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Item Open Access Adjuvant autologous melanoma vaccine for macroscopic stage III disease: survival, biomarkers, and improved response to CTLA-4 blockade(Hindawi Limited, 2016) Lotem, M.; Merims, S.; Frank, S.; Hamburger, T.; Nissan, A.; Kadouri, L.; Cohen, J.; Straussman, R.; Eisenberg, G.; Frankenburg, S.; Carmon, E.; Alaiyan, B.; Shneibaum, S.; Ayyildiz, Z. O.; Isbilen, M.; Senses, K. M.; Ron, I.; Steinberg, H.; Smith, Y.; Shiloni, E.; Gure, A. O.; Peretz, T.Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.Item Open Access Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases(BioMed Central, 2009) Chabchoub, G.; Uz, E.; Maalej, A.; Mustafa, C. A.; Rebai, A.; Mnif, M.; Bahloul, Z.; Farid, N. R.; Ozcelik, T.; Ayadi, H.Introduction The majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.Item Open Access Coagulation factor V gene mutation increases the risk of venous thrombosis in Behcet's disease(Oxford University Press, 1996) Gül, A.; Özbek, U.; Öztürk, C.; Inanç, M.; Koniçe, M.; Özçelik, T.We investigated the prevalence of the coagulation factor V gene G1691A mutation in 64 patients with Behcet's disease (BD) and in 107 apparently healthy individuals. The mutation was present in the heterozygous state in 37.5% of the patients with a history of deep vein thrombosis (12/32) and in 9.4% of the patients without any thrombotic event (3/32). Eleven healthy individuals were also heterozygous for the mutation (10.3%). The prevalence of the mutation in BD patients with and without thrombosis was significantly different (P = 0.0079). We conclude that the factor V gene mutation may play a major role in the development of venous thrombosis in BD.Item Open Access Colon cancer associated transcript-1 (CCAT1) expression in adenocarcinoma of the stomach(Ivyspring International Publisher, 2015) Mizrahi, I.; Mazeh, H.; Grinbaum, R.; Beglaibter, N.; Wilschanski, M.; Pavlov, V.; Adileh, M.; Stojadinovic, A.; Avital, I.; Gure, A. O.; Halle, D.; Nissan, A.Background: Long non-coding RNAs (lncRNAs) have been shown to have functional roles in cancer biology and are dys-regulated in many tumors. Colon Cancer Associated Transcript -1 (CCAT1) is a lncRNA, previously shown to be significantly up-regulated in colon cancer. The aim of this study is to determine expression levels of CCAT1 in gastric carcinoma (GC). Methods: Tissue samples were obtained from patients undergoing resection for gastric carcinoma (n=19). For each patient, tumor tissue and normal appearing gastric mucosa were taken. Normal gastric tissues obtained from morbidly obese patients, undergoing laparoscopic sleeve gastrectomy served as normal controls (n=19). A human gastric carcinoma cell line (AGS) served as positive control. RNA was extracted from all tissue samples and CCAT1 expression was analyzed using quantitative real time-PCR (qRT-PCR). Results: Low expression of CCAT1 was identified in normal gastric mucosa samples obtained from morbidly obese patients [mean Relative Quantity (RQ) = 1.95±0.4]. AGS human gastric carcinoma cell line showed an elevated level of CCAT1 expression (RQ=8.02). Expression levels of CCAT1 were approximately 10.8 fold higher in GC samples than in samples taken from the negative control group (RQ=21.1±5 vs. RQ=1.95±0.4, respectively, p<0.001). Interestingly, CCAT1 expression was significantly overexpressed in adjacent normal tissues when compared to the negative control group (RQ = 15.25±2 vs. RQ=1.95±0.4, respectively, p<0.001). Tissues obtained from recurrent GC cases showed the highest expression levels (RQ = 88.8±31; p<0.001). Expression levels increased with tumor stage (T4- 36.4±15, T3- 16.1±6, T2- 4.7±1), however this did not reach statistical significance (p=0.2). There was no difference in CCAT1 expression between intestinal and diffuse type GC (RQ=22.4±7 vs. 22.4±16, respectively, p=0.9). Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients (RQ= 2.4±0.9 vs. 0.93±0.2, respectively, p=0.13). Conclusion: CCAT1 is up-regulated in gastric cancer, and may serve as a potential bio-marker for early detection and surveillance.Item Open Access Data mining experiments on the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF-AFNET 2) trial: ‘exposing the invisible’(Oxford University Press, 2016) Okutucu, S.; Katircioglu-Öztürk, D.; Oto, E.; Güvenir, H. A.; Karaagaoglu, E.; Oto, A.; Meinertz, T.; Goette, A.Aims: The aims of this study include (i) pursuing data-mining experiments on the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF-AFNET 2) trial dataset containing atrial fibrillation (AF) burden scores of patients with many clinical parameters and (ii) revealing possible correlations between the estimated risk factors of AF and other clinical findings or measurements provided in the dataset. Methods: Ranking Instances by Maximizing the Area under a Receiver Operating Characteristics (ROC) Curve (RIMARC) is used to determine the predictive weights (Pw) of baseline variables on the primary endpoint. Chi-square automatic interaction detector algorithm is performed for comparing the results of RIMARC. The primary endpoint of the ANTIPAF-AFNET 2 trial was the percentage of days with documented episodes of paroxysmal AF or with suspected persistent AF. Results: By means of the RIMARC analysis algorithm, baseline SF-12 mental component score (Pw = 0.3597), age (Pw = 0.2865), blood urea nitrogen (BUN) (Pw = 0.2719), systolic blood pressure (Pw = 0.2240), and creatinine level (Pw = 0.1570) of the patients were found to be predictors of AF burden. Atrial fibrillation burden increases as baseline SF-12 mental component score gets lower; systolic blood pressure, BUN and creatinine levels become higher; and the patient gets older. The AF burden increased significantly at age >76. Conclusions: With the ANTIPAF-AFNET 2 dataset, the present data-mining analyses suggest that a baseline SF-12 mental component score, age, systolic blood pressure, BUN, and creatinine level of the patients are predictors of AF burden. Additional studies are necessary to understand the distinct kidney-specific pathophysiological pathways that contribute to AF burden. Published on behalf of the European Society of Cardiology.Item Open Access Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair(B M J Group, 2014) Dal, G. M.; Ergüner, B.; Saǧıroǧlu, M. S.; Yüksel, B.; Onat, O. E.; Alkan C.; Özçelik, T.Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 for twin II. Conclusions: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.Item Open Access The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographicaly diverse populations(Cell Press, 2000) Mazoyer, S.; Leary, J.; Kirk, J.; Fleischmann, E.; Wagner, T.; Claes, K.; Messiaen, L.; Foulkes, W.; Desrochers, M.; Simard, J.; Phelan, C. M.; Kwan, E.; Narod, S. A.; Vahteristo, P.; Nevanlinna, H.; Durando, X.; Bignon, Y. J.; Peyrat, J. P.; Bonnardel, C.; Sinilnikova, O. M.; Puget, N.; Lenoir, G. M.; Audoynaud, C.; Goldgar, D.; Maugard, C.; Caux, V.; Gad, S.; Stoppa-Lyonnet, D.; Noguès, C.; Lidereau, R.; Machavoine, C.; Bressac-De Paillerets, B.; Kuschel, B.; Betz, B.; Niederacher, D.; Beckmann, M. W.; Hamann, U.; Ponder, B. A. P.; Robinson, M.; Taylor G. R.; Bishop, T.; Catteau, A.; Solomon, E.; Cohen, B.; Steel, M.; Collins, N.; Stratton, M.; Van Der Looij, M.; Oláh, E.; Miller, N. J.; Barton, D. E.; Sverdlov, R. S.; Friedman, E.; Radice P.; Montagna, M.; Sensi, E.; Caligo, M.; Van Eijk, R.; Devilee, P.; Van Der Luijt, R.; Heimdal, K.; Møller, P.; Borg, Å.; Diez, O.; Cortes, J.; Domenech, M.; Baiget, M.; Osorio, A.; Benítez, J.; Maillet, P.; Sappino, A. P.; Özdag, H.; Özçelik, T.; Ozturk, M.; Rohlfs, E. M.; Boyd, J.; McDermott, D.; Offit, K.; Unger, M.; Nathanson, K.; Weber, B. L.; Sellers, T. A.; Hampton, E.; Couch, F. J.; Neuhausen, S.; Gayther, S. A.Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report.Item Open Access High-resolution magic anglespinning ¹H nuclear magnetic resonance spectroscopy metabolomics of hyperfunctioning parathyroid glands(Mosby, Inc., 2016) Battini, S.; Imperiale, A.; Taïeb, D.; Elbayed, K.; Cicek, A. E.; Sebag, F.; Brunaud, L.; Namer, Izzie-JacquesBackground Primary hyperparathyroidism (PHPT) may be related to a single gland disease or multiglandular disease, which requires specific treatments. At present, an operation is the only curative treatment for PHPT. Currently, there are no biomarkers available to identify these 2 entities (single vs. multiple gland disease). The aims of the present study were to compare (1) the tissue metabolomics profiles between PHPT and renal hyperparathyroidism (secondary and tertiary) and (2) single gland disease with multiglandular disease in PHPT using metabolomics analysis. Methods The method used was 1H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Forty-three samples from 32 patients suffering from hyperparathyroidism were included in this study. Results Significant differences in the metabolomics profile were assessed according to PHPT and renal hyperparathyroidism. A bicomponent orthogonal partial least square-discriminant analysis showed a clear distinction between PHPT and renal hyperparathyroidism (R2Y = 0.85, Q2 = 0.63). Interestingly, the model also distinguished single gland disease from multiglandular disease (R2Y = 0.96, Q2 = 0.55). A network analysis was also performed using the Algorithm to Determine Expected Metabolite Level Alterations Using Mutual Information (ADEMA). Single gland disease was accurately predicted by ADEMA and was associated with higher levels of phosphorylcholine, choline, glycerophosphocholine, fumarate, succinate, lactate, glucose, glutamine, and ascorbate compared with multiglandular disease. Conclusion This study shows for the first time that 1H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy is a reliable and fast technique to distinguish single gland disease from multiglandular disease in patients with PHPT. The potential use of this method as an intraoperative tool requires specific further studies.Item Open Access Integromic analysis of genetic variation and gene expression identifies networks for cardiovascular disease phenotypes(Lippincott Williams & Wilkins, 2015) Yao, C.; Chen, B. H.; Joehanes, R.; Otlu, B.; Zhang X.; Liu, C.; Huan, T.; Tastan, O.; Cupples, L. A.; Meigs, J. B.; Fox, C. S.; Freedman, J. E.; Courchesne, P.; O'Donnell, C. J.; Munson, P. J.; Keles, S.; Levy, D.BACKGROUND - : Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS - : We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS - : Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.Item Open Access Ischemic stroke phenotype in patients with nonsustained atrial fibrillation(Lippincott Williams and Wilkins, 2015) Arsava, E. M.; Bas, D. F.; Atalar, Ergin; Has, A. C.; Oguz, K. K.; Topcuoglu, M. A.Background and Purpose: The widespread use of ambulatory cardiac monitoring has not only increased the detection of high-risk arrhythmias like persistent and paroxysmal atrial fibrillation (AF), but also made it possible to identify other aberrations such as short-lasting (<30 seconds) irregular runs of supraventricular tachycardia. Ischemic stroke phenotype might be helpful in understanding whether these nonsustained episodes play a similar role in stroke pathophysiology like their persistent