The prognostic value of stromal and epithelial periostin expression in human breast cancer: Correlation with clinical pathological features and mortality outcome

open6noBackground: PN is a secreted cell adhesion protein critical for carcinogenesis. In breast cancer, it is overexpressed compared to normal breast, and a few reports suggest that it has a potential role as a prognostic marker. Methods: Tumour samples obtained at the time of mastectomy from 200 women followed for a median time of 18.7 years (range 0.5-29.5 years) were investigated through IHC with a polyclonal anti-PN antibody using tissue microarrays. Epithelial and stromal PN expression were scored independently according to the percentage of coloured cells; the 60th percentile of PN epithelial expression, corresponding to 1 %, and the median value of PN stromal expression, corresponding to 90 %, were used as arbitrary cut-offs. The relationships between epithelial and stromal PN expression and clinicalpathological features, tumour phenotype and the risk of mortality following surgery were analysed. Appropriate statistics, including the Fine and Gray competing risk proportional hazard regression model, were used. Results: The expression of PN in tumour epithelial cells was significantly lower than that which was observed in stromal cells (p < 0.000). No specific association between epithelial or stromal PN expression and any of the clinicalpathological parameters analysed was found as it was observed in respect to mortality when these variables were analysed individually. However, when both variables were considered as a function of the other one, the expression of PN in the stromal cells maintained a statistically significant predictive value with respect to both all causes and cancerspecific mortality only in the presence of high epithelial expression levels. No significant differences in either all causes or BCa-specific mortality rates were shown according to epithelial expression for tumours displaying higher stromal PN expression rates. However, the trends were opposite for the higher stromal values and the patients with high epithelial expression levels denoted the group with the worst prognosis, while higher epithelial values in patients with lower stromal expression levels denoted the group with the best prognosis, suggesting that PN epithelial/stromal interactions play a crucial role in breast carcinogenesis, most likely due to functional cross-talk between the two compartments. On the basis of PN expression in both compartments, we defined 4 subgroups of patients with different mortality rates with the group of patients characterized by positive epithelial and low stromal PN expression cells showing the lowest mortality risk as opposed to the groups of patients identified by a high PN expression in both cell compartments or those identified by a low or absent PN expression in both cell compartments showing the worst mortality rates. The differences were highly statistically significant and were also retained after multiparametric analysis. Competing risk analysis demonstrated that PN expression patterns characterizing each of previous groups are specifically associated with cancer-specific mortality. Conclusions: Although they require further validation through larger studies, our findings suggest that the patterns of expression of PN in both compartments can allow for the development of IHC "signatures" that maintain a strong independent predictive value of both all causes and, namely, of cancer-specific mortality.openNuzzo, P.V.; Rubagotti, A.; Zinoli, L.; Salvi, S.; Boccardo, S.; Boccardo, F.Nuzzo, PIER VITALE; Rubagotti, Alessandra; Zinoli, Linda; Salvi, Sara; Boccardo, S.; Boccardo, F

Autologous stem cell transplantation for aggressive non-Hodgkin's lymphomas

n/

Discovery and profiling of small RNAs responsive to stress conditions in the plant pathogen Pectobacterium atrosepticum

© 2016 Kwenda et al. Background: Small RNAs (sRNAs) have emerged as important regulatory molecules and have been studied in several bacteria. However, to date, there have been no whole-transcriptome studies on sRNAs in any of the Soft Rot Enterobacteriaceae (SRE) group of pathogens. Although the main ecological niches for these pathogens are plants, a significant part of their life cycle is undertaken outside their host within adverse soil environment. However, the mechanisms of SRE adaptation to this harsh nutrient-deficient environment are poorly understood. Results: In the study reported herein, by using strand-specific RNA-seq analysis and in silico sRNA predictions, we describe the sRNA pool of Pectobacterium atrosepticum and reveal numerous sRNA candidates, including those that are induced during starvation-activated stress responses. Consequently, strand-specific RNA-seq enabled detection of 137 sRNAs and sRNA candidates under starvation conditions; 25 of these sRNAs were predicted for this bacterium in silico. Functional annotations were computationally assigned to 68 sRNAs. The expression of sRNAs in P. atrosepticum was compared under growth-promoting and starvation conditions: 68 sRNAs were differentially expressed with 47 sRNAs up-regulated under nutrient-deficient conditions. Conservation analysis using BLAST showed that most of the identified sRNAs are conserved within the SRE. Subsequently, we identified 9 novel sRNAs within the P. atrosepticum genome. Conclusions: Since many of the identified sRNAs are starvation-induced, the results of our study suggests that sRNAs play key roles in bacterial adaptive response. Finally, this work provides a basis for future experimental characterization and validation of sRNAs in plant pathogens

