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1.  Analysis of Internet Usage Among Cancer Patients in a County Hospital Setting: A Quality Improvement Initiative 
JMIR Research Protocols  2014;3(2):e26.
Cancer is one of the most common diseases that patients research on the Internet. The Commission on Cancer (CoC) recommended that Parkland Memorial Hospital (PMH) improve the oncology services website. PMH is Dallas County’s public health care facility, serving a largely uninsured, minority population. Most research regarding patient Internet use has been conducted in insured, Caucasian populations, raising concerns that the needs of PMH patients may not be extrapolated from available data. The PMH Cancer Committee, therefore, adopted a quality improvement initiative to understand patients’ Internet usage.
The objective of the study was to obtain and analyze data regarding patients’ Internet usage in order to make targeted improvements to the oncology services section of the institutional website.
A task force developed an 11-question survey to ascertain what proportion of our patients have Internet access and use the Internet to obtain medical information as well as determine the specific information sought. Between April 2011 and August 2011, 300 surveys were administered to newly diagnosed cancer patients. Multivariate analyses were performed.
Of 300 surveys, 291 were included. Minorities, primarily African-American and Hispanic, represented 78.0% (227/291) of patients. Only 37.1% (108/291) of patients had Internet access, most (256/291, 87.9%) having access at home. Younger patients more commonly had Internet access, with a mean age of 47 versus 58 years for those without (P<.001). Education beyond high school was associated with Internet access (P<.001). The most common reason for Internet research was to develop questions for discussion with one’s physician. Patients most frequently sought information regarding cancer treatment options, outcomes, and side effects.
Less than one-half of PMH oncology patients have Internet access. This is influenced by age, educational level, and ethnicity. Those with access use it to obtain information related to their cancer diagnosis. The most effective way of addressing our patients’ needs using the institutional website is to provide links to reputable disease-specific sites.
PMCID: PMC4034116  PMID: 24824330
Internet; cancer; quality; quality improvement; patient education
2.  Axillary lymph node dissection for breast cancer utilizing Harmonic Focus® 
For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus® will decrease operative time and reduce post-operative complications.
Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study.
Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups.
In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.
PMCID: PMC3170616  PMID: 21843361
3.  Translating Research into Practice Intervention Improves Management of Acute Pain in Older Hip Fracture Patients 
Health Services Research  2009;44(1):264-287.
To test an interdisciplinary, multifaceted, translating research into practice (TRIP) intervention to (a) promote adoption, by physicians and nurses, of evidence-based (EB) acute pain management practices in hospitalized older adults, (b) decrease barriers to use of EB acute pain management practices, and (c) decrease pain intensity of older hospitalized adults.
Study Design
Experimental design with the hospital as the unit of randomization.
Study Setting
Twelve acute care hospitals in the Midwest.
Data Sources
(a) Medical records (MRs) of patients ≥65 years or older with a hip fracture admitted before and following implementation of the TRIP intervention and (b) physicians and nurses who care for those patients.
Data Collection
Data were abstracted from MRs and questions distributed to nurses and physicians.
Principal Findings
The Summative Index for Quality of Acute Pain Care (0–18 scale) was significantly higher for the experimental (10.1) than comparison group (8.4) at the end of the TRIP implementation phase. At the end of the TRIP implementation phase, patients in the experimental group had a lower mean pain intensity rating than those in the comparison group (p<.0001).
The TRIP intervention improved quality of acute pain management of older adults hospitalized with a hip fracture.
PMCID: PMC2669630  PMID: 19146568
Translation; implementation; intervention; pain; elderly; hip fracture
4.  Cost of Hospital Care for Older Adults with Heart Failure: Medical, Pharmaceutical, and Nursing Costs 
Health Services Research  2008;43(2):635-655.
To determine the impact of patient characteristics, clinical conditions, hospital unit characteristics, and health care interventions on hospital cost of patients with heart failure.
Data Sources/Study Setting
Data for this study were part of a larger study that used electronic clinical data repositories from an 843-bed, academic medical center in the Midwest.
Study Design
This retrospective, exploratory study used existing administrative and clinical data from 1,435 hospitalizations of 1,075 patients 60 years of age or older. A cost model was tested using generalized estimating equations (GEE) analysis.
Data Collection/Extraction Methods
Electronic databases used in this study were the medical record abstract, the financial data repository, the pharmacy repository; and the Nursing Information System repository. Data repositories were merged at the patient level into a relational database and housed on an SQL server.
Principal Findings
The model accounted for 88 percent of the variability in hospital costs for heart failure patients 60 years of age and older. The majority of variables that were associated with hospital cost were provider interventions. Each medical procedure increased cost by $623, each unique medication increased cost by $179, and the addition of each nursing intervention increased cost by $289. One medication and several nursing interventions were associated with lower cost. Nurse staffing below the average and residing on 2–4 units increased hospital cost.
The model and data analysis techniques used here provide an innovative and useful methodology to describe and quantify significant health care processes and their impact on cost per hospitalization. The findings indicate the importance of conducting research using existing clinical data in health care.
PMCID: PMC2442365  PMID: 18370971
Heart failure; hospital cost; interventions; RN staffing
5.  Prediction of post-operative necrosis after mastectomy: A pilot study utilizing optical diffusion imaging spectroscopy 
Flap necrosis and epidermolysis occurs in 18-30% of all mastectomies. Complications may be prevented by intra-operative detection of ischemia. Currently, no technique enables quantitative valuation of mastectomy skin perfusion. Optical Diffusion Imaging Spectroscopy (ViOptix T.Ox Tissue Oximeter) measures the ratio of oxyhemoglobin to deoxyhemoglobin over a 1 × 1 cm area to obtain a non-invasive measurement of perfusion (StO2).
This study evaluates the ability of ViOptix T.Ox Tissue Oximeter to predict mastectomy flap necrosis. StO2 measurements were taken at five points before and at completion of dissection in 10 patients. Data collected included: demographics, tumor size, flap length/thickness, co-morbidities, procedure length, and wound complications.
One patient experienced mastectomy skin flap necrosis. Five patients underwent immediate reconstruction, including the patient with necrosis. Statistically significant factors contributing to necrosis included reduction in medial flap StO2 (p = 0.0189), reduction in inferior flap StO2 (p = 0.003), and flap length (p = 0.009).
StO2 reductions may be utilized to identify impaired perfusion in mastectomy skin flaps.
PMCID: PMC2788547  PMID: 19939277
6.  Bayesian optimal discovery procedure for simultaneous significance testing 
BMC Bioinformatics  2009;10:5.
In high throughput screening, such as differential gene expression screening, drug sensitivity screening, and genome-wide RNAi screening, tens of thousands of tests need to be conducted simultaneously. However, the number of replicate measurements per test is extremely small, rarely exceeding 3. Several current approaches demonstrate that test statistics with shrinking variance estimates have more power over the traditional t statistic.
We propose a Bayesian hierarchical model to incorporate the shrinkage concept by introducing a mixture structure on variance components. The estimates from the Bayesian model are utilized in the optimal discovery procedure (ODP) proposed by Storey in 2007, which was shown to have optimal performance in multiple significance tests. We compared the performance of the Bayesian ODP with several competing test statistics.
We have conducted simulation studies with 2 to 6 replicates per gene. We have also included test results from two real datasets. The Bayesian ODP outperforms the other methods in our study, including the original ODP. The advantage of the Bayesian ODP becomes more significant when there are few replicates per test. The improvement over the original ODP is based on the fact that Bayesian model borrows strength across genes in estimating unknown parameters. The proposed approach is efficient in computation due to the conjugate structure of the Bayesian model. The R code (see Additional file 1) to calculate the Bayesian ODP is provided.
PMCID: PMC2628883  PMID: 19126217
7.  A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma 
Molecular cancer research : MCR  2013;11(9):1061-1071.
Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including VHL, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BAP1 gene is mutated in sporadic RCC. BAP1, which encodes a nuclear deubiquitinase, is a two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade ccRCC and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, we sequenced the BAP1 gene in 83 unrelated probands with unexplained familial RCC. We identified a novel variant (c.41T>A; p.L14H), which cosegregated with the RCC phenotype. The p.L14H variant disrupts a highly conserved residue in the catalytic domain, a domain frequently targeted by missense mutations. The family with the BAP1 variant was characterized by early-onset clear cell RCC, occasionally of high Fuhrman grade, and lacked other features that characterize von Hippel-Lindau syndrome. These findings suggest that BAP1 is a familial RCC predisposing gene.
PMCID: PMC4211292  PMID: 23709298
renal cell carcinoma; BAP1; cancer; inherited RCC; predisposition; tumor suppressor
8.  Cooperation and antagonism among cancer genes: the renal cancer paradigm 
Cancer research  2013;73(14):4173-4179.
It is poorly understood how driver mutations in cancer genes work together to promote tumor development. Renal cell carcinoma (RCC) offers a unique opportunity to study complex relationships among cancer genes. The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes and they cluster in a 43 Mb region on chromosome 3p that is deleted in ~90% of tumors: VHL (mutated in ~80%), PBRM1 (~50%), BAP1 (~15%) and SETD2 (~15%). Meta-analyses that we conducted show that mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone, indicating that these mutations may cooperate in tumorigenesis. In contrast, consistent with our previous results, mutations in PBRM1 and BAP1 tend to be mutually exclusive. Mutation exclusivity analyses (often confounded by lack of statistical power) raise the possibility of functional redundancy. However, mutation exclusivity may indicate negative genetic interactions, as proposed herein for PBRM1 and BAP1, and mutations in these genes define RCC with different pathologic features, gene expression profiles, and outcomes. Negative genetic interactions among cancer genes point toward broader context-dependencies of cancer gene action beyond tissue dependencies. Understanding cancer genes dependencies may unravel vulnerabilities that can be exploited therapeutically.
PMCID: PMC4051157  PMID: 23832661
9.  Differential Radiosensitivity Phenotypes of DNA-PKcs Mutations Affecting NHEJ and HRR Systems following Irradiation with Gamma-Rays or Very Low Fluences of Alpha Particles 
PLoS ONE  2014;9(4):e93579.
We have examined cell-cycle dependence of chromosomal aberration induction and cell killing after high or low dose-rate γ irradiation in cells bearing DNA-PKcs mutations in the S2056 cluster, the T2609 cluster, or the kinase domain. We also compared sister chromatid exchanges (SCE) production by very low fluences of α-particles in DNA-PKcs mutant cells, and in homologous recombination repair (HRR) mutant cells including Rad51C, Rad51D, and Fancg/xrcc9. Generally, chromosomal aberrations and cell killing by γ-rays were similarly affected by mutations in DNA-PKcs, and these mutant cells were more sensitive in G1 than in S/G2 phase. In G1-irradiated DNA-PKcs mutant cells, both chromosome- and chromatid-type breaks and exchanges were in excess than wild-type cells. For cells irradiated in late S/G2 phase, mutant cells showed very high yields of chromatid breaks compared to wild-type cells. Few exchanges were seen in DNA-PKcs-null, Ku80-null, or DNA-PKcs kinase dead mutants, but exchanges in excess were detected in the S2506 or T2609 cluster mutants. SCE induction by very low doses of α-particles is resulted from bystander effects in cells not traversed by α-particles. SCE seen in wild-type cells was completely abolished in Rad51C- or Rad51D-deficient cells, but near normal in Fancg/xrcc9 cells. In marked contrast, very high levels of SCEs were observed in DNA-PKcs-null, DNA-PKcs kinase-dead and Ku80-null mutants. SCE induction was also abolished in T2609 cluster mutant cells, but was only slightly reduced in the S2056 cluster mutant cells. Since both non-homologous end-joining (NHEJ) and HRR systems utilize initial DNA lesions as a substrate, these results suggest the possibility of a competitive interference phenomenon operating between NHEJ and at least the Rad51C/D components of HRR; the level of interaction between damaged DNA and a particular DNA-PK component may determine the level of interaction of such DNA with a relevant HRR component.
PMCID: PMC3979685  PMID: 24714417
10.  Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer 
Scientific Reports  2014;4:4480.
Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.
PMCID: PMC3967199  PMID: 24670678
11.  BAP1 loss defines a new class of renal cell carcinoma 
Nature genetics  2012;44(7):751-759.
The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
PMCID: PMC3788680  PMID: 22683710
12.  A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel 
RNA Biology  2013;10(11):1700-1713.
microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR-346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications.
PMCID: PMC3907480  PMID: 24157646
cell viability; drug response; lung cancer; miRNA; paclitaxel
13.  A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma 
Science translational medicine  2012;4(137):137ra75.
Most anticancer drugs entering clinical trials fail to achieve approval from the US FDA. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidney of mice without additives or disaggregation. Tumors from 35 patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at high frequency, and stable engraftment of primary tumors in mice correlated with decreased patient survival suggesting that tumor growth in mice may reveal the acquisition by the tumor of an ability to thrive at distant sites and metastasize. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and over 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts were able to act on the host causing paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (into which temsirolimus is converted in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.
PMCID: PMC3570965  PMID: 22674553
xenograft; tumor graft; orthotopic; PK; NOD/SCID; kidney cancer; clear-cell renal cell carcinoma
14.  Tamoxifen Downregulates Ets-oncogene Family Members ETV4 and ETV5 in Benign Breast Tissue: Implications for Durable Risk Reduction 
Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials.
Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples.
Tamoxifen downregulated ets-oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis.
A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. Multipotential progenitor cap cells of terminal end buds may be the primary target.
PMCID: PMC3208724  PMID: 21778330
Tamoxifen; Biomarkers; Gene Expression; Proliferation; DNA Methylation
15.  Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma 
Molecular cancer research : MCR  2011;9(9):1255-1265.
Mammalian target of rapamycin complex 1 (mTORC1) is implicated in cell growth control and is extensively regulated. We previously reported that in response to hypoxia, mTORC1 is inhibited by the protein regulated in development and DNA damage response 1 (REDD1). REDD1 is upregulated by HIF-1, and forced REDD1 expression is sufficient to inhibit mTORC1. REDD1-induced mTORC1 inhibition is dependent on a protein complex formed by the tuberous sclerosis complex (TSC)1 and 2 (TSC2) proteins. In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1. However, mTORC1 is frequently activated in ccRCC and mTORC1 inhibitors are effective against this tumor type; a paradox herein examined. REDD1 was upregulated in VHL-deficient ccRCC by in silico microarray analyses, as well as by quantitative real-time PCR, Western blot, and immunohistochemistry. Vhl disruption in a mouse model was sufficient to induce Redd1. Using ccRCC-derived cell lines, we show that REDD1 upregulation in tumors is VHL-dependent, and that both HIF-1 and HIF-2 are, in a cell-type dependent manner, recruited to, and essential for, REDD1 induction. Interestingly, whereas mTORC1 is responsive to REDD1 in some tumors, strategies have evolved in others, such as mutations disrupting TSC1, to subvert mTORC1 inhibition by REDD1. Sequencing analyses of 77 ccRCCs for mutations in TSC1, TSC2 and REDD1, using PTEN as a reference, implicate the TSC1 gene, and possibly REDD1, as tumor suppressors in sporadic ccRCC. Understanding how ccRCCs become refractory to REDD1-induced mTORC1 inhibition should shed light into the development of ccRCC and may aid in patient selection for molecular targeted therapies.
PMCID: PMC3234675  PMID: 21798997
REDD1; DDIT4; mTORC1; VHL; RCC; HIF; nucleolus
16.  Upregulation of TRAG3 gene in urothelial carcinoma of the bladder 
Conventional chemotherapy is commonly used for advanced stages of bladder cancer with modest success and high morbidity. Identifying markers of resistance will allow clinicians to tailor treatment to a specific patient population. T24-tumorigenic cell line was grown orthotopically in nude mice and monitored using bioluminescence imaging and microcomputed tomography until they developed metastases. Stable sublines were then developed from primary bladder (T24-P), lung (T24-L) and bone (T24-B) tissues. Chromosomal analysis and DNA microarray were used to characterize these sublines. qRT-PCR and immunohistochemistry (IHC) were used for validation. Epigenetic modifiers were used to study gene regulation. The cell viability was quantified with MTT assay. Chromosomal analysis revealed multiple alterations in metastatic cell lines compared to T24-P. DNA microarray analysis showed that Taxol-Resistance-Associated-Gene-3 (TRAG3) gene was the most upregulated gene. From qRT-PCR and IHC, TRAG3 was significantly higher in T24-L and T24-B than T24-P. TRAG3 gene expression is likely controlled by DNA methylation, but not histone acetylation. Interestingly, T24-B and T24-L cells were more resistant than T24-P to treatment with anti-microtubule agents such as docetaxel, paclitaxel and vinblastine. TRAG3 mRNA expression was higher in 20% of patients with ≤pT2 (n=10) and 60% of patients with ≥pT3 (n=20) compared to normal adjacent tissue (p=0.05). In addition, the median TRAG3 expression was 6.7-fold higher in ≥pT3 tumors compared to ≤pT2 tumors. Knowing the status of TRAG3 expression could help clinicians tailor treatment to a particular patient population that could benefit from treatment, while allocating patients with resistant tumors to new experimental therapies.
PMCID: PMC3082622  PMID: 20734393
urothelial carcinoma; bladder; TRAG3; resistance
17.  Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer 
Journal of Clinical Oncology  2011;29(15):2020-2026.
To evaluate the tolerability of escalating doses of stereotactic body radiation therapy in the treatment of localized prostate cancer.
Patients and Methods
Eligible patients included those with Gleason score 2 to 6 with prostate-specific antigen (PSA) ≤ 20, Gleason score 7 with PSA ≤ 15, ≤ T2b, prostate size ≤ 60 cm3, and American Urological Association (AUA) score ≤ 15. Pretreatment preparation required an enema and placement of a rectal balloon. Dose-limiting toxicity (DLT) was defined as grade 3 or worse GI/genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 3). Patients completed quality-of-life questionnaires at defined intervals.
Groups of 15 patients received 45 Gy, 47.5 Gy, and 50 Gy in five fractions (45 total patients). The median follow-up is 30 months (range, 3 to 36 months), 18 months (range, 0 to 30 months), and 12 months (range, 3 to 18 months) for the 45 Gy, 47.5 Gy, and 50 Gy groups, respectively. For all patients, GI grade ≥ 2 and grade ≥ 3 toxicity occurred in 18% and 2%, respectively, and GU grade ≥ 2 and grade ≥ 3 toxicity occurred in 31% and 4%, respectively. Mean AUA scores increased significantly from baseline in the 47.5-Gy dose level (P = .002) as compared with the other dose levels, where mean values returned to baseline. Rectal quality-of-life scores (Expanded Prostate Cancer Index Composite) fell from baseline up to 12 months but trended back at 18 months. In all patients, PSA control is 100% by the nadir + 2 ng/mL failure definition.
Dose escalation to 50 Gy has been completed without DLT. A multicenter phase II trial is underway treating patients to 50 Gy in five fractions to further evaluate this experimental therapy.
PMCID: PMC3138546  PMID: 21464418
18.  Bootcamp During Neoadjuvant Chemotherapy for Breast Cancer: A Randomized Pilot Trial 
Exercise may improve cancer outcomes. Neoadjuvant chemotherapy (NC) for breast cancer provides a unique setting to evaluate intervention effects. Treatments leading to decreased post-neoadjuvant Ki-67 levels, smaller tumor size, and higher pathologic response are associated with improved survival and lower recurrence. This randomized, prospective pilot trial evaluates the feasibility of supervised exercise during NC for breast cancer.
Stage II-III, ER positive, cancer patients with BMI > 25 receiving NC were randomized to standard NC with supervised bootcamp (NC + BC) or NC alone. Ki-67, C-peptide, BMI, and tumor size were measured before chemotherapy and at time of surgery.
There were no initial differences between groups in regards to tumor size, C-peptide, BMI, and Ki–67. The NC + BC (n = 5) group had a lower mean BMI at the conclusion of NC compared with those (n = 5) in the NC group (28.0 versus 35.8, P = 0.03). Final tumor size was 2.59 cm in the NC + BC group versus 3.16 cm for NC (P = 0.76) Mean Ki-67 for NC + BC was 7% versus 29% with NC (P = 0.14). C-peptide (ng/mL) was equivalent between the two groups (4.55 NC + BC versus 4.74 NC, P = 0.85).
Adding a supervised exercise program to NC is feasible, decreases BMI, and may lead to lower Ki-67 levels and improved survival.
PMCID: PMC3290117  PMID: 22399859
breast cancer; exercise; Ki-67; neoadjuvant chemotherapy
19.  Influence of Surgical Technique on Mastectomy and Reexcision Rates in Breast-Conserving Therapy for Cancer 
Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30–50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates.
PMCID: PMC3265214  PMID: 22312542
20.  Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia▿ 
Molecular and Cellular Biology  2011;31(9):1870-1884.
mTORC1 is a critical regulator of cell growth that integrates multiple signals and is deregulated in cancer. We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex. Here we show that Redd1 induction by hypoxia is tissue dependent and that hypoxia signals are relayed to mTORC1 through different pathways in a tissue-specific manner. In the liver, Redd1 induction is restricted to the centrilobular area, and in primary hepatocytes, mTORC1 inhibition by hypoxia is independent of Redd1. Furthermore, Tsc1/Tsc2 and Arnt (Hif-1β) are similarly dispensable. Hypoxia signaling in hepatocytes involves Lkb1, AMP-activated protein kinase (AMPK), and raptor. Differences in signal relay extend beyond hypoxia and involve AMPK signaling. AMPK activation (using 5-aminoimidazole-4-carboxamide riboside [AICAR]) induces raptor phosphorylation and inhibits mTORC1 in both mouse embryo fibroblasts (MEFs) and hepatocytes, but whereas mTORC1 inhibition is Tsc1/Tsc2 dependent in MEFs, it is independent in hepatocytes. In liver cells, raptor phosphorylation is essential for both AMPK and hypoxia signaling. Thus, context-specific signals are required for raptor phosphorylation-induced mTORC1 inhibition. Our data illustrate a heretofore unappreciated topological complexity in mTORC1 regulation. Interestingly, topological differences in mTORC1 regulation by the tumor suppressor proteins Lkb1 and Tsc1/Tsc2 may underlie their tissue specificity of tumor suppressor action.
PMCID: PMC3133225  PMID: 21383064
21.  Prostate cancer radiosensitization through PARP-1 hyperactivation 
Cancer research  2010;70(20):8088-8096.
The clinical experimental agent, β-lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether β-lapachone may warrant clinical evaluation as a radiosensitizer. β-lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and μ-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), β-lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, γ-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of μ-calpain-induced programmed cell death. Radiosensitization by β-lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, β-lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ~60% of human prostate tumors evaluated relative to adjacent normal tissue, where β-lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of β-lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation.
PMCID: PMC2955807  PMID: 20940411
β-Lapachone; PARP-1 Hyperactivation; Programmed Necrosis; Prostate Cancer; Radiosensitization; Synergy
22.  Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks 
Carcinogenesis  2010;31(10):1889-1896.
DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated ‘sensitized’ murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs.
PMCID: PMC2950935  PMID: 20663777
23.  Regulation of TFEB and V-ATPases by mTORC1 
The EMBO Journal  2011;30(16):3242-3258.
Regulation of TFEB and V-ATPases by mTORC1
TORC1 is a key regulator of cell growth in response to nutrients and acts at the surface of the late endosome. This study identifies V-ATPase genes as transcriptional targets of TORC1 and implicates the transcription factor TFEB as an important mediator of TORC1-dependent gene expression and TORC1-regulated endocytosis.
Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is an important, highly conserved, regulator of cell growth. Ancient among the signals that regulate mTORC1 are nutrients. Amino acids direct mTORC1 to the surface of the late endosome/lysosome, where mTORC1 becomes receptive to other inputs. However, the interplay between endosomes and mTORC1 is poorly understood. Here, we report the discovery of a network that links mTORC1 to a critical component of the late endosome/lysosome, the V-ATPase. In an unbiased screen, we found that mTORC1 regulated the expression of, among other lysosomal genes, the V-ATPases. mTORC1 regulates V-ATPase expression both in cells and in mice. V-ATPase regulation by mTORC1 involves a transcription factor translocated in renal cancer, TFEB. TFEB is required for the expression of a large subset of mTORC1 responsive genes. mTORC1 coordinately regulates TFEB phosphorylation and nuclear localization and in a manner dependent on both TFEB and V-ATPases, mTORC1 promotes endocytosis. These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis.
PMCID: PMC3160667  PMID: 21804531
autophagy; lysosome; microarray; RCC; Tcfeb
24.  Multipotent Capacity of Immortalized Human Bronchial Epithelial Cells 
PLoS ONE  2011;6(7):e22023.
While the adult murine lung utilizes multiple compartmentally restricted progenitor cells during homeostasis and repair, much less is known about the progenitor cells from the human lung. Translating the murine stem cell model to humans is hindered by anatomical differences between species. Here we show that human bronchial epithelial cells (HBECs) display characteristics of multipotent stem cells of the lung. These HBECs express markers indicative of several epithelial types of the adult lung when experimentally tested in cell culture. When cultured in three different three-dimensional (3D) systems, subtle changes in the microenvironment result in unique responses including the ability of HBECs to differentiate into multiple central and peripheral lung cell types. These new findings indicate that the adult human lung contains a multipotent progenitor cell whose differentiation potential is primarily dictated by the microenvironment. The HBEC system is not only important in understanding mechanisms for specific cell lineage differentiation, but also for examining changes that correlate with human lung diseases including lung cancer.
PMCID: PMC3131301  PMID: 21760947
25.  Components of the Hematopoietic Compartments in Tumor Stroma and Tumor-Bearing Mice 
PLoS ONE  2011;6(3):e18054.
Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment.
PMCID: PMC3064668  PMID: 21464968

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