- General Surgery
Honors & Awards
NIH T32 Fellowship, Perioperative immune landscape in inflammatory bowel disease, Stanford University, Dpt. of Anesthesiology (7/2019-7/2020)
WHSDM Grant, Sex differences in immune response to surgery among patients with IBD, Stanford University, Women's Health and Sex Differences in Medicine (2018-2019)
Stanford Accelerated Surgeon Scientist, Stanford General Surgery Residency (2013-2018)
Member, Alpha Omega Alpha Honor Medical Society (2012-current)
Medical Scientist Training Program Scholar, University of Colorado (2005-2013)
Siglec-6 and Leptin Effects on Early Placental Development, T32 Fellowship, Colorado Clinical and Translational Sciences Institute (2008)
Prehabilitation in Kidney Transplant to Decrease Frailty and Improve Outcomes, Society Grant, Stanford Society of Physician Scientists (2015)
Doctor of Philosophy, University of Colorado Denver (2011)
Doctor of Medicine, University of Colorado Denver (2013)
Bachelor of Arts, University of Colorado Boulder (1998)
Current Research and Scholarly Interests
Immunology of Inflammatory Bowel Disease in the Perioperative Period
Surgical Outcomes in Inflammatory Bowel Disease
Fitness, Frailty and Prehabilitation of Surgical Patients
Surgery, Stomas, and Anxiety and Depression in Inflammatory Bowel Disease: A Retrospective Cohort Analysis of Privately Insured Patients.
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland
AIM: Inflammatory bowel disease (IBD) patients are diagnosed with anxiety/depression at higher rates than the general population. We aimed to determine the frequency of anxiety/depression among IBD patients and temporal association with abdominal surgery and stoma formation.METHODS: We conducted a retrospective cohort study in adult IBD patients using difference-in-differences methodology using a large commercial claims database (2003-2016). Outcomes were anxiety/depression diagnoses before and after major abdominal surgery or stoma formation.RESULTS: We identified 10,481 IBD patients who underwent major abdominal surgery, 18.8% of whom underwent stoma formation, and 41,924 nonsurgical age- and sex-matched IBD controls who were assigned random index dates. Rates of anxiety and depression increased among all cohorts (p<0.001). Surgical patients had higher odds of anxiety (one surgery: adjusted odds ratio 6.90, 95% confidence interval [6.11-7.79], p<0.001; 2+ surgeries: 7.53 [5.99-9.46], p<0.001) and depression (one surgery: 6.15, [5.57-6.80], p<0.001; 2+ surgeries: 6.88 [5.66-8.36], p<0.001) than nonsurgical controls. Undergoing multiple surgeries was associated with a significant increase in depression from pre- to post-time periods (1.43, [1.18-1.73, p<0.001). Amongst surgical patients, stoma formation was independently associated with anxiety (1.40, [1.17-1.68], p<0.001) and depression (1.23, [1.05-1.45], p=0.01). New ostomates experienced a greater increase in postoperative anxiety (1.24, [1.05-1.47], p=0.01) and depression (1.19, [1.03-1.45], p=0.01) than other surgical patients.CONCLUSIONS: IBD patients who undergo surgery have higher rates of anxiety and depression than nonsurgical patients. Rates of anxiety and depression increase following surgery. Stoma formation represents an additional risk factor. These findings suggest the need for perioperative psychosocial support services.
View details for DOI 10.1111/codi.14905
View details for PubMedID 31713994
DEEP IMMUNE PROFILE OF PREOPERATIVE GLUCOCORTICOID ADMINISTRATION IN PATIENTS UNDERGOING SURGERY
LIPPINCOTT WILLIAMS & WILKINS. 2019: 140
View details for Web of Science ID 000480793600305
Prehabilitation in our most frail surgical patients: are wearable fitness devices the next frontier?
Current opinion in organ transplantation
2016; 21 (2): 188-193
Frailty is the concept of accumulating physiologic declines that make people less able to deal with stressors, including surgery. Prehabilitation is intervention to enhance functional capacity before surgery. Frailty and prehabilitation among transplant populations and the role of wearable fitness tracking devices (WFTs) in delivering fitness-based interventions will be discussed.Frailty is associated with increased complications, longer length of hospital stay and increased mortality after surgery. Frail kidney transplant patients have increased delayed graft function, mortality and early hospital readmission. Frail lung or liver transplant patients are more likely to delist or die on the waitlist. Prehabilitation can mitigate frailty and has resulted in decreased length of hospital stay and fewer postsurgical complications among a variety of surgical populations. Increasingly, WFTs are used to monitor patient activity and improve patient health. Interventions using WFTs have resulted in improved activity, weight loss and blood pressure.Frailty is a measurable parameter that identifies patients at risk for worse health outcomes and can be mitigated through intervention. Prehabilitation to reduce frailty has been shown to improve postsurgical outcomes in a variety of populations. WFTs are being integrated in healthcare delivery for monitoring and changing health behavior with promising results.
