[Recovery after gynaecological surgery in French-speaking Belgium : survey and recommendation of the GGOLFB surgical working group]. / Convalescence après chirurgie gynécologique en Belgique francophone : sondage et recommandations du groupe de travail de chirurgie du Groupement des Gynécologues et Obstétriciens de Langue Française de Belgique.

Since the introduction of laparoscopy and mini-invasive techniques, gynaecological surgery has largely evolved. However, post-operative recommendations still remain very restrictive with poor evidence from literature. The survey, performed by the GGOLFB surgical working group, shows that the post-operative advices to the patients are very heterogeneous for the sick leave period as for more specific advices like the period of disallowance of sexual intercourse, bathing and weightlifting. It is nevertheless fundamental to prescribe clear and precise advices to patients, from the first pre-operative consultation on, which will substantially improve the perception of their recovery and promote a return to their normal activity under good conditions. It is not necessary to be too restrictive concerning certain activities in the post-operative period, neither to give too long periods of work incapacity because it may have a negative impact on their quality of life. This survey and the data from literature helped our surgical taskforce group to propose and develop harmonised recommendations on recovery and work incapacity after gynaecological surgery, taking into account the actual surgical practice in 2020.

La chirurgie gynécologique a fortement évolué depuis l'introduction de la laparoscopie et le développement de la chirurgie mini-invasive. Les recommandations post-opératoires sont souvent assez restrictives, avec peu d'évidence dans la littérature sur le bien-fondé de ces limitations. Notre sondage auprès des gynécologues francophones de Belgique montre que les consignes post-opératoires délivrées aux patientes sont très hétérogènes, aussi bien pour les durées d'incapacité de travail que pour des consignes plus spécifiques sur la durée d'absence de port de charges, de bains et de rapports sexuels. Il est pourtant fondamental de délivrer aux patientes des consignes précises, dès la consultation préopératoire, afin d'améliorer le vécu de leur convalescence et favoriser un retour aux activités dans de bonnes conditions. Il n'est pas non plus nécessaire d'être trop restrictif dans la reprise de certaines activités en postopératoire ni de recommander des incapacités de travail trop longues car elle peuvent avoir un impact négatif sur la qualité de vie des patientes. Au regard du sondage et de la revue des données de la littérature, notre groupe de travail propose des recommandations harmonisées sur la convalescence et l'incapacité de travail après chirurgie gynécologique, tenant compte des pratiques chirurgicales recommandées en 2020.

Does enhanced recovery improve the survival rates of patients 3 years after undergoing surgery to remove a tumor in the colon?

PURPOSE: The advantages of enhanced recovery programs (ERP) after colorectal surgery for morbidity and length of stay are well known. On a longer term, evidence is much more limited. The aim of this study is to determine the impact of ERP on survival after 3 years of follow-up, following colorectal cancer surgery. METHODS: All the patients undergoing resection for colorectal cancer between the years 2010 and 2014 were included. Patients were classified according to their compliance with the ERP (< 70 or ≥ 70%). RESULTS: Among the 206 patients included during the period, 129 were male (62.6%). The 3-year overall survival rate was 70.4% (145 patients) and relapse-free survival was 59.2% (122 patients). The survival after 3 years was influenced by the initial metastatic status (p < 0.0001), operative morbidity (p < 0.001), and the presence of peritumoral emboli (p = 0.006). However, the compliance with the ERP ≥ 70% did not influence overall survival (p = 0.63), nor relapse-free survival (p = 0.93). The same observations were found among the "at-risk" population (synchronous metastasis and postoperative complication). CONCLUSION: The ERP does not seem to influence the 3-year relapse-free survival after colorectal resection for cancer.

[Prolapse and urinary incontinence in women : place of the general practitioner]. / Prolapsus et incontinence urinaire chez la femme : la place du médecin généraliste.

