Ilana Belitskaya-Levy, Ph.D.

Impact of population genetic substructure on association studies and risk assessment for melanoma
Lobach I; Belitskaya-Levy I; Goldberg JD; Ostrer H; Berman RS; Pavlick AC; Shapiro RL; Osman I; Manga P
2011 ;29(Suppl):?-? #8521, Journal of clinical oncology
Background: Genetic substructure due to varying allele frequencies between populations can confound association studies. Ancestry informative genetic marker (AIMs) data combined with statistical adjustment can reveal spurious associations and identify population specific risk markers. In melanoma, AIMs may also be risk markers, e.g. pigment genes contribute to melanoma susceptibility and segregate with ancestry. We have thus developed a strategy to adjust for population genetic substructure (PGS) using AIMs, while identifying potentially novel genes associated with melanoma. Methods: 326 melanoma patients and 400 controls of European ancestry from the New York area were studied. Tag SNPs spanning 14 candidate genes and 75 AIMs were genotyped and odds ratios (OR), unadjusted and adjusted for PGS, computed. Results: A PGS model based on all AIMs separated cases and controls, suggesting that some AIMs were associated with melanoma. An algorithm was developed to select AIMs least capable of separating cases and controls to infer PGS and validated using simulations. The resulting model, which was reproduced using 49 additional AIMs, separated Northern (NE) and Southern Europeans (SE) and was used to adjust ORs. Three classes of SNPs were identified 1. Associated before and after PGS correction in both groups (10 SNPs localized to MATP, TYR and ERCC5). 2. Not associated in unadjusted analysis, but significantly associated with melanoma in NEs (6 SNPs localized to XPC, ERCC4, OCA2, ASIP and TYR). 3. Associated with melanoma before but not after adjustment. To determine if AIMs that separate cases and controls can identify novel melanoma genes, we genotyped 16 SNPs localized to 4 genes that house candidate AIMs. Four SNPs at 2 different loci were associated with melanoma (e.g. AIM1: OR=0.35, p=0.01; AIM2: OR=1.77, p=0.03). Conclusions: Our approach demonstrated that ancestry is a significant confounding factor in identifying melanoma susceptibility genes. Melanoma risk markers vary significantly between groups and a DNA based risk assessment model will require adjustment for ancestry. We have also identified potentially novel susceptibility melanoma genes for futher study
— id: 132473, year: 2011, vol: 29, page: ?, stat: Journal Article,

Efficacy and safety of radical resection of primary and recurrent craniopharyngiomas in 86 children
Elliott, Robert E; Hsieh, Kevin; Hochm, Tsivia; Belitskaya-Levy, Ilana; Wisoff, Jessica; Wisoff, Jeffrey H
2010 Jan;5(1):30-48, Journal of Neurosurgery: Pediatrics
OBJECT: Optimal treatment of primary and recurrent craniopharyngiomas remains controversial. Radical resection and limited resection plus radiation therapy yield similar rates of disease control and overall survival. The data are much less clear for recurrent tumors. The authors report their experience with radical resection of both primary and recurrent craniopharyngiomas in children and compare the outcomes between the 2 groups. METHODS: A retrospective analysis was performed in 86 children younger than 21 years of age who underwent a total of 103 operations for craniopharyngioma between 1986 and 2008; these were performed by the senior author. The goal was resection with curative intent in all patients. Two patients were lost to follow-up and were excluded from analysis. The mean age at the time of surgery was 9.6 years, and the mean follow-up was 9.0 years. RESULTS: All 57 children with primary tumors underwent gross-total resection (GTR). A GTR was achieved in significantly fewer children with recurrent tumors (18 [62%] of 29). There were 3 perioperative deaths (3%). Tumor recurred after GTR in 14 (20%) of 71 patients. Overall survival and progression-free survival were significantly better in patients with primary tumors at time of presentation to the authors' institution. There were no significant differences in the neurological, endocrinological, visual, or functional outcomes between patients with primary and those with recurrent tumors. Factors negatively affecting overall survival and progression-free survival include subtotal resection (recurrent tumors only), tumor size >or= 5 cm, or presence of hydrocephalus or a ventriculoperitoneal shunt. Prior radiation therapy and increasing tumor size were both risk factors for incomplete resection at reoperation. CONCLUSIONS: In the hands of surgeons with experience with craniopharyngiomas, the authors believe that radical resection at presentation offers the best chance of disease control and potential cure with acceptable morbidity. While GTR does not preclude recurrence and is more difficult to achieve in recurrent tumors, especially large and previously irradiated tumors, radical resection is still possible in patients with recurrent craniopharyngiomas with morbidity similar to that of primary tumors
— id: 106277, year: 2010, vol: 5, page: 30, stat: Journal Article,

