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Legumes form endosymbiotic interaction with host compatible rhizobia, resulting in the development of nitrogen-fixing root nodules. Within symbiotic nodules, rhizobia are intracellularly accommodated in plant-derived membrane compartments, termed symbiosomes. In mature nodule, the massively colonized cells tolerate the existence of rhizobia without manifestation of visible defense responses, indicating the suppression of plant immunity in the nodule in the favur of the symbiotic partner. Medicago truncatula DNF2 (defective in nitrogen fixation 2) and NAD1 (nodules with activated defense 1) genes are essential for the control of plant defense during the colonization of the nitrogen-fixing nodule and are required for bacteroid persistence. The previously identified nodule-specific NAD1 gene encodes a protein of unknown function. Herein, we present the analysis of novel NAD1 mutant alleles to better understand the function of NAD1 in the repression of immune responses in symbiotic nodules. By exploiting the advantage of plant double and rhizobial mutants defective in establishing nitrogen-fixing symbiotic interaction, we show that NAD1 functions following the release of rhizobia from the infection threads and colonization of nodule cells. The suppression of plant defense is self-dependent of the differentiation status of the rhizobia. The corresponding phenotype of nad1 and dnf2 mutants and the similarity in the induction of defense-associated genes in both mutants suggest that NAD1 and DNF2 operate close together in the same pathway controlling defense responses in symbiotic nodules. [ABSTRACT FROM AUTHOR]

The aim of our study was to compare the characteristics and time to initial physician contact in patients with head and neck squamous cell carcinoma (HNSCC) before and during the COVID-19 pandemic at a large Hungarian cancer center. This was a retrospective study of patients 18 years or older presenting at the regional cancer center of Pécs Clinical Center with HNSCC between 1 January 2017, and 15 March 2020 (the pre-COVID-19 period) and between 16 March 2020, and 13 May 2021 (the COVID-19 period). Demographic and clinical data were collected, and the time between initial symptom onset and initial physician contact (TTP) was determined. Descriptive and exploratory statistical analyses were performed. On average, the number of patients diagnosed with HNSCC per month during the pandemic decreased by 12.4% compared with the pre-COVID-19 period. There was a significant increase in stage I and stage II cancers (from 15.9% to 20.3% and from 12.2% to 13.8%, respectively; p < 0.001); a decrease in stage III and IVa,c cancers; and a significant increase in stage IVb cancers (from 6% to 19.9%; p < 0.001) during the pandemic. The median TTP increased during the pandemic from 43 to 61 days (p = 0.032). To our knowledge, this is the first study investigating the effect of COVID-19 on patients with HNSCC in the Central-Eastern European region. We found a bidirectional shift in cancer stages and increased TTP during the pandemic. Our findings highlight the necessity for more nuanced analyses of the effects of COVID-19.

Background: Rheumatoid arthritis (RA) is chronically persistent synovitis and systemic inflammation. Although multiple contributors are detected, only one is pivotal in the neonatal period: the negative selection of autoimmune naïve T-cells by the autoimmune regulator (AIRE) transcriptional factor., Methods: Single-nucleotide polymorphisms (SNPs) in the DNA-binding site of AIRE may determine its function and expression. We intended to analyse site-specific allelic polymorphisms in two exon (rs878081 and rs1055311) and three intron (rs1003853, rs2075876, and rs1003854) loci with an RA risk. Our analytical case-control study analysed 270 RA patients and 322 control subjects in five different genetic models using quantitative real-time PCR (qPCR) with TaqMan ® assays., Results: Statistically significant differences were found between the odds of allelic polymorphisms in the loci of rs878081, rs1003854, and rs1003853 among the controls and RA patients, and the disease activity seemed to be significantly associated with the genotypic subgroups of rs878081 and rs1055311. Our in silico analysis supported this, suggesting that allele-specific alterations in the binding affinity of transcriptional factor families might determine RA activity., Conclusion: Our findings highlight the involvement of neonatal self-tolerance in RA pathogenesis, providing novel insights into disease development and paving the way for an analysis of further site-specific genetic polymorphisms in AIRE to expand the intervention time for RA.

Background: Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid profiles. Aromatase inhibitors (AI) are used to prevent the progression of cancer; however, a further reduction in estrogen levels may have detrimental effects on lipid levels, which was our working hypothesis. Methods: Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. Results: We identified 15 studies, including 1708 patients. Studies using anastrozole (ANA), exemestane (EXE), letrozole (LET), and tamoxifen (TMX) were involved. Subgroup analyses revealed that 3- and 12-month administrations of LET and EXE lead to negative changes in lipid profiles that tend to alter the lipid profile undesirably, unlike ANA and TMX. Conclusions: Our results suggest that, despite statistically significant results, EXE and LET may not be sufficient to cause severe dyslipidemia in patients without cardiovascular comorbidities according to the AHA/ACC Guideline on the Management of Blood Cholesterol. However, the results may raise the question of monitoring the effects of AIs in patients, especially those with pre-existing cardiovascular risk factors such as dyslipidemia.

Dermal photoaging refers to the skin's response to prolonged and excessive ultraviolet (UV) exposure, resulting in inflammation, changes to the tissue, redness, swelling, and discomfort. Betanin is the primary betacyanin in red beetroot ( Beta vulgaris ) and has excellent antioxidant properties. Yet, the specific molecular mechanisms of betanin in HaCaT cells have not been fully clarified. The objective of this study was to investigate the activity of betanin and the underlying mechanisms in HaCaT cells; furthermore, in this study, we explored the protective effect of various concentrations of betanin against UVB irradiation on HaCaT cells. Additionally, we assessed its influence on the transcription of various epigenetic effectors, including members of the DNA methyltransferase ( DNMT ) and histone deacetylase ( HDAC ) families. Our findings demonstrate a notable downregulation of genes in HaCaT cells, exhibiting diverse patterns upon betanin intake. We considered the involvement of DNMT and HDAC genes in distinct stages of carcinogenesis and the limited exploration of the effects of daily exposure dosages. Our results indicate that betanin may protect the skin from damage caused by UV exposure. Further investigation is essential to explore these potential associations.

