Oral Cavity Cancers: Ethnic Differences in Radiotherapy Outcomes in a Majority South Asian Leicester Community.

AIMS: Squamous cell carcinoma oral cavity cancers (SCCOCCs) have a higher reported incidence in South Asian countries. We sought to compare presenting stage and outcome by ethnicity in patients with SCCOCC treated with radical radiotherapy in a single centre in the UK. MATERIALS AND METHODS: All patients with SCCOCC treated with radical radiotherapy at an oncology department in Leicester (UK) between 2011 and 2017 were identified. Baseline demographic, clinical data and 2-year treatment outcomes were reported. RESULTS: Of the 109 patients included, 40 were South Asian and 59 were non-South Asian. South Asians had significantly poorer 2-year disease-free survival compared with non-South Asians (54.6% versus 73%, P = 0.01). CONCLUSION: Our analysis suggests that South Asians with SCCOCC have poorer outcomes despite a younger age and similar disease characteristics. Environmental, social factors and differing biology of disease may be responsible and further research is required to inform targeted interventions.

Timely course of SARS-CoV-2 infections and vaccinations in patients with hemato-oncological diseases: analysis of a real-life cohort.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has particularly impacted patients with hemato-oncological malignancies, as they showed not only a higher propensity for severe courses but also weaker immune responses after vaccination. Still, data on the influence of pandemic waves and vaccinations on outcomes are rare. This study aimed to analyze the timely course of infections and vaccinations in a real-life cohort of patients with hemato-oncological diseases. METHODS: In this cohort study, 1817 patients with hemato-oncological diseases from 1 February 2020 to 15 December 2022 at the 'Franz Tappeiner' Hospital in Merano/Meran, Italy, were followed for SARS-CoV-2 infections and vaccinations. RESULTS: Of 1817 patients with hemato-oncological malignancies, 735 (40.5%) were infected at least once with SARS-CoV-2, and 1614 (88.8%) received one or more doses of the approved vaccinations. Patients receiving antineoplastic treatment had a lower SARS-CoV-2 infection rate [35.1% versus 41.0%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95], but higher risk of hospitalization (13.4% versus 6.9%; OR 2.11, 95% CI 1.25-3.69) compared with untreated patients. Overall, the case fatality rate (CFR) was 3.4%. Unvaccinated patients were more prone to severe coronavirus disease 2019 (COVID-19) courses requiring hospitalization (OR 2.34, 95% CI 1.25-4.36) and had a higher CFR (7.3% versus 1.6%; OR 4.98, 95% CI 2.16-12.98) than their vaccinated counterparts. In the Delta wave, patients with two vaccinations had a lower infection risk (OR 0.18, 95% CI 0.10-0.35) and tendentially lower hospitalization rates (OR 0.25, 95% CI 0.05-1.29) than unvaccinated patients. In the Omicron wave, 345/1198 (28.8%) patients with three or more vaccinations had breakthrough infections, resulting in a similar risk for infection (OR 0.88, 95% CI 0.60-1.30) but numerically lower risk for hospitalization (24/345, 7.0%) than unvaccinated individuals (4/40, 10.0%). Scheduled visits were postponed in 128/335 (38.2%) patients due to COVID-19, and deferrals correlated with pandemic wave (P = 0.002) and vaccination status (P < 0.001). CONCLUSIONS: SARS-CoV-2 infections and outcomes differ between distinct phases of the pandemic. Vaccination with variant-specific vaccines should be prioritized as general protective measures are increasingly lifted.

Diagnostic accuracy of magnetic resonance imaging in detecting depth of invasion of tongue cancers.

