[Plan of the day adaptive radiotherapy for bladder cancer: Dosimetric and clinical results]. / Résultats dosimétriques et cliniques d'une stratégie de radiothérapie adaptativede type "bibliothèque de plans" des cancers de la vessie localisés.

PURPOSE: To account of individual intra-pelvic anatomical variations in muscle invasive bladder cancer (MIBC) irradiation, adaptive radiotherapy (ART) using a personalized plan library may have dosimetric and clinical benefits. MATERIAL AND METHODS: The data from ten patients treated for localized MIBC according to the "plan of the day" (P0oD) individualized ART technique were collected and retrospectively analysed. Target volumes and organs at risk (OAR) were delineated at different bladder fill rates, resulting in two or three treatment plans. Daily Cone-Beam CT (CBCT) was used for the selection of PoD at each fraction. Retrospectively, we delineated rectal, intestinal and target volumes on each CBCT, to assess target volume coverage and dose sparing to healthy tissues. A comparison with the conventional radiotherapy technique was performed. The secondary objectives were toxicity and efficacy. RESULTS: The target coverage was respected with the adaptive treatment: 97.3% for the bladder Clinical Target Volume (CTV) (99.5; [60.1-100]) and 98% for the bladder+lymph nodes CTV (98.6; [85.4-100]). Concerning OAR, the volume of healthy tissue spared was 43.7% on average and the V45Gy for the small bowel was 43,4cc (35; [0-129]) (versus 57,6cc). The rectal D50 was on average 18,7Gy for the adaptive treatment (15.9; [2.4-44.1]) versus 17Gy with the conventional approach. With a median follow-up of 2.94 years (95% CI: [0.92-4.02]), we observed three grade 3 toxicities (30%). No grade 4 toxicity was observed. The 2-year overall survival and progression-free survival rates were 65.6% (95% CI: [26-87.6]) and 45.7% (95% CI: [14.3-73]), respectively. CONCLUSION: The ART technique using a PoD strategy showed a reduction of the irradiated healthy tissue volume while maintaining a similar bladder coverage, with an acceptable rate of toxicity.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Impact of bedside diagnosis of influenza in the paediatric emergency ward.

OBJECTIVES: This prospective study performed in the paediatric emergency department of the University Hospital of Saint-Etienne aimed to measure the impact of the 24/7 bedside use of the Veritor™ System (Becton Dickinson) on the reduction of supplementary investigations, hospital stay and antimicrobial use. METHODS: Influenza virus A and B antigens were detected with a rapid influenza digital immunoassay (DIA) on nasopharyngeal aspirates (NPAs) sampled from the children consulting at the paediatric emergency department between January and March 2016 for influenza-like illness. The same NPA was tested by immunofluorescence and/or molecular routine assays. Before performing the DIA, the clinician filled in a questionnaire listing the tests that he/she would have prescribed in the absence of the rapid testing. The prescription of complementary investigations, antimicrobial treatments and hospital stay were also compared to those of the 3 previous years. RESULTS: A total of 514 children with flu-like symptoms were included. The use of the DIA at bedside decreased the prescription of blood puncture by 47.9% (21.2% to 6.6%), of chest X-rays by 69.0% (33.3% to 10.3%), of lumbar puncture by 77.8% (7.0% to 1.6%), of urine culture by 79.2% (23.3% to 4.9%), of antibiotic treatments by 70.1% (16.9% to 5.1%), and of hospital stay by 25.0% (27.2% to 20.4%), resulting in a reduction of medical costs estimated to more than €69 000 in a season. CONCLUSIONS: In addition to delivering a rapid aetiological diagnosis, this strategy saves medical costs and favours an antimicrobial stewardship strategy. However, further prospective studies are needed to confirm our findings.

[Between "pragmatic" interpretation and "disturbing" understanding: Embryonic cryopreservation for IVF patients]. / Entre lecture pragmatique et vision anxiogène : vécu de la cryoconservation embryonnaire par les patients en parcours de FIV.

OBJECTIVES: The aim of this article is to question the feeling of IVF patients towards embryonic cryopreservation, in order to understand their potential reluctance to freeze embryos and their difficulties to consider the fate of their frozen embryos once their parental project completed. METHODS: Twenty-seven semi-directive interviews with homologous IVF patients were conducted. These persons were followed in two fertility centres in Marseille. RESULTS: If all the patients interviewed have accepted embryonic cryopreservation or have accepted on principle, a majority have an ambivalent attitude towards this technique. If some share the "pragmatic" vision of professionals (embryologists, technicians and gynaecologists), they are numerous to worry about a possible deterioration of embryonic quality, or again about a disrupted order of generation. Finally, it appears that patients do not anticipate the possible fate of their frozen embryos if they are uninscribed from their parental project. CONCLUSIONS: Patients are mainly ambivalent towards embryonic cryopreservation. They prioritize different rationality depending on the situations and issues they are dealing with.

