New York NY 10032
Medical School: Boston University School Of Medicine - 1998
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License #: 221281
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Common Variants at the CHEK2 Gene Locus and Risk of Epithelial Ovarian Cancer. - Carcinogenesis
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here we evaluated associations between common genetic variants (single nucleotide polymorphisms (SNPs) and indels) in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15,397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P â‰¤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r(2) with rs17507066=0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1 x10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72x10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r(2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 x 10(-8)). These data suggest that common variants at 22q11.2 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.Â© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk. - Genetic epidemiology
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.Â© 2015 WILEY PERIODICALS, INC.
Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. - Nature communications
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (Pâ‰¤10(-5)). For three cis-eQTL associations (P<1.4 Ã— 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 Ã— 10(-10) for risk variants (P<10(-4)) within 10â€‰kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Determination of anthelmintic efficacy against Toxocara canis in dogs by use of capsule endoscopy. - Veterinary parasitology
Industry guidelines for anthelmintic testing call for postmortem inspection of animals to verify treatment efficacy. A previous study showed that capsule endoscopy (CE) can be performed on dogs in vivo to quantify hookworms in the small intestine. Adoption of a minimally invasive procedure such as this could reduce the need for necropsy in efficacy trials. The present study employed CE to enumerate Toxocara canis in dogs, with two main goals: to determine if multiple capsule examinations improves the accuracy of worm counts compared to a single examination, and to establish if the efficacy of an anthelmintic compound is the same whether calculated using CE or necropsy data. To avoid needless animal sacrifice, the study was carried out on beagle dogs already in a product development trial with a planned terminal endpoint. Dogs were infected by oral inoculation with T. canis eggs. Untreated control dogs (n=8) were evaluated by CE three times while dogs treated with test compounds (3 groups of 4) were examined only once. Utilizing either the average count or just the last complete capsule examination, a robust correlation was found between CE and postmortem numbers (r=0.94, p<0.001). Calculated anthelmintic efficacy was essentially identical for the two enumeration methods, ranging from 94% to 100% for the three research compounds. CE may therefore be a viable alternative to necropsy for T. canis parasiticide trials.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats. - International journal of molecular sciences
Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.
Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. Â©2015 AACR.Â©2015 American Association for Cancer Research.
Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk. - PloS one
Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance. - Veterinary parasitology
Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom(Â®) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Longer duration of transient elastography predicts unreliable liver stiffness measurements. - European journal of gastroenterology & hepatology
Transient elastography (TE) is a noninvasive, validated method to assess liver fibrosis by obtaining liver stiffness measurements (LSM). However, TE can be limited by unreliable measurement (UM). The relationship between the time taken to perform TE (duration) and UM has not been studied.To determine whether the duration of TE correlates with UM.We prospectively studied the frequency and predictors of UM over a 5-year period. UM was defined as follows: less than 10 successful measurements, success rate less than 60%, or interquartile range more than 30% of the median LSM value (IQR/LSM>30%).Among the 2834 patients with LSM analysed, UM occurred in 19.0%. Duration [odds ratio (OR) 4.2, 95% confidence interval (CI) 2.8-6.4; P<0.0001] was the strongest predictor of UM, followed by BMI more than 28â€‰kg/m (OR 2.1, 95% CI 1.5-3.0; P<0.0001), age more than 52 (OR 1.6, 95% CI 1.1-2.3; P=0.007) and non-HBV aetiology (OR 1.6, 95% CI 1.1-2.3; P=0.02). An optimal cut-off of 3â€‰min 47â€‰s was calculated for predicting UM (sensitivity 70%, specificity 65%, OR 4.2, 95% CI 2.7-6.6, P<0.0001). Examinations that took longer than 8â€‰min 10â€‰s had a 90% chance of UM.In experienced hands, duration is a strong predictor of UM in patients undergoing TE. Examinations longer than 4â€‰min are more likely to be unreliable. Examinations longer than 8â€‰min are unlikely to yield a valid result and should be considered a futility endpoint. Older age and increased BMI and nonhepatitis B aetiology are independent, albeit weaker, predictors of UM.