The recent eighth edition of the American Joint Committee on Cancer (AJCC) staging system has introduced depth of invasion (DOI) as one of its important components. DOI is also important for deciding neck management in superficial tongue cancers. Magnetic resonance imaging (MRI) is mainly used to assess DOI, and in this study we have evaluated the efficacy of MRI to detect it. This is a retrospective study consisting of 60 treatment-naïve tongue cancer patients operated on between July 2017 and June 2019. Patients underwent MR imaging on an Optima MR450W 1.5T unit, and MRI was reported by two experienced head and neck radiologists. Postoperative histological DOI was considered the gold standard. The correlation coefficient was derived for postoperative DOI and MRI-detected DOI. A subgroup analysis of superficial tongue cancer was also done. The mean MRI DOI was 13.7 mm and the mean histological DOI 12.45 mm. The shrinkage factor was 0.6 mm. Pearson's correlation coefficient was 0.80 (p=<0.001) for Radiologist 1 and 0.85 (p=<0.001) for Radiologist 2. The interobserver variation was low, with a correlation coefficient between the two radiologists of 0.965 (p=<0.001). For superficial tongue cancers there was moderate correlation for MRI and histologically-detected DOI with a kappa value of 0.681 (p=0.03). As per the ROC curve, the cut-off value for MRI DOI to predict nodal metastasis was 4.6 mm. MRI has high reliability to predict the DOI of tongue cancers. The interobserver variation was low. The diagnostic accuracy in cases of superficial tongue cancer was moderate.

Tumor mutational burden and immune infiltrates in renal cell carcinoma and matched brain metastases.

BACKGROUND: Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM). PATIENTS AND METHODS: Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software). RESULTS: No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens (P > 0.05). Higher CD8+ TIL (P = 0.053) and CD45RO+ TIL (P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples (P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival. CONCLUSION: The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC.

Safety of major reconstructive surgery during the peak of the COVID-19 pandemic in the United Kingdom and Ireland - multicentre national cohort study.

BACKGROUND: The safety of surgery during and after the coronavirus disease-2019 (COVID-19) pandemic is paramount. Early reports of excessive perioperative mortality in COVID-positive patients promoted the widespread avoidance of operations. However, cancelling or delaying operations for cancer, trauma, or functional restitution has resulted in increased morbidity and mortality. METHODS: A national multicentre cohort study of all major reconstructive operations carried out over a 12-week period of the 'COVID-19 surge' in the United Kingdom and Ireland was performed. Primary outcome was 30-day mortality and secondary outcome measures were major complications (Clavien-Dindo grade ≥3) and COVID-19 status of patients and healthcare professionals before and after surgery. RESULTS: A total of 418 patients underwent major reconstructive surgery with a mean operating time of 7.5 hours and 12 days' inpatient stay. Cancer (59.8%) and trauma (29.4%) were the most common indications. COVID-19 infection was present in 4.5% of patients. The 30-day post-operative mortality was 0.2%, reflecting the death of one patient who was COVID-negative. Overall complication rate was 20.8%. COVID status did not correlate with major or minor complications. Eight healthcare professionals developed post-operative COVID-19 infection, seven of which occurred within the first three weeks. CONCLUSIONS: Major reconstructive operations performed during the COVID-19 crisis have been mostly urgent cases involving all surgical specialties. This cohort is a surrogate for all major operations across all surgical specialties. Patient safety and surgical outcomes have been the same as in the pre-COVID era. With adequate precautions, major reconstructive surgery is safe for patients and staff. This study helps counsel patients of COVID-19 risks in the perioperative period.

Comparative analysis of paediatric and adult surgically drained dental infections at a university teaching hospital.

In the United Kingdom (UK) the estimated prevalence of dental infection involving the supporting bone is 2%, and from 2014-2015 there were 2281 admissions in England alone due to dental abscess. We undertook an analysis of 184 dental abscesses that required surgical drainage, as there is surprisingly little in the literature on the subject. This was a retrospective study of 184 consecutive patients with dental abscesses who were admitted between January 2016 and September 2019. On admission, all patients had orthopantomograms (OPG) and baseline blood tests. Surgical drainage was performed under a general or local anaesthetic and a pus swab sent for culture and sensitivity. The submandibular space was the most commonly involved site and paediatric patients most often presented with buccal space abscesses. A lower molar tooth was the cause in 132 patients. White blood cells (WBC) and C-reactive protein (CRP) were both raised in 63.6% (n=117), but were normal in 4.9% (n=9). The remaining patients had either raised WBC (2.7%) or CRP (28.8%). Streptococcus milleri was the most common organism isolated in 66.6% (n=42). There was no association between CRP or WBC values and duration of hospital stay. Paediatric patients had a shorter duration of admission (1.96 days vs 2.81 days) and significantly lower CRP values (120.9 vs 45.7; p=0.001). The submandibular space was the commonest site involved and mandibular molars the most frequent source of infection. An elevated CRP value appeared to be a more sensitive indicator of infection in this study population. Adult and paediatric patients present in a different manner.