Improved survival using specialized multidisciplinary board in sarcoma patients.

BACKGROUND: Sarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of a multidisciplinary tumor board (MDTB) presentation before treatment in a nationwide study over 5 years. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients in France. Patients' characteristics and follow-up are collected in a database regularly monitored and updated. The management and survival of patients presented to these MDTB before versus after initial treatment were analyzed. RESULTS: Out of the 12 528 patients aged ≥15 years, with a first diagnosis of soft tissue and visceral sarcoma obtained between 1 January 2010 and 31 December 2014, 5281 (42.2%) and 7247 (57.8%) were presented to the MDTB before and after the initiation of treatment, respectively. The former group had generally worse prognostic characteristics. Presentation to a MDTB before treatment was associated with a better compliance to clinical practice guidelines, for example, biopsy before surgery, imaging, quality of initial surgery, and less reoperations (all P < 0.001). Local relapse-free survival and relapse-free survival were significantly better in patients presented to a MDTB before initiation of treatment, both in univariate and multivariate analysis. CONCLUSION: The compliance to clinical practice guidelines and relapse-free survival of sarcoma patients are significantly better when the initial treatment is guided by a pre-therapeutic specialized MDTB.

[The complex phenotype of ARC syndrome: A new case]. / Le phénotype complexe du syndrome ARC : une nouvelle observation.

ARC syndrome (arthrogryposis - renal dysfunction - cholestasis) is a rare lethal multisystemic autosomal recessive disease. A newborn of consanguineous parents of Algerian descent presented cholestatic jaundice, dehydration, and Fanconi syndrome at 10 days of life. The blood smear showed a very characteristic gray appearance of platelets. A homozygous mutation was evidenced in the VPS33B gene. This gene codes for a protein involved in trafficking of intracellular vesicles. The mutation (c.604-2A>G) present in the heterozygous state in the parents affects an invariant base of the splice acceptor site and to our knowledge has not been reported yet. This child died at the age of 3 months. Prenatal diagnosis was offered to the family; another pregnancy was carried to completion and a girl was born without the disease. The combination of cholestasis and proximal tubulopathy should suggest the diagnosis in a newborn with orthopedic problems. A blood smear greatly facilitates diagnosis.

Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease.

BACKGROUND AND PURPOSE: We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor-2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of ovalbumin (OVA)-induced chronic AAD in 6­8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL(−1)), TFF2 (0.5 mg·mL(−1)), DEX (0.5 mg·mL(−1)), RLX + TFF2 or RLX + TFF2 + DEX from days 67­74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA). KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50­90%) and also normalized the reduction of cDyn. CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti-inflammatory corticosteroids

Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.

[Adenosine deaminase 1 deficiency, an inborn error of metabolism underlying a severe form of combined immunodeficiency]. / Déficit complet en adénosine-désaminase-1 : une erreur innée du métabolisme responsable d'un déficit immunitaire combiné sévère.

Severe combined immune deficiencies (SCIDs) are a heterogeneous group of severe cellular immunodeficiencies. Early diagnosis is essential to allow adapted care before life-threatening systemic infections or complications associated with live vaccines. Adenosine deaminase 1 deficiency (ADA1) is an inborn error of metabolism leading to severe lymphopenia and characteristic bone lesions. Herein, we present the typical case of a child in whom ADA SCID was diagnosed at 2 months of life, revealed by lung involvement and extreme lymphopenia. Immune restoration in terms of peripheral lymphocyte count with enzyme replacement therapy, namely pegylated bovine ADA, is satisfactory so far. The search for a compatible donor is underway. Correcting the genetic defect by gene transfer is also being considered. The phenotype of this very rare condition is described. A severe peripheral lymphopenia in a young child is a finding of utmost importance for the diagnosis of a primary cellular immunodeficiency.

Shb deficiency in endothelium but not in leucocytes is responsible for impaired vascular performance during hindlimb ischaemia.

AIM: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischaemia. This study was conducted in order to assess the contribution of Shb deficiency in myeloid cells to impaired vascular function in ischaemia. METHODS: Wild type and Shb-deficient mice were subjected to peritoneal vascular endothelial growth factor A (VEGFA) followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leucocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. RESULTS: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not lipopolysaccharide (LPS) in the absence of Shb. Furthermore, the macrophage population in ischaemic muscle was unaffected by Shb deficiency after 2 days but reduced 7 days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leucocyte genotype. CONCLUSION: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.

Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer.

Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement.

Understanding the deafened brain: implications for cochlear implant rehabilitation.