Radiographic severity of knee osteoarthritis predicts quantitative Bone Marrow Lesions on MRI
Krasnokutsky S.; Regatte R.; Bencardino J.; Rybak L.; Belitskaya-Levy I.; Samuels J.; Attur M.
2010 ;62:137-137, Arthritis & rheumatism
Objective: To evaluate the relationship of quantitative assessment of Bone Marrow Lesions (BML) with knee OA severity by radiographic findings. Methods: 58 OA patients (mean age 62+/-10, mean BMI 27+/-3, 59% female) underwent standardized nonfluoroscopic fixed-flexion knee radiographs. Two radiologists read the X-rays for KL grade, joint space width (JSW), and, using the OARSI atlas, joint space narrowing (JSN) and osteophytes; interreader agreement was assessed using Kappas and concordance correlation coefficients. Linear and logistic regression analysis was performed to assess associations while controlling the effects of age, sex and BMI. 3T-MRI included sagittal T2-weighted fat saturated spin-echo images (TR/TE=4000ms/75ms, FOV=15cm, matrix=256x128, slice thickness=3.0mm, receiver bandwidth 130Hz/pixel) and in/out of phase of FLASH images. Compartment-wise (medial tibial, lateral tibial, medial femur, lateral femur) BML volumes were quantified with T2-weighted fat saturated images and in/out of phase images respectively. BML volumes were dichotomized for statistical analysis. Results: KL score was a significant predictor of total BML volume (OR = 8.41, p = 0.0235). Medial tibial JSW, OARSI medial JSN, and medial tibial plateau osteophytes approached significance as predictors of BML volume at the medial tibia (OR = 0.71, p = 0.0551; OR = 2.16, p = 0.0597; and OR = 2.68, p = 0.0875, respectively). OARSI lateral JSN was a significant predictor of BML volume at the lateral tibia (OR = 3.62, p = 0.0169). Lateral tibial plateau osteophytes were predictors of total BML volume (OR = 4.58, p = 0.0299) and of BML volume at the lateral tibia (OR = 2.31, p = 0.0685). Lateral femoral condyle osteophytes approached significance as a predictor for BML at the lateral femur (OR = 2.25, p = 0.0651). Furthermore, quantitative BML volume strongly correlated with total quantitative synovial volume measured on MRI (beta= 0.22, p = 0.0003). Conclusions: Our data indicate that BML volume on MRI is a characteristic feature of progressive stages of OA, which not only correlates with JSN and osteophytes, but does so in a compartment-specific way. The data suggest that the altered mechanical forces that promote compartmental disease in OA lead to BML, JSN and osteophyte formation. Whether BML further contribute to cartilage loss, and are therefore targets of therapeutic intervention, remains to be determined
— id: 130946, year: 2010, vol: 62, page: 137, stat: Journal Article,

Identification of tyrosinase polymorphisms for use in melanoma risk assessment
Pervolaraki E; Lobach I; Belitskaya-Levy I; Ostrer H; Goldberg JD; Polsky D; Shapiro RL; Berman RS; Osman I; Manga P
2010 ;28(15S):?-? #8570, Journal of clinical oncology
Background: Most skin cancer-related deaths are due to malignant melanoma. Risk assessment criteria for melanoma currently include skin phenotype, family and sun exposure history, factors that are subject to observer and recall bias. Genetic markers of susceptibility have been identified in association studies; however little progress has been made in developing them to improve screening and identification of individuals at risk of melanoma. Tyrosinase (TYR), a known susceptibility gene and a determinant of skin pigmentation, was thus investigated further to characterize its association with melanoma susceptibility and to identify markers which can be used in a risk assessment model. Methods: The cohort consisted of 326 individuals diagnosed with melanoma and 400 control subjects. TYR was interrogated using fifteen tag single nucleotide polymorphisms (SNPs) spanning the gene and statistical association tests performed. Additionally, ancestry informative markers were utilized to correct for population genetic sub-structure. Haplotype analysis was performed to determine if specific regions of the gene contributed more significantly to susceptibility. Coding regions of the gene are currently being sequenced and identified variants will be tested for impact on enzymatic function. Results: Of the 15 SNPs, 8 were associated with melanoma; 4 with decreased risk (Odds ratios 0.41-0.71) and 4 with increased risk (Odds ratios 1.43-1.96). SNPs localized to 2 regions of the gene (spanning exon 1 to intron 2 and intron 3 to 4) with markers of increased as well as decreased susceptibility present in both areas. With the exception of one coding region variant, SNPs were localized to introns. Conclusions: SNPs localized to TYR may serve as useful biomarkers for determining susceptibility to melanoma. We are currently sequencing the gene in our population in order to identify additional and potentially more potent markers of melanoma susceptibility. Coding region variants are being characterized for their effect on protein stability and enzyme activity such that functional active variants (most likely to affect susceptibility to melanoma) can be identified and assessed for their utility in melanoma risk assessment
— id: 111554, year: 2010, vol: 28, page: ?, stat: Journal Article,

