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A 74-year-old man with advanced heart failure was admitted to the hospital with a diagnosis of colorectal cancer, and he underwent surgery. To maintain stable hemodynamics, the Impella CP device was used. The patient was weaned from the device shortly after surgery, and he had an uneventful postoperative course. This case may pave the way for non-procrastinating surgery in patients with poorly stable hemodynamics.

BackgroundThe Canadian 24-Hour Movement Guidelines for adults provide specific recommendations for levels of physical activity, sedentary behavior, and sleep (ie, the movement behaviors) required for optimal health. Performance of the movement behaviors is associated with improved mental well-being. However, most postsecondary students do not meet the movement behavior recommendations within the Canadian 24-Hour Movement Guidelines and experience increased stress and declining well-being, suggesting the need for an intervention targeting students’ movement behaviors. ObjectiveWe aimed to develop and implement a theory-informed intervention intended to improve the movement behaviors and mental well-being of first-year postsecondary students. MethodsThe Intervention Mapping protocol was applied in the development and implementation of the intervention. Intervention Mapping entailed performing a needs assessment, determining the intervention outcomes, selecting theory- and evidence-based change methods and applications, preparing and producing intervention plans and materials, developing the implementation plan, and finally developing an evaluation plan. The Theoretical Domains Framework and the Behavior Change Wheel were also used in conjunction with the Intervention Mapping protocol to ensure a solid theoretical basis for the intervention. This protocol led to the development and implementation of a 6-week, theory-informed ParticipACTION app–based intervention aimed at helping first-year postsecondary students improve their movement behaviors and mental well-being. The developed app content provided students with information on each of the movement behaviors and behavioral strategies (ie, goal setting, action planning, monitoring, and coping planning). The use of Intervention Mapping allowed for the continuous involvement of various multidisciplinary partners and end users, ensuring that the intervention design and implementation was appropriate for the target audience. The feasibility, acceptability, and potential impact of the intervention will be examined in a subsequent proof-of-concept study at 2 Canadian university campuses. ResultsParticipant recruitment occurred during September 2021, and the intervention was conducted from October to December 2021. The deadline for completion of the postintervention questionnaire by participants was mid-December 2021. The analysis of data examining the feasibility, acceptability, and potential impact of the intervention began in January 2022, with the publication of the proof-of-concept evaluation expected in 2023. ConclusionsIntervention Mapping with the Theoretical Domains Framework and Behavior Change Wheel was a useful approach to combine evidence and theoretical concepts to guide the design and implementation of a ParticipACTION app–based intervention targeting postsecondary students’ movement behaviors and mental well-being. This process may serve as an example for other researchers developing multiple behavior change app–based interventions. Should the forthcoming evaluation demonstrate the intervention’s acceptability, feasibility, and potential impact, the intervention may provide a scalable method of improving postsecondary students’ movement behaviors and mental well-being. International Registered Report Identifier (IRRID)RR1-10.2196/39977

Abstract Aerobic and resistance exercise during and after cancer treatment are important for health-related outcomes, however treatment-specific barriers may inhibit adherence. We explored the effect of lower-frequency exercise training on fitness, body composition, and metabolic markers (i.e. glucose and lipids) in a group of recently diagnosed breast cancer patients. Fifty-two females ≥ 18 years with stage I–IIIB breast cancer were instructed to attend 2 cardiovascular and strength training sessions/week over 12 weeks, but program length was expanded as needed to accommodate missed sessions. Pre- and post-intervention, we measured: (1) cardiovascular fitness, (2) isometric strength, (3) body composition (dual-energy X-ray absorptiometry), and (4) fasting glucose, insulin, c-peptide, and lipids. Pre-intervention, participants were 53 ± 10 years old (mean ± SD) and overweight (BMI: 27.5 ± 5.4 kg m−2, 40.1 ± 6.5% body fat). Forty participants completed the program over a median 20 weeks (range: 13–32 weeks, median frequency: 1.2 sessions/week), over which predicted VO2peak improved by 7% (2.2[0.1–4.4] mL/kg/min) (delta[95% CI]), and strength increased by 7–9% (right arm: 2.3[0.1–4.5] N m; right leg: 7.9[2.1–13.7] N m; left leg: 7.8[1.9–13.7] N m). Body composition and metabolic markers were unchanged. An exercise frequency of 1.2 sessions/week stimulated significant improvements in fitness, and may represent a practical target for patients during active treatment.

