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Despite consensus guidelines, most patients with early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer do not see a medical oncologist prior to surgery and do not receive neoadjuvant chemotherapy (NAC). To understand barriers to care, we aimed to characterize the relationship between geography (region of residence and cancer centre proximity) and receipt of a pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Using linked administrative datasets in Ontario, Canada, we performed a retrospective population-based analysis of women diagnosed with stage I-III TN or HER2+ breast cancer from 2012 to 2020. The outcomes were a pre-treatment medical oncology consultation and the initiation of NAC. We created choropleth maps to assess the distribution of the outcomes and cancer centres across census divisions. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed multivariable regression analyses adjusted for relevant factors, including tumour extent and nodal status. Of 14,647 patients, 29.9% received a pre-treatment medical oncology consultation and 77.7% received NAC. Mapping demonstrated high interregional variability, ranging across census divisions from 12.5% to 64.3% for medical oncology consultation and from 8.8% to 64.3% for NAC. In the full cohort, compared to a distance of ≤5 km from the nearest cancer centre, only 10-25 km was significantly associated with lower odds of NAC (OR 0.83, 95% CI 0.70-0.99). Greater distances were not associated with pre-treatment medical oncology consultation. The interregional variability in medical oncology consultation and NAC for patients with TN and HER2+ breast cancer suggests that regional and/or provider practice patterns underlie discrepancies in the referral for and receipt of NAC. These findings can inform interventions to improve equitable access to NAC for eligible patients.

Objectives: To synthesise and evaluate the quality of the recommendations for exercise therapy and physical activity from guidelines for the prevention and/or management of low back pain., Design: Systematic review., Methods: Included clinical practice guidelines for the management of low back pain published between 2014 and 2022 and searched in 9 databases until September 2022. The quality of evidence was evaluated with the Appraisal of Guidelines, Research and Evaluation tool (AGREE-II instrument)., Results: After screening 3448 studies, 18 clinical practice guidelines were included in this review. Only five (27 %) guidelines were judged as having a satisfactory quality of evidence (i.e., rigour of development and applicability), and 13 (72 %) of guidelines are discussed and rated as critical. Regarding physical activity, no guidelines provided recommendations for the primary prevention of low back pain or incorporated adequate physical activity aspects considering type, dosage, frequency, and intensity. For exercises, all (100 %) guidelines recommended at least one type of supervised exercise in the management of low back pain, and 16 (88 %) provided an overall recommendation for people to stay active., Conclusions: Guidelines offer minimal or, sometimes, no detail regarding physical activity or specific exercise regimens for the management and prevention of low back pain. When some guidance is provided, the recommendations typically lack specificity concerning the type, intensity, duration, and frequency of exercise and, in many cases, they represent a combination of scarce available evidence and stakeholder perspectives., Competing Interests: Declaration of interest statement The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Although placebo-controlled trials are considered the gold standard for evaluating the efficacy of healthcare interventions, they can be perceived to be controversial and challenging to conduct for surgical treatments. The SUcceSS trial is the first placebo-controlled trial of lumbar decompression surgery for symptomatic lumbar canal stenosis. The SUcceSS trial has experienced common issues affecting the implementation of randomised placebo-controlled surgery trials, accentuated by the COVID-19 pandemic. Using the SUcceSS trial as an example, we discuss key challenges and mitigation strategies specific to the conduct of a randomised placebo-controlled surgical trial. Overall, the key lessons learned were (i) involving key stakeholders early and throughout the trial design phase may increase clinician and patient willingness to participate in a placebo-controlled trial of surgical interventions, (ii) additional resources (e.g. budget, staff time) are likely required to successfully operationalise trials of this nature, (iii) the level of placebo fidelity, timing of randomisation relative to intervention delivery, and nuances of the surgical procedure under investigation should be considered carefully. Findings are based on one example of a placebo-controlled surgical trial; however, researchers may benefit from employing or building from the strategies described and lessons learned when designing or implementing future trials of this nature., (© 2023. The Author(s).)