Melanoma MicroRNA Signature Predicts Post-Recurrence Survival
Segura, Miguel F; Belitskaya-Levy, Ilana; Rose, Amy E; Zakrzewski, Jan; Gaziel, Avital; Hanniford, Douglas; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman; Hernando, Eva
2010 Mar 1;16(5):1577-1586, Clinical cancer research
PURPOSE: To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria. EXPERIMENTAL DESIGN: Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria. RESULTS: We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into 'better' and 'worse' prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma. CONCLUSIONS: MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models. Clin Cancer Res; 16(5); 1577-86
— id: 107357, year: 2010, vol: 16, page: 1577, stat: Journal Article,

Variable X-ray beam angulation improves quality of medial tibial plateau alignment in fixed-flexion knee radiographs of osteoarthritis (OA) patients
Alapati K.; Belitskaya-Levy I.; Schweitzer M.; Shabshin N.; Samuels J.; Abramson S.B.; Krasnokutsky S.
2009 ;60:1180-1180, Arthritis & rheumatism
Purpose: To assess whether variability in caudal X-ray beam angulation (CBA) improves alignment of the medial tibial plateau (MTP) versus a fixed 10degree CBA, using non-fluoroscopic fixed-flexion knee radiographs. Methods: 133 subjects with knee OA underwent fixed-flexion AP X-ray examinations as part of a longitudinal study. We performed a cross sectional substudy in which 90 subjects were imaged with a 10degree CBA (Method 1) and 43 subjects were imaged using different CBAs (choosing from 5degree, 10degree, 15degree) determined by a trained radiology technician, depending on MTP alignment assessed in real time (Method 2). After reading a blinded training set of radiographs, an experienced radiologist, who was blinded to patients and method used, read the x-rays for MTP alignment quality using a 1-5 scale (1, 2=good, 3=acceptable, 4= poor, 5= unacceptable), and for Kellgren-Lawrence (KL) grade. Results: Method 1 subjects (10degree angulation): MTP alignment quality was scored as good or acceptable 62% and 69% of the time for the right and left knees, respectively. Method 2 subjects (variable angulation): Variable angulation resulted in good or acceptable MTP alignment quality on at least one x-ray 86% and 88% of the time for right and left knees, respectively. When CBA was changed, MTP alignment quality changed 84% of the time for the right knee and 77% of the time for the left knee in subjects who had at least 2 radiographs (n=43). The KL grade changed 28% and 46% of the time in the right and left knees, respectively, when MTP alignment quality changed in the same knee. The KL grade changed 38% and 36% of the time in the right and left knees, respectively, when there was no change in MTP alignment quality but there was a change in CBA. A change in CBA resulted in MTP alignment quality change in bilateral knees 66% of the time, of which this change was in the same direction (improved vs worsened) 86% of the time. Using a CBA of 10degree resulted in improved (over other angulations) MTP alignment quality 53% and 50% of the time for the right and left knees, respectively. Using a CBA of 10degree resulted in worsened MTP alignment 33% and 22% of the time for right and left knees, respectively. Conclusion: While fixed 10degree CBA in fixed-flexion radiographs results in acceptable or good MTP alignment quality the majority of the time, variable CBA improves this frequency in knee OA subjects. Changes in CBA often change the MTP alignment quality, usually in the same direction in both knees, and sometimes change the KL grade. More studies are needed to determine the optimal CBA for non-fluoroscopic fixed-flexion protocols and all radiographic knee OA studies should report the specific techniques used, including CBA
— id: 130350, year: 2009, vol: 60, page: 1180, stat: Journal Article,

Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
Bogunovic, Dusan; O'Neill, David W; Belitskaya-Levy, Ilana; Vacic, Vladimir; Yu, Yi-Lo; Adams, Sylvia; Darvishian, Farbod; Berman, Russell; Shapiro, Richard; Pavlick, Anna C; Lonardi, Stefano; Zavadil, Jiri; Osman, Iman; Bhardwaj, Nina
2009 Dec 1;106(48):20429-20434, Proceedings of the National Academy of Sciences of the United States of America
Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging
— id: 105312, year: 2009, vol: 106, page: 20429, stat: Journal Article,

Developing genetic markers for melanoma risk assessment
Manga P.; Goldberg J.D.; Belitskaya-Levy I.; Lobach I.; Polsky D.; Pavlick A.; Shapiro R.; Berman R.; Osman I.; Ostrer H.
2009 ;27(15 Suppl 1):9046-9046, Journal of clinical oncology
Background: Risk assessment for melanoma is currently based on phenotype, family and exposure history. This approach is subject to recall bias and excludes at-risk groups such as those with darker skin pigmentation. Poorly stratified risk pools also result in unnecessary dermatologist visits and biopsies for those at lower risk. Use of genetic markers may improve risk assessment; however few susceptibility markers have been developed to date. There have been a number of reports of association between melanoma and genetic markers though few have been replicated or validated. In addition, these studies frequently utilized specific coding region variants as markers and failed to test the entire gene. We have therefore assembled a case-control cohort in which to search for potential biomarkers for melanoma risk by interrogating genes using recently developed tools for genetic analysis. A pilot study was performed to test the utility of our cohort. Methods: A cohort of 326 individuals diagnosed with melanoma and treated at the New York University Langone Medical Center and 400 controls obtained from the New York Cancer project was assembled. Candidate genes were selected based on involvement in determining melanoma predisposition factors (skin pigmentation and DNA repair capability) and previous studies showing association. Three genes, ERCC1, ERCC4 (DNA repair) and MATP (skin pigmentation) were selected. Tag Single Nucleotide Polymorphisms (tSNPs) were selected using Haploview (Hapmap.org) and DNA genotyped (Sequenom Inc, San Diego, CA). Odds ratios and confidence intervals were computed for each SNP. Results: An association was found between SNP rs11615 at the ERCC1 locus and melanoma (Odds ratio = 1.718, 95% Confidence interval: 1.259 - 2.343 for TT vs TC/CC). Conclusions: A tSNP approach is thus useful in identifying associations in our melanoma case-control cohort. Sequence variation at the ERCC1 locus contributes to melanoma risk and the gene will now be screened for clinically useful susceptibility biomarkers. Additional DNA repair and pigmentation genes will also be interrogated using this approach. Genes found to be associated with melanoma will be screened by high- density SNP analysis to identify the most appropriate biomarker/s for use in risk assessment
— id: 111805, year: 2009, vol: 27, page: 9046, stat: Journal Article,

Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor
Segura, Miguel F; Hanniford, Douglas; Menendez, Silvia; Reavie, Linsey; Zou, Xuanyi; Alvarez-Diaz, Silvia; Zakrzewski, Jan; Blochin, Elen; Rose, Amy; Bogunovic, Dusan; Polsky, David; Wei, Jianjun; Lee, Peng; Belitskaya-Levy, Ilana; Bhardwaj, Nina; Osman, Iman; Hernando, Eva
2009 Feb 10;106(6):1814-1819, Proceedings of the National Academy of Sciences of the United States of America
The highly aggressive character of melanoma makes it an excellent model for probing the mechanisms underlying metastasis, which remains one of the most difficult challenges in treating cancer. We find that miR-182, member of a miRNA cluster in a chromosomal locus (7q31-34) frequently amplified in melanoma, is commonly up-regulated in human melanoma cell lines and tissue samples; this up-regulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 down-regulation impedes invasion and triggers apoptosis. We further show that miR-182 over-expression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. In human tissues, expression of miR-182 increases with progression from primary to metastatic melanoma and inversely correlates with FOXO3 and microphthalmia-associated transcription factor levels. Our data provide a mechanism for invasion and survival in melanoma that could prove applicable to metastasis of other cancers and suggest that miRNA silencing may be a worthwhile therapeutic strategy
— id: 92154, year: 2009, vol: 106, page: 1814, stat: Journal Article,