Epistaxis as a marker for severe acute respiratory syndrome coronavirus-2 status - a prospective study.

OBJECTIVE: To evaluate the prevalence of severe acute respiratory syndrome coronavirus-2 infection in patients presenting with epistaxis to a tertiary otolaryngology unit. METHODS: A prospective study was conducted of 40 consecutive patients presenting with epistaxis referred to our tertiary otolaryngology unit. A group of 40 age-matched controls were also included. All patients underwent real-time reverse transcriptase polymerase chain reaction testing for severe acute respiratory syndrome coronavirus-2. Symptoms of fever, cough and anosmia were noted in the study group. RESULTS: The mean age was 66.5 ± 22.4 years in the study group. There were 22 males (55 per cent) and 18 females (45 per cent). The mean age in the control group was 66.3 ± 22.4 years (p = 0.935). There were six positive cases for severe acute respiratory syndrome coronavirus-2 (15 per cent) in the epistaxis group and one case (2.5 per cent) in the control group. The difference was statistically significant (p = 0.05). CONCLUSION: Epistaxis may represent a presenting symptom of severe acute respiratory syndrome coronavirus-2 infection. This may serve as a useful additional criterion for screening patients.

Morphology and molecular phylogeny of a new PST-producing dinoflagellate species: Alexandrium fragae sp. nov. (Gonyaulacales, dinophyceae).

The genus Alexandrium comprises some of the most potentially toxic marine algae. A new toxic species of Alexandrium, A. fragae sp. nov., was found in Guanabara Bay, Rio de Janeiro, southern Brazil. The new species produces GTX2&3 and STX. The cell morphology of A. fragae resembles A. minutum in many characters, including the small size; the rounded-elliptical shape; and the shapes of the apical pore complex (APC), first apical plate (1'), sixth precingular plate (6″), and anterior and posterior sulcal plates (s.a. and s.p.). The main diagnostic characters of A. fragae are the ornamentation pattern, smooth epitheca and reticulated hypotheca, all of which were present in both natural populations and cultures. Phylogenies inferred from the ITS, LSU, and SSU rDNA of A. fragae showed that A. fragae clustered in a well-supported clade, distinct from other Alexandrium species. Morphology and molecular analyses based on ITS and LSU rDNA indicated that A. fragae strains and Alexandrium sp. from Japan (D163C5, D164C6) are a single species. Our findings suggest that the Alexandrium morphotype with a smooth epitheca and reticulated hypotheca, previously identified as A. minutum in different geographic regions, may corresponds to A. fragae.

A survey of selected animal-based measures of dairy cattle welfare in the Eastern Alps: Toward context-based thresholds.

In the Alps, traditional dairy farms are small-scale operations where vertical transhumance from valley indoor housing systems to highland pasture-based systems is still practiced in summer. Vertical transhumance implies a substantial change of environment, available resources, and management practices from one season to another. In such systems, animal-based welfare measures need to be monitored throughout the year to capture the variation of welfare outcomes, based on which targeted welfare management plans can be implemented. Because the Welfare Quality assessment approach has been tailored to indoor housing and intensive farming systems, the European Food Safety Authority recently developed a welfare assessment protocol for small-scale dairy cattle farms adapted after the Welfare Quality framework. The aim of this study was to assess nonbehavioral animal-based measures as defined by this protocol at different time points for transhumant systems in the Alps. In total, 18 animal-based measures were assessed before, during, and after the mountain pasture period in a sample of 67 small-scale dairy cattle farms practicing vertical transhumance in neighboring provinces of Austria, Italy, and Slovenia. Significant differences between assessments were identified for dirtiness of legs and teats, hairless patches, lesions and swellings, claw condition, ocular discharge, and diarrhea whereas BCS, lameness/severe lameness, vulvar discharge, nasal discharge, and hampered respiration were unchanged between seasons. In addition, a benchmarking exercise was carried out to identify relative boundaries (worst quartile thresholds) for each animal-based measure and to contribute to the discussion about achievable welfare outcomes for the 2 husbandry conditions that characterize a transhumant system. Worst quartile thresholds indicated a high prevalence of dirtiness (>80%) when cows were kept indoors, high prevalence of hairless patches (65%) before pasture turnout, and high prevalence of very lean cows (>13%) throughout the assessments. On the other hand, the best quartile thresholds for most clinical conditions suggested that high welfare standards (zero prevalence) are widely achievable in mountain farms practicing vertical transhumance during all assessments. The thresholds identified through benchmarking should serve as the basis for an effective context-based welfare management strategy promoting continuous welfare improvement on-farm.

Modelling transitions in urban water systems.

Long term planning of urban water infrastructure requires acknowledgement that transitions in the water system are driven by changes in the urban environment, as well as societal dynamics. Inherent to the complexity of these underlying processes is that the dynamics of a system's evolution cannot be explained by linear cause-effect relationships and cannot be predicted under narrow sets of assumptions. Planning therefore needs to consider the functional behaviour and performance of integrated flexible infrastructure systems under a wide range of future conditions. This paper presents the first step towards a new generation of integrated planning tools that take such an exploratory planning approach. The spatially explicit model, denoted DAnCE4Water, integrates urban development patterns, water infrastructure changes and the dynamics of socio-institutional changes. While the individual components of the DAnCE4Water model (i.e. modules for simulation of urban development, societal dynamics and evolution/performance of water infrastructure) have been developed elsewhere, this paper presents their integration into a single model. We explain the modelling framework of DAnCE4Water, its potential utility and its software implementation. The integrated model is validated for the case study of an urban catchment located in Melbourne, Australia.

Role of microscopic spread beyond gross disease as an adverse prognostic factor in oral squamous cell carcinoma.

INTRODUCTION: Despite meticulous surgery and proper adjuvant treatment, outcome of oral squamous cell carcinoma remains unpredictable. This shows that there may be other factors which should be considered while prognosticating these patients. Many a times there is spread of disease beyond the gross margin which can alter the margin status. We hypothesized that microscopic spread beyond gross disease may portend a poor prognosis. METHOD: This is a retrospective study of prospectively collected data of 1025 treatment naïve oral squamous cell carcinoma patients. All patients underwent surgery from January 2012 to October 2013, this was followed by appropriate adjuvant treatment. Demographic and histopathological details were noted from the electronic medical records. RESULTS: Microscopic spread beyond gross disease (MSGD) is associated with higher incidence of nodal positivity (p < 0.046), peri-neural invasion (p < 0.001), thicker tumours (p < 0.024) and poor differentiation (p < 0.060). The overall survival in patients with MSGD was 32.45 months vs. 37.5 months in patients without MSGD (p < 0.002). CONCLUSION: Tumours with MSGD tend to have a higher incidence of nodal metastasis, PNI and thicker tumours. Presence of MSGD was associated with lower overall survival as compared to those without.

Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens. METHODS: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted. RESULTS: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment. CONCLUSIONS: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.

Skin involvement and ipsilateral nodal metastasis as a predictor of contralateral nodal metastasis in buccal mucosa cancers.