OBJECTIVE: We aimed to summarize the evidence of the effects of pain neuroscience education delivered alone or combined with other interventions for chronic pain. DESIGN: An overview of systematic reviews with meta-analysis. LITERATURE SEARCH: CINAHL (via EBSCOhost), Embase, PsycINFO (via ProQuest), PubMed, and the Cochrane Library were searched from their inception to November 14, 2022. STUDY SELECTION CRITERIA: Systematic reviews (SRs) with meta-analyses including randomized clinical trials. The outcomes were pain and psychological symptoms. DATA SYNTHESIS: AMSTAR 2 assessed the methodological quality of SRs. The primary study overlap was evaluated by calculating the corrected covered area (CCA). RESULTS: We included 8 SRs including 30 meta-analyses of interest that comprised 28 distinct clinical trials. In some meta-analyses, pain neuroscience education delivered alone or combined with other interventions was more effective than control interventions for reducing pain intensity, pain catastrophizing, kinesiophobia, anxiety symptoms, and depression symptoms at some time points. However, other meta-analyses found a lack of effects of pain neuroscience education, and there were inconsistencies between meta-analyses covering the same outcome. The methodological quality of all SRs was critically low. The overlap, including all SRs, was high (CCA = 13%), and very high for SRs covering trials on chronic low back pain (CCA = 40%), chronic spine pain (CCA = 27%), and fibromyalgia (CCA = 25%). CONCLUSION: It is impossible to make clear clinical recommendations for delivering pain neuroscience education based on current meta-analyses. Action is needed to increase and improve the quality of SRs in the field of pain neuroscience education. J Orthop Sports Phys Ther 2023;53(6):1-16. Epub: 10 May 2023. doi:10.2519/jospt.2023.11833 .

Objective: To determine the comparative effectiveness and safety of psychological interventions for chronic low back pain., Design: Systematic review with network meta-analysis., Data Sources: Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and CINAHL from database inception to 31 January 2021., Eligibility Criteria for Study Selection: Randomised controlled trials comparing psychological interventions with any comparison intervention in adults with chronic, non-specific low back pain. Two reviewers independently screened studies, extracted data, and assessed risk of bias and confidence in the evidence. Primary outcomes were physical function and pain intensity. A random effects network meta-analysis using a frequentist approach was performed at post-intervention (from the end of treatment to <2 months post-intervention); and at short term (≥2 to <6 months post-intervention), mid-term (≥6 to <12 months post-intervention), and long term follow-up (≥12 months post-intervention). Physiotherapy care was the reference comparison intervention. The design-by-treatment interaction model was used to assess global inconsistency and the Bucher method was used to assess local inconsistency., Results: 97 randomised controlled trials involving 13 136 participants and 17 treatment nodes were included. Inconsistency was detected at short term and mid-term follow-up for physical function, and short term follow-up for pain intensity, and were resolved through sensitivity analyses. For physical function, cognitive behavioural therapy (standardised mean difference 1.01, 95% confidence interval 0.58 to 1.44), and pain education (0.62, 0.08 to 1.17), delivered with physiotherapy care, resulted in clinically important improvements at post-intervention (moderate quality evidence). The most sustainable effects of treatment for improving physical function were reported with pain education delivered with physiotherapy care, at least until mid-term follow-up (0.63, 0.25 to 1.00; low quality evidence). No studies investigated the long term effectiveness of pain education delivered with physiotherapy care. For pain intensity, behavioural therapy (1.08, 0.22 to 1.94), cognitive behavioural therapy (0.92, 0.43 to 1.42), and pain education (0.91, 0.37 to 1.45), delivered with physiotherapy care, resulted in clinically important effects at post-intervention (low to moderate quality evidence). Only behavioural therapy delivered with physiotherapy care maintained clinically important effects on reducing pain intensity until mid-term follow-up (1.01, 0.41 to 1.60; high quality evidence)., Conclusions: For people with chronic, non-specific low back pain, psychological interventions are most effective when delivered in conjunction with physiotherapy care (mainly structured exercise). Pain education programmes (low to moderate quality evidence) and behavioural therapy (low to high quality evidence) result in the most sustainable effects of treatment; however, uncertainty remains as to their long term effectiveness. Although inconsistency was detected, potential sources were identified and resolved., Systematic Review Registration: PROSPERO CRD42019138074., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Among patients not undergoing curative-intent therapy for esophagogastric cancer, access to care may vary. We examined the geographic distribution of care delivery and survival and their relationship with distance to cancer centres for non-curative esophagogastric cancer, hypothesising that patients living further from cancer centres have worse outcomes., Methods: We conducted a population-based analysis of adults with non-curative esophagogastric cancer from 2005 to 2017 using linked administrative healthcare datasets in Ontario, Canada. Outcomes were medical oncology consultation, receipt of chemotherapy, and overall survival. Using geographic information system analysis, we mapped locations of cancer centres and outcomes across census divisions. Bivariate choropleth maps identified regional outcome discordances. Multivariable regression models assessed the relationship between distance from patient residence to the nearest cancer centre and outcomes, adjusting for demographic, clinical, and socioeconomic factors., Results: Of 10,228 patients surviving a median 5.1 months (IQR: 2.0-12.0), 68.5% had medical oncology consultation and 32.2% received chemotherapy. Certain distances (reference ≤ 10 km) were associated with lower consultation [relative risk 0.79 (95% CI 0.63-0.97) for ≥ 101 km], chemotherapy receipt [relative risk 0.67 (95% CI 0.53-0.85) for ≥ 101 km], and overall survival [hazard ratio 1.07 (95% CI 1.02-1.13) for 11-50 km, hazard ratio 1.13 (95% CI 1.04-1.23) for 51-100 km]., Conclusion: A third of patients did not see medical oncology and most did not receive chemotherapy. Outcomes exhibited high geographic variability. Location of residence influenced outcomes, with inferior outcomes at certain distances > 10 km from cancer centres. These findings are important for designing interventions to reduce access disparities for non-curative esophagogastric cancer care.