View details for DOI 10.1097/MOT.0000000000000295
View details for PubMedID 26859220
Maternal and fetal alternative complement pathway activation in early severe preeclampsia.
American journal of reproductive immunology (New York, N.Y. : 1989)
2014; 71 (1): 55–60
We sought to determine whether alternative complement activation fragment Bb (Bb) levels are elevated in the maternal, fetal, and placental blood in cases of severe preeclampsia (PE) compared with normotensive controls.This was a cross-sectional study of women admitted at ≥24 weeks gestation with or without severe PE. Maternal plasma was collected at the time of enrollment. Umbilical venous cord and intervillous space blood were collected at delivery. Plasma Bb levels were assessed using ELISA. Bb levels were compared between cases and controls.Median Bb levels were higher in the maternal plasma of severe PE subjects (n = 24) than in controls (n = 20), 1.45 ± 1.03 versus 0.65 ± 0.23 μg/mL, P < 0.001. In umbilical venous plasma, Bb levels were higher in severe PE subjects (n = 15) compared with controls (n = 15), 2.48 ± 1.40 versus 1.01 ± 0.57 μg/mL, P = 0.01.Activation fragment Bb is increased in the maternal and umbilical venous blood of cases of severe PE when compared with normotensive controls. These data provide support for alternative complement pathway involvement in the pathogenesis of severe PE and demonstrate that alternative complement activation occurs not only in the maternal but also in the fetal compartment.
View details for PubMedID 24128411
Siglec-6 expression is increased in placentas from pregnancies complicated by preterm preeclampsia.
Reproductive sciences (Thousand Oaks, Calif.)
2013; 20 (6): 646–53
Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds sialyl-TN glycans and leptin. Among eutherian mammals, only human placentas express Siglec-6. Previous work has implicated Siglec-6 in preeclampsia (PE). Preeclampsia, a leading cause of maternal and perinatal morbidity and mortality, is characterized by placental abnormalities. This study provides a comprehensive analysis of Siglec-6 protein expression during human pregnancy by disease state (PE), biologic compartment (basal plate, chorionic villi, or maternal plasma), gestational age (24-41 weeks), and labor status. Siglec-6 protein was increased in both the basal plate and chorionic villi of preterm PE placentas (P < .05). However, expression did not differ at term by disease state, compartment, or labor status. Siglec-6 was not detectable in maternal serum. Overexpression of Siglec-6 protein in preterm PE placentas may contribute to or represent a response to PE pathogenesis and suggests that preterm PE pathogenesis is distinct from term PE.
View details for DOI 10.1177/1933719112461185
View details for PubMedID 23171684
View details for PubMedCentralID PMC3676189
Siglec-6 is expressed in gestational trophoblastic disease and affects proliferation, apoptosis and invasion.
2012; 19 (6): 827–40
Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds leptin. Leptin is an obesity-associated peptide hormone overexpressed in gestational trophoblastic disease (GTD). GTD encompasses several placental abnormalities that range from benign to malignant. Among GTD, molar placentas are characterized by excess proliferation, whereas gestational trophoblastic neoplasias (GTN) have characteristically aggressive invasion. We hypothesized that in GTD, Siglec-6 expression would increase with disease severity and that Siglec-6 and leptin would promote proliferation, inhibit apoptosis and/or promote invasion. Siglec-6 expression patterns were evaluated with particular attention to the diagnostic utility of Siglec-6 in GTD (controls: normal placentas (n=32), hydropic abortus placentas (n=7), non-GTD reproductive tract cancers (n=2); GTD: partial moles (PM; n=11), complete moles (n=24), GTN (n=6)). In normal placentas, Siglec-6 expression dramatically decreased after 8 weeks gestation. Complete molar placentas had significantly higher Siglec-6 expression than controls, but expression was not significantly different from PM. In GTN, Siglec-6 expression was low. These data suggest that Siglec-6 may have diagnostic utility for distinguishing complete moles from normal and hydropic abortus placentas. Functional studies in choriocarcinoma-derived BeWO cells demonstrated a complex interplay between Siglec-6 expression and leptin exposure. In cells lacking Siglec-6, leptin treatment promoted invasion, likely through interaction with LepR leptin receptor, without affecting proliferation or apoptosis. Siglec-6 expression promoted proliferation in a leptin-dependent manner, but protected cells from apoptosis and promoted invasion in a leptin-independent manner. We propose that Siglec-6 and leptin play a role in the aberrant properties characteristic of GTD, namely excess proliferation and invasion.