In recent years, artificial additives, especially synthetic food colorants, were found to demonstrate wider properties compared to their natural equivalents; however, their health impact is still not totally mapped. Our study aimed to determine the long-term (30 and 90 days) exposure effect of one of the commonly used artificial food colorants, tartrazine, on NMRI mice. The applied dose of tartrazine referred to the human equivalent dose for acceptable daily intake (ADI). Further, we evaluated its impact on the transcription of a range of epigenetic effectors, members of the DNA methyltransferase ( DNMT ) as well as histone deacetylase ( HDAC) families. Following the exposure, organ biopsies were collected from the lungs, kidneys, liver, and spleen, and the gene expression levels were determined by real-time quantitative reverse transcription PCR (RT-qPCR). Our results demonstrated significant upregulation of genes in the tested organs in various patterns followed by the intake of tartrazine on ADI. Since DNMT and HDAC genes are involved in different steps of carcinogenesis, have roles in the development of neurological disorders and the effect of dose of everyday exposure is rarely studied, further investigation is warranted to study these possible associations.

Recently, the field of epigenetics has been intensively studied in relation to nutrition. In our study, the gene expression patterns of histone deacetylases ( HDAC s), which regulate the stability of histone proteins, and DNA methyltransferases ( DNMT s), which regulate DNA methylation, were determined in mice. The animals were fed a human-equivalent dose of the aqueous extract of fruit seeds and peels, which is rich in flavonoids and polyphenols, for 28 days and then exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The concentrations of trans-resveratrol and trans-piceid were determined in the consumed extract by HPLC and were 1.74 mg/L (SD 0.13 mg/L) and 2.37 mg/L (SD 0.32 mg/L), respectively, which corresponds to the consumption of 0.2-1 L of red wine, the main dietary source of resveratrol, in humans daily. Subsequently, 24 h after DMBA exposure, the expression patterns of the HDAC and DNMT genes in the liver and kidneys were determined by qRT-PCR. The DMBA-induced expression of the tested genes HDAC1 , HDAC2 , DNMT1 , DNMT3A and DNMT3B was reduced in most cases by the extract. It has already been shown that inhibition of the DNMT and HDAC genes may delay cancer development and tumour progression. We hypothesise that the extract studied may exert chemopreventive effects.

Background: Maternal overnutrition during pregnancy predisposes the offspring to cardiometabolic diseases., Objectives: This systematic review and meta-analysis aimed to investigate the association between maternal overnutrition and offspring's blood pressure (BP) and the effect of offspring's obesity on this association., Data Sources: PubMed, EMBASE, Clinicaltrials.gov, CENTRAL., Study Selection and Data Extraction: Human studies published in English before October 2021 were identified that presented quantitative estimates of association between maternal overnutrition just before or during pregnancy and the offspring's BP., Synthesis: Random-effect model with the DerSimonian and Laird weighting method was used to analyse regression coefficients or mean differences., Results: After selection, 17 observational studies (140,517 mother-offspring pairs) were included. Prepregnancy body mass index (ppBMI) showed positive correlation with BP in offspring (regression coefficient for systolic: 0.38 mmHg per kg/m 2 , 95% confidence interval (CI) 0.17, 0.58; diastolic: 0.10 mmHg per kg/m 2 , 95% CI 0.05, 0.14). These indicate 1.9 mmHg increase in systolic and 0.5 mmHg increase in diastolic BP of offspring with every 5 kg/m 2 gain in maternal ppBMI. Results on coefficients adjusted for offspring's BMI also showed association (systolic: 0.08 mmHg per kg/m 2 , 95% CI 0.04, 0.11; diastolic: 0.03 mmHg per kg/m 2 , 95% CI 0.01, 0.04). Independent from ppBMI, gestational weight gain (GWG) showed positive correlation with systolic BP (systolic BP: 0.05 mmHg per kg, 95% CI 0.01, 0.09), but not after adjustment for offspring's BMI. Mean systolic BP was higher in children of mothers with excessive GWG than in those of mothers with optimal GWG (difference: 0.65 mmHg, 95% CI 0.25, 1.05)., Conclusions: Independent from offspring's BMI, higher prepregnancy BMI may increase the risk for hypertension in offspring. The positive association between GWG and offspring's systolic BP is indirect via offspring's obesity. Reduction in maternal obesity and treatment of obesity in children of obese mothers are needed to prevent hypertension., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

The possible role of the naturally occurring deuterium in the regulation of cell division was first described in the 1990s. To investigate the mechanism of influence of deuterium (D) on cell growth, expression of 236 cancer-related and 536 kinase genes were tested in deuterium-depleted (40 and 80 ppm) and deuterium-enriched (300 ppm) media compared to natural D level (150 ppm). Among genes with expression changes exceeding 30% and copy numbers over 30 (124 and 135 genes, respectively) 97.3% of them was upregulated at 300 ppm D-concentration. In mice exposed to chemical carcinogen, one-year survival data showed that deuterium-depleted water (DDW) with 30 ppm D as drinking water prevented tumor development. One quarter of the treated male mice survived 344 days, the females 334 days, while one quarter of the control mice survived only 188 and 156 days, respectively. In our human retrospective study 204 previously treated cancer patients with disease in remission, who consumed DDW, were followed. Cumulative follow-up time was 1024 years, and average follow-up time per patient, 5 years (median: 3.6 years). One hundred and fifty-six patients out of 204 (77.9%) did not relapse during their 803 years cumulative follow-up time. Median survival time (MST) was not calculable due to the extremely low death rate (11 cancer-related deaths, 5.4% of the study population). Importantly, 8 out of 11 deaths occurred several years after stopping DDW consumption, confirming that regular consumption of DDW can prevent recurrence of cancer. These findings point to the likely mechanism in which consumption of DDW keeps D-concentration below natural levels, preventing the D/H ratio from increasing to the threshold required for cell division. This in turn can serve as a key to reduce the relapse rate of cancer patients and/or to reduce cancer incidence in healthy populations.

Propolis contains many effective antifungal compounds that have not yet been identified and evaluated. In addition, distinguishing samples of propolis with high antifungal activity from less active ones would be beneficial for effective therapy. Propolis samples were collected from four different geographical regions in Hungary and used to prepare ethanol extracts for analysis. First, an antifungal susceptibility test was performed on Candida albicans . Then, gas chromatography-mass spectrometry (GC-MS) and an opto-electronic nose were applied for the classification of propolis samples. In three propolis samples, the IC 50 was measured between 72 and 134 µg/mL, but it was not calculable in the fourth sample. GC-MS analysis of the four propolis samples identified several compounds belonging to the various chemical classes. In the antifungal samples, the relative concentration of 11,14-eicosadienoic acid was the highest. Based on the opto-electronic electronic nose measurements, 98.4% of the original grouped antifungal/non-antifungal cases were classified correctly. We identified several molecules from propolis with potential antifungal properties. In addition, this is the first report to demonstrate the usefulness of a portable opto-electronic nose to identify propolis samples with high antifungal activity. These results may contribute to the rapid and efficient selection of new fungicide-candidate molecules and effective propolis samples for treatment.