Abstract Neoadjuvant chemo-radiotherapy (CRT) followed by total mesorectal excision (TME) represents the standard treatment for patients with locally advanced (≥ T3 or N+) rectal cancer (LARC). Approximately 15% of patients with LARC shows a complete response after CRT. The use of pre-treatment MRI as predictive biomarker could help to increase the chance of organ preservation by tailoring the neoadjuvant treatment. We present a novel machine learning model combining pre-treatment MRI-based clinical and radiomic features for the early prediction of treatment response in LARC patients. MRI scans (3.0 T, T2-weighted) of 72 patients with LARC were included. Two readers independently segmented each tumor. Radiomic features were extracted from both the “tumor core” (TC) and the “tumor border” (TB). Partial least square (PLS) regression was used as the multivariate, machine learning, algorithm of choice and leave-one-out nested cross-validation was used to optimize hyperparameters of the PLS. The MRI-Based “clinical-radiomic” machine learning model properly predicted the treatment response (AUC = 0.793, p = 5.6 × 10–5). Importantly, the prediction improved when combining MRI-based clinical features and radiomic features, the latter extracted from both TC and TB. Prospective validation studies in randomized clinical trials are warranted to better define the role of radiomics in the development of rectal cancer precision medicine.

BackgroundUPnGO with ParticipACTION (UPnGO) was a commercialized 12-month workplace physical activity intervention, aimed at encouraging employees to sit less and move more at work. Its design took advantage of the ubiquitous nature of mobile fitness trackers and aimed to be implemented in any office-based workplace in Canada. The program was available at cost from June 2017 to April 2020. The objectives of this study are to evaluate the program and identify key lessons from the commercialization of UPnGO.MethodsUsing a quasi-experimental design over 3 time points: baseline, 6 months, 12 months, five evaluation indicators were measured as guided by the RE-AIM framework. Reach was defined as the number and percentage of employees who registered for UPnGO and the number and percentage of sedentary participants registered. Effectiveness was assessed through average daily step count. Adoption was determined by workplace champion and senior leadership responses to the off-platform survey. Implementation was assessed as the percentage of participants who engaged with specific program elements at the 3-evaluation time points. Maintenance was assessed by the number of companies who renewed their contracts for UPnGO.ResultsReach across 17 organizations, 1980 employees participated in UPnGO, with 27% of participants identified as sedentary at baseline. Effectiveness Daily step count declined from 7,116 ± 3,558 steps at baseline to 6,969 ± 6,702 (p =

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

Preimplantation culture of mouse embryos has been suggested to result in reduced anxiety-like behavior in adulthood. Here, we investigated the effects of in vitro fertilization (IVF), embryo culture, and different diets on anxiety-like behavior using the elevated plus maze (EPM). We hypothesized that exposure to suboptimal conditions during the preimplantation stage would interact with the suboptimal diet to alter behavior. The expression of genes related to anxiety was then assessed by quantitative real-time polymerase chain reaction in various brain regions. When fed a normal diet during gestation and a moderately high-fat Western diet (WD) postnatally, naturally conceived (NC) and IVF mice showed similar anxiety-like behavior on the EPM. However, when fed a low-protein diet prenatally and a high-fat diet postnatally (LP/HF), NC mice showed a modest increase in anxiety-like behavior, whereas IVF mice showed the opposite: a strongly reduced anxiety-like behavior on the EPM. The robust reduction in anxiety-like behavior in IVF males fed the LP/HF diets was, intriguingly, associated with reduced expression of MAO-A, CRFR2, and GABA markers in the hypothalamus and cortex. These findings are discussed in relation to the developmental origin of health and disease hypothesis and the 2-hit model, which suggests that 2 events, occurring at different times in development, can act synergistically with long-term consequences observed during adulthood.