The ageing of the population, having access to good quality of care, will result in an increase in the prevalence of pelvic floor diseases. Those persons, often in good general health, may experience difficulties in accepting functional pathologies, associated with loss in quality of life. One out of 2 women will have a pelvic floor problem and 1 out of 9 will have a surgical perineal procedure before the age of 80 years. The unitary character of the pelvic floor, a complex functional anatomic region, is often forgotten, essentially because the patients complain about one main pathology like urinary incontinence, genital prolapse, constipation and sexual disorders or chronic pain and will consult one specific specialist. Our role as health care professionals is to be aware of those associated pathologies and to obtain an optimal quality of care. The actual evolution towards specific clinical pathways with the integration of office provided care outside the hospital, needs to become the new standard of care. We try to give an overview of the different preventive, diagnostic and therapeutic options, available in a general practitioner's office. Taking care of the pelvic floor needs to be done in a global and pluridisciplinar setting. Referring towards specialised centres as well as the integration of the general practitioner, especially for the more complex cases, is essential.

Le vieillissement de la population ayant un accès à des soins de santé de qualité, mène à une augmentation de la prévalence des pathologies du périnée. Ces personnes, souvent en bonne santé, auront des difficultés à accepter des pathologies fonctionnelles associées à une perte de qualité de vie car ces pathologies du périnée représentent un large éventail de pathologies fonctionnelles. On estime qu'une femme sur 2 aura un jour un problème périnéal, 1 sur 9 devra subir une intervention chirurgicale périnéale avant l'âge de 80 ans. Le caractère unitaire du périnée, région anatomique fonctionnelle complexe, est malheureusement souvent oublié, au départ parce que les patientes se présentent chez leur médecin pour une plainte bien spécifique sans se rendre compte de cette unité et de l'association de différents symptômes comme l'incontinence urinaire, le prolapsus génital, la constipation et des troubles sexuels et douloureux. Notre rôle en tant que professionnel de santé est de ne pas négliger ces plaintes associées, afin d'avoir une qualité de soin optimale. L'évolution actuelle vers le développement des trajets de soin avec l'intégration standardisée des soins en extrahospitalier est évidente. Nous avons tenté dans cet article de donner une revue des moyens préventifs, diagnostiques et thérapeutiques applicables dans le cabinet du médecin généraliste. La prise en charge du périnée devrait toutefois avoir lieu de manière globale et de préférence pluridisciplinaire. La référence vers les centres pluridisciplinaires comme également l'intégration du médecin généraliste dans les trajets de soin, surtout pour les cas plus complexes, est essentielle.

TAp73 loss favors Smad-independent TGF-ß signaling that drives EMT in pancreatic ductal adenocarcinoma.

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-ß (TGF-ß) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-ß pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-ß signaling through a SMAD-independent pathway, favoring oncogenic TGF-ß effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-ß signaling. By suggesting TAp73 as a predictive marker for response to TGF-ß inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-ß inhibitors.

Lipid metabolic reprogramming in cancer cells.

Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression.

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling.

Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.

TAp73 is required for macrophage-mediated innate immunity and the resolution of inflammatory responses.

The multiple isoforms of p73, a member of the p53 family, share the ability to modulate p53 activities but also have unique properties, leading to a complex and poorly understood functional network. In vivo, p73 isoforms have been implicated in tumor suppression (TAp73(-/-) mice), DNA damage (ΔNp73(-/-) mice) and development (p73(-/-) mice). In this study, we investigated whether TAp73 contributes to innate immunity and septic shock. In response to a lethal lipopolysaccharide (LPS) challenge, TAp73(-/-) mice showed higher blood levels of proinflammatory cytokines and greater mortality than their wild-type littermates. In vitro, TAp73(-/-) macrophages exhibited elevated production of tumor necrosis factor alpha , interleukin-6 and macrophage inflammatory protein-2 as well as prolonged survival, decreased phagocytosis and increased major histocompatibility complex class II expression. Mice depleted of endogenous macrophages and reconstituted with TAp73(-/-) macrophages showed increased sensitivity to LPS challenge. These results suggest that macrophage polarization is altered in the absence of TAp73 such that maintenance of the M1 effector phenotype is prolonged at the expense of the M2 phenotype, thus impairing resolution of the inflammatory response. Our data indicate that TAp73 has a role in macrophage polarization and innate immunity, enhancing the action field of this important regulatory molecule.