In Sub-Saharan Africa, African giant pouched rats (Cricetomys gambianus) are trained to identify TB patients by smelling sputum. We conducted a systematic review and meta-analysis of the data to see if this novel method is comparable to traditional laboratory screening and detection methods like Ziehl-Neelsen stain-based assays (ZN) and bacterial culture. The search and data processing strategy is registered at PROSPERO (CRD42019123629). Medline via PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for the keywords "pouched rat" and "tuberculosis". Data from 53,181 samples obtained from 24,600 patients were extracted from seven studies. Using sample-wise detection, the sensitivity of the studies was 86.7% [95% CI 80.4-91.2%], while the specificity was 88.4% [95% CI 79.7-93.7%]. For patient-wise detection, the sensitivity was 81.3% [95% CI 64.0-91.4%], while the specificity was 73.4% [95% CI 62.8-81.9%]. Good and excellent classification was assessed by hierarchical summary receiver-operating characteristic analysis for patient-wise and sample-wise detections, respectively. Our study is the first systematic review and meta-analysis of the above relatively inexpensive and rapid screening method. The results indicate that African giant pouched rats can discriminate healthy controls from TB individuals by sniffing sputum with even a higher accuracy than a single ZN screening.

Background: The quadrivalent human papillomavirus (HPV) vaccine has been assumed to give protection against genital warts (GW) as well as cervical cancer. Our main question was whether HPV vaccine has any effects on the prevention of GW reported in randomised controlled clinical trials (RCTs) and time-trend analyses., Methods: This meta-analysis was performed according to the PRISMA guidelines using the PICO format. We searched in three electronic databases (PubMed, Embase, Cochrane Trials), and assessed heterogeneity using the Q-test and I-squared statistics, meta-regression was also performed. Odds ratios (OR) and their confidence intervals (CI) were calculated. The sensitivity was tested by leave-one-out method. We evaluated the presence of publication bias using the funnel plot graph and the Copas selection model. The strength of evidence was assessed using the GRADE approach., Results: Eight RCTs (per-protocol populations) and eight time-trend ecological studies were included in this meta-analysis. A significant reduction (pooled OR = 0.03, 95% CI: 0.01-0.09; I-squared = 53.6%) of GW in young women was recorded in RCTs, and in time-trend analyses both in young women (pooled OR = 0.36, CI 95% = 0.26-0.51; I-squared = 98.2%), and in young men (pooled OR = 0.69, 95% CI = 0.61-0.78; I-squared = 92.7%). In subgroup analysis, a significant reduction of the number of GW events was observed especially in women under 21 years (pooled OR = 0.33, 95% CI = 0.17-0.63). Leave-one-out analysis showed that similar results could be obtained after excluding one study, meta-regression did not show significant difference., Conclusions: Prophylactic, quadrivalent HPV vaccination can prevent GW in healthy women and men, therefore, it should be included in routine immunization programme.

