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author:("Kang, ruining")
2.  BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint 
Nature medicine  2013;19(8):1014-1022.
The B cell-specific transcription factor BACH2 is required for affinity maturation of mature B cells. Here, we show that Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B ALL, BACH2-mediated checkpoint control is frequently compromised. Low levels of BACH2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53, and fail to initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses reveal that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and other checkpoint control genes. These findings identify Bach2 as a critical mediator negative selection at the pre-B cell receptor checkpoint and a safeguard against leukemogenesis.
PMCID: PMC3954721  PMID: 23852341
3.  Polymorphisms in cytokine genes and serum cytokine levels among New Mexican women with and without breast cancer 
Cytokine  2010;51(1):18-24.
Among New Mexican Hispanic women, breast cancer is detected at a more advanced stage than compared to Non-Hispanic White women. One central factor that has been little studied is the role of critical cytokines. We genotyped incident breast cancer cases and their age-, gender- and smoking-matched controls (N = 40 matched pairs) for 25 single nucleotide polymorphisms (SNPs) in cytokine genes. We measured corresponding serum cytokine levels as well. Five cytokines (IL-1β, IL-5, TNF-α, IL-6 and IL-2) were significantly associated with disease and based on their serum levels, concentrations were higher in the cases than in the controls. Disease odds ratios corresponding to one standard deviation change in log-transformed concentrations of these cytokines were 18.87, 4.10, 3.61, 3.27 and 2.52. Three most statistically significant SNPs were rs2069705, located in the promoter region of the interferon gamma gene (INF-γ); rs2243248, in the promoter of IL-4 (rs2243248); and rs1800925, in the promoter of the IL-13 gene. Increased serum cytokine levels at diagnosis are indicative for immunological alterations and possibly related to genetic susceptibility markers as well. These findings might guide us to understand the presence of SNPs in cytokine genes and serum concentrations among breast cancer patients and potentially in other cancers.
PMCID: PMC3705637  PMID: 20418110
Breast cancer; Cytokine; Th1/Th2 balance; Serum cytokine level
4.  Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen 
ACS Chemical Biology  2012;7(4):715-722.
TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFP-tagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors.
PMCID: PMC3331904  PMID: 22260433
5.  Redesign of an Internal Medicine Ward Rotation: Operational Challenges and Outcomes 
In anticipation of the 2011 ACGME duty hour requirements, we redesigned our internal medicine resident ward experience. Our previous ward structure included a maximum 30-hour duty period for postgraduate year-1 (PGY-1) residents. In the redesigned ward structure, PGY-1 residents had a maximum 18-hour duty period.
We evaluated resident conference attendance and duty hour violations before and after implementation of our new ward redesign. We administered a satisfaction survey to residents and faculty 6 months after implementation of the new ward redesign.
Before implementation of the ward redesign, 30-hour continuous and 80-h/wk duty violations were each 2/year, and violations of the 10-hour rest between duty periods were 10/year for 74 residents. After implementation of the ward redesign, there were no 30-hour continuous or 80-h/wk duty violations, but violations of the 10-hour rest between duty periods more than doubled (26/year for 75 residents). Duty hours were reported by different mechanisms for the 2 periods. Conference attendance improved. Resident versus faculty satisfaction scores were similar. Both groups judged overall professional satisfaction as slightly worse after implementation.
Our ward rotation redesign eliminated 30-hour continuous and 80-h/wk duty violations as well as improved conference attendance. These benefits occurred at the cost of more faculty hires, decreased resident elective time, and slightly worse postimplementation satisfaction scores.
PMCID: PMC3312544  PMID: 23451316
6.  Method of Detection and Breast Cancer Survival Disparities in Hispanic Women 
Hispanic women in New Mexico (NM) are more likely to die of breast cancer-related causes than non-Hispanic women. We determined whether survival differences between Hispanic and non-Hispanic women might be attributable to the method of detection, an independent breast cancer prognostic factor in previous studies.
White women diagnosed with invasive breast cancer from 1995 through 2004 were identified from NM Surveillance Epidemiology End Results (SEER) files (n=5067), and matched to NM Mammography Project records. Method of cancer detection was categorized as “symptomatic” or “screen-detected”. The proportion of Hispanic survival disparity accounted for by included variables was assessed using Cox models.
During 87 months median follow-up, 490 breast cancer deaths occurred. Symptomatic vs. screen-detection was classifiable for 3891 women (76.8%), and was independently related to breast cancer-specific survival (Hazard ratio (HR) 1.6; 95% confidence interval (CI) 1.3–2.0). Hispanic women had a 1.5-fold increased risk of breast cancer-related death, relative to non-Hispanic women (95% CI 1.2–1.8). After adjustment for detection method, the Hispanic HR declined from 1.50 to 1.45 (10%), but after inclusion of other prognostic indicators, the Hispanic HR=1.23 (95% CI 1.01–1.48).
Although the Hispanic HR declined 50% after adjustment, the decrease was largely due to adverse tumor prognostic characteristics.
Reduction of disparate survival in Hispanic women may rely not only on increased detection of tumors when asymptomatic but on development of greater understanding of biological factors that predispose to poor prognosis tumors.
