Honors & Awards
Post-doctoral Fellow, Stanford Spectrum TL1 Mentored Career Development Award (10/2016-6/2017)
Jack Remington, MD Infectious Diseases Fellow's Award for Clinical Excellence, Stanford University School of Medicine (2014-2015)
Boards, Advisory Committees, Professional Organizations
Member, Infectious Diseases Society of America (2016 - Present)
Doctor of Medicine, Universita Degli Studi Di Padova (2008)
Board Certification, Americal Board of Internal Medicine, Infectious Diseases (2017)
Fellowship, Stanford University, Infectious Diseases (2018)
Board Certification, Americal Board of Internal Medicine, Internal Medicine (2014)
Residency, Pennsylvania Hospital of the University of Pennsylvania Health System, Internal Medicine (2014)
Internship, Pennsylvania Hospital of the University of Pennsylvania Health System, Pennsylvania Hospital of the University of Pennsylvania Health System (2012)
Postdoctoral Researcher, University of California, Los Angeles, AIDS-related lymphoma (2011)
Mass Cytometry Analytical Approaches Reveal Cytokine-Induced Changes in Natural Killer Cells.
Cytometry. Part B, Clinical cytometry
2017; 92 (1): 57-67
Natural killer (NK) cells have antiviral and antitumor activity that could be harnessed for the treatment of infections and malignancies. To maintain cell viability and enhance antiviral and antitumor effects, NK cells are frequently treated with cytokines. Here we performed an extensive assessment of the effects of cytokines on the phenotype and function of human NK cells.We used cytometry by time-of-flight (CyTOF) to evaluate NK cell repertoire changes after stimulation with interleukin (IL)-2, IL-15 or a combination of IL- 12/IL-15/IL-18. To analyze the high dimensional CyTOF data, we used several statistical and visualization tools, including viSNE (Visualization of t-Distributed Stochastic Neighbor Embedding), Citrus (Cluster identification, characterization, and regression), correspondence analysis, and the Friedman-Rafsky test.All three treatments (IL-2, IL-15, and IL-12/IL-15/IL-18) increase expression of CD56 and CD69. The effects of treatment with IL-2 and IL-15 are nearly indistinguishable and characterized principally by increased expression of surface markers including CD56, NKp30, NKp44, and increased expression of functional markers, such as perforin, granzyme B, and MIP-1β. The combination of IL-12/IL-15/IL- 18 induces a profound shift in the repertoire structure, decreasing expression of CD16, CD57, CD8, NKp30, NKp46, and NKG2D, and dramatically increasing expression of IFN-γ.CyTOF provides insights into the effects of cytokines on the phenotype and function of NK cells, which could inform future research efforts and approaches to NK cell immunotherapy. There are several analytical approaches to CyTOF data, and the appropriate method should be carefully selected based on which aspect of the dataset is being explored. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/cyto.b.21500
View details for PubMedID 27933717
Polymorphism in apoptotic BAX (-248G > A) gene but not in anti-apoptotic BCL2 (-938C > A) gene and its protein and mRNA expression are associated with cervical intraepithelial neoplasia
2015; 20 (10): 1347-1357
HPV is associated with cervical cancer and plays a crucial role in tumor formation. Apoptosis is regulated by different pathways involving genes that either promote (BCL2 gene) or inhibit (BAX gene) cell death. Our goal was to determine whether the BCL2-938C>A (rs2279115) and BAX-248G>A (rs4645878) single nucleotide polymorphisms (SNPs) are associated with squamous intraepithelial neoplasia (SIL) risk, and whether their phenotypic expression was impaired in these lesions. Two hundred and thirty-one cases showing SIL were classified as low SIL (LSIL, n = 101) or high SIL (HSIL, n = 130), and control subjects (n = 266) with no gynecologically proven SIL were recruited. No statistical difference in the genotype and allelic frequency of the BCL-2-938C>A polymorphism was observed among the groups. BCL2-938C/A and A/A homozygotes carriers had higher distribution of BCL-2-expressing cells in stroma in the SIL group. BCL2 mRNA-expression was not correlated with BCL2-938C>A SNPs in both groups. We did find a strong association of the BAX GG genotype and risk for SIL. No difference was observed between LSIL and HSIL groups. In BAX-248G/A and A/A homozygote carriers, the number of BAX-expressing cells was lower the epithelium area in SIL. However, mRNA expression was higher in SIL patients than in the control group. In conclusion, our data provide evidence that allele G carriers in the BAX-248G>A promoter SNP may influence the development of SIL. However, this genotype does not influence the SIL outcome. Additionally, we suggest a possible role of HPV infection in the inhibition of the expression of BAX protein, decreasing cell death, and favoring cervical carcinogenesis.