Introduction: Acute pancreatitis (AP) is a life-threatening inflammatory disease of the exocrine pancreas which needs acute hospitalisation. Despite its importance, we have significant lack of knowledge whether the lifestyle factors elevate or decrease the risk of AP or influence the disease outcome. So far, no synthetising study has been carried out examining associations between socioeconomic factors, dietary habits, physical activity, chronic stress, sleep quality and AP. Accordingly, LIFESPAN identifies risk factors of acute pancreatitis and helps to prepare preventive recommendations for lifestyle elements., Methods and Analysis: LIFESPAN is an observational, multicentre international case-control study. Participating subjects will create case and control groups. The study protocol was designed according to the SPIRIT guideline. Patients in the case group (n=1700) have suffered from AP (alcohol-induced, n=500; biliary, n=500; hypertriglyceridemiainduced, n=200; other, n=500); the control group subjects have no AP in their medical history. Our study will have three major control groups (n=2200): hospital-based (n=500), population-based (n=500) and aetiology-based (alcohol, n=500; biliary, n=500 and hypertriglyceridemia, n=200). All of them will be matched to the case group individually by gender, age and location of residence. Aggregately, 3900 subjects will be enrolled into the study. The study participants will complete a complex questionnaire with the help of a clinical research administrator/study nurse. Analysis methods include analysis of the continuous and categorical values., Ethics and Dissemination: The study has obtained the relevant ethical approval (54175-2/2018/EKU) and also internationally registered (ISRCTN25940508). After obtaining the final conclusions, we will publish the data to the medical community and will also disseminate our results via open access., Trial Registration Number: ISRCTN25940508; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pancreatic pseudocyst (PP) and walled-off necrosis can be managed endoscopically, percutaneously or surgically, but with diverse efficacy., Aims & Methods: A comprehensive literature search was carried out from inception to December 2018, to identify articles which compared at least two of the three kinds of treatment modalities, regarding the mortality, clinical success, recurrence, complications, cost and length of hospitalisation (LOH)., Results: The outcomes of endoscopic (ED) and percutaneous drainage (PD) were comparable in six articles. The clinical success of endoscopic intervention was better considering any types of fluid collections (OR = 3.36; 95% confidence interval (CI) 1.48, 7.63; p = 0.004). ED was preferable regarding recurrence of PP (OR = 0.23; 95% CI 0.08, 0.66; p = 0.006). Fifteen articles compared surgical intervention with ED. Significant difference was found in postoperative LOH (WMD (days) = -4.61; 95%CI -7.89, -1.33; p = 0.006) and total LOH (WMD (days) = -3.67; 95%CI -5.00, -2.34; p < 0.001) which favored endoscopy, but ED had lower rate of clinical success (OR = 0.54; 95% CI 0.35, 0.85; p = 0.007) and higher rate of recurrence (OR = 1.80; 95% CI 1.16, 2.79; p = 0.009) in the treatment of PP. Eleven studies compared surgical and percutaneous intervention. PD resulted in higher rate of recurrence (OR = 4.91; 95% CI 1.82, 13.22; p = 0.002) and lower rate of clinical success (OR = 0.13; 95% CI 0.07, 0.22, p < 0.001)., Conclusion: Both endoscopy and surgery are preferable over percutaneous intervention, furthermore endoscopic treatment is associated with shorter hospitalisation than surgery., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Herpes zoster (HZ) causes considerable pain and distress, and γ-Aminobutyric acid (GABA) and its derivatives are assumed to control this, but the available data are inconsistent. This meta-analysis and systematic review aimed to assess the effectiveness of GABA derivatives in the prevention of acute herpetic pain. The metaanalysis was conducted following the PRISMA guidelines using PICO format, registered in PROSPERO number CRD42018095758. PubMed, Web of Science, Ovid, Scopus, and EMBASE databases were searched. Records were included if they were randomized controlled trials of patients undergoing HZ infection, investigating the effect of GABA derivatives versus placebo in the treatment of HZ pain. Eligible trials were evaluated for the risk of bias. Then data were extracted and analysed. The number of patients with observed presence of pain after treatment was used to calculate odds ratio in a random effect model with the DerSimonian-Laird estimator. The I2 statistic was analysed for heterogeneity. The potential risk of bias was measured using Egger's regression test. The meta-analysis included three randomized controlled trials with a total of 297 patients. The incidence of acute HZ pain events for GABA group was significantly lower compared to placebo group,18/148 vs 44/149, respectively (OR = 0.36; 95% CI = 0.14 to 0.93; Z = 2.11; P = 0.035), Egger's test yielded P = 0.308. In conclusion, the present meta-analysis demonstrates that GABA derivatives reduce the incidence of acute herpetic pain. However, additional, well-designed randomized clinical trials are needed to determine their dose- and time-dependency regarding this symptom., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Although chasteberry (Vitex agnus-castus, VAC) has been studied in several clinical trials and available as medicine for the alleviation of premenstrual syndrome (PMS) symptoms, the efficacy of properly characterised preparations has not been assessed in meta-analyses. The aim of our work was to evaluate the efficacy of VAC in PMS. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, taking into account the CONSORT recommendations. PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for studies on VAC. The analysis assessed the efficacy of properly characterised products VAC compared to a placebo for the alleviation of PMS symptoms in terms of responder rate, considering the decrease of Total Symptom Score or PMS Diary score. The random effects model was used to calculate summary relative risk (RR) and 95% confidence interval (CI). Only those randomised, double-blind, placebo-controlled trials were included that fulfilled the criteria of the CONSORT recommendations aiming at the proper characterization of herbal products. Out of the 21 clinical trials, three studies (520 females) fulfilled the inclusion criteria, comparing the efficacy of special extracts Ze 440 and BNO 1095 to a placebo for the treatment of PMS. VAC preparations were confirmed to be effective in the reduction of PMS symptoms: women taking VAC were 2.57 (95% CI 1.52-4.35) times more likely to experience a remission in their symptoms compared to those taking the placebo. Although several clinical trials have been carried out with VAC, the majority of the studies cannot be used as evidence for efficacy due to incomplete reporting, especially concerning the description of the used medication. More trials following the CONSORT recommendations are needed to assess the efficacy of VAC extracts., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A fixed combination of hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen ® ) has been used in the therapy of hypotension for decades. Although its efficacy was evaluated in clinical trials, these studies have not been critically assessed in meta-analyses., Purpose: To systematically evaluate the efficacy of a fix combination of camphor and hawthorn extract (Korodin ® ) on blood pressure and cognition compared to placebo, in a meta-analysis based on randomized controlled trials (RCTs)., Study Design: The meta-analysis was carried out following the PRISMA guidelines, using the PICO format, and it was registered in the PROSPERO register., Methods: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and Web of Science databases were searched for relevant studies. Placebo-controlled clinical studies involving adult patients receiving a fix combination of hawthorn extract and camphor were included. No language or publication year restrictions were applied., Results: Four randomized trials including a total of 221 patients were pooled for statistical analysis. According to the present meta-analysis, the fixed combination of hawthorn and camphor significantly increases systolic and diastolic blood pressure compared to placebo (p-values: 0.017 and 0.049, respectively) and had a beneficial, but not statistically significant effect on the cognitive performance in the connect-the-numbers test (p-value: 0.071)., Conclusion: Korodin ® is an effective and presumably safe complementary therapy for the treatment of hypotension. Its blood pressure increasing effect is confirmed; however, the evidence supporting its use is very limited. The optimum dose and duration of treatment is still unclear. The comprehensive evaluation of efficacy and safety is required in further, high-quality clinical studies, involving larger patient populations and comparable endpoints., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Balneotherapy has been used to treat several diseases including locomotor, neurological and dermatological conditions. The basis of the "organic hypothesis" of medical balneology is that medicinal waters, especially thermal spa and hot spring waters, contain a high variability of organic components with possible biological effects, including UV photo-protection. The recent study aims to clarify this effect in a human keratinocyte cell line model. Results confirm that organic-rich extract of selected medicinal waters might protect skin-derived cells from DNA damage. These results give a clinical relevance to medicinal waters or pharmaceutical products prepared from them in preventing the adverse effects of solar or artificial UV radiation on the human skin.

Background: Obesity rates have increased sharply in recent decades. As there is a growing number of cases in which acute pancreatitis (AP) is accompanied by obesity, we found it clinically relevant to investigate how body-mass index (BMI) affects the outcome of the disease., Aim: To quantify the association between subgroups of BMI and the severity and mortality of AP., Methods: A meta-analysis was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Protocols. Three databases (PubMed, EMBASE and the Cochrane Library) were searched for articles containing data on BMI, disease severity and mortality rate for AP. English-language studies from inception to 19 June 2017 were checked against our predetermined eligibility criteria. The included articles reported all AP cases with no restriction on the etiology of the disease. Only studies that classified AP cases according to the Atlanta Criteria were involved in the severity analyses. Odds ratios (OR) and mean differences (MD) were pooled using the random effects model with the DerSimonian-Laird estimation and displayed on forest plots. The meta-analysis was registered in PROSPERO under number CRD42017077890., Results: A total of 19 articles were included in our meta-analysis containing data on 9997 patients. As regards severity, a subgroup analysis showed a direct association between AP severity and BMI. BMI < 18.5 had no significant effect on severity; however, BMI > 25 had an almost three-fold increased risk for severe AP in comparison to normal BMI (OR = 2.87, 95%CI: 1.90-4.35, P < 0 .001). Importantly, the mean BMI of patients with severe AP is higher than that of the non-severe group (MD = 1.79, 95%CI: 0.89-2.70, P < 0.001). As regards mortality, death rates among AP patients are the highest in the underweight and obese subgroups. A BMI < 18.5 carries an almost two-fold increase in risk of mortality compared to normal BMI (OR = 1.82, 95%CI: 1.32-2.50, P < 0.001). However, the chance of mortality is almost equal in the normal BMI and BMI 25-30 subgroups. A BMI > 30 results in a three times higher risk of mortality in comparison to a BMI < 30 (OR = 2.89, 95%CI: 1.10-7.36, P = 0.026)., Conclusion: Our findings confirm that a BMI above 25 increases the risk of severe AP, while a BMI > 30 raises the risk of mortality. A BMI < 18.5 carries an almost two times higher risk of mortality in AP., Competing Interests: Conflict-of-interest statement: The authors declare that no conflict of interest exists. There are no financial or other competing interests for principal investigators, patients included or any member of the trial.