PMCID: PMC3402167  PMID: 20841385
Breast Neoplasms; Mortality; Hispanic Americans; Mammography; Survival analysis
7.  In Utero Exposure of Female CD-1 Mice to AZT and/or 3TC: II. Persistence of Functional Alterations in Cardiac Tissue 
Cardiovascular toxicology  2010;10(2):87-99.
To delineate temporal changes in the integrity and function of mitochondria/cardiomyocytes in hearts from mice exposed in utero to commonly used nucleoside analogs (NRTIs), CD-1 mice were exposed in utero to 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during days 12–18 of gestation and hearts from female mouse offspring were examined at 13 and 26 weeks postpartum. Alterations in cardiac mitochondrial DNA (mtDNA) content, oxidative phosphorylation (OXPHOS) enzyme activities, mtDNA mutations, and echocardiography of NRTI-exposed mice were assessed and compared with findings in vehicle-exposed control mice. A hybrid capture-chemiluminescence assay showed significant twofold increases in mtDNA levels in hearts from AZT- and AZT/3TC-exposed mice at 13 and 26 weeks postpartum, consistent with near doubling in mitochondrial numbers over time compared with vehicle-exposed mice. Echocardiographic measurements at 13 and 26 weeks postpartum indicated progressive thinning of the left ventricular posterior wall in NRTI-exposed mice, relative to controls, with differences becoming statistically significant by 26 weeks. Overall, progressive functional changes occurred in mouse mitochondria and cardiac tissue several months after in utero NRTI exposures; AZT and 3TC acted in concert to cause additive cardiotoxic effects of AZT/3TC compared with either drug alone.
PMCID: PMC3189686  PMID: 20155331
AZT; 3TC; Cardiotoxicity; Echocardiography Mitochondrial; Mitochondrial DNA content; Mitochondrial DNA mutation; Mitochondrial dysfunction; Mitochondrial toxicity; OXPHOS; Transplacental exposure
8.  Multi-Vitamins, Folate, and Green Vegetables Protect Against Gene Promoter Methylation in the Aerodigestive Tract of Smokers 
Cancer research  2010;70(2):568-574.
The detection of gene promoter hypermethylation in sputum is a promising molecular marker for early lung cancer detection. Epidemiologic studies suggest that dietary fruits and vegetables and the micronutrients they contain may reduce risk of lung cancer. This investigation evaluated whether diet and multi-vitamin use influence the prevalence for gene methylation in the cells exfoliated from the aerodigestive tract of current and former smokers. Members (n = 1101) of the Lovelace Smokers Cohort completed the Harvard Food Frequency Questionnaire and provided a sputum sample that was assessed for promoter methylation of eight genes commonly silenced in lung cancer and associated with risk for this disease. Methylation status was categorized as low (< 2 genes methylated) or high (≥2 genes methylated). Logistic regression models were used to identify associations between methylation status and 21 dietary variables hypothesized to affect the acquisition of gene methylation. Significant protection against methylation was observed for leafy green vegetables (OR = 0.83 per 12 monthly servings, CI: 0.74, 0.93) and folate (OR = 0.84 per 750 mcg/day, CI: 0.72, 0.99). Protection against gene methylation was also seen with current use of multi-vitamins (OR = 0.57, CI: 0.40, 0.83). This is the first cohort-based study to identify dietary factors associated with reduced promoter methylation in cells exfoliated from the airway epithelium of smokers. Novel interventions to prevent lung cancer should be developed based on the ability of diet and dietary supplements to affect reprogramming of the epigenome.
PMCID: PMC3076796  PMID: 20068159
gene methylation; folate; multi-vitamins; green vegetables; smokers
9.  Gene Expression Signatures Predictive of Early Response and Outcome in High-Risk Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study 
Journal of Clinical Oncology  2008;26(27):4376-4384.
To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures.
Patients and Methods
Gene expression profiles were generated from bone marrow blasts at initial diagnosis from a cohort of 99 children with National Cancer Institute–defined high-risk ALL who were treated uniformly on the Children's Oncology Group (COG) 1961 study. For prediction of early response, genes that correlated to marrow status on day 7 were identified on a training set and were validated on a test set. An additional signature was correlated with long-term outcome, and the predictive models were validated on three large, independent patient cohorts.
We identified a 24–probe set signature that was highly predictive of day 7 marrow status on the test set (P = .0061). Pathways were identified that may play a role in early blast regression. We have also identified a 47–probe set signature (which represents 41 unique genes) that was predictive of long-term outcome in our data set as well as three large independent data sets of patients with childhood ALL who were treated on different protocols. However, we did not find sufficient evidence for the added significance of these genes and the derived predictive models when other known prognostic features, such as age, WBC, and karyotype, were included in a multivariate analysis.
Genes and pathways that play a role in early blast regression may identify patients who may be at risk for inferior responses to treatment. A fully validated predictive gene expression signature was defined for high-risk ALL that provided insight into the biologic mechanisms of treatment failure.
PMCID: PMC2736991  PMID: 18802149

Results 1-9 (9)