Role of tumoural markers in the treatment and the prognosis of head and neck cancer

Head and neck cancer has important mortality, incidence and prevalence in Romania, therefore prompting for studies meant to detect reliable markers capable of predicting the disease’s progression and its response to treatment. The study was conducted in the Oncology Clinic of Craiova, Romania during ianuarie 2000-decembrie 2009. Patients were randomized 1:1 (using a simple randomization software) in 2 groups: A receiving standard radiotherapy, В comprising patients who received radiochemotherapy (protocol 5-fluorouracil 1000 mg/mp/d iv Cl + Cisplatin 20 mg/mp/d IV Cl x 4 days/4 week or Cisplatin 20 mg/mp IV Cl weekly or 20 mg/mp/d IV 0 x 5 days/3 week). The endpoints of the study were: response rate, median overall survival, disease progression free survival and quality of life in each group. Kaplan Meier curves were used for statistical analysis - for overall survival and the logrank test. The response rate was high for patients with radiochemotherapy which was possible radical surgery. Is significant difference between median overall survival appeared between the 2 groups: 18,8 months in group A and 17,2 months in group В with a hazard ratio for survival of 0,88 (95%CI, 0,75-1,12, p<0.004). Progression free survival was not significant different between these 2 groups: 6.9 months for group A and 7.2 months for group B. Multivariate analysis revealed TNM stage and site of the tumor significant factors for overall survival, and TNM stage, site of the tumor and EGFR expression as significant factors for time to progression. The molecular biomarkers EGFR and VEGF have a prognostic significance in head and neck cancer in addition to the established clinical prognostic factors such as the stage and site of the tumor.Also hypermethylated TSG promoters were detected in saliva using microarray based (DCC, MINT31, pl6, cyclin Al, MINŢI, T1MP3, DAPK) and this test can be a surveillance prediction and model of recurrence that might be applied to screening the population. First line chemoradiotherapy regimen associated with molecular target therapy in advanced head and neck carcinoma remains a decision of the physician. New approaches include the combination of anti VEGFR agents and antiEGFR monoclonal antibodies, and combined antiEGFR therapy with small molecule tyrosine kinase inhibitors

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

INTRODUCTION: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. METHODS: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome. RESULTS: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive (N = 372) compared with both the unaffected control (N = 4,929) and anti-THSD7A-positive (N = 31) groups (p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset (p = 0.009). Further, the GRS in the dual antibody-negative group (N = 355) was intermediate between controls and the PLA2R1-positive group (p < 0.0001). CONCLUSION: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1

Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity

<p>Abstract</p> <p>Background</p> <p>Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes.</p> <p>Methods</p> <p>We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802).</p> <p>Results</p> <p>Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids.</p> <p>Conclusion</p> <p>Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution.</p

Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1 We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1 Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation

Noncoding deletions reveal a gene that is critical for intestinal function.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes

Epilepsy in kcnj10 Morphant Zebrafish Assessed with a Novel Method for Long-Term EEG Recordings.

We aimed to develop and validate a reliable method for stable long-term recordings of EEG activity in zebrafish, which is less prone to artifacts than current invasive techniques. EEG activity was recorded with a blunt electrolyte-filled glass pipette placed on the zebrafish head mimicking surface EEG technology in man. In addition, paralysis of agarose-embedded fish using D-tubocurarine excluded movement artifacts associated with epileptic activity. This non-invasive recording technique allowed recordings for up to one hour and produced less artifacts than impaling the zebrafish optic tectum with a patch pipette. Paralyzed fish survived, and normal heartbeat could be monitored for over 1h. Our technique allowed the demonstration of specific epileptic activity in kcnj10a morphant fish (a model for EAST syndrome) closely resembling epileptic activity induced by pentylenetetrazol. This new method documented that seizures in the zebrafish EAST model were ameliorated by pentobarbitone, but not diazepam, validating its usefulness. In conclusion, non-invasive recordings in paralyzed EAST syndrome zebrafish proved stable, reliable and robust, showing qualitatively similar frequency spectra to those obtained from pentylenetetrazol-treated fish. This technique may prove particularly useful in zebrafish epilepsy models that show infrequent or conditional seizure activity

STAG3 truncating variant as the cause of primary ovarian insufficiency

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk