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Gene expression profile and cancer-associated pathways linked to progesterone receptor isoform a (PRA) predominance in transgenic mouse mammary glands
No full textAbstract
Background
Progesterone receptor (PR) is expressed from a single gene as two isoforms, PRA and PRB. In normal breast human tissue, PRA and PRB are expressed in equimolar ratios, but isoform ratio is altered during malignant progression, usually leading to high PRA:PRB ratios. We took advantage of a transgenic mouse model where PRA isoform is predominant (PRA transgenics) and identified the key transcriptional events and associated pathways underlying the preneoplastic phenotype in mammary glands of PRA transgenics as compared with normal wild-type littermates.
Methods
The transcriptomic profiles of PRA transgenics and wild-type mammary glands were generated using microarray technology. We identified differentially expressed genes and analyzed clustering, gene ontology (GO), gene set enrichment analysis (GSEA), and pathway profiles. We also performed comparisons with publicly available gene expression data sets of human breast cancer.
Results
We identified a large number of differentially expressed genes which were mainly associated with metabolic pathways for the PRA transgenics phenotype while inflammation- related pathways were negatively correlated. Further, we determined a significant overlap of the pathways characterizing PRA transgenics and those in breast cancer subtypes Luminal A and Luminal B and identified novel putative biomarkers, such as PDHB and LAMB3.
Conclusion
The transcriptional targets identified in this study should facilitate the formulation or refinement of useful molecular descriptors for diagnosis, prognosis, and therapy of breast cancer
Decision-making process in the pre-dialysis CKD patients: do anxiety, stress and depression matter?
No full textAbstract\ud
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Background\ud
The transition from pre-dialysis chronic kidney disease (CKD) to renal replacement therapy (RRT) is a stressful event. Anxiety, depression and stress are frequent conditions in this population, and might play a role on the choice of dialysis modality.\ud
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Methods\ud
This is a prospective study that included stages 4-5 CKD patients during a dialysis multi-disciplinary education program. Demographic, clinical, and laboratory data were evaluated. Hospital Anxiety and Depression Scale and a Perceived Stress Scale assessed levels of anxiety, depression and stress, respectively.\ud
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Results\ud
A total of 67 from 190 recruited patients were included (59 ± 15 years, 54% males). Comparing patients who chose peritoneal dialysis (PD) and hemodialysis (HD), there were no differences on anxiety (p = 0.55), and depression scores (p = 0.467), and stress (p = 0.854). Anxious (p = 0.007) and depressive (p = 0.030) patients presented lower levels of phosphate than those not affected. There was a significant correlation (p < 0.0001) between anxiety and depression scores (R2 = 0.573), anxiety and stress scores (R2 = 0.542), depression and stress scores (R2 = 0.514). At the end of study, 29.8% of patients had already started on dialysis, and scores of anxiety, depression and stress reduced significantly (all p values < 0.0001), from 5.9 ± 3.3 to 1.8 ± 1.8, from 7.7 ± 4.0 to 3.8 ± 2.9 and from 28.6 ± 7.8 to 10.0 ± 6.2, respectively, regardless of which therapy was chosen.\ud
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Conclusion\ud
Depression, anxiety and perceived stress during final stages of CKD do not seem to be related to the choice of dialysis therapy and tend to decrease after dialysis initiation
Rigorous and optimized few-mode erbium-doped fiber amplifier design by using topology optimization and genetic algorithms
No full textWe develop a rigorous procedure for the optimum design of few-mode erbium (Er)-doped fiber amplifiers,\ud
which is tackled as a multiobjective optimization problem, in an approach based on the combination of the\ud
topology optimization and genetic algorithm techniques. We demonstrated that the usual ring-like doping distributions\ud
are necessarily the best choices only if the pump intensity shows no azimuthal dependence.\ud
Additionally, in general, the optimum doping distribution will be a function of the signal and pump azimuthal\ud
mode numbers. For the particular case of the LP11 pump, we also provide a triple-ring Er-doping profile that\ud
maximizes modal equalization for seven-group modes over the whole C-band, the highest modal count proposed\ud
in the literature so far.CNP
Inequalities in mortality of men by oral and pharyngeal cancer in Barcelona, Spain and São Paulo, Brazil, 1995–2003
No full textAbstract
Background
Large inequalities of mortality by most cancers in general, by mouth and pharynx cancer in particular, have been associated to behaviour and geopolitical factors. The assessment of socioeconomic covariates of cancer mortality may be relevant to a full comprehension of distal determinants of the disease, and to appraise opportune interventions. The objective of this study was to compare socioeconomic inequalities in male mortality by oral and pharyngeal cancer in two major cities of Europe and South America.