Evaluation of the melanocortin-1-receptor gene in melanoma predisposition, progression and recurrence
Sidash S; Ostrer H; Goldberg JD; Belitskaya-Levy I; Lobach I; Polsky D; Shapiro RL; Berman RS; Osman I; Manga P
2009 ;27:15S-15S, Journal of clinical oncology
— id: 102306, year: 2009, vol: 27, page: 15S, stat: Journal Article,

Synovial but not cartilage volumes on MRI predict radiographic severity of knee Osteoarthritis (OA)
Krasnokutsky, S; Samuels, J; Attur, M; Regatte, R; Belitskaya-Levy, I; Babb, J; Rosenthal, P; Al-Mussawir, H; Abellana, V; Greenberg, J; Schweitzer, M; Abramson, SB
2008 SEP ;58(9):S889-S890, Arthritis & rheumatism
— id: 88577, year: 2008, vol: 58, page: S889, stat: Journal Article,

Re: Letter to the editor on "Bias in clinical intervention research"
Marmor, Michael; Belitskaya-Levy, Ilana; Arslan, Alan A
2008 Feb 15;167(4):500-501, American journal of epidemiology
— id: 91966, year: 2008, vol: 167, page: 500, stat: Journal Article,

Gene expression profiles of bronchoalveolar cells in pulmonary TB
Raju, Bindu; Hoshino, Yoshihiko; Belitskaya-Levy, Ilana; Dawson, Rod; Ress, Stanley; Gold, Jeffrey A; Condos, Rany; Pine, Richard; Brown, Stuart; Nolan, Anna; Rom, William N; Weiden, Michael D
2008 Jan;88(1):39-51, Tuberculosis (Edinburgh, Scotland)
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity
— id: 74211, year: 2008, vol: 88, page: 39, stat: Journal Article,

Gene profiling of normal human bronchial epithelial cells in response to asbestos and benzo(a)pyrene diol epoxide (BPDE)
Belitskaya-Levy, Ilana; Hajjou, Mustapha; Su, Wei-cheng; Yie, Ting-An; Tchou-Wong, Kam-Meng; Tang, Moon-shong; Goldberg, Judith D; Rom, William N
2007 ;26(4):281-294, Journal of environmental pathology, toxicology & oncology
Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair
— id: 76391, year: 2007, vol: 26, page: 281, stat: Journal Article,

Distribution and evolution of T-cell receptor Vbeta repertoire on peripheral blood lymphocytes of newborn infants of human immunodeficiency virus (HIV)-infected mothers: differential display on CD4 and CD8 T cells and effect of HIV infection
Borkowsky, William; Chen, Song-He; Belitskaya-Levy, Ilana
2007 Sep;14(9):1215-1222, Clinical & vaccine immunology
Neonatal human peripheral blood mononuclear cells from 12 human immunodeficiency virus (HIV)-infected and 84 uninfected children were assessed for their distribution of T-cell receptors (TCRs) by flow cytometry employing monoclonal antibodies to 14 Vbeta types. Vbeta 2, 5c, and 13 were the most commonly found on CD4 cells (in that order). There was a bimodal distribution of Vbeta 2, being most common in 48% of individuals but in limiting frequency (<2% of CD4) in 21%. Vbeta 2, 3, 8b, and 13 were most commonly expressed on CD8 cells at similar frequencies. There was little difference in the pattern displayed among the infected compared to that of the uninfected. The variation of the distribution over time was studied in 12 infants (7 infected). Only a single HIV-infected child had a significant difference in the interquartile range; none of the HIV-negative patients showed a significant difference. In conclusion, newborns demonstrate different distributions of TCR Vbeta types on CD4 and CD8 cells. HIV infection produces no change in neonatal TCR and little change over the course of 2 years compared to that seen in the uninfected
— id: 75411, year: 2007, vol: 14, page: 1215, stat: Journal Article,