Background: Previous studies have only investigated how symptom presentation and socio-demographic factors influence care-seeking for low back pain (LBP). However, the influence of health and lifestyle factors remains unclear, and the potential confounding effects of aggregated familial factors (including genetics and the early shared environment) has not been considered extensively., Methods: A cross-sectional analysis was performed on 1605 twins enrolled in the Murcia Twin Registry (Spain). The outcome was seeking medical care for LBP and various self-reported demographic, health and lifestyle factors were considered predictors. All variables except sleep quality and diabetes were collected in 2013, which were cross-referenced from 2009 to 2010. A multivariate logistic regression model was performed on the total sample, followed by a co-twin case-control analysis., Results: The only significant factor found to increase the odds of seeking medical care for LBP without being affected by familial factors was poor sleep quality (total sample OR = 1.58, 95%CI 1.24-2.01; case-control OR = 1.75, 95%CI 1.14-2.69). The factors that were associated with reduced odds of seeking medical care for LBP and not confounded by familial factors were male sex (case-control OR = 0.55, 95%CI 0.33-0.93), alcohol intake (case-control OR = 0.90, 95%CI 0.82-0.99) and a history of diabetes (case-control OR = 0.50, 95%CI 0.25-0.97). No other factors significantly influenced medical care-seeking for LBP., Conclusions: People reporting poor sleep quality are more likely to seek medical care for LBP in the long term, with this relationship being independent from aggregated familial factors. Conversely, males, people reporting higher alcohol intake, and people with a history of diabetes are less likely to seek medical care for LBP., Significance: This is the first study investigating the factors that influence seeking medical care for LBP, while adjusting for the influence of familial factors using a co-twin control design. Poor sleep quality is associated with seeking medical care for LBP in the long term and does not appear to be confounded by familial factors. Early screening for indicators of poor sleep quality and appropriate referral to interventions for improving sleep quality or reducing pain in sleep may improve LBP management., (© 2021 European Pain Federation - EFIC®.)

