HER2 Status in Premalignant, Early, and Advanced Neoplastic Lesions of the Stomach

Objectives. HER2 expression in gastric cancer (GC) has received attention as a potential target for therapy with Trastuzumab. We reviewed the current knowledge on HER2 status in premalignant gastric lesions and in early (EGC) and advanced (AGC) GC to discuss the possible pathogenetic and prognostic roles of HER2 overexpression in GC. Results. HER2 overexpression was documented in gastric low-grade (LG) and high-grade intraepithelial neoplasia (HG-IEN), with higher frequency in gastric type dysplasia. HER2 overexpression was significantly associated with disease recurrence and poor prognosis in EGC representing an independent risk factor for lymph node metastases. HER2 overexpression was more frequent in AGC characterized by high grade, advanced stage, and high Ki-67 labeling index. The discordance in HER2 status was evidenced between primitive GC and synchronous or metachronous metastases. Conclusions. HER2 overexpression in premalignant gastric lesions suggests its potential involvement in the early steps of gastric carcinogenesis. The assessment of HER2 status in EGC may be helpful for the identification of patients who are at low risk for developing nodal metastases. Finally, the possible discordance in HER2 status between primary GC and its synchronous metastases support routine assessment of HER2 both in the primary GC and in its metastatic lesions

Active Inference, epistemic value, and vicarious trial and error

Balancing habitual and deliberate forms of choice entails a comparison of their respective merits—the former being faster but inflexible, and the latter slower but more versatile. Here, we show that arbitration between these two forms of control can be derived from first principles within an Active Inference scheme. We illustrate our arguments with simulations that reproduce rodent spatial decisions in T-mazes. In this context, deliberation has been associated with vicarious trial and error (VTE) behavior (i.e., the fact that rodents sometimes stop at decision points as if deliberating between choice alternatives), whose neurophysiological correlates are “forward sweeps” of hippocampal place cells in the arms of the maze under consideration. Crucially, forward sweeps arise early in learning and disappear shortly after, marking a transition from deliberative to habitual choice. Our simulations show that this transition emerges as the optimal solution to the trade-off between policies that maximize reward or extrinsic value (habitual policies) and those that also consider the epistemic value of exploratory behavior (deliberative or epistemic policies)—the latter requiring VTE and the retrieval of episodic information via forward sweeps. We thus offer a novel perspective on the optimality principles that engender forward sweeps and VTE, and on their role on deliberate choice

Connexin43 ablation in foetal atrial myocytes decreases electrical coupling, partner connexins, and sodium current

Aims Remodelling and regional gradients in expression of connexins (Cx) are thought to contribute to atrial electrical dysfunction and atrial fibrillation. We assessed the effect of interaction between Cx43, Cx40, and Cx45 on atrial cell-to-cell coupling and inward Na current (INa) in engineered pairs of atrial myocytes derived from wild-type mice (Cx43+/+) and mice with genetic ablation of Cx43 (Cx43−/−). Methods and results Cell pairs were engineered by microcontact printing from atrial Cx43+/+ and Cx43−/− murine myocytes (1 day before birth, 3-5 days in culture). Dual and single voltage clamp were used to measure intercellular electrical conductance, gj, and its dependence on transjunctional voltage, Vj, single gap junction channel conductances, and INa. 3D reconstructions of Cx43, Cx40, and Cx45 immunosignals in gap junctions were made from confocal slices. Full genetic Cx43 ablation produced a decrease in immunosignals of Cx40 to 62 ± 10% (mean ± SE; n= 17) and Cx45 to 66 ± 8% (n= 16). Gj decreased from 80 ± 9 nS (Cx43+/+, n= 17) to 24 ± 2 nS (Cx43−/−, n= 35). Single channel analysis showed a shift in the main peak of the channel histogram from 49 ± 1.7 nS (Cx43+/+) to 67 ± 1.8 nS (Cx43−/−) with a second minor peak appearing at 27 ± 1.5 pS. The dependence of gj on Vj decreased with Cx43 ablation. Importantly, peak INa decreased from −350 ± 44 pA/pF (Cx43+/+) to −154 ± 28 pA/pF (Cx43−/−). Conclusions The dependence of Cx40, Cx45, and INa on Cx43 expression indicates a complex interaction between connexins and INa in the atrial intercalated discs that is likely to be of relevance for arrhythmogenesi