Respiratory disturbance during sleep in COPD patients without daytime hypoxemia
Krieger, Ana C; Patel, Nilam; Green, Daniel; Modersitzki, Frank; Belitskaya-Levy, Ilana; Lorenzo, Angela; Cutaia, Michael
2007 ;2(4):609-615, International journal of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. Its possible association with obstructive sleep apnea is a major cause of concern for clinicians. As the prevalence of both COPD and sleep apnea continues to rise, further investigation of this interaction is needed. In addition, COPD patients are at risk for hypoventilation during sleep due to the underlying respiratory dysfunction. In this study, 13 COPD subjects and 13 non-COPD control subjects were compared for the presence and severity of obstructive sleep apnea and nocturnal hypoventilation. All 26 subjects had presented to a sleep clinic and showed no signs of daytime hypoxemia. After matching for BMI and age, COPD subjects had a similar prevalence of sleep apnea with a lower degree of severity compared to the control subjects. However, less severe events, such as RERA, occurred at similar rates between the two groups. There was no significant difference between groups in the magnitude of oxyhemoglobin desaturation during sleep. Interestingly, severity and presence of nocturnal hypoxemia correlated with that of sleep apnea in the control group, but not in the COPD subjects. In conclusion, COPD without daytime hypoxemia was not a risk factor for sleep apnea or nocturnal hypoventilation in this study
— id: 133535, year: 2007, vol: 2, page: 609, stat: Journal Article,

A generalized clustering problem, with application to DNA microarrays
Belitskaya-Levy, Ilana
2006 ;5(1):Article2-Article2, Statistical applications in genetics & molecular biology
We think of cluster analysis as class discovery. That is, we assume that there is an unknown mapping called clustering structure that assigns a class label to each observation, and the goal of cluster analysis is to estimate this clustering structure, that is, to estimate the number of clusters and cluster assignments. In traditional cluster analysis, it is assumed that such unknown mapping is unique. However, since the observations may cluster in more than one way depending on the variables used, it is natural to permit the existence of more than one clustering structure. This generalized clustering problem of estimating multiple clustering structures is the focus of this paper. We propose an algorithm for finding multiple clustering structures of observations which involves clustering both variables and observations. The number of clustering structures is determined by the number of variable clusters. The dissimilarity measure for clustering variables is based on nearest-neighbor graphs. The observations are clustered using weighted distances with weights determined by the clusters of the variables. The motivating application is to gene expression data
— id: 64656, year: 2006, vol: 5, page: Article2, stat: Journal Article,

Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study
Bhojwani, Deepa; Kang, Huining; Moskowitz, Naomi P; Min, Dong-Joon; Lee, Hokyung; Potter, Jeffrey W; Davidson, George; Willman, Cheryl L; Borowitz, Michael J; Belitskaya-Levy, Ilana; Hunger, Stephen P; Raetz, Elizabeth A; Carroll, William L
2006 Jul 15;108(2):711-717, Blood
Outcome for children with childhood acute lymphoblastic leukemia (ALL) who relapse is poor. To gain insight into the mechanisms of relapse, we analyzed gene-expression profiles in 35 matched diagnosis/relapse pairs as well as 60 uniformly treated children at relapse using the Affymetrix platform. Matched-pair analyses revealed significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis between diagnostic and early-relapse samples. Many of these pathways have been implicated in tumorigenesis previously and are attractive targets for intervention strategies. In contrast, no common pattern of changes was observed among late-relapse pairs. Early-relapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene-expression patterns among late-relapse pairs. Comparison of expression profiles of early- versus late-relapse samples indicated that early-relapse clones were characterized by overexpression of biologic pathways associated with cell-cycle regulation. These results suggest that early-relapse results from the emergence of a related clone, characterized by the up-regulation of genes mediating cell proliferation. In contrast, late relapse appears to be mediated by diverse pathways
— id: 68296, year: 2006, vol: 108, page: 711, stat: Journal Article,

Peripheral blood leukocytes (PBL) gene expression profiles as biomarkers in patients with human knee osteciarthritis (OA)
Krasnokutsky, S; Attur, M; Belitskaya-Levy, I; Patel, J; Al-Mussawir, H; Smiles, S; Lee, S; Kraus, V; Kong, SY; McDaniel, G; Abramson, SB
2006 DEC ;54(12):4103-4103, Arthritis & rheumatism
— id: 70764, year: 2006, vol: 54, page: 4103, stat: Journal Article,

Oxidative stress in periodic breathing: It's relationship with intermittent hypoxemia
Krieger, AC; Green, D; Yitta, G; May, M; Belitskaya-Levy, I; Tse, D; Sedlis, S
2006 ;29:A195-A195, Sleep
— id: 67524, year: 2006, vol: 29, page: A195, stat: Journal Article,