Background: Juvenile Idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. The diagnosis is based on the underlying symptoms of arthritis with an exclusion of other diseases Biologic agents are increasingly used on the side of disease-modifying anti-rheumatic drugs (DMARD) in JIA treatment., Main Body: The aim of this meta-analysis was to investigate the observed infections in JIA children during tumor necrosis factor (TNF)-alpha inhibitor therapy. A systematic search of three databases (Medline via PubMed, Embase, Cochrane Library) was carried out up to May 2018. Published trials that evaluated the infectious adverse events in patients receiving TNF-alpha inhibitor vs. a control group were included in the analysis. Full-text data extraction was carried out independently by the investigators from ten relevant publications. 1434 patients received TNF-alpha inhibitor therapy; the control group consisted of 696 subjects. The analysis presented the risk of infection in the active treatment group (OR = 1.13; 95% CI: 0.76-1.69; p = 0.543). The majority of infections were upper respiratory tract infections (URTIs). Furthermore, the subgroup analysis demonstrated a higher infection rate in the observed localization., Conclusion: Anti-TNF therapy slightly but not significantly increases the incidence of infection in JIA children compared to other therapies (GRADE: moderate evidence). The most common infections reported were mild URTIs. Further studies with larger patients number with a strong evidence level are crucially needed to finalize the answer whether anti-TNF therapy elevates and if yes on what extent the incidence of infection in JIA children., Trial Registration: Prospero: CRD42017067873 .

Background: Metformin is the first-choice drug for patients with Type 2 diabetes, and this therapy is characterized by being weight neutral. However, in the elderly an additional unintentional weight loss could be considered as an adverse effect of the treatment., Objectives: We aimed to perform a meta-analysis of placebo-controlled studies investigating the body weight changes upon metformin treatment in participants older than 60 years., Materials and Methods: PubMed, EMBASE and the Cochrane Library were searched. We included at least 12 week-long studies with placebo control where the mean age of the metformin-treated patients was 60 years or older and the body weight changes of the patients were reported. We registered our protocol on PROSPERO (CRD42017055287)., Results: From the 971 articles identified by the search, 6 randomized placebo-controlled studies (RCTs) were included in the meta-analysis (n = 1541 participants). A raw difference of -2.23 kg (95% CI: -2.84 --1.62 kg) body weight change was detected in the metformin-treated groups as compared with that of the placebo groups (p<0.001). Both total cholesterol (-0.184 mmol/L, p<0.001) and LDL cholesterol levels (-0.182 mmol/L, p<0.001) decreased upon metformin-treatment., Conclusions: Our meta-analysis of RCTs showed a small reduction of body weight together with slight improvement of the blood lipid profile in patients over 60 years. With regard to the risk of unintentional weight loss, metformin seems to be a safe agent in the population of over 60 years. Our results also suggest that metformin treatment may reduce the risk of major coronary events (-4-5%) and all-cause mortality (-2%) in elderly diabetic populations., Competing Interests: The authors have declared that no competing interests exist.

Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies [randomized controlled trials (RCTs) and observational studies] using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316). Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR = 1.22, 95% CI = 1.06-1.396, p = 0.004) and MI (RR = 1.43, 95% CI = 1.24-1.66, p < 0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR = 0.99, 95% CI = 0.76-1.28, p = 0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR = 1.21, 95% CI = 0.97-1.50, p = 0.09). Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.

Background: Postoperative nausea and vomiting (PONV) is a distressing outcome related to surgeries. Traditionally, ginger has been used in the treatment of nausea and vomiting for thousands of years. Recently, several randomized, placebo-controlled clinical trials (RCTs) have been conducted to evaluate the efficacy of ginger in PONV., Purpose: To systematically evaluate the efficacy of ginger on postoperative nausea and vomiting (PONV) compared to placebo, based on RCTs., Study Design: The meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register., Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for relevant studies. Human, placebo-controlled clinical studies of patients undergoing any types of surgery, receiving pharmacological doses of ginger per os were included. Only clinical trials with explicit description of the ginger preparation used were analysed. No language or publication year restrictions was applied., Results: Ten randomized trials including a total of 918 patients were pooled for the statistical analysis. The present meta-analysis supports that ginger has a significant effect on the severity of PONV based on visual analogue scale (VAS) results: in a fixed effects model the pooled standardized mean difference (SMD) was -0.247 (favouring ginger; [LL]: -0.455, [UL]: -0.040, p-value: 0.019). Moreover, our results suggest that ginger reduces the incidence of postoperative nausea and vomiting, as well antiemetic drug demand; however, these effects are not statistically significant compared to placebo, which may be explained by underdosing., Conclusions: According to our thorough meta-analysis ginger is safe and well tolerated, and decreases the severity of PONV, and may lower the incidence of postoperative nausea and vomiting, which in turn may reduce antiemetic drug demand, suggesting that ginger may be a useful alternative to antiemetic medications to alleviate PONV., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: Colorectal cancer is an increasing cause of death. Circulating microRNAs (miRs) could be great diagnostic and prognostic biomarkers of colorectal cancer, but further continuation of their utility is needed for their comprehensive application., Materials and Methods: Twenty-seven patients with colonic cancer, 16 with rectal cancer and 12 healthy volunteers as controls, were involved in this study. Expression of miR-155, miR-21, miR-221, miR-30a, miR-34a and miR-29a were determined by reverse transcription polymerase chain reaction (RT-PCR) from sera of patients., Results: Expression of miR-155, miR-21 and miR-221 was significantly higher in rectal cancer than in colonic cancer. There was no difference found between those with TNM1 cancer and controls for both cancer types. miR-155, miR-34a and miR-29a were down-regulated in all patients with cancer compared to controls. We did not find any statistically significant up-regulation of miR-221 in patients with colonic cancer compared to controls. In contrast, in patients with rectal cancer, miR-221 expression was higher than in controls. Advanced stage was also linked to higher miR-221 expression compared to early stage. Slight, but statistically significant increase was observed in miR-30a expression in patients with colon cancer compared to control individuals., Conclusion: Our results partly support previous findings. Here we report on differences in the expression of circulating microRNA between colonic and rectal tumours for the first time., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: The aim of this study was to evaluate the connection between pancreatic cancer (PC) and genetic variants associated with chronic pancreatitis via systematic review and meta-analysis., Methods: The data search was performed in 3 major databases (PubMed, Embase, and Cochrane Library). The selected studies have looked into the presence of the pancreatitis-associated genes in patients with PC and in control subjects, the outcome being the frequency of the mutations in the 2 groups. For the binary outcomes, pooled odds ratio (OR) and 95% confidence interval (CI) were calculated., Results: Ten articles proved to be eligible for the qualitative synthesis, and 8 articles were suitable for statistical analysis. Six case-control studies, comprising 929 PC cases and 1890 control subjects for serine protease inhibitor Kazal type 1 (SPINK1) mutations, and 5 case-control studies, comprising 1674 PC cases and 19,036 control subjects for CFTR mutations, were enrolled in our analysis. SPINK1 mutations showed no association with PC (OR, 1.52; 95% CI, 0.67-3.45; P = 0.315), whereas mutations in CFTR modestly increased the risk of PC (OR, 1.41; 95% CI, 1.07-1.84; P = 0.013)., Conclusion: Our meta-analysis showed that mutations in CFTR modestly increase the risk of PC, whereas no association was found between SPINK1 and PC.