Consequences of DJ-1 upregulation following p53 loss and cell transformation.

p53 is a tumor suppressor that responds to various stress signals by initiating cell-cycle arrest, senescence and apoptosis. Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression. Numerous studies have reported on the interactions between p53, IGF-1-AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53-AKT axis. In this study, we show that DJ-1 and p53 are tightly 'linked': p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells. Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation. We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production. These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.

Silica encapsulated manganese perovskite nanoparticles for magnetically induced hyperthermia without the risk of overheating.

Nanoparticles of manganese perovskite of the composition La(0.75)Sr(0.25)MnO(3) uniformly coated with silica were prepared by encapsulation of the magnetic cores (mean crystallite size 24 nm) using tetraethoxysilane followed by fractionation. The resulting hybrid particles form a stable suspension in an aqueous environment at physiological pH and possess a narrow hydrodynamic size distribution. Both calorimetric heating experiments and direct measurements of hysteresis loops in the alternating field revealed high specific power losses, further enhanced by the encapsulation procedure in the case of the coated particles. The corresponding results are discussed on the basis of complex characterization of the particles and especially detailed magnetic measurements. Moreover, the Curie temperature (335 K) of the selected magnetic cores resolves the risk of local overheating during hyperthermia treatment.

Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families.

We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.

Sr-hexaferrite/maghemite composite nanoparticles-possible new mediators for magnetic hyperthermia.

Composite nanoparticles with variable ratios of M-type Sr-hexaferrite and maghemite phases were prepared via the sol-gel method employing polyvinylalcohol as the stabilizing agent, followed by thermal treatment at 600 °C for 32-190 min. The measurements in static magnetic field revealed considerable variation of the coercivity and remanence depending on the relative content of the highly magnetically anisotropic Sr-hexaferrite phase. Calorimetric heating experiments were carried out on aqueous gel suspensions under an alternating magnetic field of maximum amplitude H(max) = 15.1-68.4 kA m(-1) and frequency ν = 108 kHz. They showed a strong dependence of the heating efficiency on the coercivity and remanence of the composites, with a specific absorption rate (SAR) value ranging from units to tens of W/g(Fe(ferrimagnetic)).

Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome.

Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.

Choosing where to deliver: decision criteria among women with low-risk pregnancies in France.

As in the rest of Europe, the supply of maternity hospitals has progressively decreased over the past few decades in France. An understanding of user choice criteria is important to help health planners reorganize obstetrical services and to predict changes in utilization patterns in response to supply changes. The objectives were to understand the criteria that women use to select their maternity hospital in France and to analyse the relation to individual and community characteristics. A survey of 536 recently delivered women with low-risk pregnancies explored the factors motivating user choice in three territories with distinct geographical and health service supply characteristics: four districts in Burgundy, two districts in Pays de la Loire, and the district of Seine-Saint-Denis in Ile-de-France. Women were asked to select a principal choice criterion. Their responses were grouped into categories: Accessibility/proximity, reputation of the establishment among users, advice of treating physician, technical quality and cost. Accessibility and proximity were the most selected criteria (33%), followed by the reputation of the maternity (29%), technical quality (15%) and advice of treating physician (13%). Age, parity and education influenced choice criteria. After controlling for individual determinants, region of residence was highly related to choice criteria; women living in Burgundy were more likely to select an establishment based on proximity, in Seine-Saint-Denis women were more likely to follow the advice of their physician, and in Pays de la Loire, more likely to base their decisions on the reputation of the establishment. The association between choice criteria and community characteristics could explain the failure of previous models to predict behaviour in different contexts. It is important to carry out local surveys of user perceptions before restructuring in order to take into consideration women's opinions on their future places of delivery and to refine geographic models.

