the cell and at the cell surface, whereas the β3 subtype was reduced intracellularly but elevated at the plasma membrane. In RCC(par), blocking α5 surface receptors enhanced RCC-collagen but reduced RCC-fibronectin interaction, whereas the opposite was true for RCC(res). Chemotaxis of RCC(par) but not of RCC(res) was strongly diminished by the α5 antibody. Blocking β3 significantly lowered chemotaxis with stronger effects on RCC(res), compared to RCC(par). Importantly, β3 knockdown reduced chemotaxis of RCC(par) but upregulated the motile behavior of RCC(res). Temsirolimus resistance is characterized by quantitative alterations of integrin α5 and β3 expression, coupled to functional changes of the integrin molecules, and forces a switch from RCC adhesion to RCC migration.
Human serum albumin (HSA) nanoparticles represent a promising tool for targeted drug delivery to tumor cells. The coupling of the antibody trastuzumab to nanoparticles uses the capability of human epidermal growth factor receptor 2 (HER2)-positive cells to incorporate agents linked to HER2. In our present study, we developed targeted nanoparticles loaded with antisense oligonucleotides (ASOs) against polo-like kinase 1 (Plk1). We evaluated the receptor-mediated uptake into HER2-positive and -negative breast cancer and murine cell lines. We performed quantitative real-time PCR and Western blot analyses to monitor the impact on Plk1 expression in HER2-positive breast cancer cells. Antibody-conjugated nanoparticles showed a specific targeting to HER2-overexpressing cells with cellular uptake by receptor-mediated endocytosis and a release into HER2-positive BT-474 cells. We observed a significant reduction of Plk1 mRNA and protein expression and increased activation of Caspase 3/7. Thus, this is the first report about ASO-loaded HSA nanoparticles, where an impact on gene expression could be observed. The data provide the basis for the further development of carrier systems for Plk1-specific ASOs to reduce off-target effects evoked by systemically administered ASOs and to achieve a better penetration into primary and metastatic target cells. Treatment of tumors using trastuzumab-conjugated ASO-loaded HSA nanoparticles could be a promising approach to reach this goal.
Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease.
Objective: To develop a reliable and valid scoring tool, the Pediatric Bowel Management Scoring Tool (PBMST), to better guide management of constipation in pediatric patients.
Study design: The project comprised 2 stages, development of the questionnaire and construction of the bowel management score. Two questionnaires were created, one for children aged 8-18 years to self-report and one parent proxy-report for children aged 4-8 years. Questions regarding physical symptoms (n = 6), emotional aspects (n = 2), social activities/school (n = 1), and treatment (n = 1) were included. Patients (or parents of patients) with symptoms of constipation completed the questionnaire. The reproducibility of each question was computed using the Cohen weighted kappa coefficient (κ). A bowel management score was developed using logistic regression analysis, assessing the associations between the questions and impact on self-reported quality of life (QoL). Questions with adequate reproducibility and significantly associated with QoL were incorporated into the score.
Results: The questionnaire was completed by 385 patients. Six questions met the inclusion criteria and were incorporated into the score: stool shape (range, 0-3 points), anorectal pain (0-4 points), abdominal pain (0-3 points), frequency of fecal incontinence (0-3 points), assistance of caregivers (0-3 points), and interference with social activities (0-6 points). Differences in bowel management scores among patients reporting no, little, some, or major impact on QoL were statistically significant (P < .001).
Conclusions: The newly developed and validated PBMST is a reliable tool for evaluating bowel management strategies in children with constipation.
Highlights
• Cryo-EM structure of a yeast F1Fo-ATP synthase dimer
• Inhibitor-free X-ray structure of the F1 head and rotor complex
• Mechanism of ATP generation by rotary catalysis
• Structural basis of cristae formation in the inner mitochondrial membrane
Summary
We determined the structure of a complete, dimeric F1Fo-ATP synthase from yeast Yarrowia lipolytica mitochondria by a combination of cryo-EM and X-ray crystallography. The final structure resolves 58 of the 60 dimer subunits. Horizontal helices of subunit a in Fo wrap around the c-ring rotor, and a total of six vertical helices assigned to subunits a, b, f, i, and 8 span the membrane. Subunit 8 (A6L in human) is an evolutionary derivative of the bacterial b subunit. On the lumenal membrane surface, subunit f establishes direct contact between the two monomers. Comparison with a cryo-EM map of the F1Fo monomer identifies subunits e and g at the lateral dimer interface. They do not form dimer contacts but enable dimer formation by inducing.
