Canonical WNT/β-catenin signaling is involved in most of the mechanisms that lead to the formation and development of cancer cells. It plays a central role in three cyclic processes, which are the ...cell division cycle, the immune cycle, and circadian rhythms. When the canonical WNT pathway is upregulated as in cancers, the increase in β-catenin in the nucleus leads to activation of the expression of numerous genes, in particular CYCLIN D1 and cMYC, where the former influences the G1 phase of the cell division cycle, and the latter, the S phase. Every stage of the immune cycle is disrupted by the canonical WNT signaling. In numerous cancers, the dysfunction of the canonical WNT pathway is accompanied by alterations of the circadian genes (CLOCK, BMAL1, PER). Induction of these cyclic phenomena leads to the genesis of thermodynamic mechanisms that operate far from equilibrium, and that have been called "dissipative structures." Moreover, upregulation of the canonical WNT/β-catenin signaling is important in the myofibroblasts of the cancer stroma. Their differentiation is controlled by the canonical WNT /TGF-β1 signaling. Myofibroblasts present ultraslow contractile properties due to the presence of the non-muscle myosin IIA. Myofibroblats also play a role in the inflammatory processes, often found in cancers and fibrosis processes. Finally, upregulated canonical WNT deviates mitochondrial oxidative phosphorylation toward the Warburg glycolysis metabolism, which is characteristic of cancers. Among all these cancer-generating mechanisms, the upregulated canonical WNT pathway would appear to offer the best hope as a therapeutic target, particularly in the field of immunotherapy.
Thermodynamic consequences of a three-hour long anoxia were investigated on the isolated mammalian rat myocardium. The anoxic heart operated in a far-from-equilibrium manner as attested by the ...non-linearity between the thermodynamic force and the thermodynamic flow. When subjected to slight fluctuations due to anoxia, the open far-from-equilibrium cardiac system presented a thermodynamic bifurcation at ~ 60 minutes of anoxia. The bifurcation was characterized by a sudden change of direction in the bifurcation diagram of a one-dimensional nonlinear differential equation with one parameter and occurred at a non-hyperbolic fixed point at which moment the heart lost its thermodynamic stability. The parameter of the differential equation was the single force of the myosin molecular motor. These results helped to reflect a self-organized process and the occurrence of a dissipative structure. This offers valuable insights into our understanding of myocardial protection and could be of considerable interest, especially for heart transplants where the recipient must benefit from the donor's heart in the shortest possible time.
Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their ...respective impact on long-term survival in resected non-small cell lung cancers (NSCLC).
Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p<0.05). In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34 0.16-0.73, p = 0.0056), CD8+ cell count in tumor tissue (RR = 0.37 0.16-0.83, p = 0.0162), and disease stage (RR 1.73 1.03-2.89; 2.991.07-8.37, p = 0.0374- stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% 60.9-91.1 as compared to 18% 7.9-35.6 in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced.
Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome.
Purpose of Review
Blood pressure (BP) follows a circadian rhythm (CR) in normotensive subjects. BP increases in the morning and decreases at night. This review aims at providing an up-to-date ...overview regarding the molecular mechanisms underlying the circadian regulation of BP.
Recent Findings
The suprachiasmatic nucleus (SCN) is the regulatory center for CRs. In SCN astrocytes, the phosphorylated glycogen synthase kinase-3β (pGSK-3β) also follows a CR and its expression reaches a maximum in the morning and decreases at night. pGSK-3β induces the β-catenin migration to the nucleus. During the daytime, the nuclear β-catenin increases the expression of the glutamate excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). In SCN, EAAT2 removes glutamate from the synaptic cleft of glutamatergic neurons and transfers it to the astrocyte cytoplasm where GS converts glutamate into glutamine. Thus, glutamate decreases in the synaptic cleft. This decreases the stimulation of the glutamate receptors AMPA-R and NMDA-R located on glutamatergic post-synaptic neurons. Consequently, activation of NTS is decreased and BP increases. The opposite occurs at night.