Transforming growth factor beta-1 enhances Smad transcriptional activity through activation of p8 gene expression.

We report that exposure of mouse embryonic fibroblasts to transforming growth factor beta-1 (TGFbeta-1) (5 ng/ml) results in a strong activation of p8 mRNA expression that precedes the induction of cell growth. Involvement of the p8 promoter in the regulation was demonstrated by using a p8-chloramphenicol acetyltransferase construct. We therefore speculated that p8 might be a mediator of TGFbeta-1 in these cells. The incorporation of [(3)H]thymidine on treatment with TGFbeta-1 was indeed significantly higher in p8(+/+) fibroblasts than in p8(-/-) fibroblasts. Smad transcriptional activity was used as marker of the TGFbeta-1 signalling pathway, to probe the lower p8(-/-) response to TGFbeta-1. Two Smad-binding elements (SBEs)-luciferase constructs were transfected into p8(-/-) and p8(+/+) embryonic fibroblasts before treatment with TGFbeta-1. A lower level of Smad transactivation was observed in p8(-/-) embryonic fibroblasts, under basal conditions and after stimulation with TGFbeta-1. To test whether Smad underexpression in p8(-/-) cells was actually due to p8 depletion, p8(-/-) embryonic fibroblasts were transfected with a human p8 expression plasmid together with an SBE-luciferase construct. The expression of p8 restored Smad transactivation in unstimulated and TGFbeta-1-treated cells to the level found in p8(+/+) cells. We concluded that TGFbeta-1 activates p8 expression, which in turn enhances the Smad-transactivating function responsible for TGFbeta-1 activity.

Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I.

Expression of the Cdx1 homeobox gene in epithelial intestinal cells promotes cellular growth and differentiation. Cdx1and the Pancreatitis Associated Protein I (PAP I) are concomitantly expressed in the epithelial cells of the lower part of the intestinal crypts. Because Cdx1 is a transcription factor and PAP I, in other tissues, is a proliferative factor, we looked for a relationship between these two proteins in the intestinal-derived IEC-6 cells. After stable transfection with a Cdx1 expression vector, they produce high levels of the PAP I transcript and protein indicating a functional link between the two genes. Demonstration of Cdx1 binding to the PAP I promoter region and suppression of PAP I induction after deletion of the corresponding sequence indicated that Cdx1 is a transcription factor controlling PAP I gene expression in intestinal cells. By infecting IEC-6 cells with adenoviruses expressing PAP I, we demonstrated that PAP I induces mitosis in these cells. On the other hand, inhibition of the PAP I expression in the IEC-6 Cdxl-expressing cells using an antisense strategy confirmed the requirement of this protein for the effect of Cdx1 on cell growth. Finally, addition of the immunopurified PAP I to the culture medium promotes cell growth of the IEC-6 cells in a dose-dependent manner. Maximal effect was obtained at 1 ng/ml. Taken together these results demonstrate that PAP I is a target of the Cdx1 homeobox gene in intestinal cells which participates in the regulation of intestinal cell growth via an autocrine and/or paracrine mechanism.

Pancreatitis associated protein I (PAP-I) alters adhesion and motility of human melanocytes and melanoma cells.

Pancreatitis associated protein I is a secretory stress protein first characterized in pancreas during pancreatitis but also expressed in several tissues including hepatic, gastric, and colon cancer. Its concentration in serum can be significant. The relationship of pancreatitis associated protein I to skin cancers was investigated in normal melanocytes, melanoma tumors, and melanoma cell lines. None of them expressed pancreatitis associated protein I, even after stress induction. Adenovirus-mediated pancreatitis associated protein I expression, however, reduced cell adhesion to laminin-1 and fibronectin with a loss of integrin participation. Pancreatitis associated protein I expression stimulated haptotactic and directed migrations of some melanoma cells, but only directed migration was activated in normal melanocytes. Importantly, directed migration and spreading on fibronectin of the responsive melanoma cells were also enhanced when purified rat pancreatitis associated protein I was added to the culture medium of noninfected cells. This indicates that effects in infected cells were elicited by pancreatitis associated protein I after its secretion. Exogenous pancreatitis associated protein I can therefore modify the adhesion and motility of normal and transformed melanocytes, suggesting a potential interaction with melanoma invasivity.