Although an extensive research is being undertaken, the ideal bone graft and evaluation method of the bone formation draw still a warranted attention. The purpose of this study was to develop a novel multimodal radiomics evaluation method, utilizing X-ray computed tomography (CT) and single photon emission computed tomography (SPECT) with Tc-99m-Methyl diphosphonate (Tc-99m-MDP) tracer. These modalities are intended to provide quantitative data concerning the mineral bone density (after evaluation it is referred to as opacity) and the osteoblast activity, at the same time. The properties of bone formation process within poly (methyl methacrylate)-based bone cement graft (PMMA) was compared to that of albumin coated, sterilized, antigen-extracted freeze-dried human bone grafts (HLBC), in caudal vertebrae (C5) of rats. The animals were scanned at 3 and 8 weeks after surgery. In both groups, the mean opacity increased, while the mean Tc-99m-MDP activity decreased. The later parameter was significant (n = 4, p = 0.002) only in HLBC group. The linear regression analysis of PMMA-treated group variables (mean opacity increase; mean Tc-99m-MDP activity decrease), revealed a negative correlation with the medium strength (r = 0.395, p = 0.605). Whereas, it showed strong positive correlation when HLBC group variables were analyzed (r = 0.772, p = 0.012). These results indicate that using HLBC grafts is advantageous in terms of the osteoblast activity and bone vascularization over PMMA cement. Using this regression analysis method, we were able to distinguish characteristics that otherwise could not be distinguished by a regular data analysis. Hence, we propose utilizing this novel method in preclinical tests, and in clinical monitoring of bone healing, in order to improve diagnosis of bone-related diseases., Competing Interests: Ferenc Budán is employed by MedProDevelop. Domokos Máthé is employed by CROmed Translational Research Centers. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Elevated serum triglyceride concentration (seTG, >1.7 mM or >150 mg/dL) or in other words hypertriglyceridemia (HTG) is common in the populations of developed countries. This condition is accompanied by an increased risk for various diseases, such as acute pancreatitis (AP). It has been proposed that HTG could also worsen the course of AP. Therefore, in this meta-analysis, we aimed to compare the effects of various seTGs on the severity, mortality, local and systemic complications of AP, and on intensive care unit admission. 16 eligible studies, including 11,965 patients were retrieved from PubMed and Embase. The results showed that HTG significantly elevated the odds ratio (OR = 1.72) for severe AP when compared to patients with normal seTG (<1.7 mM). Furthermore, a significantly higher occurrence of pancreatic necrosis, persistent organ failure and renal failure was observed in groups with HTG. The rates of complications and mortality for AP were significantly increased in patients with seTG >5.6 mM or >11.3 mM versus <5.6 mM or <11.3 mM, respectively. We conclude that the presence of HTG worsens the course and outcome of AP, but we found no significant difference in AP severity based on the extent of HTG.

Objective: Preeclampsia (PE) is the leading cause of maternal and perinatal mortality around the world. The impaired function of fetal-placental vasculature is a key factor in PE. Several studies have investigated the connection between PE and endothelial dysfunction. Also, many authors have examined the changes in asymmetric dimethylarginine (ADMA) as a prominent marker of endothelial dysfunction. Our study aim is to review and analyse the connections between PE and ADMA levels., Methods: To obtain data we performed a comprehensive literature search in Pubmed, Embase and Web of Science. Standardized mean differences were used to estimate the differences in ADMA levels., Results: The quantitative analysis included 10 studies reporting a total number of 631 PE and 498 healthy pregnant individuals. We found significantly higher ADMA levels in PE patients compared to controls, when comparing the ADMA levels of the patients to the ADMA levels of the controls (z = 5.93, p < 0.001). This difference was present regardless of the measurement method. Regarding the onset of PE, we found significantly higher ADMA levels in patients suffering from early-onset PE when comparing the ADMA levels of the early-onset PE patients to that of the controls (z = 2.82, p = 0.005). However, we did not find such difference when we compared late-onset PE patients' ADMA levels to controls., Conclusion: ADMA is significantly higher in PE patients than in the controls. Elevated ADMA levels can play a major role in the development of PE, but more research is needed to clarify the connection between the two., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: To analyze the effect of intralesional steroid injections in addition to endoscopic dilation of benign refractory esophageal strictures., Methods: A comprehensive search was performed in three databases from inception to 10 April 2017 to identify trials, comparing the efficacy of endoscopic dilation to dilation combined with intralesional steroid injections. Following the data extraction, meta-analytical calculations were performed on measures of outcome by the random-effects method of DerSimonian and Laird. Heterogeneity of the studies was tested by Cochrane's Q and I 2 statistics. Risk of quality and bias was assessed by the Newcastle Ottawa Scale and JADAD assessment tools., Results: Eleven articles were identified suitable for analyses, involving 343 patients, 235 cases and 229 controls in total. Four studies used crossover design with 121 subjects enrolled. The periodic dilation index (PDI) was comparable in 4 studies, where the pooled result showed a significant improvement of PDI in the steroid group (MD: -1.12 dilation/month, 95%CI: -1.99 to -0.25 P = 0.012; I 2 = 74.4%). The total number of repeat dilations (TNRD) was comparable in 5 studies and showed a non-significant decrease (MD: -1.17, 95%CI: -0.24-0.05, P = 0.057; I 2 = 0), while the dysphagia score (DS) was comparable in 5 studies and did not improve (SMD: 0.35, 95%CI: -0.38, 1.08, P = 0.351; I 2 = 83.98%) after intralesional steroid injection., Conclusion: Intralesional steroid injection increases the time between endoscopic dilations of benign refractory esophageal strictures. However, its potential role needs further research., Competing Interests: Conflict-of-interest statement: The authors deny any conflict of interest.