CONTEXT: In view of low incidence of contralateral nodal metastasis and increase in the morbidity, the opposite neck is not routinely addressed. However, contralateral nodal metastasis is seen frequently in a certain group of patients. Identifying those factors associated with higher chances of contralateral nodal metastasis may help in optimizing the treatment. AIMS: The aim of this study was to identify prognostic factors associated with contralateral nodal metastasis in cases of buccal mucosa cancers. SETTINGS AND DESIGN: A retrospective audit of 125 patients with squamous cell carcinoma of buccal mucosa at a tertiary cancer center. SUBJECTS AND METHODS: Those cases in which lesions were reaching or crossing midline were included in this study. All cases underwent surgery as primary modality of treatment and had bilateral neck dissection. STATISTICAL ANALYSIS USED: Chi-square test is used for evaluating the variables predicting contralateral nodal metastasis. Finally, a multivariate analysis was performed using binomial logistic regression to identify those variables that were independently associated with the risk of contralateral nodal metastasis. RESULTS: Among 125 patients, 53 cases were node negative. Ipsilateral nodal metastasis was seen in 44/125 (35.2%) patients, 26/125 (20.8%) had bilateral neck node metastasis, and 2/125 (1.6%) had isolated contralateral nodal metastasis. Among these 28 patients with contralateral nodal metastasis, 26 patients had ipsilateral nodal metastasis. Ipsilateral nodal metastasis and skin involvement were independently predictive of contralateral nodal metastasis. CONCLUSIONS: Contralateral nodal metastasis in the absence of ipsilateral nodal metastasis is very rare and frozen section of ipsilateral neck dissection specimen can be an important pointer for addressing contralateral neck.

The application of a Web-geographic information system for improving urban water cycle modelling.

Research in urban water management has experienced a transition from traditional model applications to modelling water cycles as an integrated part of urban areas. This includes the interlinking of models of many research areas (e.g. urban development, socio-economy, urban water management). The integration and simulation is realized in newly developed frameworks (e.g. DynaMind and OpenMI) and often assumes a high knowledge in programming. This work presents a Web based urban water management modelling platform which simplifies the setup and usage of complex integrated models. The platform is demonstrated with a small application example on a case study within the Alpine region. The used model is a DynaMind model benchmarking the impact of newly connected catchments on the flooding behaviour of an existing combined sewer system. As a result the workflow of the user within a Web browser is demonstrated and benchmark results are shown. The presented platform hides implementation specific aspects behind Web services based technologies such that the user can focus on his main aim, which is urban water management modelling and benchmarking. Moreover, this platform offers a centralized data management, automatic software updates and access to high performance computers accessible with desktop computers and mobile devices.

Efficacy and safety of an anti-IL-13 mAb in patients with severe asthma: a randomized trial.

BACKGROUND: Approximately 5% to 10% of asthmatic patients achieve incomplete symptom control on current therapies. The association of IL-13 with asthma pathology and reduced corticosteroid sensitivity suggests a potential benefit of anti-IL-13 therapy in refractory asthma. GSK679586, a humanized mAb, inhibits IL-13 binding to both IL-13 receptor α1 and α2. OBJECTIVES: We sought to evaluate the efficacy and safety of GSK679586 in patients with severe asthma refractory to maximally indicated doses of inhaled corticosteroids. METHODS: Patients who remained symptomatic (Asthma Control Questionnaire score ≥1.5) after uptitration to 1000 µg/d fluticasone propionate or greater were randomized to 3 once-monthly intravenous infusions of 10 mg/kg GSK679586 (n = 99) or placebo (n = 99). RESULTS: Treatment differences in adjusted mean change from baseline over 12 weeks were nonsignificant for Asthma Control Questionnaire symptom scores (the primary end point; GSK679586 = -0.31, placebo = -0.17, P = .058) and FEV1 (GSK679586 = -0.01, placebo = 0.03, P = .276). Similar analyses in patients with increased serum IgE levels, blood eosinophil counts, or both were also negative. Incidence of asthma exacerbations was similar between treatments. Most adverse events were nonserious and unrelated to treatment. Two GSK679586-treated patients had treatment-related serious adverse events (lethargy and supraventricular extrasystoles). CONCLUSIONS: Although well tolerated, GSK679586 did not demonstrate clinically meaningful improvements in asthma control, pulmonary function, or exacerbations in patients with severe asthma. Further studies are needed to determine whether therapies targeting IL-13, the functionally related IL-4 cytokine, or both can provide clinical benefit in patients with severe refractory asthma or a subpopulation of these patients beyond that achievable with high-dose corticosteroids.

GIS-based applications of sensitivity analysis for sewer models.