Summary
Despite several studies resulting from animal studies, the circadian regulation of BP appears largely controlled in normotensive subjects by the canonical WNT/β-catenin pathway involving the SCN, astrocytes, and glutamatergic neurons.
Currently, the clinical impact of cell therapy after a myocardial infarction (MI) is limited by low cell engraftment due to low cell retention, cell death in inflammatory and poor angiogenic ...infarcted areas, secondary migration. Cells interact with their microenvironment through integrin mechanoreceptors that control their survival/apoptosis/differentiation/migration and proliferation. The association of cells with a three-dimensional material may be a way to improve interactions with their integrins, and thus outcomes, especially if preparations are epicardially applied. In this review, we will focus on the rationale for using collagen as a polymer backbone for tissue engineering of a contractile tissue. Contractilities are reported for natural but not synthetic polymers and for naturals only for: collagen/gelatin/decellularized-tissue/fibrin/Matrigel™ and for different material states: hydrogels/gels/solids. To achieve a thick/long-term contractile tissue and for cell transfer, solid porous compliant scaffolds are superior to hydrogels or gels. Classical methods to produce solid scaffolds: electrospinning/freeze-drying/3D-printing/solvent-casting and methods to reinforce and/or maintain scaffold properties by reticulations are reported. We also highlight the possibility of improving integrin interaction between cells and their associated collagen by its functionalizing with the RGD-peptide. Using a contractile patch that can be applied epicardially may be a way of improving ventricular remodeling and limiting secondary cell migration.
Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy, the extracellular matrix is deeply altered; ...therefore, it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated the feasibility and safety of intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles.
In 20 consecutive patients presenting with left ventricular postischemic myocardial scars and indication for coronary artery bypass graft surgery, bone marrow cells were implanted during surgery. In the last 10 patients, we added a collagen matrix seeded with bone marrow cells, placed onto the scar.
There was no mortality and any related adverse events (follow-up 10 +/- 3.5 months). New York Heart Association functional class improved in both groups from 2.3 +/- 0.5 to 1.3 +/- 0.5 (matrix, p = 0.0002) versus 2.4 +/- 0.5 to 1.5 +/- 0.5 (no matrix, p = 0.001). Left ventricular end-diastolic volume evolved from 142.4 +/- 24.5 mL to 112.9 +/- 27.3 mL (matrix, p = 0.02) versus 138.9 +/- 36.1 mL to 148.7 +/- 41 mL (no matrix, p = 0.57), left ventricular filling deceleration time improved significantly in the matrix group from 162 +/- 7 ms to 198 +/- 9 ms (p = 0.01) versus the no-matrix group (from 159 +/- 5 ms to 167 +/- 8 ms, p = 0.07). Scar area thickness progressed from 6 +/- 1.4 to 9 mm +/- 1.1 mm (matrix, p = 0.005) versus 5 +/- 1.5 mm to 6 +/- 0.8 mm (no matrix, p = 0.09). Ejection fraction improved in both groups, from 25.3% +/- 7.3% to 32% +/- 5.4% (matrix, p = 0.03) versus 27.2% +/- 6.9% to 34.6% +/- 7.3% (no matrix, p = 0.031).
This tissue-engineered approach is feasible and safe and appears to improve the efficiency of cellular cardiomyoplasty. The cell-seeded collagen matrix increases the thickness of the infarct scar with viable tissue and helps to normalize cardiac wall stress in injured regions, thus limiting ventricular remodeling and improving diastolic function.
