Faculty Bibliography
Searched for:
person:martif02
Total Results:
134
Primary mucosal melanoma arising from the eustachian tube with CTLA-4, IL-17A, IL-17C, and IL-17E upregulation
Primary malignant melanoma arising from the eustachian tube is extremely rare. We report the case of a 63-year-old white man who presented with a 1-month history of left-sided hearing loss and aural fullness. Flexible fiberoptic laryngoscopy detected a blue-purple mass that appeared to arise from the left lateral nasopharynx. Computed tomography demonstrated an enhancing mass arising from an orifice of the left eustachian tube. The tumor was debulked endoscopically and was confirmed to have originated in the left eustachian tube. Histologically, the tumor was made up of heavily pigmented pleomorphic spindle cells with frequent mitoses. The tumor cells were immunohistochemically positive for S-100 protein, HMB-45, Melan-A, and PNL-2. The final diagnosis was a mucosal malignant melanoma. We also performed a nested polymerase chain reaction assay for several genes of interest, including CTLA-4, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, PLZF, Foxp3, RORgammat, CD27, and CD70. These genes have been studied mainly in cutaneous melanomas, especially for the development of immunotherapy, but only very limited studies have been done on mucosal melanomas. Our investigation found upregulation of CTLA-4, IL-17A, IL-17C, and IL-17E. Based on our finding of CTLA-4 upregulation, it may be suggested that our patient might have had low antitumor immunity and that he might have benefited from CTLA-4 blockade. On the other hand, upregulation of IL-17A and IL-17E might reflect increased antitumor immunity, which could suggest that patients with a mucosal melanoma might benefit from immunomodulators associated with the effect of Th17. These genes also have great potential to help melanoma patients obtain tailored treatment, and they can be used as biomarkers for predicting prognosis.
PMCID:3969881
PMID: 23354891
ISSN: 0145-5613
CID: 214112
SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians
To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2x10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33x10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77x10(-9)) and rs3781834 (P = 1.04x10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71x10(-5)) and rs744373 near BIN1 (P = 1.39x10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
PMCID:3614978
PMID: 23565137
ISSN: 1932-6203
CID: 627162
Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer
PURPOSE: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. EXPERIMENTAL DESIGN: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. RESULTS: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%-56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. CONCLUSION: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses.
PMCID:3580198
PMID: 22767669
ISSN: 1078-0432
CID: 1395722
Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 x 10(-12)) and X-linked CLDN2 (P < 1 x 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
PMCID:3510344
PMID: 23143602
ISSN: 1061-4036
CID: 205272
Expression of Sox10 and c-kit in sinonasal mucosal melanomas arising in the Chinese population
Sinonasal mucosal melanomas (SNMM) of the head and neck regions are rare and aggressive malignancies. Although they can affect patients of any ethnicity, they are more numerous in Chinese patients. The diagnosis and treatment of these tumors can be challenging. Recent studies have reported that Sox10 is a sensitive melanocytic marker for cutaneous melanoma (Nonaka et al. in Am J Surg Pathol 32:1291-1298, 2008). In addition, a CD117 (c-kit) gene mutation has been identified in cutaneous melanomas, indicating that there may be potential therapeutic benefits of tyrosine kinase inhibitors, such as Imatinib. The purpose of this study was to detect and test the immunohistochemical expression of Sox10 and c-kit in mucosal melanomas (MM) arising in the nasal cavities of Chinese patients. Twenty eight patients with mucosal melanomas of the nasal cavity were treated in two major hospitals in China. All cases had been locally diagnosed as primary SNMM. We confirmed all diagnoses with positive immunohistochemical stains for S100 and HMB-45. Additionally, automated immunohistochemistry was performed using a goat polyclonal Sox10 antibody and a monoclonal c-kit antibody counterstained using a standard avidin-biotin complex method. Immunohistochemical positive expression of Sox10 was defined by nuclear stain; and positivity for c-kit resulted in a distinct membranous staining. The extent of nuclear positivity for Sox10 and membranous stain for c-kit was graded by 4 board certified pathologists as follows: 1+, 1-25 % of positive tumor cells; 2+, 25-50 %; 3+, 50-75 %; and 4+, >/=75 %. Sox10 nuclear expression was found in all cases (100 %), with 4+ staining in 26 out of 28 cases (92.8 %) and 3+ staining in two cases with (7.1 %). The overall positivity for S100 staining was 23 out of 28 (82.1 %), with 1+ staining in 10 cases, 2+ staining in 6 cases, 3+ staining in 7 cases, and no staining in 5 cases. The sensitivity and intensity of Sox10 immunohistochemistry were both higher than with S100 immunohistochemistry. Immunopositivity of membranous stain for c-kit (CD117) was seen in 24 out of 28 cases (85.7 %), including 6 tumors that were 4+, eight that were 3+, six that were 2+, and four that showed 1+ staining. Our results demonstrate that Sox10 is a sensitive marker for SNMM and it may possess diagnostic value in addition to that of S100 protein. The expression of c-kit in the majority of MMs suggests that it may be useful in the assessment of these tumors for potential treatment with tyrosine kinase inhibitors.