Methods
The official system of information on mortality provided data on deaths in each city; general censuses informed population data. Age-adjusted death rates by oral and pharyngeal cancer for men were independently assessed for neighbourhoods of Barcelona, Spain, and São Paulo, Brazil, from 1995 to 2003. Uniform methodological criteria instructed the comparative assessment of magnitude, trends and spatial distribution of mortality. General linear models assessed ecologic correlations between death rates and socioeconomic indices (unemployment, schooling levels and the human development index) at the inner-city area level. Results obtained for each city were subsequently compared.
Results
Mortality of men by oral and pharyngeal cancer ranked higher in Barcelona (9.45 yearly deaths per 100,000 male inhabitants) than in Spain and Europe as a whole; rates were on decrease. São Paulo presented a poorer profile, with higher magnitude (11.86) and stationary trend. The appraisal of ecologic correlations indicated an unequal and inequitably distributed burden of disease in both cities, with poorer areas tending to present higher mortality. Barcelona had a larger gradient of mortality than São Paulo, indicating a higher inequality of cancer deaths across its neighbourhoods.
Conclusion
The quantitative monitoring of inequalities in health may contribute to the formulation of redistributive policies aimed at the concurrent promotion of wellbeing and social justice. The assessment of groups experiencing a higher burden of disease can instruct health services to provide additional resources for expanding preventive actions and facilities aimed at early diagnosis, standardized treatments and rehabilitation
The share of ultra-processed foods and the overall nutritional quality of diets in the US: evidence from a nationally representative cross-sectional study
No full textAbstract\ud
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Background\ud
Recent population dietary studies indicate that diets rich in ultra-processed foods, increasingly frequent worldwide, are grossly nutritionally unbalanced, suggesting that the dietary contribution of these foods largely determines the overall nutritional quality of contemporaneous diets. Yet, these studies have focused on individual nutrients (one at a time) rather than the overall nutritional quality of the diets. Here we investigate the relationship between the energy contribution of ultra-processed foods in the US diet and its content of critical nutrients, individually and overall.\ud
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Methods\ud
We evaluated dietary intakes of 9,317 participants from 2009 to 2010 NHANES aged 1+ years. Food items were classified into unprocessed or minimally processed foods, processed culinary ingredients, processed foods, and ultra-processed foods. First, we examined the average dietary content of macronutrients, micronutrients, and fiber across quintiles of the energy contribution of ultra-processed foods. Then, we used Principal Component Analysis (PCA) to identify a nutrient-balanced dietary pattern to enable the assessment of the overall nutritional quality of the diet. Linear regression was used to explore the association between the dietary share of ultra-processed foods and the balanced-pattern PCA factor score. The scores were thereafter categorized into tertiles, and their distribution was examined across ultra-processed food quintiles. All models incorporated survey sample weights and were adjusted for age, sex, race/ethnicity, family income, and educational attainment.\ud
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Results\ud
The average content of protein, fiber, vitamins A, C, D, and E, zinc, potassium, phosphorus, magnesium, and calcium in the US diet decreased significantly across quintiles of the energy contribution of ultra-processed foods, while carbohydrate, added sugar, and saturated fat contents increased. An inverse dose–response association was found between ultra-processed food quintiles and overall dietary quality measured through a nutrient-balanced-pattern PCA-derived factor score characterized by being richer in fiber, potassium, magnesium and vitamin C, and having less saturated fat and added sugars.\ud
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Conclusions\ud
This study suggests that decreasing the dietary share of ultra-processed foods is a rational and effective way to improve the nutritional quality of US diets.This research received funding from Conselho Nacional de Desenvolvimento\ud
Científico e Tecnológico, Edital MCTI/CNPq/Universal (Processo CNPq nº\ud
443477/2014-0) and from Fundação de Amparo à Pesquisa do Estado de São\ud