The cochlear implant (CI), by enabling oral communication in severely to profoundly deaf subjects, is one of the major medical advances over the last fifty years. Despite the globally very satisfactory results, individual outcomes vary considerably. The objective of this review is to describe the various factors influencing the results of CI rehabilitation with particular emphasis on the better understanding of neurocognitive mechanisms provided by functional brain imaging. The following aspects will be discussed: 1. Peripheral predictors such as the degree of preservation of nerve structures and the positioning of the electrode array. 2. The duration of auditory deprivation whose influence on brain reorganization is now becoming more clearly understood. 3. The age of initiation of hearing rehabilitation in subjects with pre-lingual deafness influencing the possibility of physiological maturation of nerve structures. 4. The concepts of sensitive period, decoupling and cross-modality. 5. In post-lingually deaf adults, brain plasticity can allow adaptation to the disability induced by deafness, subsequently potentiating CI rehabilitation, particularly as a result of audiovisual interactions. 6. Several studies provide concordant evidence that implanted patients present different phonological analysis and primary linguistic capacities. The results of CI rehabilitation are dependent on factors situated between the cochlea and cortical associative areas. The importance of higher cognitive influences on the functional results of cochlear implantation justify adaptation of coding strategies, as well as global cognitive management of deaf patients by utilising brain plasticity capacities.

Evolution of non-speech sound memory in postlingual deafness: implications for cochlear implant rehabilitation.

Neurofunctional patterns assessed before or after cochlear implantation (CI) are informative markers of implantation outcome. Because phonological memory reorganization in post-lingual deafness is predictive of the outcome, we investigated, using a cross-sectional approach, whether memory of non-speech sounds (NSS) produced by animals or objects (i.e. non-human sounds) is also reorganized, and how this relates to speech perception after CI. We used an fMRI auditory imagery task in which sounds were evoked by pictures of noisy items for post-lingual deaf candidates for CI and for normal-hearing subjects. When deaf subjects imagined sounds, the left inferior frontal gyrus, the right posterior temporal gyrus and the right amygdala were less activated compared to controls. Activity levels in these regions decreased with duration of auditory deprivation, indicating declining NSS representations. Whole brain correlations with duration of auditory deprivation and with speech scores after CI showed an activity decline in dorsal, fronto-parietal, cortical regions, and an activity increase in ventral cortical regions, the right anterior temporal pole and the hippocampal gyrus. Both dorsal and ventral reorganizations predicted poor speech perception outcome after CI. These results suggest that post-CI speech perception relies, at least partially, on the integrity of a neural system used for processing NSS that is based on audio-visual and articulatory mapping processes. When this neural system is reorganized, post-lingual deaf subjects resort to inefficient semantic- and memory-based strategies. These results complement those of other studies on speech processing, suggesting that both speech and NSS representations need to be maintained during deafness to ensure the success of CI.

Phonological processing in post-lingual deafness and cochlear implant outcome.

Cochlear implants work well, yet the outcome is not fully accounted by the data routinely available to the clinician, and remains unpredictable. A more in-depth understanding of the neural mechanisms that determine the clinical recovery after cochlear implantation is warranted, as they may provide the background for an accurate individual prognosis. In this study in post-lingually deaf adults, we show that while clinical data offer only prognosis trends, fMRI data can prospectively distinguish good from poor implant performers. We show that those deaf cochlear implant (CI) candidates who will become good performers rely on a dorsal phonological route when performing a rhyming task on written regular words. In contrast, those who will become poor performers involve a ventral temporo-frontal route to perform the same task, and abnormally recruit the right supramarginal gyrus, a region that is contralateral to classical phonological regions. These functional patterns reveal that deafness either enhances "normal" phonological processing, or prompts a substitution of phonological processing by lexico-semantic processing. These findings thus suggest that a simple behavioral pre-operative exploration of phonological strategies during reading, to determine which route is predominantly used by CI candidates, might fruitfully inform the outcome.

Isolation, identification and biological activity of gastrin-releasing peptide 1-46 (oGRP 1-46), the primary GRP gene-derived peptide product of the pregnant ovine endometrium.

