Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer.

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined activating transcription factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germline mutation of Atf3 (Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasG12D/+). Atf3-/- mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/- mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1acreERT/+KrasG12D/+ mice. In response to injury, KRASG12D bypassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. Compared to Ptf1acreERT/+KrasG12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.

Inclusion of People Poststroke in Cardiac Rehabilitation Programs in Canada: A Missed Opportunity for Referral.

BACKGROUND: Evidence supports establishing a continuum of care from stroke rehabilitation (SR) to cardiac rehabilitation programs (CRPs). It is not known to what extent people poststroke are being integrated. This study aimed to determine the proportion of CRPs that accept referrals poststroke, barriers/facilitators, and eligibility criteria. METHODS: A web-based questionnaire was sent to CRPs across Canada. RESULTS: Of 160 questionnaires sent, 114 representatives (71%) of 130 CRPs responded. Of respondents, 65% (n = 74) reported accepting people with a diagnosis of stroke and doing so for a median of 11 years, 11 offering stroke-specific classes and an additional 6 planning inclusion. However, 62.5% of CRPs reported that < 11 patients participated in the last calendar year despite 88.5% reporting no limit to the number they could enroll. Among CRPs, 25% accepted only patients with concurrent cardiac diagnoses, living in the community (47.8%), and without severe mobility (70.1%), communication (80.6%), or cognitive (85.1%) deficits. The 2 most influential barriers and facilitators among all CRPs were funding and staffing. The fourth greatest barrier was lack of poststroke referrals, and third to sixth facilitators were SR/CRP collaboration to ensure appropriate referrals (third) and to increase referrals (sixth), toolkits for prescribing resistance (fourth), and aerobic training (fifth). CRP characteristics associated with accepting stroke were a hybrid program model, a medium program size, and having a falls prevention component. CONCLUSIONS: Most CRPs accept patients poststroke, but few participate. Therefore, establishing SR/CRP partnerships to increase appropriate referrals, using a toolkit to help operationalize exercise components, and allocating funding/resources to CRPs may significantly increase access to secondary prevention strategies.

CONTEXTE: Les données recueillies appuient la continuité des soins entre les programmes de réadaptation après un accident vasculaire cérébral (PR-AVC) et les programmes de réadaptation cardiaque (PRC). On ne sait toutefois pas dans quelle mesure les patients qui ont subi un accident vasculaire cérébral (AVC) sont intégrés à un PRC. L'étude visait donc à déterminer la proportion de PRC admettant les patients ayant subi un AVC, les obstacles à l'intégration de ces derniers et les éléments qui la facilitent, ainsi que les critères d'admissibilité. MÉTHODOLOGIE: Des responsables de PRC de partout au Canada ont été invités à répondre à un questionnaire en ligne. RÉSULTATS: Au total, 160 invitations ont été envoyées et 114 (71 %) responsables rattachés à 130 PRC y ont répondu. Parmi ces répondants, 65 % (n = 74) ont dit que leur programme admettait depuis un nombre médian de 11 ans les patients ayant reçu un diagnostic d'AVC; 11 programmes offraient des cours spécialement destinés aux patients ayant subi un AVC et 6 autres prévoyaient de le faire. Toutefois, 62,5 % des répondants ont souligné que moins de 11 patients avaient participé à leur programme au cours de l'année qui précédait, malgré le fait que dans 88,5 % des cas, il n'y avait pas de limite au nombre de participants admis. Parmi les PRC, 25 % n'admettaient que des patients ayant aussi reçu un diagnostic d'atteinte cardiaque, vivant dans la collectivité (47,8 %) et n'ayant pas de déficit sévère sur les plans de la mobilité (70,1 %), de la communication (80,6 %) ou de la fonction cognitive (85,1 %). Dans tous les cas, les deux facteurs influant le plus (positivement ou négativement, selon le cas) sur l'intégration des patients ayant subi un AVC étaient les ressources financières et les ressources humaines. Le quatrième obstacle en importance était le faible nombre de patients ayant subi un AVC orientés vers les programmes; les autres éléments facilitateurs également recensés étaient la collaboration entre les PR-AVC et les PRC afin d'assurer l'orientation des patients concernés (3e place), l'augmentation du nombre de ces orientations (6e place), ainsi que les outils permettant de prescrire un programme d'entraînement musculaire (4e place) et un programme d'entraînement aérobique (5e place). Les PRC admettant des patients ayant subi un AVC avaient en commun les caractéristiques suivantes : ils reposaient sur un modèle hybride, ils étaient de taille moyenne et ils comprenaient un volet sur la prévention des chutes. CONCLUSIONS: Si la plupart des PRC admettent les patients qui ont subi un AVC, ces derniers sont peu nombreux à y participer. L'établissement de partenariats entre les PR-AVC et les PRC afin d'augmenter le nombre de patients orientés, la mise en place d'outils facilitant l'exécution de programmes d'exercice physique et l'affectation de fonds et de ressources aux PRC pourraient donc augmenter considérablement l'accès aux stratégies de prévention secondaire.