and paroxysmal counterparts. Methods: In a consecutive series of patients with ischemic stroke, we retrospectively determined clinical and imaging features associated with nonsustained AF (n=126), defined as <30-second-lasting supraventricular tachyarrhythmias with irregular RR interval on 24-hour Holter monitoring, and compared them to patients with persistent/paroxysmal AF (n=239) and no AF (n=246). Results: Patients with persistent/paroxysmal AF significantly differed from patients with nonsustained AF by a higher prevalence of female sex (odds ratio [95% confidence interval], 1.8 [1.1-2.9]), coronary artery disease (1.9 [1.1-3.0]), and embolic imaging features (2.7 [1.1-6.5]), and lower frequency of smoking (0.4 [0.2-0.8]) and hyperlipidemia (0.5 [0.3-0.8]). In contrast, patients with no AF were younger (0.5 [0.4-0.6] per decade) and more likely to be male (1.7 [1.0-2.8]) in comparison with nonsustained AF population. The prevalence of nonsustained AF was similar among cryptogenic and noncryptogenic stroke patients (32% versus 29%). Voxel-wise comparison of lesion probability maps revealed no significant difference between cryptogenic stroke patients with and without nonsustained AF. Conclusions: Clinical features of patients with nonsustained AF exhibited an intermediary phenotype in between patients with persistent/paroxysmal AF and no AF. Furthermore, imaging features did not entirely resemble patterns observed in patients with longer durations of AF.Item Open Access Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer(International Institute of Anticancer Research, 2004) Sevinç, A.; Yannoukakos, D.; Konstantopoulou, I.; Manguoglu, E.; Lüleci, G.; Çolak, T.; Akyerli, C.; Çolakoglu, G.; Tez, M.; Sayek, I.; Gerassimos, V.; Nasioulas, G.; Papadopoulou, E.; Florentin, L.; Kontogianni, E.; Bozkurt, B.; Kocabas, N. A.; Karakaya, A. E.; Yulug, I. G.; Özçelik, T.Background: The RNASEL G1385A variant was recently found to be implicated in the development of prostate cancer. Considering the function of RNase L and the pleiotropic effects of mutations associated with cancer, we sought to investigate whether the RNASEL G1385A variant is a risk factor for breast cancer. Patients and Methods: A total of 453 breast cancer patients and 382 age- and sex-matched controls from Greece and Turkey were analyzed. Genotyping for the RNASEL G1385A variant was performed using an Amplification Refractory Mutation System (ARMS). Results: Statistical evaluation of the RNASEL G1385A genotype distribution among breast cancer patients and controls revealed no significant association between the presence of the risk genotype and the occurrence of breast cancer. Conclusion: Although an increasing number of studies report an association between the RNASEL G1385A variant and prostate cancer risk, this variant does not appear to be implicated in the development of breast cancer.Item Open Access MDM2 T309G polymorphism is associated with bladder cancer(International Institute of Anticancer Research, 2006) Onat, O. E.; Tez, M.; Özçelik, T.; Törüner, G. A.Recently, a functional T to G polymorphism at nucleotide 309 in the promoter region of the MDM2 gene (rs: 2279744, SNP 309) has been identified. This polymorphism has an impact on the expression of the MDM2 gene, which is a key negative regulator of the tumor suppressor molecule p53. The effect of T309G polymorphism of the MDM2 gene on bladder cancer susceptibility was investigated in a case-control study of 75 bladder cancer patients and 103 controls from Turkey. The G/G genotype exhibited an increased risk of 2.68 (95% CI, 1.34-5.40) for bladder cancer compared with the combination of low-risk genotypes T/T and T/G at this locus. These results show an association between MDM2 T309G polymorphism