NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Human papillomavirus infections among Hungarian female sex workers.

The purpose of this study was to assess the human papillomavirus (HPV) prevalence in cervical, oropharyngeal and anal samples of the high-risk population of Hungarian female sex workers (FSWs). HPV testing of swab specimens from FSWs (n = 34) using polymerase chain reaction (PCR) methodology was performed. Results were compared with control group (n = 52) matched for age. Questionnaires were used to obtain data regarding participants' sexual behaviour. Data were analysed using SPSS. HPV DNA was detected in at least one location in a great majority of FSWs (82.4%), compared with 46.2% of the general female population (P < 0.05). Both the cervical and the anal samples of sex workers showed higher infection rates than those of controls (64.7% vs. 34.6% and 50.0% vs. 15.4%, respectively, P < 0.05). High-risk HPV prevalence was also significantly higher in sex workers (55.9% vs. 25.0%, P < 0.05). A significantly higher proportion of FSWs had a history of genital warts (26.5% vs. 3.8%, P < 0.05). The results suggest that condom use may not result in adequate protection from HPV infection. The high infection rates among FSWs should be viewed as a priority group for HPV and cervical cancer prevention programmes since they are sources of HPV infection for the general population.

Relation of circulating T cell profiles to airway inflammation and asthma control in asthmatic pregnancy.

Asthmatic inflammation during pregnancy poses a risk for maternal and fetal morbidities. Circulating T cell immune phenotype is known to correlate with airway inflammation (detectable by fractional concentration of nitric oxide present in exhaled breath (FENO)) in non-pregnant allergic asthmatics. The aim of this study was to assess the relationship of peripheral T cell phenotype to FENO and clinical variables of asthma during pregnancy.We examined 22 pregnant women with allergic asthma in the 2nd/3rd trimester. The prevalence of Th1, Th2, regulatory T (Treg) and natural killer (NK) cell subsets was identified with flow cytometry using cell-specific markers. FENO, Asthma Control Test (ACT) total score and lung function were evaluated.Peripheral blood Th1, Th2, Treg, and NK cell prevalence were not significantly correlated to airway inflammation assessed by FENO in asthmatic pregnant women (all cells p > 0.05; study power > 75%). However, an inverse correlation was detected between Th2 cell prevalence and ACT total scores (p = 0.03) in asthmatic pregnancy.Blunted relationship between T cell profile and airway inflammation may be the result of pregnancy induced immune tolerance in asthmatic pregnancy. On the other hand, increased Th2 response impairs disease control that supports direct relationship between symptoms and cellular mechanisms of asthma during pregnancy.

Factors influencing skin autofluorescence of patients with peritoneal dialysis.

Skin autofluorescence (SAF) measurement is a simple, noninvasive method to assess tissue advanced glycation end products (AGE). In patients with end-stage renal disease and in those on hemodialysis AGE production is increased. Less is known about those treated with peritoneal dialysis (PD). In this study we tested if SAF is influenced by clinical and treatment characteristics in PD patients.This cross-sectional study included 198 PD patients (of those, 128 were on traditional glucose-based solutions and 70 patients were partially switched to icodextrin-based PD). SAF measurements were done with a specific AGE Reader device. The impact of patients' age, gender, current diabetes, duration of PD, cumulative glucose exposure, body mass index, smoking habits and use of icodextrin on SAF values were tested with multiple regression analysis.Our analysis revealed that patients' age, current diabetes and icodextrin use significantly increase patients' SAF values (p = 0.015, 0.012, 0.005, respectively). AGE exposure of PD patients with diabetes and on icodextrin solution is increased. Further investigation is required whether this finding is due to the icodextrin itself or for a still unspecified clinical characteristic of PD population treated with icodextrin.

Characterization of a new 4BS.7HL wheat-barley translocation line using GISH, FISH, and SSR markers and its effect on the ß-glucan content of wheat.