Contraction of the heart is caused by actin filaments sliding along myosin filaments. This generates a frictional force inducing wear of the contractile apparatus. We postulated that this process ...could be exacerbated when the heart was submitted to severe anoxia. Anoxia induced dramatic abnormalities in the molecular properties of actin-myosin crossbridges. We applied the formalism of far-from-equilibrium thermodynamics to the left ventricular papillary muscles (LVPMs) of mammalian rat hearts which had been subjected to a prolonged anoxia (3 h). We showed that when subjected to prolonged anoxia, the heart operated far-from-equilibrium as evidenced by the non-linearity between thermodynamic force (F/T: Frictional force/Kelvin temperature) and thermodynamic flow (v0: myofilament sliding velocity). The rate of entropy production (EPR) was the product of (F/T) and v0. The excess entropy production (EEP) was equal to ∂δ2S∂t = ∂FTδvo; (S: entropy). The tribological system remained stable when EEP was positive and became unstable when EEP became negative, thus characterizing instability of the system and reflecting the occurrence of self-organization and possibly dissipative structures. After 3 h anoxia, re-oxygenation induced significant reversibility. About 20% of the myosin heads did not recover despite re-oxygenation. These results may be of importance in the context of heart transplantation where the delay between the time of sampling from the donor and the time of the graft installation in the recipient should be as short as possible.
Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung ...resection for NSCLC.
A retrospective analysis of a prospectively collected database was made on 304 consecutive patients.
Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 5% and 44.4% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m
(
< 0.000001). Overall survival was positively affected by pre-disease (
= 0.036) and pre-surgery (
0.017) BMI > 25 kg/m
, and, even more, in case of BMI > 25 kg/m
and increasing weight (
= 0.012). Long-term outcome was negatively influenced by low muscle mass (
= 0.042) and weight loss (
0.0052) as well as age (
0.017), ASA categories (
0.025), extent of resection (
0.0001), pleural invasion (
0.0012) and higher pathologic stage (
< 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.660.49-0.89,
0.006) and pre-surgery BMI (RR 0.720.54-0.98,
0.034), and the absence of low muscle mass (RR 0.560.37-0.87,
0.0091).
Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered.
Myofibroblasts are contractile cells found in multiple tissues. They are physiological cells as in the human placenta and can be obtained from bone marrow mesenchymal stem cells after differentiation ...by transforming growth factor-β (TGF-β). They are also found in the stroma of cancerous tissues and can be located in non-muscle contractile tissues. When stimulated by an electric current or after exposure to KCl, these tissues contract. They relax either by lowering the intracellular Ca2+ concentration (by means of isosorbide dinitrate or sildenafil) or by inhibiting actin-myosin interactions (by means of 2,3-butanedione monoxime or blebbistatin). Their shortening velocity and their developed tension are dramatically low compared to those of muscles. Like sarcomeric and smooth muscles, they obey Frank-Starling’s law and exhibit the Hill hyperbolic tension-velocity relationship. The molecular motor of the myofibroblast is the non-muscle myosin type IIA (NMIIA). Its essential characteristic is the extreme slowness of its molecular kinetics. In contrast, NMIIA develops a unitary force similar to that of muscle myosins. From a thermodynamic point of view, non-muscle contractile tissues containing NMIIA operate extremely close to equilibrium in a linear stationary mode.
Mesenchymal stem cells (MSCs) were obtained from human bone marrow and amplified in cultures supplemented with human platelet lysate in order to generate myofibroblasts. When MSCs were seeded in ...solid collagen scaffolds, they differentiated into myofibroblasts that were observed to strongly bind to the substrate, forming a 3D cell scaffold network that developed tension and shortening after KCl stimulation. Moreover, MSC-laden scaffolds recapitulated the Frank-Starling mechanism so that active tension increased in response to increases in the initial length of the contractile system. This constituted a bioengineering tissue that exhibited the contractile properties observed in both striated and smooth muscles. By using the A. F. Huxley formalism, we determined the myosin crossbridge (CB) kinetics of attachment (f1) and detachment (g1 and g2), maximum myosin ATPase activity, molar myosin concentration, unitary CB force and maximum CB efficiency. CB kinetics were dramatically slow, characterizing the non-muscle myosin type IIA (NMMIIA) present in myofibroblasts. When MSCs were seeded in solid collagen scaffolds functionalized with Arg-Gly-Asp (RGD), contractility increased and CB kinetics were modified, whereas the unitary NMMIIA-CB force and maximum CB efficiency did not change. In conclusion, we provided a non-muscle bioengineering tissue whose molecular mechanical characteristics of NMMIIA were very close to those of a non-muscle contractile tissue such as the human placenta.
PDF