Background: Little is known about how the geographic distribution of cancer services may influence disparities in outcomes for noncurable pancreatic adenocarcinoma. We therefore examined the geographic distribution of outcomes for this disease in relation to distance to cancer centers., Methods: We conducted a retrospective population-based analysis of adults in Ontario, Canada, diagnosed with noncurable pancreatic adenocarcinoma from 2004 through 2017 using linked administrative healthcare datasets. The exposure was distance from place of residence to the nearest cancer center providing medical oncology assessment and systemic therapy. Outcomes were medical oncology consultation, receipt of cancer-directed therapy, and overall survival. We examined the relationship between distance and outcomes using adjusted multivariable regression models., Results: Of 15,970 patients surviving a median of 3.3 months, 65.6% consulted medical oncology and 38.5% received systemic therapy. Regions with comparable outcomes were clustered throughout Ontario. Mapping revealed regional discordances between outcomes. Increasing distance (reference, ≤10 km) was independently associated with lower likelihood of medical oncology consultation (relative risks [95% CI] for 11-50, 51-100, and ≥101 km were 0.90 [0.83-0.98], 0.78 [0.62-0.99], and 0.77 [0.55-1.08], respectively) and worse survival (hazard ratios [95% CI] for 11-50, 51-100, and ≥101 km were 1.08 [1.04-1.12], 1.17 [1.10-1.25], and 1.10 [1.02-1.18], respectively), but not with likelihood of receiving therapy. Receipt of therapy seems less sensitive to distance, suggesting that distance limits entry into the cancer care system via oncology consultation. Regional outcome discordances suggest inefficiencies within and protective factors outside of the cancer care system., Conclusions: These findings provide a basis for clinicians to optimize their practices for patients with noncurable pancreatic adenocarcinoma, for future studies investigating geographic barriers to care, and for regional interventions to improve access.

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a subtype of non-small cell lung cancer (NSCLC) characterized by marked lymphocytic infiltration and association with Epstein-Barr virus (EBV). The molecular basis underlying the disease remains unclear. We sought to study the molecular landscape by multiple approaches including whole genomic sequencing, capture-based targeted sequencing, fluorescent in situ hybridization and immunohistochemistry. Tumor cells from 57 EBV-positive pulmonary LELCs were isolated by careful microdissection prior to genomic sequencing. Integrated analysis revealed a distinct genomic landscape of low TP53 mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-κB pathway. High level programmed cell death ligand-1 (PD-L1) expression was shown with 47% and 79% of the cases showing positive PD-L1 immunoreactivity at ≥50% and ≥1% tumor proportion score, respectively. Subsets of the patients with actionable fibroblast growth factor receptor 3 ( FGFR3) aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine. Pulmonary LELC showed a distinct genomic landscape, different from major NSCLC subtypes but resembled that of EBV-associated nasopharyngeal carcinoma. Our work facilitated the understanding of molecular basis underlying pulmonary LELC to explore potential therapeutic options.

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.

The TP53 -induced glycolysis and apoptosis regulator (TIGAR) is the protein product of the p53 target gene, C12orf5 . TIGAR blocks glycolysis and promotes cellular metabolism via the pentose phosphate pathway; it promotes the production of cellular nicotinamide adenine dinucleotide phosphate (NADPH), which leads to enhanced scavenging of intracellular reactive oxygen species, and inhibition of oxidative stress-induced apoptosis in normal cells. Our previous study identified a novel nucleoside analog that inhibited cellular growth and induced apoptosis in nasopharyngeal carcinoma (NPC) cell lines via downregulation of TIGAR expression. Furthermore, the growth inhibitory effects of c-Met tyrosine kinase inhibitors were ameliorated by the overexpression of TIGAR in the NPC cell lines. These results indicate a significant role for TIGAR expression in the survival of NPCs. The present study aimed to further define the function of TIGAR expression in NPC cells. In total, 36 formalin-fixed, paraffin-embedded NPC tissue samples were obtained for the immunohistochemical determination of TIGAR expression. The effects of TIGAR expression on cell proliferation, NADPH production and cellular invasiveness were also assessed in NPC cell lines. Overall, TIGAR was overexpressed in 27/36 (75%) of the NPC tissues compared with the adjacent non-cancer epithelial cells. Similarly, TIGAR overexpression was also observed in a panel of six NPC cell lines compared with normal NP460 hTert and Het1A cell lines. TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness of the NPC cell lines, whereas a knockdown of TIGAR expression resulted in significant inhibition of cellular growth and invasiveness. The expression of the two mesenchymal markers, fibronectin and vimentin, was increased by TIGAR overexpression, but reduced following TIGAR-knockdown. The present study revealed that TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness, and the maintenance of a mesenchymal phenotype, in NPC tissues.