Aim: To understand the influence of chronic kidney disease (CKD) on mortality, need for transfusion and rebleeding in gastrointestinal (GI) bleeding patients., Methods: A systematic search was conducted in three databases for studies on GI bleeding patients with CKD or end-stage renal disease (ESRD) with data on outcomes of mortality, transfusion requirement, rebleeding rate and length of hospitalization (LOH). Calculations were performed with Comprehensive Meta-Analysis software using the random effects model. Heterogeneity was tested by using Cochrane's Q and I 2 statistics. Mean difference (MD) and OR (odds ratio) were calculated., Results: 1063 articles (EMBASE: 589; PubMed: 459; Cochrane: 15) were found in total. 5 retrospective articles and 1 prospective study were available for analysis. These 6 articles contained data on 406035 patients, of whom 51315 had impaired renal function. The analysis showed a higher mortality in the CKD group (OR = 1.786, 95%CI: 1.689-1.888, P < 0.001) and the ESRD group (OR = 2.530, 95%CI: 1.386-4.616, P = 0.002), and a rebleeding rate (OR = 2.510, 95%CI: 1.521-4.144, P < 0.001) in patients with impaired renal function. CKD patients required more unit red blood cell transfusion (MD = 1.863, 95%CI: 0.812-2.915, P < 0.001) and spent more time in hospital (MD = 13.245, 95%CI: 6.886-19.623, P < 0.001) than the controls., Conclusion: ESRD increases mortality, need for transfusion, rebleeding rate and LOH among GI bleeding patients. Prospective patient registries and observational clinical trials are crucially needed., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this article.

Autoimmune regulator (AIRE) is a transcription factor that functions as a novel player in immunological investigations. In the thymus, it has a pivotal role in the negative selection of naive T-cells during central tolerance. Experimental studies have shown that single nucleotide polymorphism (SNP) alters transcription of the AIRE gene. SNPs thereby provide a less efficient negative selection, propagate higher survival of autoimmune T-cells, and elevate susceptibility to autoimmune diseases. To date, only rheumatoid arthritis (RA) has been analysed by epidemiological investigations in relation to SNPs in AIRE. In our meta-analysis, we sought to encompass case-control studies and confirm that the association between SNP occurrence and RA. After robust searches of Embase, PubMed, Cochrane Library, and Web of Science databases, we found 19 articles that included five independent studies. Out of 11 polymorphisms, two (rs2075876, rs760426) were common in the five case-control studies. Thus, we performed a meta-analysis for rs2075876 (7145 cases and 8579 controls) and rs760426 (6696 cases and 8164 controls). Our results prove that rs2075876 and rs760426 are significantly associated with an increased risk of RA in allelic, dominant, recessive, codominant heterozygous, and codominant homozygous genetic models. These findings are primarily based on data from Asian populations.

Background: Lung diseases (resulting from air pollution) require a widely accessible method for risk estimation and early diagnosis to ensure proper and responsive treatment. Radiomics-based fractal dimension analysis of X-ray computed tomography attenuation patterns in chest voxels of mice exposed to different air polluting agents was performed to model early stages of disease and establish differential diagnosis., Methods: To model different types of air pollution, BALBc/ByJ mouse groups were exposed to cigarette smoke combined with ozone, sulphur dioxide gas and a control group was established. Two weeks after exposure, the frequency distributions of image voxel attenuation data were evaluated. Specific cut-off ranges were defined to group voxels by attenuation. Cut-off ranges were binarized and their spatial pattern was associated with calculated fractal dimension, then abstracted by the fractal dimension -- cut-off range mathematical function. Nonparametric Kruskal-Wallis (KW) and Mann-Whitney post hoc (MWph) tests were used., Results: Each cut-off range versus fractal dimension function plot was found to contain two distinctive Gaussian curves. The ratios of the Gaussian curve parameters are considerably significant and are statistically distinguishable within the three exposure groups., Conclusions: A new radiomics evaluation method was established based on analysis of the fractal dimension of chest X-ray computed tomography data segments. The specific attenuation patterns calculated utilizing our method may diagnose and monitor certain lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, tuberculosis or lung carcinomas.

Medical significance of the organic fractions of natural waters is still poorly understood. Nevertheless, there are putative biologically active organic compounds found in natural medical waters and related clay or mud samples. Organic fractions of five thermal (spa) water samples of different geochemical origin were tested for photo-biological effects. To study possible effects on the UV sensitivity of Salmonella typhimurium TA strains, the organic isolates were applied in the "plate incorporation" Ames test combined with UV-irradiation. Four samples showed measurable survival of TA100 his+ revertants following exposure to a normally lethal UV dose. Metabolic activation with a mammalian microsomal fraction (S9) elevated the effect detected (up to 61% survival). This is the first study to demonstrate the UV-protective property of organic matter in natural thermal water samples used in balneotherapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel dicistrovirus (strain NB-1/2011/HUN, KJ802403) genome was detected from guano collected from an insectivorous bat (species Pipistrellus pipistrellus) in Hungary, using viral metagenomics. The complete genome of NB-1 is 9136 nt in length, excluding the poly(A) tail. NB-1 has a genome organization typical of a dicistrovirus with multiple 3B(VPg) and a cripavirus-like intergenic region (IGR)-IRES. NB-1 shares only 41 % average amino acid sequence identity with capsid proteins of Himetobi P virus, indicating a potential novel species in the genus Cripavirus, family Dicistroviridae.