A spontaneous interspecific Robertsonian translocation was revealed by genomic in situ hybridization (GISH) in the progenies of a monosomic 7H addition line originating from a new wheat 'Asakaze komugi' × barley 'Manas' hybrid. Fluorescence in situ hybridization (FISH) with repetitive DNA sequences (Afa family, pSc119.2, and pTa71) allowed identification of all wheat chromosomes, including wheat chromosome arm 4BS involved in the translocation. FISH using barley telomere- and centromere-specific repetitive DNA probes (HvT01 and (AGGGAG)(n)) confirmed that one of the arms of barley chromosome 7H was involved in the translocation. Simple sequence repeat (SSR) markers specific to the long (L) and short (S) arms of barley chromosome 7H identified the translocated chromosome segment as 7HL. Further analysis of the translocation chromosome clarified the physical position of genetically mapped SSRs within 7H, with a special focus on its centromeric region. The presence of the HvCslF6 gene, responsible for (1,3;1,4)-ß-D-glucan production, was revealed in the centromeric region of 7HL. An increased (1,3;1,4)-ß-D-glucan level was also detected in the translocation line, demonstrating that the HvCslF6 gene is of potential relevance for the manipulation of wheat (1,3;1,4)-ß-D-glucan levels.

Maternal cytokine balance on the third postpartum day is not affected by the mode of delivery after healthy pregnancies.

Previous reports have suggested that delivery is associated with the induction of inflammatory cytokines. The present study was designed to investigate whether increased cytokine production was present on postpartum day 3 after a normal pregnancy and whether any changes were associated with the mode of delivery. In total, 33 pregnant women were enrolled; 18 delivered vaginally and 15 underwent an elective caesarean section (C-section). The levels of 17 cytokines and growth hormones were measured at the beginning of delivery or before anaesthesia and on postpartum day 3. While interleukin (IL)-6 and IL-8 levels decreased significantly postpartum, other cytokine concentrations were comparable before and after delivery. Only IL-7 levels were significantly increased in the C-section patients compared with the vaginal birth patients postpartum. In conclusion, there was no risk of a prolonged maternal inflammatory reaction after an uncomplicated vaginal birth or elective C-section, so it is probably not necessary to consider this as an issue when making a decision on the mode of delivery following uncomplicated pregnancy.

Molecular characterization of atrazine resistance in common ragweed (Ambrosia artemisiifolia L.).

Common ragweed (Ambrosia artemisiifolia L.) is the most frequent weed in the Carpathian Basin and is spreading fast in other parts of Europe. In recent years, besides the wild type, a mutant genotype resistant to atrazine herbicides has evolved and is now widespread in many areas. The present study demonstrates that the atrazine resistance of ragweed is maternally inherited, and is caused by a point mutation in the psbA chloroplast gene. The promoter 5'-untranslated region and the open reading frame regions of the gene were analysed, and a homology search was performed. Both the atrazine-resistant and susceptible types of cpDNA were present in atrazine-resistant plants, while the mixed presence of both genotypes in the same plant, known as heteroplasmy, was not unequivocally detectable in susceptible plants.

Effect of 3 months of doxazosin therapy on T-cell subsets in type 2 diabetic patients.

Doxazosin, an alpha(1)-adrenergic receptor inhibitor, is commonly administered to patients with type 2 diabetes, hypertension and nephropathy. The impact of 3 months' doxazosin therapy on the prevalence of activated and regulatory T lymphocytes was analysed in this pilot study of men with type 2 diabetes (n = 10) who received doxazosin 4 mg/day in addition to their ongoing therapy. The prevalence of CD4(+), CD8(+), CD25(+) and CD69(+) cells at baseline and after 3 months of add-on therapy was determined. The prevalence of regulatory T-cells was detected by two different approaches: forkhead box P3 (FoxP3) positivity; and the number of CD4(+)CD25(+high) cells. During 3 months of doxazosin therapy, patients' blood pressure, blood glucose control and lipid profiles all significantly improved. Simultaneously, the prevalence of activated T-cells (CD4(+)CD69(+) and CD8(+)CD69(+) cells) decreased, whereas that of regulatory T-cells increased. These results indicate an immunomodulatory action of doxazosin in type 2 diabetic patients.

Human heart-type fatty-acid-binding protein as a point-of-care test in the early diagnosis of acute myocardial infarction.