Introduction: This study aimed to evaluate whether multimedia counselling (MC) using a touchscreen computer is as effective and time-efficient as conventional counselling (CC) in promoting correct metered-dose inhaler (MDI) technique, with or without the valved holding chamber (VHC)., Methods: Participants in the MDI-only and MDI-with-VHC groups were randomly assigned to the MC group or CC group. No blinding was imposed. Inhalation technique was assessed using checklists before and after counselling. Time spent on counselling was determined for all participants, while time taken to perfect the technique was determined only for participants who achieved perfect technique within one hour., Results: The CC group had more elderly participants than the MC group, but the difference was not significant. MDI-only and MDI-with-VHC users showed significant improvement in their inhaler technique after multimedia (44.5 ± 28.0% and 44.1 ± 14.4%, respectively) and conventional counselling (36.8 ± 20.5% and 37.0 ± 14.6%, respectively). No significant difference in MDI technique enhancement was found between the two groups. Although no significant difference was found between the MC and CC groups with regard to the time spent on counselling and the time taken to perfect the technique, the average time spent on counselling was longer for MDI-only users. MDI-only users had 13.5 times the odds of failing to achieve perfect technique compared to MDI-with-VHC users (95% confidence interval 1.50-121.32, p = 0.020)., Conclusion: MC and CC significantly improved MDI technique. Both methods showed comparable short-term effectiveness and time-efficiency in MDI technique education. VHC was beneficial, especially for MDI-users with hand-lung coordination problems.

Cigarette smoking has been implicated in colon cancer. Nicotine is a major alkaloid in cigarette smoke. In the present study, we showed that nicotine stimulated HT-29 cell proliferation and adrenaline production in a dose-dependent manner. The stimulatory action of nicotine was reversed by atenolol and ICI 118,551, a beta(1)- and beta(2)-selective antagonist, respectively, suggesting the role of beta-adrenoceptors in mediating the action. Nicotine also significantly upregulated the expression of the catecholamine-synthesizing enzymes [tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DbetaH) and phenylethanolamine N-methyltransferase]. Inhibitor of TH, a rate-limiting enzyme in the catecholamine-biosynthesis pathway, reduced the actions of nicotine on cell proliferation and adrenaline production. Expression of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) was demonstrated in HT-29 cells. Methyllycaconitine, an alpha7-nAChR antagonist, reversed the stimulatory actions of nicotine on cell proliferation, TH and DbetaH expression as well as adrenaline production. Taken together, through the action on alpha7-nAChR nicotine stimulates HT-29 cell proliferation via the upregulation of the catecholamine-synthesis pathway and ultimately adrenaline production and beta-adrenergic activation. These data reveal the contributory role alpha7-nAChR and beta-adrenoceptors in the tumorigenesis of colon cancer cells and partly elucidate the carcinogenic action of cigarette smoke on colon cancer.