Expression of the stress-induced p8 mRNA is transiently activated after culture medium change.

We report here that the mere fact of changing culture medium for fresh medium induced in several cell lines the expression of stress-activated genes including protein kinases p38, JNK and ERK1/2 and the transcription factor C/EBPbeta. As a consequence, p8, a gene induced by stress in several tissues, was strongly up-regulated. Induction did not occur after change for cell-conditioned medium. Induction was however transient, with a peak at 60 min for p38, at 15-30 min for JNK and at 15 min for ERK1/2, at 2-3 hours for C/EBPbeta and at 4-6 hours for p8. Repression of the induction was due to the secretion of thermolabile molecule(s) that progressively conditioned the medium. As low as 25% of conditioned medium added to fresh culture medium was sufficient to abolish the stress response. Taken together, our data indicate that the renewal of culture medium induces a transient cellular stress that may be a source of artifacts in experiments performed shortly after a change of culture medium.

Tumor necrosis factor alpha triggers antiapoptotic mechanisms in rat pancreatic cells through pancreatitis-associated protein I activation.

BACKGROUND & AIMS: Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because TNF-alpha is involved in the control of apoptosis, we studied its interaction with the pancreatic apoptotic pathway. METHODS: Pancreatic acinar AR4-2J cells were used. Apoptosis was monitored by morphologic and biochemical criteria. RESULTS: TNF-alpha induced apoptosis in AR4-2J cells. Induction was strongly enhanced in cells treated with actinomycin D, suggesting that TNF-alpha activated concomitantly an antiapoptotic mechanism through newly synthesized proteins. This mechanism involved activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases because their inhibition worsened TNF-alpha-induced apoptosis. The antiapoptotic pancreatitis-associated protein (PAP) I is a candidate for mediating TNF-alpha activity. Its expression is induced by TNF-alpha, and cells overexpressing PAP I show significantly less apoptosis on exposure to TNF-alpha. We examined whether TNF-alpha induction of PAP I expression was mediated by NF-kappaB or MAP kinases by using specific inhibitors of both pathways. Inhibition of NF-kappaB had no effect. However, inhibitors of MEK1 eliminated PAP I induction. CONCLUSIONS: TNF-alpha induces concomitantly proapoptotic and antiapoptotic mechanisms in pancreatic AR4-2J cells. Antiapoptotic mechanisms are mediated by NF-kappaB and MAP kinases, and PAP I is one of the effectors of apoptosis inhibition.

Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway.

Cytokines that are related to ciliary neurotrophic factor (CNTF) are physiologically important survival factors for motoneurons, but the mechanisms by which they prevent neuronal cell death remain unknown. Reg-2/PAP I (pancreatitis-associated protein I), referred to here as Reg-2, is a secreted protein whose expression in motoneurons during development is dependent on cytokines. Here we show that CNTF-related cytokines induce Reg-2 expression in cultured motoneurons. Purified Reg-2 can itself act as an autocrine/paracrine neurotrophic factor for a subpopulation of motoneurons, by stimulating a survival pathway involving phosphatidylinositol-3-kinase, Akt kinase and NF-kappaB. Blocking Reg-2 expression in motoneurons using Reg-2 antisense adenovirus specifically abrogates the survival effect of CNTF on cultured motoneurons, indicating that Reg-2 expression is a necessary step in the CNTF survival pathway. Reg-2 shows a unique pattern of expression in late embryonic spinal cord: it is progressively upregulated in individual motoneurons on a cell-by-cell basis, indicating that only a fraction of motoneurons in a given motor pool may be exposed to cytokines. Thus, Reg-2 is a neurotrophic factor for motoneurons, and is itself an obligatory intermediate in the survival signalling pathway of CNTF-related cytokines.