View details for PubMedID 23089140
Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels.
American journal of clinical and experimental immunology
2012; 1 (1): 12–19
OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. METHODS: Cohorts of zymosan-treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. CONCLUSIONS: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration.
View details for PubMedID 23097751
View details for PubMedCentralID PMC3478147
Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2
2009; 150 (1): 452–62
Preeclampsia (PE), which affects 4-8% of human pregnancies, causes significant maternal and neonatal morbidity and mortality. Within the basal plate, placental cytotrophoblasts (CTBs) of fetal origin invade the uterus and extensively remodel the maternal vasculature. In PE, CTB invasion is often shallow, and vascular remodeling is rudimentary. To better understand possible causes, we conducted a global analysis of gene expression at the maternal-fetal interface in placental samples from women with PE (n = 12; 24-36 wk) vs. samples from women who delivered due to preterm labor with no evidence of infection (n = 11; 24-36 wk), a condition that our previous work showed is associated with normal CTB invasion. Using the HG-U133A&B Affymetrix GeneChip platform, and statistical significance set at log odds-ratio of B >0, 55 genes were differentially expressed in PE. They encoded proteins previously associated with PE [e.g. Flt-1 (vascular endothelial growth factor receptor-1), leptin, CRH, and inhibin] and novel molecules [e.g. sialic acid binding Ig-like lectin 6 (Siglec-6), a potential leptin receptor, and pappalysin-2 (PAPP-A2), a protease that cleaves IGF-binding proteins]. We used quantitative PCR to validate the expression patterns of a subset of the genes. At the protein level, we confirmed PE-related changes in the expression of Siglec-6 and PAPP-A2, which localized to invasive CTBs and syncytiotrophoblasts. Notably, Siglec-6 placental expression is uniquely human, as is spontaneous PE. The functional significance of these novel observations may provide new insights into the pathogenesis of PE, and assaying the circulating levels of these proteins could have clinical utility for predicting and/or diagnosing PE.
View details for DOI 10.1210/en.2008-0990
View details for Web of Science ID 000262052300050
View details for PubMedID 18818296
View details for PubMedCentralID PMC2630905
Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis.
The American journal of pathology
2006; 168 (2): 608–20
The mammary gland microenvironment during postlactational involution shares similarities with inflammation, including high matrix metalloproteinase activity, fibrillar collagen deposition, and release of bioactive fragments of fibronectin and laminin. Because inflammation can promote tumorigenesis, we evaluated whether the tissue microenvironment of the involuting gland is also promotional. Extracellular matrix was isolated from mammary glands of nulliparous rats or rats with mammary glands undergoing weaning-induced involution. Using these matrices as substratum, nulliparous matrix was found to promote ductal organization of normal mammary epithelial MCF-12A cells in three-dimensional culture and to suppress invasion of mammary tumor MDA-MB-231 cells in transwell filter assays. Conversely, involution matrix failed to support ductal development in normal cells and promoted invasiveness in tumor cells. To evaluate the effects of these matrices on metastasis in vivo, MDA-MB-231 cells, premixed with Matrigel, nulliparous matrix, or involution matrix, were injected into mammary fat pads of nude mice. Metastases to lung, liver, and kidney were increased in the involution matrix group, and correlated with a twofold increase in tumor vascular endothelial growth factor expression and increased angiogenesis. These data suggest that the mammary gland microenvironment becomes promotional for tumor cell dissemination during involution, thus providing a plausible mechanism to explain the high rate of metastases that occur with pregnancy-associated breast cancer.
View details for DOI 10.2353/ajpath.2006.050677
View details for PubMedID 16436674
View details for PubMedCentralID PMC1606507
Global regulation of post-translational modifications on core histones.
