Person: Lin, Jennifer
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Lin
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Jennifer
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Lin, Jennifer
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Publication Current evidence and applications of photodynamic therapy in dermatology(Dove Medical Press, 2014) Wan, Marilyn T; Lin, JenniferIn photodynamic therapy (PDT) a photosensitizer – a molecule that is activated by light – is administered and exposed to a light source. This leads both to destruction of cells targeted by the particular type of photosensitizer, and immunomodulation. Given the ease with which photosensitizers and light can be delivered to the skin, it should come as no surprise that PDT is an increasingly utilized therapeutic in dermatology. PDT is used commonly to treat precancerous cells, sun-damaged skin, and acne. It has reportedly also been used to treat other conditions including inflammatory disorders and cutaneous infections. This review discusses the principles behind how PDT is used in dermatology, as well as evidence for current applications of PDT.Publication Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas(BioMed Central, 2015) Lee, Jonathan J.; Sholl, Lynette; Lindeman, Neal; Granter, Scott; Laga, Alvaro; Shivdasani, Priyanka; Chin, Gary; Luke, Jason J.; Ott, Patrick; Hodi, F. Stephen; Mihm, Martin; Lin, Jennifer; Werchniak, Andrew E.; Haynes, Harley; Bailey, Nancy; Liu, Robert; Murphy, George; Lian, ChristineBackground: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. Results: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. Conclusions: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0091-3) contains supplementary material, which is available to authorized users.Publication Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma(Impact Journals LLC, 2017) Timerman, Dmitriy; McEnery-Stonelake, Melissa; Joyce, Cara J; Nambudiri, Vinod; Stephen, F Hodi; Claus, Elizabeth; Ibrahim, Nageatte; Lin, JenniferVitamin D deficiency (≤20 ng/mL) is associated with an increased incidence and worse prognosis of various types of cancer including melanoma. A retrospective, single-center study of individuals diagnosed with melanoma from January 2007 through June 2013 who had a vitamin D (25(OH)D3) level measured within one year of diagnosis was performed to determine whether vitamin D deficiency and repletion are associated with melanoma outcome. A total of 409 individuals diagnosed with histopathology-confirmed melanoma who had an ever measured serum 25(OH)D3 level were identified. 252 individuals with a 25(OH)D3 level recorded within one year after diagnosis were included in the study and the individual and melanoma characteristics such as age, sex, Breslow thickness, ulceration, stage, mitotic rate, and LDH were obtained from the medical record. A worse melanoma prognosis was associated with vitamin D deficiency (P=0.012), higher stage (P<0.001), ulceration (P=0.001), and higher mitotic rate (P=0.001) (HR 1.93, 95% CI 1.15-3.22). In patients with stage IV metastatic melanoma, vitamin D deficiency was associated with significantly worse melanoma-specific mortality (adjusted HR 2.06, 95% CI 1.10-3.87). Patients with metastatic melanoma who were initially vitamin D deficient and subsequently had a decrease or ≤20 ng/mL increase in their 25(OH)D3 concentration had significantly worse outcomes (HR 4.68, 95% CI 1.05-20.88) compared to non-deficient patients who had a >20 ng/mL increase. Our results suggest that initial vitamin D deficiency and insufficient repletion is associated with a worse prognosis in patients with metastatic melanoma.Publication Nestin depletion induces melanoma matrix metalloproteinases and invasion(2015) Lee, Chung-Wei; Zhan, Qian; Lezcano, Cecilia; Frank, Markus; Huang, John; Larson, Allison; Lin, Jennifer; Wan, Marilyn T.; Lin, Ping-I; Ma, Jie; Kleffel, Sonja; Schatton, Tobias; Lian, Christine; Murphy, GeorgeMatrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-β), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.Publication Linkage and Association Analyses of Microsatellites and Single-Nucleotide Polymorphisms in Nuclear Families(BioMed Central, 2005) Lin, Jennifer; Liu, Kuang-YuSeveral simulation studies have suggested that a high-density single-nucleotide polymorphisms (SNPs) marker set may be as useful as a traditional microsatellites (MS) marker set in performing whole-genome linkage analysis. However, very few studies have directly tested the SNPs-based genome-wide scan. In the present study, we compared the linkage results from the SNPs-based scan with a map density of 3-cM spacing with those from the MS scan using a 10-cM marker set among 300 nuclear families each from the Aipotu (AI), Danacaa (DA), and Karangar (KA) populations from the simulated Genetic Analysis Workshop 14 Problem 2 data. We found that information contents obtained from the SNPs scan