Genomics of Klebsiella pneumoniae ST16 producing NDM-1, CTX-M-15, and OXA-232

OBJECTIVES: Genomic characterization of the internationally spread sequence type (ST) 16 carbapenem-resistant Klebsiella pneumoniae. METHODS: The complete genomes of three carbapenem producing ST16 K. pneumoniae from Italian patients were analysed by single-nucleotide polymorphism-based phylogeny, core genome multilocus sequence typing, resistance, plasmid, and virulence content and compared with ten genomes of ST16 strains isolated in other countries. Plasmids carrying blaNDM-1 or blaOXA-232 carbapenemase genes were assembled and sequences were analysed. RESULTS: The internationally spread ST16 K. pneumoniae clone showed variability in terms of distribution of NDM-1 and OXA-232 type carbapenemases. In some ST16 strains, up to six plasmids can be simultaneously present in the same cell, including ColE-like plasmids carrying blaOXA-232 and IncF plasmids carrying blaNDM-1. The differences observed in plasmid, resistance, and virulence content and core genome suggested that there is not a unique, highly conserved ST16 clone, but instead different variants of this lineage circulate worldwide. CONCLUSIONS: The ST16 K. pneumoniae clone has spread worldwide and may become a high-risk clone

Gastric adenomas: relationship between clinicopathological findings, Helicobacter pylori infection, APC mutations and COX-2 expression.

Gastric adenomas are rare neoplastic growths characterized by localized polypoid proliferations of dysplastic epithelium that tend to progress to infiltrating adenocarcinoma. Therefore, the identification of molecular markers that could reliably recognize adenomas at risk of progression is advocated in the clinical management. In this study we investigated, in a series of gastric adenoma specimens from an area at high risk of gastric cancer, the relationship between clinicopathological characteristics of adenoma and Helicobacter pylori infection, APC mutational status, and COX-2 and the down-stream enzyme mPGES1 expression. Helicobacter pylori infection, detected in 24%, and 33% by histology and PCR analyses, respectively, did not show any relationship with growth pattern, localization, size, dysplasia grade and presence of synchronous cancer. Pathogenetic mutations of MCR region (codons 1269-1589) of the APC gene were detected only in one case corresponding to a single, small size, low grade, H. pylori-negative adenoma. The expression of COX-2 largely matched that of mPGES(1). Both were overexpressed in 79% of cases showing a relationship with high-grade dysplasia, size >10 mm and presence of a synchronous carcinoma. In conclusion, COX-2 may play a key role in the development and progression of gastric adenoma and could be an attractive target in the management of gastric adenoma at major risk of cancer development

On Vanishing Theorems For Vector Bundle Valued p-Forms And Their Applications

Let $F: [0, \infty) \to [0, \infty)$ be a strictly increasing $C^2$ function with $F(0)=0$. We unify the concepts of $F$-harmonic maps, minimal hypersurfaces, maximal spacelike hypersurfaces, and Yang-Mills Fields, and introduce $F$-Yang-Mills fields, $F$-degree, $F$-lower degree, and generalized Yang-Mills-Born-Infeld fields (with the plus sign or with the minus sign) on manifolds. When $F(t)=t, \frac 1p(2t)^{\frac p2}, \sqrt{1+2t} -1,$ and $1-\sqrt{1-2t},$ the $F$-Yang-Mills field becomes an ordinary Yang-Mills field, $p$-Yang-Mills field, a generalized Yang-Mills-Born-Infeld field with the plus sign, and a generalized Yang-Mills-Born-Infeld field with the minus sign on a manifold respectively. We also introduce the $E_{F,g}-$energy functional (resp. $F$-Yang-Mills functional) and derive the first variational formula of the $E_{F,g}-$energy functional (resp. $F$-Yang-Mills functional) with applications. In a more general frame, we use a unified method to study the stress-energy tensors that arise from calculating the rate of change of various functionals when the metric of the domain or base manifold is changed. These stress-energy tensors, linked to $F$-conservation laws yield monotonicity formulae. A "macroscopic" version of these monotonicity inequalities enables us to derive some Liouville type results and vanishing theorems for $p-$forms with values in vector bundles, and to investigate constant Dirichlet boundary value problems for 1-forms. In particular, we obtain Liouville theorems for $F-$harmonic maps (e.g. $p$-harmonic maps), and $F-$Yang-Mills fields (e.g. generalized Yang-Mills-Born-Infeld fields on manifolds). We also obtain generalized Chern type results for constant mean curvature type equations for $p-$forms on $\Bbb{R}^m$ and on manifolds $M$ with the global doubling property by a different approach. The case $p=0$ and $M=\mathbb{R}^m$ is due to Chern.Comment: 1. This is a revised version with several new sections and an appendix that will appear in Communications in Mathematical Physics. 2. A "microscopic" approach to some of these monotonicity formulae leads to celebrated blow-up techniques and regularity theory in geometric measure theory. 3. Our unique solution of the Dirichlet problems generalizes the work of Karcher and Wood on harmonic map