Determining the sound speed cs in compact stars is an important open question with numerous implications on the behavior of matter at large densities and hence on gravitational-wave emission from neutron stars. To this scope, we construct more than 107 equations of state (EOSs) with continuous sound speed and build more than 108 nonrotating stellar models consistent not only with nuclear theory and perturbative QCD, but also with astronomical observations. In this way, we find that EOSs with subconformal sound speeds, i.e., with cs 1 3 2 < within the stars, are possible in principle but very unlikely in practice, being only 0.03% of our sample. Hence, it is natural to expect that cs 1 3 2 > somewhere in the stellar interior. Using our large sample, we obtain estimates at 95% credibility of neutron-star radii for representative stars with 1.4 and 2.0 solar masses, R1.4 12.42 km 0.99 0.52 = - + , R2.0 12.12 km 1.23 1.11 = - + , and for the binary tidal deformability of the GW170817 event, 1.186 485 211 225 L = - ˜ + . Interestingly, our lower bounds on the radii are in very good agreement with the prediction derived from very different arguments, namely, the threshold mass. Finally, we provide simple analytic expressions to determine the minimum and maximum values of L˜ as a function of the chirp mass.
Using more than a million randomly generated equations of state that satisfy theoretical and observational constraints, we construct a novel, scale-independent description of the sound speed in neutron stars, where the latter is expressed in a unit cube spanning the normalized radius, r/R, and the mass normalized to the maximum one, M/MTOV. From this generic representation, a number of interesting and surprising results can be deduced. In particular, we find that light (heavy) stars have stiff (soft) cores and soft (stiff) outer layers, or that the maximum of the sound speed is located at the center of light stars but moves to the outer layers for stars with M/MTOV ≳ 0.7, reaching a constant value of cs = 1 2 2 as M → MTOV. We also show that the sound speed decreases below the conformal limit cs = 1 3 2 at the center of stars with M = MTOV. Finally, we construct an analytic expression that accurately describes the radial dependence of the sound speed as a function of the neutron-star mass, thus providing an estimate of the maximum sound speed expected in a neutron star.
We have investigated the systematic differences introduced when performing a Bayesian-inference analysis of the equation of state (EOS) of neutron stars employing either variable- or constant-likelihood functions. The former has the advantage of retaining the full information on the distributions of the measurements, making exhaustive usage of the data. The latter, on the other hand, has the advantage of a much simpler implementation and reduced computational costs. In both approaches, the EOSs have identical priors and have been built using the sound speed parameterization method so as to satisfy the constraints from X-ray and gravitational waves observations, as well as those from chiral effective theory and perturbative quantum chromodynamics. In all cases, the two approaches lead to very similar results and the 90% confidence levels essentially overlap. Some differences do appear, but in regions where the probability density is extremely small and are mostly due to the sharp cutoff on the binary tidal deformability L˜ 720 set in the constant-likelihood approach. Our analysis has also produced two additional results. First, an inverse correlation between the normalized central number density, nc,TOV/ns, and the radius of a maximally massive star, RTOV. Second, and most importantly, it has confirmed the relation between the chirp mass and the binary tidal deformability. The importance of this result is that it relates chirp, which is measured very accurately, and L˜ , which contains important information on the EOS. Hence, when chirp is measured in future detections, our relation can be used to set tight constraints on L˜ .
A considerable effort has been dedicated recently to the construction of generic equations of state (EOSs) for matter in neutron stars. The advantage of these approaches is that they can provide model-independent information on the interior structure and global properties of neutron stars. Making use of more than 106 generic EOSs, we assess the validity of quasi-universal relations of neutron-star properties for a broad range of rotation rates, from slow rotation up to the mass-shedding limit. In this way, we are able to determine with unprecedented accuracy the quasi-universal maximum-mass ratio between rotating and nonrotating stars and reveal the existence of a new relation for the surface oblateness, i.e., the ratio between the polar and equatorial proper radii. We discuss the impact that our findings have on the imminent detection of new binary neutron-star mergers and how they can be used to set new and more stringent limits on the maximum mass of nonrotating neutron stars, as well as to improve the modeling of the X-ray emission from the surface of rotating stars.
The amplification of magnetic fields plays an important role in explaining numerous astrophysical phenomena associated with binary neutron star mergers, such as mass ejection and the powering of short gamma-ray bursts. Magnetic fields in isolated neutron stars are often assumed to be confined to a small region near the stellar surface, while they are normally taken to fill the whole star in numerical modeling of mergers. By performing high-resolution, global, and high-order general-relativistic magnetohydrodynamic simulations, we investigate the impact of a purely crustal magnetic field and contrast it with the standard configuration consisting of a dipolar magnetic field with the same magnetic energy but filling the whole star. While the crust configurations are very effective in generating strong magnetic fields during the Kelvin–Helmholtz-instability stage, they fail to achieve the same level of magnetic-field amplification of the full-star configurations. This is due to the lack of magnetized material in the neutron-star interiors to be used for further turbulent amplification and to the surface losses of highly magnetized matter in the crust configurations. Hence, the final magnetic energies in the two configurations differ by more than 1 order of magnitude. We briefly discuss the impact of these results on astrophysical observables and how they can be employed to deduce the magnetic topology in merging binaries.