Activating transcription factor 3 promotes loss of the acinar cell phenotype in response to cerulein-induced pancreatitis in mice.

Pancreatitis is a debilitating disease of the exocrine pancreas that, under chronic conditions, is a major susceptibility factor for pancreatic ductal adenocarcinoma (PDAC). Although down-regulation of genes that promote the mature acinar cell fate is required to reduce injury associated with pancreatitis, the factors that promote this repression are unknown. Activating transcription factor 3 (ATF3) is a key mediator of the unfolded protein response, a pathway rapidly activated during pancreatic insult. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that ATF3 is bound to the transcriptional regulatory regions of >30% of differentially expressed genes during the initiation of pancreatitis. Of importance, ATF3-dependent regulation of these genes was observed only upon induction of pancreatitis, with pathways involved in inflammation, acinar cell differentiation, and cell junctions being specifically targeted. Characterizing expression of transcription factors that affect acinar cell differentiation suggested that acinar cells lacking ATF3 maintain a mature cell phenotype during pancreatitis, a finding supported by maintenance of junctional proteins and polarity markers. As a result, Atf3-/- pancreatic tissue displayed increased tissue damage and inflammatory cell infiltration at early time points during injury but, at later time points, showed reduced acinar-to-duct cell metaplasia. Thus our results reveal a critical role for ATF3 as a key regulator of the acinar cell transcriptional response during injury and may provide a link between chronic pancreatitis and PDAC.

Niacin promotes revascularization and recovery of limb function in diet-induced obese mice with peripheral ischemia.

Niacin can reduce vascular disease risk in individuals with metabolic syndrome, but in light of recent large randomized controlled trials outcomes, its biological actions and clinical utility remain controversial. Niacin can improve endothelial function, vascular inflammation, and vascular regeneration, independent of correcting dyslipidemia, in various lean rodent models of vascular injury. Here, we tested whether niacin could directly improve endothelial cell angiogenic function during combined exposure to excess fatty acids and hypoxia, and whether intervention with niacin during continued feeding of western diet could improve revascularization and functional recovery in obese, hyperlipidemic mice with peripheral ischemia. Treatment with niacin (10 µmol/L) increased human microvascular endothelial cell angiogenic function during exposure to high fatty acids and hypoxia (2% oxygen), as determined by tube formation on Matrigel. To assess revascularization in vivo, we used western diet-induced obese mice with unilateral hind limb femoral artery ligation and excision. Treatment for 14 days postinjury with once daily i.p. injections of a low dose of niacin (50 mg/kg) improved recovery of hind limb use, in association with enhanced revascularization and decreased inflammation of the tibialis anterior muscle. These effects were concomitant with decreased plasma triglycerides, but not increased plasma apoAI. Thus, niacin improves endothelial tube formation under lipotoxic and hypoxic conditions, and moreover, promotes revascularization and functional hind limb recovery following ischemic injury in diet-induced obese mice with hyperlipidemia. These data may have implications for niacin therapy in the treatment of peripheral ischemic vascular disease associated with metabolic syndrome.

Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity.

OBJECTIVE: Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD(+), niacin could elicit these vascular benefits through NAD(+)-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved. METHODS AND RESULTS: Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 µM), or nicotinamide mononucleotide (NMN) (1 µM), a direct NAD(+) precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD(+) and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin. CONCLUSION: Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD(+) biosynthesis and SIRT1 activation, but rather through niacin receptor activation.