A third generation regimen VACOP-B with or without adjuvant radiotherapy for aggressive localized non-Hodgkin's lymphoma: report from the Italian Non-Hodgkin's Lymphoma Co-operative Study Group

The objective of this multicenter prospective study was to determine the clinical efficacy and toxicity of a polychemotherapeutic third generation regimen, VACOP-B, with or without radiotherapy as front-line therapy in aggressive localized non-Hodgkin's lymphoma. Ninety-three adult patients (47 males and 46 females, median age 45 years) with aggressive localized non-Hodgkin's lymphoma, 43 in stage I and 50 in stage II (non-bulky), were included in the study. Stage I patients received VACOP-B for 6 weeks plus involved field radiotherapy and stage II patients received 12 weeks VACOP-B plus involved field radiotherapy on residual masses. Eighty-six (92.5%) achieved complete remission and 4 (4.3%) partial remission. Three patients (3.2%) were primarily resistant. Ten-year probability of survival, progression-free survival and disease-free survival were 87.3, 79.9 and 83.9%, respectively. Eighty-four patients are surviving at a median observation time of 57 months (range: 6-126). Statistical analysis showed no difference between stages I and II in terms of response, ten-year probability of survival, progression-free survival or disease-free survival. Side effects and toxicity were negligible and were similar in the two patient groups. The results of this prospective study suggest that 6 weeks of VACOP-B treatment plus radiotherapy may be the therapy of choice in stage I aggressive non-Hodgkin's lymphoma. Twelve weeks of VACOP-B treatment with or without radiotherapy was shown to be effective and feasible for stage II. These observations need to be confirmed by a phase III study comparing first and third generation protocols in stage I-II aggressive non-Hodgkin's lymphoma.71972

Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival

BACKGROUND: MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression. METHODS: we analysed 12 SNPs in POLR2A, RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t-tests and global permutation tests. RESULTS: a haplotype in RNASEN (Drosha) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19-2.92, P=0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression (P=0.013) and with miR expression changes (global P=0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a). CONCLUSION: inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival

Cancer incidence in the population exposed to dioxin after the "Seveso accident": twenty years of follow-up

<p>Abstract</p> <p>Background</p> <p>The Seveso, Italy accident in 1976 caused the contamination of a large population by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Possible long-term effects have been examined through mortality and cancer incidence studies. We have updated the cancer incidence study which now covers the period 1977-96.</p> <p>Methods</p> <p>The study population includes subjects resident at the time of the accident in three contaminated zones with decreasing TCDD soil levels (zone A, very high; zone B, high; zone R, low) and in a surrounding non-contaminated reference territory. Gender-, age-, and period-adjusted rate ratios (RR) and 95% confidence intervals (95% CI) were calculated by using Poisson regression for subjects aged 0-74 years.</p> <p>Results</p> <p>All cancer incidence did not differ from expectations in any of the contaminated zones. An excess of lymphatic and hematopoietic tissue neoplasms was observed in zones A (four cases; RR, 1.39; 95% CI, 0.52-3.71) and B (29 cases; RR, 1.56; 95% CI, 1.07-2.27) consistent with the findings of the concurrent mortality study. An increased risk of breast cancer was detected in zone A females after 15 years since the accident (five cases, RR, 2.57; 95% CI, 1.07-6.20). No cases of soft tissue sarcomas occurred in the most exposed zones (A and B, 1.17 expected). No cancer cases were observed among subjects diagnosed with chloracne early after the accident.</p> <p>Conclusion</p> <p>The extension of the Seveso cancer incidence study confirmed an excess risk of lymphatic and hematopoietic tissue neoplasms in the most exposed zones. No clear pattern by time since the accident and zones was evident partly because of the low number of cases. The elevated risk of breast cancer in zone A females after 15 years since the accident deserves further and thorough investigation. The follow-up is continuing in order to cover the long time period (even decades) usually elapsing from exposure to carcinogenic chemicals and disease occurrence.</p

Environment And Genetics in Lung cancer Etiology (EAGLE) study: An integrative population-based case-control study of lung cancer