BACKGROUND: At very early stages of acute myocardial infarction (AMI), highly sensitive biomarkers are still lacking. AIM: To evaluate the utility of human heart-type fatty acid-binding protein (h-FABP) for early diagnosis of AMI. DESIGN: Prospective diagnostic study. METHODS: Consecutive patients presenting to the emergency department with chest pain or dyspnoea within 24 h of symptom onset were included. At presentation, the h-FABP test result was compared to the standard diagnostic work-up, including repeated ECG and troponin T measurements. Sensitivity analysis was performed for inconclusive tests. RESULTS: We enrolled 280 patients presenting to hospital with a median symptom onset of 3 h (IQR 2-6 h): 109 (39%) had AMI. At presentation, h-FABP had a sensitivity of 69% (95%CI 59-77) and specificity of 74% (95%CI 66-80); 45 tests were false-positive and 34 were false-negative. Omitting inconclusive tests increased sensitivity and specificity only slightly. AMI was identified significantly earlier by h-FABP than by troponin T (24 vs. 8 patients, p=0.005). DISCUSSION: Although h-FABP can help to detect myocardial damage at an early stage in patients with chest pain or dyspnoea, it appears unsuitable as a stand-alone test for ruling out AMI.

Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis.

Microarray studies generating lists of genes with altered expression in placentas from pregnancies complicated with pre-eclampsia (PE) have so far been published in several different studies. Working under the assumption that altered gene expression in PE may be the result of altered expression of regulatory transcription factors (TFs), we looked for over-represented TF-binding sites (TFBSs)-which indicate the involvement of TFs in gene regulatory networks-in lists of genes (n = 143) compiled in these studies. We compared the prevalence of TFBSs in the promoter regions of 68 genes with the background prevalence of TFBSs in promoters of the human genome. The prevalence of the E47, sterol regulatory element binding protein (SREBP) and NFKB-p50 TFBSs was higher (P < 0.005) in the promoter sequences of the PE gene lists than in the background model. Each of these TFBSs could be implicated in the development of PE. The E47 protein is an E-protein or basic helix-loop-helix (bHLH) TF. Data support the role of bHLHs in the differentiation of placental tissue. SREBP-1, a lipid-sensing sterol regulatory element-binding protein, is a critical regulator of fatty acid homeostasis in the placenta. The target genes of NFKB-p50 determine inflammatory response, and aberrant cytokine homeostasis is a further sign of PE. These TFs may provide an insight into the pathogenesis of the disease.

Suicidal behavior in patients with schizophrenia is related to COMT polymorphism.

A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients.

[Stomatologic implications of Turner syndrome II. Orthodontic disorders and some characteristics of the temporomandibular joint]. / A Turner-szindróma stomatológiai vonatkozásai II. Orthodontiai rendellenességek és a temporomandibularis ízület néhány jellemzöje.

Turner syndrome is a disease belonging to the group of chromosome disorders, which affect sexual chromosomes. The present study aims at analysing and describing orthodontic and TMI joint disorders in patients with Turner's syndrome, and comparing the results with those healthy controls. Data of 24 patients with Turner's syndrome as well as 24 healthy controls were collected and analysed. No significant alteration in TMI was found in any of the two groups. Both groups presented orthodontic anomalies, however, crowding was the most common anomaly in the control group, whereas in the case of patients with Turner's syndrome, other anomalies (protrusion, open bite, cross bite) could also be found more frequently.

[Stomatologic implications of Turner syndrome. I. Dental caries and periodontal status]. / A Turner-szindróma stomatológiai vonatkozásai. I. Cariologiai és parodontológiai status.

Turner's syndrome is a chromosomal abnormality with additional deficiency in gonadal and adrenocorticotropic secretions. The most frequent oral findings are: high palatal vault and hypoplastic mandible. The aim of the present study was to investigate the caries prevalence and periodontal condition of patients with Turner's syndrome. The study population consisted of 24 patients with Turner's syndrome and 24 healthy control girls. Mean age were 24.5 years in both groups. Significantly lower DMF-T mean values were found in patients with Turner's syndrome compared with the healthy controls. From among the investigated periodontal parameters probing depth showed no difference between the two groups, but gingival index and plaque index were significantly higher in patients with Turner's syndrome.