Paulo (Processo FAPESP nº 2015/14900-9)
Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus
No full textAbstract\ud
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Background\ud
The fungal genus Aspergillus is of critical importance to humankind. Species include those with industrial applications, important pathogens of humans, animals and crops, a source of potent carcinogenic contaminants of food, and an important genetic model. The genome sequences of eight aspergilli have already been explored to investigate aspects of fungal biology, raising questions about evolution and specialization within this genus.\ud
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Results\ud
We have generated genome sequences for ten novel, highly diverse Aspergillus species and compared these in detail to sister and more distant genera. Comparative studies of key aspects of fungal biology, including primary and secondary metabolism, stress response, biomass degradation, and signal transduction, revealed both conservation and diversity among the species. Observed genomic differences were validated with experimental studies. This revealed several highlights, such as the potential for sex in asexual species, organic acid production genes being a key feature of black aspergilli, alternative approaches for degrading plant biomass, and indications for the genetic basis of stress response. A genome-wide phylogenetic analysis demonstrated in detail the relationship of the newly genome sequenced species with other aspergilli.\ud
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Conclusions\ud
Many aspects of biological differences between fungal species cannot be explained by current knowledge obtained from genome sequences. The comparative genomics and experimental study, presented here, allows for the first time a genus-wide view of the biological diversity of the aspergilli and in many, but not all, cases linked genome differences to phenotype. Insights gained could be exploited for biotechnological and medical applications of fungi.Members of the University of Debrecen were supported financially by the\ud
Hungarian Scientific Research Fund (grant K100464 to IP) as well as by the\ud
TÁMOP 4.2.1./B-09/1/KONV-2010-0007 and SROP-4.2.2.B-15/1/KONV-2015-\ud
0001 projects, which were supported by the European Union, co-financed by\ud
the European Social Fund. EO was a recipient of a Campus Hungary\ud
Programme scholarship to the CBS-KNAW Fungal Biodiversity Centre. The\ud
authors aknowledge support from the Federal Ministery of Education and\ud
Research (BMBF) BioFung and the Deutsche Forschungsgemeinschaft (DFG)\ud
to GB, ES, and AAB. The work conducted by the U.S. Department of Energy\ud
Joint Genome Institute is supported by the Office of Science of the U.S.\ud
Department of Energy under Contract No. DE-AC02-05CH11231. FC was\ud
supported by the Major Program of National Natural Science Foundation of\ud
China (No. 31330059). WC was supported by the National Natural Science\ud
Foundation of China (No. 31601446) and the Fundamental Research Funds\ud
for the Central Universities (Nos. 2662014BQ051 and 2662015QC003). TB and\ud
IB were supported by grants of the Dutch Technology Foundation STW,\ud
Applied Science division of NWO, and the Technology Program of the\ud
Ministry of Economic Affairs UGC 14270 to RPdV. PAvK, MaA, and DvRU\ud
were supported by the Netherlands Technology Foundation STW (LGC 7393).\ud
We acknowledge financial support from the FWF (M01693-B22) to DCa.\ud
This work was in part supported by the Intelligent Synthetic Biology Center\ud
of Global Frontier Project (2011-0031955) funded by the Ministry of\ud
Education, Science and Technology grants to JHY and Science Foundation Ireland 13/CDA/2142 to OB. NS was supported by a scholarship from the\ud
Kurdistan Regional Government of Iraq. HSP was supported by the National\ud
Research Foundation of Korea (NRF) grant founded by the Korean Government\ud
(no. 2016010945).\ud
The work at UW-Madison (JHY) was supported by the Intelligent Synthetic\ud
Biology Center of Global Frontier Project (2011-0031955) funded by the\ud
Ministry of Science, ICT and Future Planning.\ud
PSD, RH, and RH were supported by the British Mycological Society and the\ud
Biotechnology and Biological Sciences Research Council (UK). ES and AAB\ud
were supported by CRC 1127 ChemBioSys and CRC-Transregio FungiNet by\ud
Deutsche Forschungsgemeinschaft (DFG). JCF was supported by Agilent\ud
Technologies (Agilent Thought Leader Award #2871) and the Novo Nordisk\ud
Foundation (Grant NNF 13OC0005201). LK was supported by the Hungarian\ud
Scientific Research Fund (NN116519) and a Bólyai János Research Fellowship.\ud