Cigarette smoking is a putative environmental risk factor for colon cancer. Nicotine, an active alkaloid in tobacco, has been implicated in carcinogenesis. In the present study, we demonstrated that oral nicotine administration (50 or 200 microg/ml) for 25 days stimulated growth of human colon cancer xenograft in nude mice. It also increased vascularization in the tumors and elevated cotinine and adrenaline plasma levels. beta-Adrenoceptors, cyclooxygenase-2 (COX-2), prostaglandin E(2) (PGE(2)), and vascular endothelial growth factor (VEGF) in tumor tissues were also increased by nicotine. I.p. injection of beta(1)-selective antagonist (atenolol, 5 or 10 mg/kg) or beta(2)-selective antagonist (ICI 118,551, 5, or 10 mg/kg) blocked the nicotine-stimulated tumor growth dose dependently, in which beta(2)-selective antagonist produced a more prominent effect. beta-Adrenoceptors blockade also abrogated the stimulatory action of nicotine on microvessel densities as well as cell expression of COX-2, PGE(2), and VEGF, in which beta(2)-selective antagonist produced a significant effect. These findings provide a direct evidence that nicotine can enhance colon tumor growth mediated partly by stimulation of beta-adrenoceptors, preferentially the beta(2)-adrenoceptors. Activation of beta-adrenoceptors and the subsequent stimulation of COX-2, PGE(2), and VEGF expression is perhaps an important mechanism in the tumorigenic action of nicotine on colon tumor growth. These data suggest that beta-adrenoceptors play a modulatory role in the development of colon cancer and partly elucidate the carcinogenic action of cigarette smoke.

We previously reported that nicotine promoted gastric cancer cell growth via upregulation of cyclooxygenase 2 (COX-2). In the present study, we further investigated whether beta-adrenoceptors, protein kinase C (PKC), and extracellular signal-regulated kinase-1/2 (ERK1/2) were involved in the modulation of COX-2 expression and cell proliferation by nicotine in AGS, a human gastric adenocarcinoma cell line. Results showed that nicotine dose dependently increased the phosphorylation of EKR1/2 and the expression of AP-1 subunits c-fos and c-jun. In this connection, the ERK1/2 inhibitor U0126 abrogated the upregulation of AP-1 and COX-2 as well as cell proliferation induced by nicotine. Moreover, nicotine induced the translocation of PKC-betaI from cytosol to membrane and increased the total levels of PKC expression. Inhibition of PKC by staurosporine attenuated nicotine-induced ERK1/2 phosphorylation and COX-2 expression. Furthermore, atenolol and ICI 118,551, a beta1- and beta2-adrenoceptor antagonist, respectively, reversed the stimulatory action of nicotine on the expression of PKC, ERK1/2 phosphorylation, and COX-2 together with cell proliferation. Collectively, these results suggest that nicotine stimulates gastric cancer cell growth through the activation of beta-adrenoceptors and the downstream PKC-betaI/ERK1/2/COX-2 pathway.

Wound healing in the gastrointestinal tract is an orderly process involving orchestrated responses of various cell types. Lipopolysaccharides (LPS) are major components of the outer membrane of Gram-negative bacteria, which are known to impair gastric ulcer healing in animals. The influence of LPS on intercellular communication in wound healing, however, is unknown. We examined the effects of LPS-induced macrophage activation on the proliferative response in cultured rat gastric epithelial cells (RGM-1) and fibroblasts JHU-25. Rat peritoneal resident macrophages were activated with increasing doses of LPS. The supernatant from the activated macrophage preparation, designated as macrophage-conditioned medium, was then used to treat RGM-1 or JHU-25 cells. Cell proliferation and migration were determined by [(3)H]-thymidine incorporation and a monolayer wound-healing assay, respectively. Macrophage-conditioned medium significantly suppressed RGM-1 cell proliferation but had no effect on cell migration. The same medium, however, increased JHU-25 cell proliferation. LPS treatment alone suppressed JHU-25 cell proliferation while it had no effect on RGM-1 cell proliferation, indicating that the differential effects of the macrophage-conditioned medium on cell proliferation were elicited by the factors derived from macrophages. In this regard, tumor necrosis factor (TNF)-alpha stimulated while interleukin (IL)-1beta suppressed RGM-1 cell proliferation, suggesting that IL-1beta but not TNF-alpha may play a part in the mediation of the antiproliferative effect of macrophage-conditioned medium on gastric epithelial cells. In contrast, IL-1beta suppressed while TNF-alpha had no effect on JHU-25 cell proliferation. Collectively, LPS-activated macrophages delay gastric mucosal regeneration but promote fibroblast proliferation in vitro. Such changes may partly elucidate the detrimental effect of bacterial infection on tissue repair in the stomach.

In the present study, patch clamp experiments demonstrated the expression of multiple ionic currents, including a Ba2+-sensitive inward rectifier K+ current (IKir), a 4-aminopyridine- (4-AP) sensitive delayed rectifier K+ current (IKDR), and a nifedipine-sensitive, tetrodotoxin-resistant inward Na+ current (INa.TTXR) in the non-transformed rat gastric epithelial cell line RGM-1. RT-PCR revealed molecular identities of mRNAs for the functional ionic currents, including Kir1.2 for IKir, Kv1.1, Kv1.6, and Kv2.1 for IKDR, and Nav1.5 for INa.TTXR. Pharmacologic blockade of Kv and Nav, but not Kir, suppressed RGM-1 cell proliferation. To further elucidate which subtypes of the ion channels were involved in cell proliferation, RNA interference was employed to knockdown specific gene expression. Downregulation of Kv1.1 or Nav1.5 by RNA interference suppressed RGM-1 cell proliferation. To conclude, our study is the first to delineate the expression of ion channels and their functions as growth modulators in gastric epithelial cells.

Background: Heparin has been widely used to prevent cancer-associated thromboembolism in cancer patients. Recent evidence reveals that heparin could modulate cell proliferation in the stomach. The effect of heparin on gastric cancer growth, however, is unknown. The effect of heparin on the proliferation of a human gastric adenocarcinoma cell line, BGC-823, was investigated., Materials and Methods: Cell proliferation was assessed by [3H]-thymidine incorporation. The expressions of several growth-related genes were determined by RT-PCR and Western blot., Results: Heparin significantly increased cell proliferation in BGC-823 cancer cells by 15.5% at the dose of 0.2 microg/ml. Heparin also up-regulated c-Myc protein expression by 14.4%. In contrast, mRNA and protein levels of epidermal growth factor receptor (EGFR) were, respectively, down-regulated by 12.7% and 8.2% with no effect on cyclooxygenase-2 mRNA or protein expression., Conclusion: Our results suggest that heparin can promote the proliferation and up-regulation of c-Myc protein expression in gastric cancer cells.

Objective: The emergence of multidrug resistance within Streptococcus pneumoniae population was analysed, correlating penicillin resistance Pen(R) with secondary antibiotic resistance, capsular serotype, and genetic diversity among isolates., Methods: DNA fingerprinting, following macro-restriction enzyme digestion and pulse field gel electrophoresis (PFGE), and restriction fragment analysis of the PBP 2b gene, following PCR amplification, were performed on the Pen(R) S. pneumoniae, among 377 clinical isolates obtained from the clinical microbiology laboratory (University of Michigan Medical Center)., Results: Overall 35% of the isolates were Pen(R) of which 45% demonstrated high-level penicillin (Pen(R)-R, MIC>1). Respiratory isolates were more likely to be Pen(R) (p <0.001) than non-respiratory isolates and the rate of Pen(R)-R was significantly increased in children <10 years of age (59.6%, p <0.02). Secondary antibiotic resistance was more frequently associated with Pen(R)-R. Genomic DNA fingerprinting analysis and restriction fragment analysis of the PBP 2b gene demonstrated genomic divergence with discrete conserved pattern in the PBP 2b gene among the resistant isolates., Conclusion: The emergence of multidrug resistance in the S. pneumoniae population in SE Michigan is not due to expansion of a single or limited number of resistant clones, is occurring most frequently in the paediatric population and is associated with a decreased susceptibility to penicillin.

While all features of the inflammatory response induced by IL-1 are not observed following IL-4 stimulation, suboptimal concentrations both cytokines result in synergistic VCAM-1 expression in HUVEC. We have shown that, while IL-1 stimulated HUVEC express GM-CSF, tissue factor and VCAM-1, only VCAM-1 is detectable after exposure to IL-4. While kB was found essential for both basal and IL-1-mediated activity of VCAM-1, IL-4 induction was kB-independent. Inducible kB-binding proteins were identified in IL-1-, but not IL-4-stimulated nuclear extracts. Our results indicate that IL-4 exerts its transcriptional effects on the VCAM-1 gene through element(s) which do not require kB.