Abstract Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal disease, lacking effective therapeutic approaches. Available therapies only marginally prolong patient survival and are frequently coupled with severe adverse events. It is therefore pivotal to investigate novel and safe pharmacological approaches. We have recently identified the ABC transporter, ABCC3, whose expression is dependent on mutation of TP53, as a novel target in PDAC. ABCC3-mediated regulation of PDAC cell proliferation and tumour growth in vivo was demonstrated and was shown to be conferred by upregulation of STAT3 signalling and regulation of apoptosis. Methods To verify the potential of ABCC3 as a pharmacological target, a small molecule inhibitor of ABCC3, referred to here as MCI-715, was designed. In vitro assays were performed to assess the effects of ABCC3 inhibition on anchorage-dependent and anchorage-independent PDAC cell growth. The impact of ABCC3 inhibition on specific signalling pathways was verified by Western blotting. The potential of targeting ABCC3 with MCI-715 to counteract PDAC progression was additionally tested in several animal models of PDAC, including xenograft mouse models and transgenic mouse model of PDAC. Results Using both mouse models and human cell lines of PDAC, we show that the pharmacological inhibition of ABCC3 significantly decreased PDAC cell proliferation and clonal expansion in vitro and in vivo, remarkably slowing tumour growth in mice xenografts and patient-derived xenografts and increasing the survival rate in a transgenic mouse model. Furthermore, we show that stromal cells in pancreatic tumours, which actively participate in PDAC progression, are enriched for ABCC3, and that its inhibition may contribute to stroma reprogramming. Conclusions Our results indicate that ABCC3 inhibition with MCI-715 demonstrated strong antitumor activity and is well tolerated, which leads us to conclude that ABCC3 inhibition is a novel and promising therapeutic strategy for a considerable cohort of patients with pancreatic cancer.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients. Methods DNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed. Results In an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2, complete methylation for PCDHGC5. Conversely, the third protocadherin analyzed, PCDH10, showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan–Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates (P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3–12.3; P = 0.016), but not the OS. Conclusions In this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.

Background: In addition to its physical health benefits, physical activity is increasingly recognized as a means to support mental health. Regular moderate-to-vigorous physical activity (MVPA) is associated with improved mental well-being, reduced likelihood of developing mental illness, and improved symptom management. Despite these benefits, most people fail to achieve minimum recommended levels of MVPA. Population levels of physical activity have further declined since the onset of the COVID-19 pandemic and implementation of public health measures (e.g., shelter-in-place protocols). The potential impact of this decline on mental heath outcomes warrants ongoing investigation.Purpose: To investigate associations between changes in MVPA and mental health (depressive symptoms, anxiety symptoms, and life satisfaction) in adults impacted by the COVID-19 pandemic.Method: Research followed a cross-sectional design. English-speaking adults were invited to complete an online questionnaire. MVPA was assessed retrospectively (before COVID-19) and currently (during COVID-19) with the International Physical Activity Questionnaire. Mental health was assessed with the Patient Health Questionnaire, 9-Item (PHQ-9), the Generalized Anxiety Disorder, 7-Item (GAD-7), and the Satisfaction with Life Scale (SWLS). Regression was used to assess relationships between MVPA and mental health. ANOVA with follow-up tests examined whether participants who differed in mental health status (e.g., no symptoms vs. severe symptoms) differed in their change in MVPA. T-tests were used to examine differences in mental health symptomatology between participants who were sufficiently (i.e., achieving MVPA guidelines of ≥ 150 min/week) vs. insufficiently active.Results: Prior to COVID-19, 68.2% of participants were classified as being sufficiently active, vs. 60.6% during COVID-19. The majority of participants reported experiencing some level of depressive symptoms (62.0%) or anxiety symptoms (53.7%). After controlling for covariates, changes in MVPA accounted for significant variability in the PHQ-9 (7.7%), GAD-7 (2.5%), and SWLS (1.5 %). Participants with clinically significant mental health symptomatology reported greater declines in MVPA than those who reported no symptoms. Conversely, participants who were sufficiently active during COVID-19 reported significantly lower depression and anxiety, and higher life satisfaction.Conclusion: Participants who experienced the greatest declines in MVPA reported relatively greater psychological distress and lower life satisfaction. While preliminary, these findings suggest the importance of maintaining and promoting physical activity during a period of pandemic.