The sugar transporter analysis was supported by grants AGL2011-29925 and\ud
AGL2015-66131- AGL2015-66131-C2-2-R (MINECO/FEDER). BRO was supported\ud
by the Irving S. Johnson fund of the Kansas University endowment. We are\ud
grateful to FAPESP (The State of São Paulo Research Foundation) for the\ud
financial support (2014/06923-6 to FMS; 2012/20549-4 to ARLD; 2011/08945-9\ud
and 2014/11766-7 to JVCO; 2012/19040-0 and 2014/10351-8 to CAU). We are\ud
grateful to the Fundação de Amparo à Pesquisa do Estado de São Paulo\ud
(FAPESP) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico\ud
(CNPq) for the financial support (310186/2014-5 and 442333/2014-5 to FMS;\ud
441912/2014-1 to ARLD). We acknowledge the financial support of the Dirección\ud
General de Apoyo al Personal Académico, UNAM, projects IN 225710 and\ud
IN219813, and The Slovenian Research Agency (P1-0207, P1-0391, and J4-7162).\ud
KS was supported by the Slovenian Research Agency (P1-0207) and KS and NK\ud
were supported by the Slovenian Research Agency (J4-7162). TCV and MRA\ud
acknowledge support from the Villium Foundation, Project VKR023437. GB was\ud
supported by a grant from the Deutsche Forschungsgemeinschaft\ud
(BR1502/11-2). GB and RF were supported by a grant from the Deutsche\ud
Forschungsgemeinschaft (FOR1334/2). AL was supported by St. Petersburg\ud
State University, St. Petersburg, Russia (grant no. 15.61.951.2015).\ud
The Authors thank A Gazdag, R Mohácsi, and LG Tóth (University of Debrecen) for\ud
contributing to the experimental work; and V Szabó and T Koszó (University of\ud
Debrecen) for the literature search during the construction of FSD and FSRD,\ud
respectively. The authors thank C Toft for her help in conducting the phylogenetic\ud
analysis of the sugar transporters. The authors thank DG Panaccione for providing\ud
the A. fumigatus easC mutant strain prior to publication and DR Nelson for naming\ud
CYP51 and CYP53 family representatives according to CYP nomenclature. The\ud
authors thank Arle Kruckeberg (yeast strain KY73; plasmid pYEX-BX), Barbara Bakker\ud
(yeast strain EB.VW4000), Remi Lemoine (yeast strain MaDH4), Jeremy Thorner (yeast\ud
strain SEY6210), and Ian Dawes (CMY1050) for kindly providing material used in this\ud
study
Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune arthritis
No full textAbstract\ud
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Background\ud
The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties.\ud
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Methods\ud
Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP.\ud
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Results\ud
We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation.\ud
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Conclusions\ud
Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.The research leading to these results received funding from the European\ud
Union Seventh Framework Programme (FP7-2007-2013) under grant\ud
agreement n° HEALTH-F4-2011-281608 (TIMER), from the São Paulo Research\ud
Foundation (FAPESP) under grant agreements n° 2009/54014-7, 2011/1967-0,\ud
2012/25075-0, 2014/50265-3, 2012/20990-2 and 2013/08216-2 (Center for\ud
Research in Inflammatory Diseases), and from the University of São Paulo\ud
NAP-DIN and NPPNS under grant agreement n° 11.1.21625.01.0 and\ud
2012.1.17587.1.1, respectivel
Can anti-bothropstoxin-I antibodies discriminate between Bothrops jararaca and Bothrops jararacussu venoms?
No full textAbstract
Background
Snakes of the genus Bothrops, popularly known as pit vipers, are responsible for most cases of snakebite in Brazil. Within this genus, Bothrops jararacussu and B. jararaca deserve special attention due to the severity of their bites and for inhabiting densely populated areas. Regarding the treatment of snakebites by Bothrops jararacussu, questions have been raised about the effectiveness of the specific bothropic antivenom in neutralizing myotoxic effects; however, there are no accurate data for humans. Thus, the development of a differential diagnostic kit for this species would be of great interest because it provides, for healthcare professionals, a tool that would allow us to determine whether the accident was caused by B. jararacussu or other species of the genus. It would also make it possible to evaluate the specificity of the treatment and to provide data for epidemiological studies.
Methods
First, we produced a species-specific polyclonal antibody – a potential biomarker of Bothrops jararacussu venom – against bothropstoxin-I (BthTx-I), which is also found in smaller quantities in the venoms of B. jararaca from southern Brazil.