were somewhat lower than those from the MS scan. However, the linkage results obtained from the two scans showed a high degree of similarity. Both scans identified a similar number of chromosomal regions attaining nominal significance (p < 0.05). Specifically, both scans detected confirmed evidence for linkage (NPL ≥ 4.07, p = 2 × 10-5) to chromosome 1 in the AI families, chromosomes 1 and 3 in the DA families, and chromosomes 3, 5, and 9 in the KA families. An additional confirmed linkage to chromosome 5 in the AI families was detected only by the MS scan. We also observed slightly wider 1-LOD intervals for more of the SNP peaks than for the MS peaks, which is likely due to lower information contents for the SNPs. Subsequent fine-mapping association analysis further identified 2 to 3 markers significantly associated with disease status in each population; B03T3056, B03T3058, and B05T4139 in the AI population, B03T3056 and B03T3058 in the KA population, and B03T3056, B03T3057, and B03T3058 in the DA population. Among the four markers, three were chosen based on results obtained from the two scans, but one was solely from the SNP scan. In summary, our finding suggests that the SNP-based genome scan has the potential to be as powerful as the traditional MS-based scan and offers good identification of peak location for further fine-mapped association analysis.Publication Boosting Alternating Decision Trees Modeling of Disease Trait Information(BioMed Central, 2005) Liu, Kuang-Yu; Lin, Jennifer; Zhou, Xiaobo; Wong, Stephen TCWe applied the alternating decision trees (ADTrees) method to the last 3 replicates from the Aipotu, Danacca, Karangar, and NYC populations in the Problem 2 simulated Genetic Analysis Workshop dataset. Using information from the 12 binary phenotypes and sex as input and Kofendrerd Personality Disorder disease status as the outcome of ADTrees-based classifiers, we obtained a new quantitative trait based on average prediction scores, which was then used for genome-wide quantitative trait linkage (QTL) analysis. ADTrees are machine learning methods that combine boosting and decision trees algorithms to generate smaller and easier-to-interpret classification rules. In this application, we compared four modeling strategies from the combinations of two boosting iterations (log or exponential loss functions) coupled with two choices of tree generation types (a full alternating decision tree or a classic boosting decision tree). These four different strategies were applied to the founders in each population to construct four classifiers, which were then applied to each study participant. To compute average prediction score for each subject with a specific trait profile, such a process was repeated with 10 runs of 10-fold cross validation, and standardized prediction scores obtained from the 10 runs were averaged and used in subsequent expectation-maximization Haseman-Elston QTL analyses (implemented in GENEHUNTER) with the approximate 900 SNPs in Hardy-Weinberg equilibrium provided for each population. Our QTL analyses on the basis of four models (a full alternating decision tree and a classic boosting decision tree paired with either log or exponential loss function) detected evidence for linkage (Z ≥ 1.96, p less than 0.01) on chromosomes 1, 3, 5, and 9. Moreover, using average iteration and abundance scores for the 12 phenotypes and sex as their relevancy measurements, we found all relevant phenotypes for all four populations except phenotype b for the Karangar population, with suggested subgroup structure consistent with latent traits used in the model. In conclusion, our findings suggest that the ADTrees method may offer a more accurate representation of the disease status that allows for better detection of linkage evidence.Publication Are there mappable genes for family resemblance for the magnitude of intra-individual variation in systolic blood pressure?(BioMed Central, 2003) Lin, Jennifer; Hinrichs, Anthony; Suarez, Brian KBackground: The genetic regulation of variation in intra-individual fluctuations in systolic blood pressure over time is poorly understood. Analysis of the magnitude of the average fluctuation of a person's systolic blood pressure around his or her age-adjusted trend line, however, shows moderate, albeit significant, family resemblance in Cohort 1 of the Framingham Heart Study. To determine whether genomic regions affecting this phenotype could be identified, we pursued a "model-free" multipoint quantitative linkage analysis.Results Two different linkage methods revealed multiple nominally significant signals, two to four of which are "replicated" in Cohort 2. When both cohorts are assembled into extended pedigrees, three linkage signals remain nominally significant by one or both methods.Conclusion Any or all of the genomic regions in the vicinity of D5S1456, D11S2359, and D20S470 may contain elements that regulate systolic blood pressure homeostasis.