Background: Lung cancer is the leading cause of cancer mortality worldwide. Tobacco smoking is its primary cause, and yet the precise molecular alterations induced by smoking in lung tissue that lead to lung cancer and impact survival have remained obscure. A new framework of research is needed to address the challenges offered by this complex disease. Methods/Design: We designed a large population-based case-control study that combines a traditional molecular epidemiology design with a more integrative approach to investigate the dynamic process that begins with smoking initiation, proceeds through dependency/smoking persistence, continues with lung cancer development and ends with progression to disseminated disease or response to therapy and survival. The study allows the integration of data from multiple sources in the same subjects (risk factors, germline variation, genomic alterations in tumors, and clinical endpoints) to tackle the disease etiology from different angles. Before beginning the study, we conducted a phone survey and pilot investigations to identify the best approach to ensure an acceptable participation in the study from cases and controls. Between 2002 and 2005, we enrolled 2101 incident primary lung cancer cases and 2120 population controls, with 86.6% and 72.4% participation rate, respectively, from a catchment area including 216 municipalities in the Lombardy region of Italy. Lung cancer cases were enrolled in 13 hospitals and population controls were randomly sampled from the area to match the cases by age, gender and residence. Detailed epidemiological information and biospecimens were collected from each participant, and clinical data and tissue specimens from the cases. Collection of follow-up data on treatment and survival is ongoing. Discussion: EAGLE is a new population-based case-control study that explores the full spectrum of lung cancer etiology, from smoking addiction to lung cancer outcome, through examination of epidemiological, molecular, and clinical data. We have provided a detailed description of the study design, field activities, management, and opportunities for research following this integrative approach, which allows a sharper and more comprehensive vision of the complex nature of this disease. The study is poised to accelerate the emergence of new preventive and therapeutic strategies with potentially enormous impact on public health

Heterogeneous nuclear ribonucleoprotein K: altered pattern of expression associated with diagnosis and prognosis of prostate cancer

Using proteomic analysis of the nuclear matrix (NM), we found that heterogeneous nuclear ribonucleoprotein K (hnRNP K), a member of the hnRNP family with pleiotropic functions, was differentially expressed in prostate cancer (PCa) tissues. This study aimed to characterise the expression of hnRNP K and its subcellular localisation in PCa, utilising immunohistochemical and quantitative western blot techniques. Furthermore, the hnRNP K expression was studied in human PCa cell lines in order to determine its modulation by bicalutamide, the anti-androgen widely used in PCa therapy. Immunohistochemical staining of paraffin-embedded tissues showed that hnRNP K was overexpressed in PCa, where it was localised both in the cytoplasm and in the nucleus. Staining of non-tumour tissues showed exclusively nuclear localisation and a less intense or absent signal. Immunoblot analysis demonstrated that the hnRNP K level within the NM was higher in PCa compared with non-tumour tissues and closely correlated with Gleason score (P=0.008). Higher expression within the NM was significantly (P=0.032) associated with poor prognosis. In two-dimensional western blot analysis hnRNP K presented several isoforms; the one with pI 5.1 was the most differently expressed between non-tumour and PCa tissues. Preliminary results indicate that hnRNP K can be modulated in vitro by a non-steroidal anti-androgen. Taken together, our findings suggest that hnRNP K has potential implications at the diagnostic, prognostic and therapeutic levels in PCa

Predicting the environmental suitability for onchocerciasis in Africa as an aid to elimination planning

Recent evidence suggests that, in some foci, elimination of onchocerciasis from Africa may be feasible with mass drug administration (MDA) of ivermectin. To achieve continental elimination of transmission, mapping surveys will need to be conducted across all implementation units (IUs) for which endemicity status is currently unknown. Using boosted regression tree models with optimised hyperparameter selection, we estimated environmental suitability for onchocerciasis at the 5 × 5-km resolution across Africa. In order to classify IUs that include locations that are environmentally suitable, we used receiver operating characteristic (ROC) analysis to identify an optimal threshold for suitability concordant with locations where onchocerciasis has been previously detected. This threshold value was then used to classify IUs (more suitable or less suitable) based on the location within the IU with the largest mean prediction. Mean estimates of environmental suitability suggest large areas across West and Central Africa, as well as focal areas of East Africa, are suitable for onchocerciasis transmission, consistent with the presence of current control and elimination of transmission efforts. The ROC analysis identified a mean environmental suitability index of 0.71 as a threshold to classify based on the location with the largest mean prediction within the IU. Of the IUs considered for mapping surveys, 50.2% exceed this threshold for suitability in at least one 5×5-km location. The formidable scale of data collection required to map onchocerciasis endemicity across the African continent presents an opportunity to use spatial data to identify areas likely to be suitable for onchocerciasis transmission. National onchocerciasis elimination programmes may wish to consider prioritising these IUs for mapping surveys as human resources, laboratory capacity, and programmatic schedules may constrain survey implementation, and possibly delaying MDA initiation in areas that would ultimately qualify

Mapping development and health effects of cooking with solid fuels in low-income and middle-income countries, 2000–18: a geospatial modelling study

Background: More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels. Methods: We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km × 5 km resolution in 98 LMICs based on 2·1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution. Findings: Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205 000 (95% uncertainty interval 147 000–257 000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution. Interpretation: Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Funding: Bill &amp; Melinda Gates Foundation