Publications

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b GR1 and CD11b F4/80 myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc.

Relatively little is known regarding factors associated with the choice of a research career among practicing physicians, and most investigations of this issue have been conducted in the absence of a theoretical/conceptual model. Therefore we designed a survey to identify the determinants of decisions to pursue a biomedical research career based upon the Theory of Planned Behavior and the concept of stereotype threat. From October 2012 through January 2014 electronic surveys were sent to four consecutive Harvard Medical School graduating classes, 1996-1999. Respondents provided demographic information, indicated their current research involvement, and provided retrospective reports of their experiences and attitudes when they were making career choices as they completed medical school. Multivariable ordinal regression was used to identify factors independently associated with current research involvement. Completed questionnaires were received from 358 respondents (response rate 65 %). In unadjusted analyses, variables associated with more extensive research involvement included non-minority status, male gender, lower debt at graduation, strong attitudes toward research at time of graduation, and greater social pressures to pursue research (all P < .001). These associations remained significant in multivariable regression analysis (all P < 0.01). However, an interaction between sex and prior research publications was also detected, indicating that more extensive research involvement during medical school doubled the likelihood of a research career for women (OR 2.53, 95 % CI 1.00-6.40; P = 0.05). Most of the factors predicting research career choice involve factors that are potentially modifiable, suggesting that appropriately designed behavioral interventions may help to expand the size and diversity of the biomedical research community.

OBJECTIVE

Among HIV-infected persons, tenofovir disoproxil fumarate (TDF) use is associated with higher risk of developing chronic kidney disease (CKD). Because lower serum bicarbonate concentrations may precede CKD onset, this study investigated the associations between TDF use and bicarbonate concentrations, and between bicarbonate with CKD risk among TDF users and nonusers.

METHODS

Retrospective cohort study of 16,070 HIV-infected US veterans who initiated antiretroviral therapy between 1997-2011. The association between TDF use with longitudinal bicarbonate concentrations and associations between bicarbonate with incident CKD stratified by TDF use (never, initial, and later user) were evaluated.

RESULTS

Compared with TDF users, never users had faster declines in bicarbonate concentrations: change in bicarbonate -0.11 mmol/l per year (95% confidence interval -0.16, -0.05), compared with -0.04 mmol/l per year (-0.06, 0.05) in initial users and -0.02 mmol/l per year (-0.05, 0.01) in later users. Low baseline bicarbonate (<22 mmol/l) was significantly associated with CKD risk among TDF never users (1.80; 1.21, 2.68), but not among TDF users (0.98; 0.69, 1.38). Similarly, declining bicarbonate concentrations were associated with higher CKD risk among never users (hazard ratio 1.67 per mmol/l; 1.34, 2.08), but not among TDF users (1.09; 0.98, 1.22). Interactions were highly significant for both analyses (P value = 0.001).

CONCLUSION

Despite associations with nephrotoxicity, TDF use was associated with higher serum bicarbonate concentrations longitudinally. Additionally, TDF use obscured the strong associations of bicarbonate with CKD risk in HIV-infected persons. Therefore, the role of bicarbonate concentrations as a tool to monitor kidney health in HIV-infected persons may be limited in the setting of TDF use.

BACKGROUND

Frequent premature ventricular contractions (PVCs) can cause a reversible reduction in systolic function. Most studies use 24-hour ambulatory electrocardiograms (AECGs) to assess PVC burden; however, PVC counts vary across 24-hour periods. We hypothesized that extended AECG monitoring would better identify clinically significant ectopy.

METHODS

All 14-day AECGs performed at the San Francisco Veterans Affairs Medical Center between 2012 and 2015 (N = 694) were reviewed, and individuals with PVC counts ≥1.0% of total heartbeats were included (N = 101). Daily PVC counts and the range of these values across 24-hour periods were assessed. Median time for these ranges to cross clinically significant thresholds (PVCs ≥ 10%, 15%, or 20% of total heartbeats) was determined.

RESULTS

Median PVC burden was 2.6% of total heartbeats (interquartile range [IQR]: 1.6-5.4%) and the median range across 24-hour periods was 3.6% (IQR: 2.0-9.1%). Individual ranges of daily PVC burden crossed thresholds of 10%, 15%, and 20% of total heartbeats in 26.7%, 16.8%, and 6.9% of patients, respectively. Median time to detecting an individual's maximum PVC burden was 6 days (IQR: 2-11 days). While 75% of those who reached the 20% threshold did so on day one of monitoring, only 53% of those reaching the 10% threshold did similarly, with a continually increasing yield throughout the 14-day monitoring period.

CONCLUSIONS

PVC burden varies widely from day-to-day. While most patients with PVC burdens ≥20% were detected with 24 hours of monitoring, extended monitoring nearly doubled the identification of those reaching the 10% threshold.