Results
Polyclonal antibodies against bothropstoxin-I could be separated into several species-specific immunoglobulins. Then, aiming to develop a system of safe and standardized immunoassay, we produced monoclonal antibodies. Seven hybridomas were obtained. Five of them were specific to the venom of B. jararacussu and two recognized the venom of B. jararaca from the southeastern population. The use of monoclonal antibodies also made it possible to differentiate B. jararacussu from B. jararaca venom obtained from the southern population. Analyzing the reactivity of monoclonal antibodies against other bothropic venoms, we found mAb Bt-3 to be more specific than others for B. jararacussu venom.
Conclusions
These results show the potential of BthTx-I for producing monoclonal antibodies that differentiate between B. jararacussu and other Bothrops species venoms
Immunolocalization of steroidogenic enzymes in the vaginal mucous of Galea spixii during the estrous cycle
No full textAbstract\ud
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Background\ud
The synthesis of sex steroids is controlled by several enzymes such as17α-hydroxylase cytochrome P450 (P450c17) catalyzing androgen synthesis and aromatase cytochrome P450 (P450arom) catalyzing estrogen synthesis, both of which must complex with the redox partner NADPH-cytochrome P450 oxidoreductase (CPR) for activity. Previous studies have identified expression of steroidogenic enzymes in vaginal tissue, suggesting local sex steroid synthesis. The current studies investigate P450c17, P450aromatase and CPR expression in vaginal mucosa of Galea spixii (Spix cavy) by immuno-histochemical and western immunoblot analyses.\ud
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Methods\ud
Stages of estrous cyclicity were monitored by vaginal exfoliative cytology. After euthanasia, vaginal tissues were retrieved, fixed and frozen at diestrus, proestrus, estrus and metestrus. The ovaries and testis were used as positive control tissues for immunohistochemistry.\ud
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Results\ud
Data from cytological study allowed identification of different estrous cycle phases. Immunohistochemical analysis showed different sites of expression of steroidogenic enzymes along with tissue response throughout different phases of the estrous cycle. However, further studies are needed to characterize the derived hormones synthesized by, and the enzymes activities associated with, vaginal tissues.\ud
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Conclusion\ud
Current results not only support the expression of enzymes involved in sex steroid synthesis in the wall of the vagina, they also indicate that expression changes with the stage of the cycle, both the levels and types of cells exhibiting expression. Thus, changes in proliferation of vaginal epithelial cells and the differentiation of the mucosa may be influenced by local steroid synthesis as well as circulating androgens and estrogens.This work was supported by grants from São Paulo Research Foundation/\ud
FAPESP, Sao Paulo, Brazil (Process Number: 2011/03655-2) and the National\ud
Council of Scientific Researches/CNPq (Process Number: 402220/2010-2)
Continuous femoral nerve blockade and single-shot sciatic nerve block promotes better analgesia and lower bleeding for total knee arthroplasty compared to intrathecal morphine: a randomized trial
No full textAbstract\ud
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Background\ud
Knee arthroplasty leads to postoperative pain. This study compares analgesia and postoperative bleeding achieved by intrathecal morphine with a continuous femoral plus single-shot sciatic nerve block.\ud
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Methods\ud
A randomized non-blinded clinical trial enrolled patients aged over 18 years old, ASA I to III who underwent total knee arthroplasty. All patients underwent spinal anesthesia with isobaric bupivacaine, 20 mg. One group received 100 mcg of intrathecal morphine (M group), and the other received a femoral nerve block by continuous infusion plus a "single shot" block of the sciatic nerve at the end of the surgery (FI group). Pain score from verbal numeric rating scale (VNRS) and morphine consumption during the first 72 h, as well as motor blockade, adverse effects, and postoperative bleeding were recorded. Analysis of variance of repeated measures with Bonferroni post-test, t-test and Fisher exact test were used for statistical analysis.\ud
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Results\ud
Thirty nine patients completed the study (M = 20; FI = 19 patients) and were similar except for higher age in the FI group. Motor blockade as well as movement pain during postanesthesia care unit (PACU) staying were not different between the groups, but movement pain was significantly lower in FI group after 24 h. Postoperative bleeding (ml) was lower in FI group.\ud
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Conclusions\ud
Continuous femoral nerve block combined with sciatic nerve block provides effective for postoperative analgesia in patients undergoing total knee arthroplasty, with lower pain scores after 24 h and a lower incidence of adverse effects and bleeding compared to intrathecal morphine.\ud
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Trial registration\ud
Retrospectively registered on \ud
https://clinicaltrials.gov/\ud
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under identifier \ud
NCT02882152\ud
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, 23rd December, 2016