View details for DOI 10.1007/s10495-015-1156-7
View details for Web of Science ID 000360839500007
View details for PubMedID 26272263
Serum Levels of Cytokines and Biomarkers for Inflammation and Immune Activation, and HIV-Associated Non-Hodgkin B-Cell Lymphoma Risk
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2014; 23 (2): 343-349
HIV infection is associated with a marked increase in risk for non-Hodgkin lymphoma (AIDS-NHL). However, the mechanisms that promote the development of AIDS-NHL are not fully understood.In this study, serum levels of several cytokines and other molecules associated with immune activation were measured in specimens collected longitudinally during 1 to 5 years preceding AIDS-NHL diagnosis, in 176 AIDS-NHL cases and 176 HIV(+) controls from the Multicenter AIDS Cohort Study (MACS).Multivariate analyses revealed that serum levels of immunoglobulin free light chains (FLC), interleukin (IL)-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α were elevated in those HIV(+) individuals who went on to develop AIDS-NHL. In addition, the fraction of specimens with detectable IL-2 was increased and the fraction with detectable IL-4 was decreased in these subjects.These results suggest that long-term, chronic immune activation, possibly driven by macrophage-produced cytokines, precedes development of NHL in HIV(+) individuals.FLC, IL-6, IL-10, IP-10/CXCL10, neopterin, and TNF-α may serve as biomarkers for AIDS-NHL. .
View details for DOI 10.1158/1055-9965.EPI-13-0714
View details for Web of Science ID 000335143900012
View details for PubMedID 24220912
Serum Levels of the Chemokine CXCL13, Genetic Variation in CXCL13 and Its Receptor CXCR5, and HIV-Associated Non-Hodgkin B-Cell Lymphoma Risk
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2013; 22 (2): 295-307
CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B-cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated before HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points. TagSNPs in CXCL13 (n = 16) and CXCR5 (n = 11) were genotyped in 183 AIDS-NHL cases and 533 controls. OR and 95% confidence intervals (CI) for the associations between one unit increase in log CXCL13 levels and AIDS-NHL, as well as tagSNP genotypes and AIDS-NHL, were computed using logistic regression. Mixed linear regression was used to estimate mean ratios (MR) for the association between tagSNPs and CXCL13 levels.CXCL13 levels were elevated for more than 3 years (OR = 3.24; 95% CI = 1.90-5.54), 1 to 3 years (OR = 3.39; 95% CI = 1.94-5.94), and 0 to 1 year (OR = 3.94; 95% CI = 1.98-7.81) before an AIDS-NHL diagnosis. The minor allele of CXCL13 rs355689 was associated with reduced AIDS-NHL risk (OR(TCvsTT) = 0.65; 95% CI = 0.45-0.96) and reduced CXCL13 levels (MR(CCvsTT) = 0.82; 95% CI = 0.68-0.99). The minor allele of CXCR5 rs630923 was associated with increased CXCL13 levels (MR(AAvsTT) = 2.40; 95% CI = 1.43-4.50).CXCL13 levels were elevated preceding an AIDS-NHL diagnosis, genetic variation in CXCL13 may contribute to AIDS-NHL risk, and CXCL13 levels may be associated with genetic variation in CXCL13 and CXCR5. Impact: CXCL13 may serve as a biomarker for early AIDS-NHL detection.
View details for DOI 10.1158/1055-9965.EPI-12-1122
View details for Web of Science ID 000314700800014
View details for PubMedID 23250934
Assessment of Pre-Diagnosis Biomarkers of Immune Activation and Inflammation: Insights on the Etiology of Lymphoma
JOURNAL OF PROTEOME RESEARCH
2011; 10 (1): 113-119
The DNA-modifying processes that are involved in B lymphocyte activation, somatic hypermutation (SHM), and IgH class switch recombination (CSR) have the potential to lead to genetic errors that lead to the genesis of B cell cancers, such as lymphoma. Given the potential contribution of these immune mechanisms to the development of cancer, assessment of the expression of cytokines, and other immune stimulatory molecules that drive B cell activation, prior to lymphoma diagnosis, may provide insights into the etiology of these cancers. Here, we review studies that have examined prediagnosis protein biomarkers for non-Hodgkin lymphoma (NHL), both AIDS-related NHL, as well as NHL seen in immunocompetent populations. Overall, these studies provide support for the notion that B cell hyper-activation is elevated preceding the appearance of AIDS-NHL, particularly those forms of AIDS-NHL that are not driven by EBV infection and that presumably arise from errors in IgH CSR and SHM. In more limited studies, it appears that dysregulation of cytokine production also precedes the diagnosis of NHL in HIV-negative persons. The availability of prediagnosis serum/plasma from cohort studies provides unique opportunities for proteomic approaches to identify novel prediagnosis etiologic biomarkers for NHL.
View details for DOI 10.1021/pr100729z
View details for Web of Science ID 000285812000014
View details for PubMedID 20886858
HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma
2010; 48 (1-3): 72-83
HIV infection is associated with a much higher risk for the development of non-Hodgkin lymphoma (AIDS-NHL). The principal causes of lymphomagenesis in HIV-infected individuals are thought to be the loss of immune function seen in HIV infection, which results in the loss of immunoregulation of Epstein-Barr virus-infected B cells, as well as HIV infection-associated immune dysregulation, including chronic B-cell activation. In this review, we discuss recent reports that further support the importance of these factors, and we highlight emerging evidence of different mechanisms that potentially drive lymphomagenesis in HIV-infected individuals.
View details for DOI 10.1007/s12026-010-8168-8
View details for Web of Science ID 000284275400007
View details for PubMedID 20717742
Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
2010; 95 (10): 1722-1729
Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes.We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population.We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls.In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
View details for DOI 10.3324/haematol.2010.023358
View details for Web of Science ID 000283275000016
View details for PubMedID 20410181