Non-speech oral motor treatment for children with developmental speech sound disorders. - The Cochrane database of systematic reviews
Children with developmental speech sound disorders have difficulties in producing the speech sounds of their native language. These speech difficulties could be due to structural, sensory or neurophysiological causes (e.g. hearing impairment), but more often the cause of the problem is unknown. One treatment approach used by speech-language therapists/pathologists is non-speech oral motor treatment (NSOMT). NSOMTs are non-speech activities that aim to stimulate or improve speech production and treat specific speech errors. For example, using exercises such as smiling, pursing, blowing into horns, blowing bubbles, and lip massage to target lip mobility for the production of speech sounds involving the lips, such as /p/, /b/, and /m/. The efficacy of this treatment approach is controversial, and evidence regarding the efficacy of NSOMTs needs to be examined.To assess the efficacy of non-speech oral motor treatment (NSOMT) in treating children with developmental speech sound disorders who have speech errors.In April 2014 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (R) and Ovid MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Education Resources Information Center (ERIC), PsycINFO and 11 other databases. We also searched five trial and research registers, checked the reference lists of relevant titles identified by the search and contacted researchers to identify other possible published and unpublished studies.Randomised and quasi-randomised controlled trials that compared (1) NSOMT versus placebo or control; and (2) NSOMT as adjunctive treatment or speech intervention versus speech intervention alone, for children aged three to 16 years with developmental speech sound disorders, as judged by a speech and language therapist. Individuals with an intellectual disability (e.g. Down syndrome) or a physical disability were not excluded.The Trials Search Co-ordinator of the Cochrane Developmental, Psychosocial and Learning Problems Group and one review author ran the searches. Two review authors independently screened titles and abstracts to eliminate irrelevant studies, extracted data from the included studies and assessed risk of bias in each of these studies. In cases of ambiguity or information missing from the paper, we contacted trial authors.This review identified three studies (from four reports) involving a total of 22 children that investigated the efficacy of NSOMT as adjunctive treatment to conventional speech intervention versus conventional speech intervention for children with speech sound disorders. One study, a randomised controlled trial (RCT), included four boys aged seven years one month to nine years six months - all had speech sound disorders, and two had additional conditions (one was diagnosed as "communication impaired" and the other as "multiply disabled"). Of the two quasi-randomised controlled trials, one included 10 children (six boys and four girls), aged five years eight months to six years nine months, with speech sound disorders as a result of tongue thrust, and the other study included eight children (four boys and four girls), aged three to six years, with moderate to severe articulation disorder only. Two studies did not find NSOMT as adjunctive treatment to be more effective than conventional speech intervention alone, as both intervention and control groups made similar improvements in articulation after receiving treatments. One study reported a change in postintervention articulation test results but used an inappropriate statistical test and did not report the results clearly. None of the included studies examined the effects of NSOMTs on any other primary outcomes, such as speech intelligibility, speech physiology and adverse effects, or on any of the secondary outcomes such as listener acceptability.The RCT was judged at low risk for selection bias. The two quasi-randomised trials used randomisation but did not report the method for generating the random sequence and were judged as having unclear risk of selection bias. The three included studies were deemed to have high risk of performance bias as, given the nature of the intervention, blinding of participants was not possible. Only one study implemented blinding of outcome assessment and was at low risk for detection bias. One study showed high risk of other bias as the baseline characteristics of participants seemed to be unequal. The sample size of each of the included studies was very small, which means it is highly likely that participants in these studies were not representative of its target population. In the light of these serious limitations in methodology, the overall quality of the evidence provided by the included trials is judged to be low. Therefore, further research is very likely to have an important impact on our confidence in the estimate of treatment effect and is likely to change the estimate.The three included studies were small in scale and had a number of serious methodological limitations. In addition, they covered limited types of NSOMTs for treating children with speech sound disorders of unknown origin with the sounds /s/ and /z/. Hence, we judged the overall applicability of the evidence as limited and incomplete. Results of this review are consistent with those of previous reviews: Currently no strong evidence suggests that NSOMTs are an effective treatment or an effective adjunctive treatment for children with developmental speech sound disorders. Lack of strong evidence regarding the treatment efficacy of NSOMTs has implications for clinicians when they make decisions in relation to treatment plans. Well-designed research is needed to carefully investigate NSOMT as a type of treatment for children with speech sound disorders.
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