Gene expression studies provide clues to the pathogenesis of uterine leiomyoma: new evidence and a systematic review
Arslan, Alan A; Gold, Leslie I; Mittal, Khushbakhat; Suen, Ting-Chung; Belitskaya-Levy, Ilana; Tang, Moon-Shong; Toniolo, Paolo
2005 Apr;20(4):852-863, Human reproduction
BACKGROUND: Uterine leiomyomas are extremely common and a major cause of pelvic pain, bleeding, infertility, and the leading indication for hysterectomy. Familial and epidemiological studies provide compelling evidence that genetic alterations play an important role in leiomyoma development. METHODS: Using Affymetrix U133A GeneChip we analysed expression profiles of 22,283 genes in paired samples of leiomyoma and adjacent normal myometrium. We compared our results with previously published data on gene expression in uterine leiomyoma and identified the overlapping gene alterations. RESULTS: We detected 80 genes with average differences of > or = 2-fold and false discovery rates of < 5% (14 overexpressed and 66 underexpressed). A comparative analysis including eight previous gene expression studies revealed eight prominent genes (ADH1, ATF3, CRABP2, CYR61, DPT, GRIA2, IGF2, MEST) identified by at least five different studies, eleven genes (ALDH1, CD24, CTGF, DCX, DUSP1, FOS, GAGEC1, IGFBP6, PTGDS, PTGER3, TYMS) reported by four studies, twelve genes (ABCA, ANXA1, APM2, CCL21, CDKN1A, CRMP1, EMP1, ESR1, FY, MAP3K5, TGFBR2, TIMP3) identified by three studies, and 40 genes reported by two different studies. CONCLUSIONS: Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis, IGF metabolism, TGF-beta signaling and extracellular matrix formation. Gene expression studies provide clues to the relevant pathways of leiomyoma development
— id: 55957, year: 2005, vol: 20, page: 852, stat: Journal Article,

Renal masses: quantitative analysis of enhancement with signal intensity measurements versus qualitative analysis of enhancement with image subtraction for diagnosing malignancy at MR imaging
Hecht, Elizabeth M; Israel, Gary M; Krinsky, Glenn A; Hahn, Winnie Y; Kim, Danny C; Belitskaya-Levy, Ilana; Lee, Vivian S
2004 Aug;232(2):373-378, Radiology
PURPOSE: To retrospectively compare quantitative and qualitative methods of assessing magnetic resonance (MR) imaging contrast enhancement as the basis for diagnosing renal malignancy. MATERIALS AND METHODS: MR imaging was performed by using a gadolinium-enhanced breath-hold fat-suppressed three-dimensional T1-weighted gradient-echo sequence in 71 patients (48 men and 23 women; mean age, 62 years; age range, 26-87 years) with 93 renal lesions for which pathologic correlation was available. For quantitative measurements of enhancement, the relative increase in signal intensity values was measured by one investigator with manually defined regions of interest, and the threshold of an increase of 15% or greater was used to distinguish malignant from benign masses. For qualitative assessment, two investigators independently reviewed the subtracted images of all lesions and subjectively determined whether enhancement was present or absent. The sensitivity, specificity, and positive and negative predictive values for each method were calculated and compared. Mean (+/- standard deviation) and median values of relative enhancement were also calculated for benign and malignant lesions. RESULTS: At pathologic analysis, 74 (80%) of the 93 lesions were malignant, and 19 (20%)-including seven oncocytomas-were benign. For diagnosing malignancy based on enhancement alone, sensitivity and specificity, respectively, were 95% (70 of 74 lesions) and 53% (10 of 19 lesions) at quantitative analysis and 99% (73 of 74 lesions) and 58% (11 of 19 lesions) at qualitative analysis. All seven oncocytomas were considered to be malignant with both methods. When the oncocytomas were excluded, specificities increased to 83% (10 of 12 lesions) and 92% (11 of 12 lesions) for the quantitative and qualitative evaluations, respectively. Three of the four malignant lesions incorrectly characterized as benign at quantitative assessment were hyperintense on unenhanced MR images; all were diagnosed correctly at qualitative evaluation. CONCLUSION: Image subtraction enables accurate assessment of renal tumor enhancement, particularly in the setting of masses that are hyperintense on unenhanced MR images
— id: 48195, year: 2004, vol: 232, page: 373, stat: Journal Article,

