Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients

Background: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods: We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta 1, which is upregulated in lung cancer.Results: Nintedanib dose-dependently inhibited the TGF-beta 1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours

On the symmetries of BF models and their relation with gravity

The perturbative finiteness of various topological models (e.g. BF models) has its origin in an extra symmetry of the gauge-fixed action, the so-called vector supersymmetry. Since an invariance of this type also exists for gravity and since gravity is closely related to certain BF models, vector supersymmetry should also be useful for tackling various aspects of quantum gravity. With this motivation and goal in mind, we first extend vector supersymmetry of BF models to generic manifolds by incorporating it into the BRST symmetry within the Batalin-Vilkovisky framework. Thereafter, we address the relationship between gravity and BF models, in particular for three-dimensional space-time.Comment: 29 page

Solitons of Sigma Model on Noncommutative Space as Solitons of Electron System

We study the relationship of soliton solutions for electron system with those of the sigma model on the noncommutative space, working directly in the operator formalism. We find that some soliton solutions of the sigma model are also the solitons of the electron system and are classified by the same topological numbers.Comment: 12 pages, LaTeX2e, improvements to discussions, Version to be published in JHE

New BPS Solitons in 2+1 Dimensional Noncommutative CP^1 Model

Investigating the solitons in the non-commutative $CP^{1}$ model, we have found a new set of BPS solitons which does not have counterparts in the commutative model.Comment: 8 pages, LaTeX2e, references added, improvements to discussions, Version to be published in JHE

Lost equivalence of nonlinear sigma and CP1CP^{1} models on noncommutative space

We show that the equivalence of nonlinear sigma and $CP^{1}$ models which is valid on the commutative space is broken on the noncommutative space. This conclusion is arrived at through investigation of new BPS solitons that do not exist in the commutative limit.Comment: 17 pages, LaTeX2

Topological 2-form Gravity in Four Dimensions

A kind of topological field theory is proposed as a candidate to describe the global structure of the 2-form Einstein gravity with or without a cosmological constant. Indeed in the former case, we show that a quantum state in the candidate gives an exact solution of the Wheeler-DeWitt equation. The BRST quantization based on the Batalin-Fradkin-Vilkovisky (BFV) formalism is carried out for this topological version of the 2-form Einstein gravity.Comment: 15 page

Sum-over-histories origin of the composition laws of relativistic quantum mechanics and quantum cosmology

The scope of the paper has been broadened to include a more complete discussion of the following topics: The derivation of composition laws in quantum cosmology. The connection between the existence of a composition law in the sum over histories approach to relativistic quantum mechanics and quantum cosmology, and the existence of a canonical formulation.Comment: 36 page

3D collagen migration patterns reveal a SMAD3-dependent and TGF-β1-independent mechanism of recruitment for tumour-associated fibroblasts in lung adenocarcinoma

The TGF-β1 transcription factor SMAD3 is epigenetically repressed in tumour-associated fibroblasts (TAFs) from lung squamous cell carcinoma (SCC) but not adenocarcinoma (ADC) patients, which elicits a compensatory increase in SMAD2 that renders SCC-TAFs less fibrotic. Here we examined the effects of altered SMAD2/3 in fibroblast migration and its impact on the desmoplastic stroma formation in lung cancer.We used a microfluidic device to examine descriptors of early protrusions and subsequent migration in 3D collagen gels upon knocking down SMAD2 or SMAD3 by shRNA in control fibroblasts and TAFs.High SMAD3 conditions as in shSMAD2 fibroblasts and ADC-TAFs exhibited a migratory advantage in terms of protrusions (fewer and longer) and migration (faster and more directional) selectively without TGF-β1 along with Erk1/2 hyperactivation. This enhanced migration was abrogated by TGF-β1 as well as low glucose medium and the MEK inhibitor Trametinib. In contrast, high SMAD2 fibroblasts were poorly responsive to TGF-β1, high glucose and Trametinib, exhibiting impaired migration in all conditions.The basal migration advantage of high SMAD3 fibroblasts provides a straightforward mechanism underlying the larger accumulation of TAFs previously reported in ADC compared to SCC. Moreover, our results encourage using MEK inhibitors in ADC-TAFs but not SCC-TAFs.© 2022. The Author(s)

Riemannian Gauge Theory and Charge Quantization

In a traditional gauge theory, the matter fields \phi^a and the gauge fields A^c_\mu are fundamental objects of the theory. The traditional gauge field is similar to the connection coefficient in the Riemannian geometry covariant derivative, and the field-strength tensor is similar to the curvature tensor. In contrast, the connection in Riemannian geometry is derived from the metric or an embedding space. Guided by the physical principal of increasing symmetry among the four forces, we propose a different construction. Instead of defining the transformation properties of a fundamental gauge field, we derive the gauge theory from an embedding of a gauge fiber F=R^n or F=C^n into a trivial, embedding vector bundle F=R^N or F=C^N where N>n. Our new action is symmetric between the gauge theory and the Riemannian geometry. By expressing gauge-covariant fields in terms of the orthonormal gauge basis vectors, we recover a traditional, SO(n) or U(n) gauge theory. In contrast, the new theory has all matter fields on a particular fiber couple with the same coupling constant. Even the matter fields on a C^1 fiber, which have a U(1) symmetry group, couple with the same charge of +/- q. The physical origin of this unique coupling constant is a generalization of the general relativity equivalence principle. Because our action is independent of the choice of basis, its natural invariance group is GL(n,R) or GL(n,C). Last, the new action also requires a small correction to the general-relativity action proportional to the square of the curvature tensor.Comment: Improved the explanations, added references, added 3 figures and an appendix, corrected a sign error in the old figure 4 (now figure 5). Now 33 pages, 7 figures and 2 tables. E-mail Serna for annimation

Identification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx300103jTienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 non-redundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2–4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver (Methogo, R., Dansette, P. and Klarskov, K. (2007) Int. J. Mass Spectrom., 268, 284–295), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e. rat vs. human), and still another may be the method of detection of adducted proteins (i.e. Western blot vs. C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from human and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future