PMCID:3500896
PMID: 22736149
ISSN: 1936-0568
CID: 335902
Pseudoepitheliomatous hyperplasia and transepidermal elimination in lepromatous leprosy: does T-cell plasticity play a role? [Case Report]
BACKGROUND: The longstanding concept of a Th1-Th2 dichotomy in leprosy, with Th1-predominant tuberculoid leprosy and Th2-predominant lepromatous leprosy (LL), has recently been challenged, and Cbl-b overexpression may emerge as an important factor in anergy and progression of LL. Moreover, Th17 and Th22 subsets have been identified as Th1-Th2 modulators in inflammatory skin diseases, most notably psoriasis, but their roles in leprosy have not yet been elucidated. The occurrence of pseudoepitheliomatous hyperplasia (PEH) with transepidermal elimination of mycobacteria in LL patients, which could theoretically be a portal for contact transmission, thus raises important immunological questions: Do Th17 and/or Th22 subsets mediate epidermal proliferation akin to Th1-driven psoriasis in supposedly Th2-predominant LL disease, and is the Th1-Th2 immunostat set systemically or locally? Furthermore, which microRNAs (miRs), signal transducers, and activators of transcription (STAT) proteins regulate this transition in leprosy, if any, and does differential Cb1-b expression play a role? OBSERVATION: A 71-year-old man presented with an infiltrative dermopathy characteristic of LL, as well as several hyperkeratotic plaques. Microscopic examination of the hyperkeratotic lesions demonstrated PEH with loss of the grenz zone and transepidermal elimination of acid-fast bacilli, whereas classic histopathologic features of LL were present at other sites. HYPOTHESES: We hypothesize that: Th17 and Th22 T-cell subsets act locally to induce T-cell plasticity in LL lesions, manifesting PEH; miR-181a is normal or increased in LL lesions with PEH compared to its expressional loss in classic LL lesions; miR-21 and STAT3 are increased in LL lesions with PEH, given their association with epithelial hyperproliferation; and Cbl-b is diminished in LL lesions with PEH compared to classic LL lesions. CONCLUSION: By understanding the factors that regulate T-cell and cytokine responses in leprosy, it should be possible to recognize these dynamic immunologic processes clinically and histopathologically and devise specific immunologic interventions.
PMID: 23134990
ISSN: 1545-9616
CID: 335892
Comprehensive search for Alzheimer disease susceptibility loci in the APOE region
OBJECTIVE: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN: Conditional logistic regression models and survival analysis. SETTING: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. PARTICIPANTS: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. MAIN OUTCOME MEASURES: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. RESULTS: In models adjusting for APOE epsilon4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of epsilon3/epsilon3 subjects. CONCLUSIONS: APOE alleles epsilon2, epsilon3, and epsilon4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
PMCID:3579659
PMID: 22869155
ISSN: 0003-9942
CID: 627172
Novel late-onset Alzheimer disease loci variants associate with brain gene expression
OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies ( approximately 400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes +/-100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs +/-100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 x 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 x 10(-4)-1.86 x 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 x 10(-5)-9.09 x 10(-9)), some of which also associate with AD risk (p = 2.64 x 10(-2)-6.25 x 10(-5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
PMCID:3398432
PMID: 22722634
ISSN: 0028-3878
CID: 1435652
Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity
BACKGROUND: Leprosy was the first disease classified according to the thymus derived T-cell in the 1960s and the first disease classified by the cytokine profile as intact interferon-gamma (IFN-gamma) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-gamma and IL2 or TH2 (lepromatous), in the 1980s. Objective: In the present study, we set out to explore the T helper 17 (TH17) lymphocyte subset, the hallmark of T-cell plasticity, in skin biopsies from patients with erythema nodosum leprosum (ENL) who were treated with thalidomide. METHOD: RNA was extracted from paraffin embedded tissue before and after thalidomide treatment of ENL and RT-PCR was performed. RESULTS: IL17A, the hallmark of TH17, was consistently seen before and after thalidomide treatment, confirming the TH17 subset to be involved in ENL and potentially up-regulated by thalidomide. CONCLUSION: A reduction in CD70, GARP, IDO, IL17B (IL-20), and IL17E (IL-25), coupled with increases in RORgammaT, ARNT, FoxP3, and IL17C (IL-21) following thalidomide treatment, opens the door to understanding the complexity of the immunomodulatory drug thalidomide, which can operate as an anti-inflammatory while simultaneously stimulating cell-mediated immunity (CMI). We conclude that TH17 is involved in the immunopathogenesis of ENL and that thalidomide suppresses inflammatory components of TH17, while enhancing other components of TH17 that are potentially involved in CMI.
PMCID:3412264
PMID: 22527432
ISSN: 1545-9616
CID: 335912
Mycobacterium lepromatosis: emerging strain or species? [Comment]
PMID: 22402645
ISSN: 1545-9616
CID: 335922