Although advances in cancer therapies continue to develop, the shortness of the survival of lung cancer patients is still disappointing. Therefore, finding new adjuvant strategies is within the focus of cancer cure. Based on observations that deuterium depletion inhibits the growth of cancer cell lines and suppresses certain proto-oncogenes, we have conducted a clinical study in 129 patients with small cell and nonsmall cell lung cancers who consumed deuterium-depleted drinking water (DDW) as a nontoxic agent in addition to conventional chemotherapy and radiotherapy. Median survival time (MST) was 25.9 mo in males and 74.1 mo in female patients; the difference between genders was statistically significant (p < 0.05). Median survival of subjects with brain metastasis was 27.1 mo. Cumulative 5-yr survival probabilities were 19%, 52%, and 33% in males, females, and all patients with brain metastasis, respectively. Gene expression analysis in mouse lung indicated that DDW attenuates 7,12-dimethylbenz(a)anthracene (DMBA)-induced expression of Bcl2, Kras, and Myc in females. In conclusion, DDW counteracts the DMBA-induced overexpression of Bcl2, Kras and Myc genes in mouse lung, and it may extend survival of lung cancer patients as a nontoxic anticancer dietary supplement, especially for women with tumors overexpressing cancer-related genes, because MST of DDW-consuming group was 2-4 times longer than it is generally observed in lung cancer patients.

Patulin (PAT), is one of the most widely disseminated mycotoxins found in agricultural products. In this study the PAT-induced accumulation of reactive oxygen species (ROS) and the regulation of the specific activities of antioxidant enzymes were investigated in the single cell eukaryotic organism Schizosaccharomyces pombe. In comparison with the untreated cells, 500 μM PAT treatment caused a 43% decrease in the concentration of the main intracellular antioxidant, glutathione (GSH); this depletion of GSH initiated a 2.44- and a 2.6-fold accumulation of superoxide anion and hydrogen peroxide, respectively, but did not increase the concentration of hydroxyl radicals; the reduction of ROS-induced adaptation processes via the activation of Pap1 transcription factor resulted in significantly increased specific activities of Cu/Zn superoxide dismutase, catalase and glutathione S-transferase to protect the cells against the ROS-induced unbalanced redox state. However, no change was measured in the activities of glutathione reductase, glutathione peroxidase and glucose-6-phosphate dehydrogenase. It seems reasonable to assume that the temporary PAT-induced ROS accumulation plays a crucial role in adaptation processes. The adverse effects of PAT may be exerted mainly through the destruction of cellular membranes and protein/enzyme functions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis. The effect of fenugreek on ALOX and COX genes was examined in AKR/J H-2(k) mice exposed to dimethylbenz[α]anthracene (DMBA), a potent carcinogen. The expression pattern of these genes was determined by detecting the mRNA expression in various tissues (the lungs, liver, spleen and the kidneys) in four groups of mice. Two groups were fed with normal and two of them with fenugreek containing nutriment. Each group divided into DMBA treated and control groups. Mice were autopsied on day 7 after DMBA treatment for mRNA isolation. Fenugreek consumption itself did not change gene expression compared with the control group. DMBA could increase the expression of ALOX12, ALOX15, ALOX5 genes mainly in all organs. Fenugreek consumption was generally protective in each organ in a different manner. DMBA treatment increased COX2 gene expression, but fenugreek was protective in all tissues examined. In COX1 gene, the fenugreek diet could suppress the expression, except for spleen, independently from carcinogen exposure. Therefore by inhibiting the arachidonic acid metabolism fenugreek may prevent tumorigenesis., (Copyright © 2010 John Wiley & Sons, Ltd.)

Methylnitrosourea (MNU) is a well-known pluripotent direct-acting carcinogen. Formation of MNU following incubation of various meats with additional nitrite under in vitro acidic conditions is possible. It is possible that many species, including humans, are exposed to carcinogenic MNU, generated in their alimentary tract. Previously, an animal model was developed by our research group to investigate the expression of three genes c-myc, Ha-ras and p53 as early molecular epidemiological biomarkers of carcinogenic exposure or carcinogenesis caused by DMBA (dimethylbenz[alpha]anthracene). The aim of this study was to investigate the early effect of MNU on the gene expression levels. MNU is a direct-acting carcinogen which spontaneously and rapidly degrades, so any effect on the gene expression is observed in 24 hours. Our results show the maximum effect in vivo on the gene expression at 12 hours after the MNU treatment; on the other hand, 24 hours after the treatment, the elevated gene expressions decreased in target organs (bone marrow, lung, lymph nodes). Our results correspond to "long-term" experiments of the carcinogenic effect of MNU in different target organs. Our findings suggest that MNU has an impact on the expression of c-myc, Ha-ras and p53 genes in 12 hours, especially in bone marrow. Overexpression of these genes occurs as an early biological effect of exposure to chemical carcinogens. According to our results, the high expression of these genes could indicate MNU exposure and these genes could take part in MNU-induced tumorigenesis.

For many years the molecular biology has been one of the most promising fields of science and its several methods have been used in practice. These new methods of molecular biology made impression on epidemiology and developed a new discipline, called molecular epidemiology. The molecular and predictive epidemiology play more and more important roles in the prevention of cancers. Early biomarkers could identify the high risk population to have the possibilities of primary preventive interventions. It uses both molecular biological methods and the elements of epidemiology. Its specificity is not high enough to establish the diagnosis but it can be used to follow the "minimal residual disease" and with markers of individual susceptibility, to assess the risk of tumors. As to the practice there are many problems because of the limited therapeutic possibilities, but the molecular and predictive epidemiology becomes an important part of medicine in the future.

In vivo investigations on oncogenes and onco-suppressor genes may provide new findings on the potential carcinogenic effects of various cytostatic protocols inducing secondary tumours of the head and neck. Further surgeries are often necessary due to regional recurrence after the Cisplatin-supplemented BVM (Bleomycin, Vincristine, Methotrexate) protocol in the treatment of human head and neck tumours. Our earlier studies have illustrated the carcinogenic and mutagenic potential of Cisplatin. The effect of Cisplatin on the alteration of different onco- and suppressor genes has also been proven. Our present study aimed at investigating the early effects of the BVM and the CFu (Cisplatin, 5-Fluorouracil) protocols on early oncogene and tumour suppressor gene expressions in mice. Body weight equivalent amounts of cytostatics were administered intraperitoneally to 6- to 8-week-old, inbred, female CBA/Ca mice. Twenty-four, 48 and 72 hours after the treatment, RNA was isolated from the target organs and the quantitative expression of c-myc, Ha-ras and p53 genes were examined. The protocols caused detectable changes. A "short-term" in vivo test, the 24-hour examination of gene expression, is suitable for detecting early effects of carcinogen exposure. The alterations of gene expression, caused by the Cisplatin-containing protocol, draw attention to the probable role of Cisplatin in the development of regional recurrence and to the possibility of prevention.