We have previously demonstrated that pregnant ovine endometrium expresses the gastrin-releasing peptide (GRP) gene at a high level following conceptus implantation. Here we report the isolation, characterization and biological activity of ovine GRP 1-46, the primary product of this gene in the pregnant endometrium. Full thickness 125-140-day pregnant sheep uterus (term is 145 day) was homogenized in 80% acetonitrile/2% trifluoroacetic acid (1:7 ACN/TFA), concentrated on reverse-phase C18 cartridges and chromatographed successively on gel filtration (Sephadex G-50) and reverse-phase HPLC (C18 muBondapak). Purification was monitored by RIA. Purified GRP peptide was analysed by mass spectrometry giving a major mass ion at 4963 which corresponds exactly to GRP 1-46. Other mass ions from pro-GRP did not contain a biologically active N-terminus or antigenic determinant. Proteolytic cleavage of pro-GRP to give rise to GRP(1-46) would require preferential cleavage at the Glu-Glu bond by a Glu-C2-like enzyme, rather than the trypsin-like and C-terminal amidation enzymes (PAM) that produce GRP(18-27) and GRP(1-27) in other tissues. GRP 1-46 was synthesized and receptor binding and biological activity tested on a range of rodent and human cell lines that express GRP-related receptors GRPR, NMBR and BRS3. GRP 1-46 bound GRPR and NMBR with low affinity, and mobilized inositol phosphate in cell lines expressing the GRPR and NMBR, but not BRS-3. This study describes a new processed product of the GRP gene, GRP 1-46, which is highly expressed in the pregnant sheep endometrium and which acts as a weak agonist at the GRPR and NMBR.

Cytokine signalling via gp130 in gastric cancer.

Cytokine signalling pathways that depend on gp130 are dysregulated in several epithelial cancers including gastric cancer. It has been established that blockade of SHP2 activation of MAPK signalling results in hyperactivation of STAT3 resulting in increased cell proliferation, angiogenesis, inflammation and inhibition of both immunocyte and epithelial cell apoptosis. Additionally, key genes regulated downstream of gp130 via MAPK activation such as the stomach-specific tumor suppressor gene tff1 are suppressed, contributing to the oncogenic outcome. The main cytokine driver of gp130 signalling in the stomach is IL-11, with IL-6 having little activity in the antral stomach in which most pathology initiates. IL-11 is up-regulated in both mouse and human gastric cancer and in pre-neoplastic mucosa. A characteristic gene signature specifically associated with IL-11 drive has been observed, although the prognostic value of the signature has not yet been assessed. Infection of human or mouse stomach with Helicobacter pylori, especially that expressing the CagA cytotoxin, produces constitutive MAPK activation, but also activated STAT3 and increases IL-11 expression. The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics.

Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression.

H. pylori infection accounts for most cases of gastric cancer, but the initiating events remain unclear. The principal H. pylori pathogenicity-associated CagA protein disrupts intracellular SHP-2 signalling pathways including those used by the IL-6 family cytokines, IL-6 and IL-11. Imbalanced IL-6 family cytokine signalling in the gp130(757FF) mouse model of gastric cancer arising from hyperactivation of oncogenic STAT3 after altered SHP-2 : ERK1/2 signalling produces dysplastic antral tumours preceded by gastritis and metaplasia. In a cohort of patient gastric biopsies with known H. pylori and CagA status, we investigated whether (i) STAT3 and ERK1/2 activation is altered in H. pylori-dependent gastritis; (ii) these profiles are more pronounced in CagA+ H. pylori infection; and (iii) the expression of pro-inflammatory cytokines that activate STAT3 and ERK 1/2 pathways is associated with progression to gastric cancer. IL-6, IL-11, and activated STAT3 and ERK1/2 were quantified in antral biopsies from gastritic stomach, metaplastic tissue, and resected gastric cancer tissues. We observed significantly increased STAT3 and ERK1/2 activation (p = 0.001) in H. pylori-dependent gastritis, which was further enhanced in the presence of CagA+ H. pylori strains. Of known gastric ligands that drive STAT3 activation, IL-6 expression was increased after H. pylori infection and both IL-6 and IL-11 were strongly up-regulated in the gastric cancer biopsies. This suggests a mechanism by which IL-11 drives STAT3 activation and proliferation during gastric cancer progression. We addressed this using an in vitro approach, demonstrating that recombinant human IL-11 activates STAT3 and concomitantly increases proliferation of MKN28 gastric epithelial cells. In summary, we show increased STAT3 and ERK1/2 activation in H. pylori-dependent gastritis that is likely driven in an IL-6-dependent fashion. IL-11 expression is associated with adenocarcinoma development, but not gastritic lesions, and we identify a novel mechanism for IL-11 as a potent inducer of proliferation in the human gastric cancer setting.

Differentiation of the Gastric Mucosa IV. Role of trefoil peptides and IL-6 cytokine family signaling in gastric homeostasis.

Gastric trefoil peptides mediate mucosal repair by stimulating cell migration, inhibiting apoptosis and inflammation, and likely augmenting the barrier function of mucus. One of these, tff1, is a gastric-specific tumor suppressor gene, which when repressed is associated with gastric cancer progression. IL-6 family cytokines play an important role in maintaining gastric homeostasis by regulating tff1 and other mediators of mucosal proliferation, inflammation, angiogenesis, and apoptosis. In this review the signaling cascades downstream of the common IL-6 cytokine family coreceptor gp130 that contribute to control of this homeostasis are described, as are the pathological outcomes of imbalancing these pathways.