The Journal of biological chemistry
2002; 277 (4): 2579–88
Full-length masses of histones were analyzed by mass spectrometry to characterize post-translational modifications of bulk histones and their changes induced by cell stimulation. By matching masses of unique peptides with full-length masses, H4 and the variants H2A.1, H2B.1, and H3.1 were identified as the main histone forms in K562 cells. Mass changes caused by covalent modifications were measured in a dose- and time-dependent manner following inhibition of phosphatases by okadaic acid. Histones H2A, H3, and H4 underwent changes in mass consistent with altered acetylation and phosphorylation, whereas H2B mass was largely unchanged. Unexpectedly, histone H4 became almost completely deacetylated in a dose-dependent manner that occurred independently of phosphorylation. Okadaic acid also partially blocked H4 hyperacetylation induced by trichostatin-A, suggesting that the mechanism of deacetylation involves inhibition of H4 acetyltransferase activity, following perturbation of cellular phosphatases. In addition, mass changes in H3 in response to okadaic acid were consistent with phosphorylation of methylated, acetylated, and phosphorylated forms. Finally, kinetic differences were observed with respect to the rate of phosphorylation of H2A versus H4, suggesting differential regulation of phosphorylation at sites on these proteins, which are highly related by sequence. These results provide novel evidence that global covalent modifications of chromatin-bound histones are regulated through phosphorylation-dependent mechanisms.
View details for DOI 10.1074/jbc.M107894200
View details for PubMedID 11709551
Phosphorylation and subcellular redistribution of high mobility group proteins 14 and 17, analyzed by mass spectrometry.
Protein science : a publication of the Protein Society
2000; 9 (1): 170–79
High mobility group (HMG) proteins 14 and 17 are nonhistone nuclear proteins that have been implicated in control of transcription and chromatin structure. To examine the posttranslational modifications of HMG-14 and -17 in vivo, HMG proteins were prepared from nuclear vs. cytosolic fractions of human K562 cells treated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or okadaic acid (OA) and examined by electrospray mass spectrometry. Analysis of full-length masses demonstrated mono-, di-, and triphosphorylation of HMG-14 and mono- and diphosphorylation of HMG-17 from OA treated cells, whereas HMG-14 and -17 from TPA treated cells were monophosphorylated. Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at Ser24 and Ser28 in HMG-17, and Ser20 and Ser24 in HMG-14. These sites were found in the consensus sequence RRSARLSAK, within the nucleosomal binding domain of each protein. A third phosphorylation site in HMG-14 was located at either Ser6 or Ser7. Interestingly, the proportion of HMG-14 and -17 found in cytosolic pools increased significantly after 1 h of treatment compared to control cells and showed preferential phosphorylation compared with proteins from nuclear fractions. These results suggest that phosphorylation of HMG-14 and -7 interferes with nuclear localization mechanisms in a manner favoring release from nuclei.
View details for DOI 10.1110/ps.9.1.170
View details for PubMedID 10739259
View details for PubMedCentralID PMC2144438
Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses.
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
1996; 7 (2): 243–50
Both mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 function downstream of the proto-oncogene product Raf in signaling pathways that affect cell proliferation and differentiation. The isoforms were previously shown to be differentially regulated in two significant ways: (a) MAPKK1, but not MAPKK2, was phosphorylated and inactivated by the cyclin-dependent kinase p34cdc2; and (b) p21 Ras formed a ternary complex with Raf/MAPKK1 but not with Raf/MAPKK2. To further characterize the regulation and function of the two isoforms, we compared their mode of activation by v-Mos and examined the transcriptional and morphological responses that they mediate in cultured mammalian cells. v-Mos enhanced the enzymatic activity of both isoforms to the same extent, by about 600-fold. Constitutively active MAPKK2 mutants were generated by introducing the same deletion and amino acid substitutions that have been shown to activate MAPKK1, suggesting that the conformational changes that lead to their activation are analogous. These mutants potentiated transcription from a promoter containing AP1-responsive elements and induced morphological transformation when expressed in mammalian cells, matching outcomes observed with constitutively active MAPKK1. The specific activity of p42 MAPK in the transformed cells was 3-fold higher than in cells expressing wild-type MAPKK, thereby implicating p42 MAPK as a common effector in vivo, and suggesting that sustained activation of p42 MAPK may represent a critical factor that contributes to the development of the transformed state. Altogether, the results demonstrate that the two isoforms elicit similar responses in vivo despite differences in their regulation.
View details for PubMedID 8822208