Aerosolized gamma interferon (IFN-gamma) induces expression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but not inducible nitric oxide synthase in the lung during tuberculosis
Raju, Bindu; Hoshino, Yoshihiko; Kuwabara, Kenichi; Belitskaya, Ilana; Prabhakar, Savita; Canova, Antony; Gold, Jeffrey A; Condos, Rany; Pine, Richard I; Brown, Stuart; Rom, William N; Weiden, Michael D
2004 Mar;72(3):1275-1283, Infection & immunity
Gamma interferon (IFN-gamma) is critical in the immune response against Mycobacterium tuberculosis. In an ongoing trial of aerosol IFN-gamma in conjunction with standard drug therapy, we have observed activation of IFN signaling in bronchoalveolar lavage (BAL) cells from tuberculosis (TB) patients. We hypothesized that aerosol IFN-gamma treatment of pulmonary TB would increase expression of genes important for the control of TB. We investigated the expression of downstream genes by measuring inducible nitric oxide synthase (iNOS) and the chemokine IFN-inducible 10-kDa protein (IP-10) by real-time quantitative reverse transcription-PCR. In vitro, M. tuberculosis induced IP-10, and IFN-gamma stimulated this further, with no effect on iNOS expression. We studied 21 patients with pulmonary TB and 7 healthy subjects. Similar to the in vitro model, IP-10 mRNA was increased in BAL cells from TB patients and was augmented after treatment with aerosolized IFN-gamma. TB was also associated with elevated iNOS mRNA, but aerosolized IFN-gamma did not further enhance expression. Genomic analysis identified 1,300 of 4,058 genes expressed in BAL cells from six TB patients before and after 1 month of therapy, including aerosolized IFN-gamma. However, only 15 genes were differentially regulated by IFN-gamma. We conclude that iNOS and IP-10 mRNA expression is increased in TB but that aerosol IFN-gamma treatment increases expression of few genes in the human lung
— id: 42241, year: 2004, vol: 72, page: 1275, stat: Journal Article,

A generalized clustering problem, with applications to DNA microarrays
Belitskaya-Levy I
2003 ;?:?-?, Proceedings (American Statistical Association)
— id: 43259, year: 2003, vol: ?, page: ?, stat: Journal Article,

Protease and reverse transcriptase mutation patterns in HIV type 1 isolates from heavily treated persons: comparison of isolates from Northern California with isolates from other regions
Gonzales, Matthew J; Belitskaya, Ilana; Dupnik, Kathryn M; Rhee, Soo-Yon; Shafer, Robert W
2003 Oct;19(10):909-915, AIDS research & human retroviruses
We compared HIV-1 subtype B reverse transcriptase (RT) and protease mutation patterns in isolates from heavily treated persons in Northern California with those from persons described in the published literature predominantly from other parts of the United States and Europe. There were few differences in the prevalence of single, double, and triple mutations between the two sets of sequences. More complex patterns of mutations could be characterized by clustering the sequences into eight groups of RT sequences and nine groups of protease sequences according to the presence of known drug-resistance mutations. This clustering accounted for 63% of the variation at RT inhibitor-resistance positions and 68% of the variation at protease inhibitor-resistance positions. The majority of clusters contained Northern California and literature sequences in similar proportions
— id: 43211, year: 2003, vol: 19, page: 909, stat: Journal Article,

Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors
Gonzales, Matthew J; Wu, Thomas D; Taylor, Jonathan; Belitskaya, Ilana; Kantor, Rami; Israelski, Dennis; Chou, Sunwen; Zolopa, Andrew R; Fessel, W Jeffrey; Shafer, Robert W
2003 Apr 11;17(6):791-799, AIDS
OBJECTIVETo characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI.DESIGNA total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published.METHODSChi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini-Hochberg procedure was used to correct for multiple comparisons.RESULTSMutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228.CONCLUSIONSMutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts
— id: 34169, year: 2003, vol: 17, page: 791, stat: Journal Article,

Finding multiple clustering structures in data, with applications to DNA microarrays
Belitskaya, Ilana; Tibshirani, Robert J
[S.l. : s.n.], 2002,
Thesis (Ph.D.) -- Stanford University, 2002
— id: 1214, year: 2002, vol: , page: , stat: ,

Finding multiple clustering structures in data, with applications to DNA microarrays
Belitskaya, Ilana; Tibshirani, Robert J
[S.l. : s.n.], 2002,
Thesis (Ph.D.) -- Stanford University, 2002
— id: 1933, year: 2002, vol: , page: , stat: ,

A new approach for item choice recommendations
Hong SJ; Natarjan R; Belitskaya I
Data warehousing and knowledge discovery, 3rd international conference, DaWaK 2001 Berlin : Springer Verlag, 2001,
— id: 3198, year: 2001, vol: , page: 131, stat: Chapter,