Human bioequivalence study of a new nifedipine containing retard filmtablet after single and repeated administration.

A clinical pharmacokinetic bioequivalence study with two retard filmtablet preparations, both containing 20 mg of nifedipine (CAS 219829-25-4) was carried out. The investigated test preparation was Cordaflex 20 mg retard filmtablet. The pharmacokinetic parameters were determined after single and repeated administration in 15 and 16 healthy male volunteers, respectively, in open, randomised studies of cross-over design. Plasma levels of nifedipine were determined by HPLC with electrochemical detection using a robotic sample preparation technique. Statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss, tau tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from plasma concentration-time curves by ANOVAlog, confidence interval, Schuirman's, Westlake's, Anderson's and Wilcoxon's tests, furthermore the comparison of the clinical results did not show any significant difference between the two preparations. It is concluded that the two preparations are bioequivalent after repeated administration.

[Uvulo-palatopharyngioplasty: indication, technique and results in relation to ronchopathy and sleep apnea syndrome]. / Die Uvulopalatopharyngoplastik: Indikation, Technik und Resultate in bezug auf Rhonchopathie und Schlafapnoesyndrom.

56 patients with habitual snoring (n = 43) or with complicated snoring accompanied by sleep apnea syndrome (n = 13) under went uvulopalatopharyngoplasty. The patients were observed for a period of 2 to 84 months (average: 20,8 months). Postoperatively, 80 % showed a disappearance or great reduction of snoring intensity. Other symptoms of obstructive sleep apnea syndrome such as apneas, tiredness during the day and deterioration of sleep quality also improved markedly. In ten out of 13 patients with a demonstrated sleep apnea syndrome, the apneas disappeared or became noticeably reduced (in seven patients shown by means of a polysomnographic check-up). Two patients developed velopharyngeal stenosis, which was subsequently corrected. Other operative side effects were temporary (from days to weeks) and only minor (transient speaking problems, nasal regurgitation, rhinopharyngitis sicca, taste disturbances).

[Comparative human pharmacokinetic studies of 20 mg nifedipine-containing Cordaflex and Adalat film coated retared tablets]. / Cordaflex és Adalat 20 mg filmtabletták összehasonlító humán farmakokinetikája egyszeri és ismételt dozírozás után.

Comparative pharmacokinetic studies have been carried out with two 20 mg nifedipine active substance-containing retard film coated tablets, Cordaflex produced by EGIS Pharmaceuticals Co., Ltd. and Adalat of Bayer AG. The pharmacokinetic parameters and the relative bioavailability were determined in 15 and 16 healthy male volunteers, respectively after single and repeated administration in open, randomized cross over study. The plasma concentration of nifedipine was determined by HPLC-ED method, using laboratory robot for automated sample preparation. On the basis of graphical and statistical comparison of the pharmacokinetic parameters (AUC0-infinity, AUCss,0-tau, tmax, Cmax, Css,min, Css,av, MRT, etc.) calculated from the time-plasma concentration curve, moreover on the basis of clinical results, there was no significant difference between the two preparations. In conclusion, the relative bioavailability of Cordaflex and Adalat 20 mg retard tablets did not show significant difference after single and repeated administration.

Fibrinolysis-resistant fibrin deposits in minor labial salivary glands of patients with Sjögren's syndrome.

Minor labial salivary glands obtained at biopsy from 12 patients with Sjögren's syndrome were investigated by immunomorphological methods for the presence of fibrinolysis-resistant fibrin deposition. Fibrin could be found in extracellular localization between individual inflammatory cells infiltrating minor salivary glands. In the areas surrounding mononuclear infiltrations the labeling for fibrin showed an essentially fibrillar pattern. Staining for factor XIII A was observed over fibrin deposits and in large, stellate cells not showing reaction for fibrin. Here it is demonstrated that factor XIII A+ tissue macrophages are in an intimate relationship with fibrin deposits. The authors suggest that tissue macrophages may play a regulatory role in fibrin accumulation in association with autoimmune inflammation and consequently in demarcation of the inflamed tissue.