Background. Laparoscopic reversal of Hartmann’s procedure (LHR) offers reduced morbidity compared with open Hartmann’s reversal (OHR). The aim of this study is to compare the outcome of laparoscopic versus open Hartmann reversal. Materials and Methods. Thirty-four patients who underwent Hartmann reversal between January 2017 and July 2019 were evaluated. Patients underwent either LHR (n = 17) or OHR (n = 17). Variables such as numbers of patients, patient’s age, sex, body mass index (BMI), comorbidities, ASA (American Society of Anesthesiology) score, indication for previous open sigmoid resection, mean operation time, rate of conversion to open surgery, length of hospital stay, mortality, and morbidity were retrospectively evaluated. Results. The two groups of patients were homogeneous for gender, age, body mass index, cause of primary surgery, time to reversal, and comorbidities. In 97% of the cases, HP was done by open surgery. Our data revealed no difference in mean operation time (LHR: 180.5 ± 35.1 vs. OHR: 225.2 ± 48.4) and morbidity rate, although, in OHR group, there were more severe complications. Less intraoperative blood loss (LHR: 100 ± 40 mL vs. OHR: 450 ± 125 mL; p value

The purpose of this study was to provide a detailed and systematic outline of how a theoretical behaviour change framework was applied in the development of ParticipACTION’s app to support a more active Canada. The app development process was guided by the Behaviour Change Wheel (BCW) framework, a theoretically-based approach for intervention development, in collaboration with the commercial app industry. Specifically, a behavioural diagnosis was used to understand what needs to change for the targeted behaviour to occur. Current literature, along with a series of surveys, and market research informed app development. Additionally, a validated app behaviour change scale, was consulted throughout development to help ensure app features maximized behaviour change potential. The behavioural diagnosis revealed that the app needed to target individuals’ physical and psychological capabilities, physical and social opportunities, and reflective and automatic motivations in order to increase physical activity levels. To accomplish this, 6 of a possible 9 intervention functions and 2 of 7 policy categories were selected from the BCW to be included in the app. Goals and planning, feedback and monitoring, behaviour identification, action planning and knowledge shaping were selected as the main behaviour change techniques for the app. Collaboration with a mobile app development firm helped to embed the selected behaviour change techniques, policy categories, intervention functions, and sources of behaviour within the app. Using a systematic approach, this study used the BCW to ensure the health promotion app was theoretically informed. Future research will evaluate its effectiveness in increasing the physical activity of Canadians.

In adults, coffee, sugar-sweetened beverage (SSB) and high energy drink consumption have been related to increases in risky behaviour, including smoking. However, these associations are not well understood during adolescence. The purpose of this study was to examine the association between beverage consumption and smoking behaviour among Canadian adolescents. Using data from the COMPASS study (2016–2017; n = 46,957), four models were developed to investigate whether beverage consumption explained variability in smoking behaviour in adolescence (age = 15.7 ± 1.2 yrs); 1) smoking status; 2) e-cigarette use status; 3) days smoking cigarettes per month; and 4) days using an e-cigarette per month. Models were adjusted for demographic factors. Logistic (models 1 and 2) and ordinal logistic (models 3 and 4) were used for analysis. An association between the frequency of SSBs, coffee/tea or high energy drinks consumption and smoking behaviour was identified in all models. Greater beverage consumption was associated with being a current smoker (OR = 2.46 (2.02, 2.99)), former smoker, (OR = 2.50 (1.53, 4.08)), and currently using an e-cigarette (OR = 4.66 (3.40, 6.40)). Higher beverage consumption was also associated with more days smoking/using an e-cigarette per month (OR = 2.67 (1.92, 3.70) and 3.45 (2.32, 5.12), respectively). High energy drink consumption on 4 or 5 days of the school week was the best predictor of smoking behaviour in all models. Given the health consequences of smoking and e-cigarette use and their association with SSB, high energy drinks and coffee consumption, policy initiatives to prevent smoking initiation and limit access to these beverages needs ongoing attention and implementation.