and bladder cancer in our study group. To the best of our knowledge, this is the first study reporting that MDM2 T309G polymorphism may be a potential genetic susceptibility factor for bladder cancer.Item Open Access Mutations in RAD21 disrupt regulation of apob in patients with chronic intestinal pseudo-obstruction(W.B. Saunders, 2015) Bonora, E.; Bianco, F.; Cordeddu, L.; Bamshad, M.; Francescatto, L.; Dowless, D.; Stanghellini, V.; Cogliandro, R. F.; Lindberg, G.; Mungan, Z.; Cefle, K.; Ozcelik, T.; Palanduz, S.; Ozturk, S.; Gedikbasi, A.; Gori, A.; Pippucci, T.; Graziano, C.; Volta, U.; Caio, G.; Barbara, G.; D'Amato, M.; Seri, M.; Katsanis, N.; Romeo, G.; De Giorgio, R.Background Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.Item Open Access A retrospective comparison of allogeneic peripheral blood stem cell and bone marrow transplantation results from a single center: a focus on the incidence of graft-vs.-host disease and relapse(Elsevier, 1999) Üstün, C.; Arslan, Ö.; Beksaç, M.; Koç, H.; Gürman, G.; Özçelik, T.; Yilmaz, B.; İlban, O.; Akan, H.; Özcan, M.; Demirer, T.; Uysal, A.; Konuk, N.; Arat, M.; Dilek, İ.; Çelebi, H.; Coskun, H. S.To detect the effect of the stem cell source, allogeneic peripheral blood stem cell transplantations (alloPBSCTs) performed between 1995 and 1997 from human leukocyte antigen (HLA)-identical siblings in 40 patients with acute and chronic hematological disorders were compared with a historical group of 40 patients with similar variables who had received allogeneic bone marrow transplants (alloBMTs) between 1993 and 1995. Patients in both groups were identical except that both the recipient and the donor ages were, on average, higher in the alloPBSCT group (26 vs. 36 [p = 0.005] and 27 vs. 32 [p = 0.024], respectively). Patients received similar therapy excluding posttransplant granulocyte colony-stimulating factor administration (97% in alloBMT vs. 12.5% in alloPBSCT). The median time to reach neutrophil counts >0.5×109/L and platelet counts >20×109/L was 13 and 14 days, respectively, in patients receiving alloPBSCTs compared with 19 and 27 days in patients receiving alloBMTs (p = 0.0014 and p = 0.0002). The alloPBSCT group required similar transfusions of red blood cells or platelets. The incidence of grade II-IV acute graft-vs.-host disease (aGVHD) was similar in both groups. However, chronic GVHD (cGVHD) of all grades developed in 78.1% of patients in the alloPBSCT group after a median follow-up period of 12.5 (range 0.5-34) months. In alloBMT recipients, cGVHD of all grades developed in 21.4% after a median follow-up period of 38 (range 0.5-62) months (p = 0.00001). Day 100 transplant-related mortality was also similar: 20% (8 of 40) in the alloBMT patients and 17.5% (7 of 40) in the alloPBSCT group. Although not statistically significant, a relatively higher relapse rate occurred in the alloBMT group (21.4 vs. 10.7%). The estimated disease-free survival in month 24 was 51.3% for alloBMT and 54.6% for alloPBSCT, and the estimated overall survival in month 24 was 56.1% for alloBMT and 64.6% for alloPBSCT. In conclusion, this retrospective comparison suggests that alloPBSCT from HLA-identical donors is associated with faster engraftment, fewer transfusions, and no greater incidence of aGVHD, but a high incidence of cGVHD.Item Open Access Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene(BMJ Group, 2008) Kaplan, Y.; Vargel, I.; Kansu, T.; Akin, B.; Rohmann, E.; Kamaci, S.; Uz, E.; Ozcelik, T.; Wollnik, B.; Akarsu, N. A.Aims: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. Methods: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. Results: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. Conclusions: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.