Sensitivity analysis (SA) evaluates the impact of changes in model parameters on model predictions. Such an analysis is commonly used when developing or applying environmental models to improve the understanding of underlying system behaviours and the impact and interactions of model parameters. The novelty of this paper is a geo-referenced visualization of sensitivity indices for model parameters in a combined sewer model using geographic information system (GIS) software. The result is a collection of maps for each analysis, where sensitivity indices (calculated for model parameters of interest) are illustrated according to a predefined symbology. In this paper, four types of maps (an uncertainty map, calibration map, vulnerability map, and design map) are created for an example case study. This article highlights the advantages and limitations of GIS-based SA of sewer models. The conclusion shows that for all analyzed applications, GIS-based SA is useful for analyzing, discussing and interpreting the model parameter sensitivity and its spatial dimension. The method can lead to a comprehensive view of the sewer system.

Cascade vulnerability for risk analysis of water infrastructure.

One of the major tasks in urban water management is failure-free operation for at least most of the time. Accordingly, the reliability of the network systems in urban water management has a crucial role. The failure of a component in these systems impacts potable water distribution and urban drainage. Therefore, water distribution and urban drainage systems are categorized as critical infrastructure. Vulnerability is the degree to which a system is likely to experience harm induced by perturbation or stress. However, for risk assessment, we usually assume that events and failures are singular and independent, i.e. several simultaneous events and cascading events are unconsidered. Although failures can be causally linked, a simultaneous consideration in risk analysis is hardly considered. To close this gap, this work introduces the term cascade vulnerability for water infrastructure. Cascade vulnerability accounts for cascading and simultaneous events. Following this definition, cascade risk maps are a merger of hazard and cascade vulnerability maps. In this work cascade vulnerability maps for water distribution systems and urban drainage systems based on the 'Achilles-Approach' are introduced and discussed. It is shown, that neglecting cascading effects results in significant underestimation of risk scenarios.

Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice.

AIMS/HYPOTHESIS: Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the pathogenesis of NAFLD. Here we aimed to identify the role of OPN in obesity-associated hepatic steatosis and impaired hepatic glucose metabolism. METHODS: Wild-type (WT) and Opn (also known as Spp1) knockout (Opn (-/-)) mice were fed a high-fat or low-fat diet to study OPN effects in obesity-driven hepatic alterations. RESULTS: We show that genetic OPN deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis. Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver. Euglycaemic-hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (-/-) mice. OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes. In addition, obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency. CONCLUSIONS/INTERPRETATION: Our data strongly emphasise OPN as mediator of obesity-associated hepatic alterations including steatosis, inflammation, insulin resistance and excess gluconeogenesis. Targeting OPN action could therefore provide a novel therapeutic strategy to prevent obesity-related complications such as NAFLD and type 2 diabetes.

Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge.

The tumor-stroma crosstalk is a dynamic process fundamental in tumor development. In hepatocellular carcinoma (HCC), the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-beta provided by stromal cells. TGF-beta induces an epithelial to mesenchymal transition (EMT) of oncogenic Ras-transformed hepatocytes and an upregulation of platelet-derived growth factor (PDGF) signaling. To analyse the influence of the hepatic tumor-stroma crosstalk onto tumor growth and progression, we co-injected malignant hepatocytes and myofibroblasts (MFBs). For this, we either used in vitro-activated p19(ARF) MFBs or in vivo-activated MFBs derived from physiologically inflamed livers of Mdr2/p19(ARF) double-null mice. We show that co-transplantation of MFBs with Ras-transformed hepatocytes strongly enhances tumor growth. Genetic interference with the PDGF signaling decreases tumor cell growth and maintains plasma membrane-located E-cadherin and beta-catenin at the tumor-host border, indicating a blockade of hepatocellular EMT. We further generated a collagen gel-based three dimensional HCC model in vitro to monitor the MFB-induced invasion of micro-organoid HCC spheroids. This invasion was diminished after inhibition of TGF-beta or PDGF signaling. These data suggest that the TGF-beta/PDGF axis is crucial during hepatic tumor-stroma crosstalk, regulating both tumor growth and cancer progression.