Background: In response to the COVID-19 pandemic, physical distancing measures have been implemented globally. Canadians have been instructed to stay at home, which has likely resulted in significant changes in their physical activity. Using data from a national physical activity tracking app (PAC app), we aimed to determine device-measured physical activity levels immediately prior to and following the implementation of physical distancing measures in Canada to provide evidence for the development of physical activity recommendations for future pandemics or second wave infections.Methods: Demographic and physical activity data were extracted from the ParticipACTION app (PAC app), using a 10-week (10 February to 19 April 2020) quasi-experimental design to determine changes in physical activity 4 weeks pre-pandemic and 6 weeks post-pandemic declaration. Weekly physical activity levels were monitored through wearable fitness trackers and health apps linked to the PAC app, to record moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and steps. Repeated measure ANOVA was used to determine changes over time (mean ± SE).Findings: A total of 2,338 Canadians who were mostly 35–44 years old (26.6%) and female (90.2%) were included in the analysis. MVPA, LPA, and steps significantly declined immediately following the declaration of the pandemic (MVPA: pre-pandemic: 194.2 ± 5.2 min, post-pandemic: 176.7 ± 5.0 min, p < 0.001; LPA: pre-pandemic: 1,000.5 ± 17.0 min, post-pandemic: 874.1 ± 15.6 min, p < 0.001; steps: pre-pandemic: 48,625 ± 745 steps, post-pandemic: 43,395 ± 705 steps, p < 0.001). However, 6 weeks following pandemic declaration, MVPA (week 6: 204.4 ± 5.4 min, p = 0.498) had returned to pre-pandemic levels. LPA (week 6: 732.0 ± 14.3 min, p = < 0.001) and steps (week 6: 41,946 ± 763, p < 0.001) remained significantly lower than pre-pandemic levels at week 6.Interpretation: Although MVPA returned to pre-pandemic levels, significant and sustained declines in incidental LPA and steps were observed. Attenuating the loss of incidental physical activity should be a public health priority in response to future pandemics or a second wave of a COVID-19 infection, as it may have significant long-term implications for the physical and mental health of Canadians.

Abstract Background Pancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment. Methods The effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay. Results When used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines. Conclusions This study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.

Abstract Glioblastoma (GBM) is the leading cause of high fatality cancer arising within the adult brain. Electrotherapeutic approaches offer new promise for GBM treatment by exploiting innate vulnerabilities of cancer cells to low intensity electric fields. This report describes the preclinical outcomes of a novel electrotherapeutic strategy called Intratumoral Modulation Therapy (IMT) that uses an implanted stimulation system to deliver sustained, titratable, low intensity electric fields directly across GBM-affected brain regions. This pilot technology was applied to in vitro and animal models demonstrating significant and marked reduction in tumor cell viability and a cumulative impact of concurrent IMT and chemotherapy in GBM. No off target neurological effects were observed in treated subjects. Computational modeling predicted IMT field optimization as a means to further bolster treatment efficacy. This sentinel study provides new support for defining the potential of IMT strategies as part of a more effective multimodality treatment platform for GBM.

Prostate cancer is the second most common cancer diagnosed world-wide; however, patients demonstrate exceptionally high survival rates. Many lifestyle factors, including obesity and diet, are considered risk factors for advanced prostate cancer. Dietary fat is a fundamental contributor to obesity and may be specifically important for prostate cancer patients. Prostate cancer treatment can result in changes in body composition, affecting quality of life for survivors by increasing the risk of co-morbidities, like cardiovascular disease and diabetes. We aim to examine dietary fat throughout the prostate cancer treatment trajectory, including risk, cancer development and survivorship. Focusing on one specific nutrient throughout the prostate cancer trajectory provides a unique perspective of dietary fat in prostate cancer and the mechanisms that may exacerbate prostate cancer risk, progression and recurrence. Through this approach, we noted that high intake of dietary fat, especially, high intake of animal and saturated fats, may be associated with increased prostate cancer risk. In contrast, a low-fat diet, specifically low in saturated fat, may be beneficial for prostate cancer survivors by reducing tumor angiogenesis and cancer recurrence. The insulin-like growth factor (IGF)/Akt signaling pathway appears to be the key pathway moderating dietary fat intake and prostate cancer development and progression.

Emerging evidence indicates that peroxisome proliferator-activated receptor γ (PPARγ) and DNA methyltransferases (DNMTs) play a role in carcinogenesis. In this study we aimed to evaluate the expression of PPARγ, DNMT1, and DNMT3B and their correlation with clinical-pathological features in patients with pancreatic cancer (PC), and to define the effect of PPARγ activation on DNMTs expression in PC cell lines. qRT-PCR analysis showed that DNMT3B expression was downregulated in tumors compared to normal tissues (𝑃=0.03), whereas PPARγ and DNMT1 levels did not show significant alterations in PC patients. Expression levels between PPARγ and DNMT1 and between DNMT1 and DNMT3B were highly correlated (𝑃=0.008 and 𝑃=0.05 resp.). DNMT3B overexpression in tumor tissue was positively correlated with both lymph nodes spreading (𝑃=0.046) and resection margin status (𝑃=0.04), and a borderline association with perineural invasion (𝑃=0.06) was found. Furthermore, high levels of DNMT3B expression were significantly associated with a lower mortality in the whole population (HR=0.485; 95%CI=0.262–0.895, 𝑃=0.02) and in the subgroup of patients without perineural invasion (HR=0.314; 95%CI=0.130–0.758; 𝑃=0.01), while such association was not observed in patients with tumor invasion into perineural structures (𝑃=0.70). In conclusion, in vitro and in vivo PPARγ and DNMTs appear interrelated in PC, and this interaction might influence cell phenotype and disease behavior.

Altered expression of microRNAs (miRNAs) hallmarks many cancer types. The study of the associations of miRNA expression profile and cancer phenotype could help identify the links between deregulation of miRNA expression and oncogenic pathways.Expression profiling of 866 human miRNAs in 19 colorectal and 17 pancreatic cancers and in matched adjacent normal tissues was investigated. Classical paired t-test and random forest analyses were applied to identify miRNAs associated with tissue-specific tumors. Network analysis based on a computational approach to mine associations between cancer types and miRNAs was performed.The merge between the two statistical methods used to intersect the miRNAs differentially expressed in colon and pancreatic cancers allowed the identification of cancer-specific miRNA alterations. By miRNA-network analysis, tissue-specific patterns of miRNA deregulation were traced: the driving miRNAs were miR-195, miR-1280, miR-140-3p and miR-1246 in colorectal tumors, and miR-103, miR-23a and miR-15b in pancreatic cancers.MiRNA expression profiles may identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of tissue specific cancers. miRNA-network analysis help identify altered miRNA regulatory networks that could play a role in tumor pathogenesis.

Carcinogenesis is related to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms. Among these, the activities of peroxisome proliferator-activated receptors (PPARs) and DNA methyltransferases (DNMTs) are crucial and intertwined. PPARγ is a key regulator of cell fate, linking nutrient sensing to transcription processes, and its expression oscillates with circadian rhythmicity. Aim of our study was to assess the periodicity of PPARγ and DNMTs in pancreatic cancer (PC). We investigated the time-related patterns of PPARG, DNMT1, and DNMT3B expression monitoring their mRNA levels by qRT-PCR at different time points over a 28-hour span in BxPC-3, CFPAC-1, PANC-1, and MIAPaCa-2 PC cells after synchronization with serum shock. PPARG and DNMT1 expression in PANC-1 cells and PPARG expression in MIAPaCa-2 cells were characterized by a 24 h period oscillation, and a borderline significant rhythm was observed for the PPARG, DNMT1, and DNMT3B expression profiles in the other cell lines. The time-qualified profiles of gene expression showed different shapes and phase relationships in the PC cell lines examined. In conclusion, PPARG and DNMTs expression is characterized by different time-qualified patterns in cell lines derived from human PC, and this heterogeneity could influence cell phenotype and human disease behaviour.

Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS(3)) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.

Chronic pancreatitis (CP) is an inflammatory, often painful, disease of the exocrine pancreas which leads to exocrine insufficiency. The pathophysiology of pain in CP is incompletely understood. Several hypotheses have [...]