Publications by authors named "David Hoang"

26 Publications

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Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation.

Authors:
Lingling Duan Zhenhua Chen Jun Lu Yanping Liang Ming Wang Carlos M Roggero Qing-Jun Zhang Jason Gao Yong Fang Jiazheng Cao Jian Lu Hongwei Zhao Andrew Dang Rey-Chen Pong Elizabeth Hernandez Chun-Mien Chang David T Hoang Jung-Mo Ahn Guanghua Xiao Rui-Tao Wang Kai-Jiang Yu Payal Kapur Josep Rizo Jer-Tsong Hsieh Junhang Luo Zhi-Ping Liu

Nucleic Acids Res 2019 12;47(22):11623-11636

Department of Internal Medicine-Cardiology Division, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5'-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.
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http://dx.doi.org/10.1093/nar/gkz1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145715PMC
December 2019

Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors.

Authors:
Vindhya Udhane Cristina Maranto David T Hoang Lei Gu Andrew Erickson Savita Devi Pooja G Talati Anjishnu Banerjee Kenneth A Iczkowski Kenneth Jacobsohn William A See Tuomas Mirtti Deepak Kilari Marja T Nevalainen

Mol Cancer Ther 2020 01 23;19(1):231-246. Epub 2019 Sep 23.

Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate cancer (CRPC) and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of prostate cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate cancer to enzalutamide. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in prostate cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in mice bearing prostate cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to Stat5 blockade as second-line treatment after enzalutamide in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate cancer leading to the formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, enzalutamide-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted prostate cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate cancer, which is readily targetable by Jak2 inhibitors in clinical development.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946850PMC
January 2020

STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair.

Authors:
Cristina Maranto Vindhya Udhane David T Hoang Lei Gu Vitali Alexeev Kareem Malas Karmel Cardenas Jonathan R Brody Ulrich Rodeck Carmen Bergom Ken A Iczkowski Ken Jacobsohn William See Sara M Schmitt Marja T Nevalainen

Clin Cancer Res 2018 04 26;24(8):1917-1931. Epub 2018 Feb 26.

Department of Pathology, Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy. Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in mice bearing prostate cancer xenograft tumors. Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036914PMC
April 2018

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles.

Authors:
David T Hoang Kenneth A Iczkowski Deepak Kilari William See Marja T Nevalainen

Oncotarget 2017 Jan;8(2):3724-3745

Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms.
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http://dx.doi.org/10.18632/oncotarget.12554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356914PMC
January 2017

Overtreatment of Heparin-Induced Thrombocytopenia in the Surgical ICU.

Authors:
Megan Y Harada David M Hoang Andrea A Zaw Jason S Murry Oksana Volod Beatrice J Sun Miriam Nuño Russell Mason Daniel R Margulies Eric J Ley

Crit Care Med 2017 Jan;45(1):28-34

1Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA. 2Division of Coagulation Service, Department of Hematology, Cedars-Sinai Medical Center, Los Angeles, CA. 3Center for Neurosurgical Outcomes Research, Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: Recent studies reveal a high occurrence of overdiagnosis of heparin-induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment. We reviewed patients who were admitted to surgical ICUs and were suspected of heparin-induced thrombocytopenia to identify how often patients were correctly treated.

Design: In this clinical prospective study, data were collected including age, sex, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, serotonin release assay, and Warkentin 4Ts scores. Heparin-induced thrombocytopenia-positive patients were defined as those with both positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay (optical density, ≥ 0.40) and positive serotonin release assay results.

Setting: Urban tertiary medical center.

Patients: Patients admitted to the surgical and cardiac ICU who were presumed to have heparin-induced thrombocytopenia and underwent antiplatelet factor 4/heparin enzyme-linked immunosorbent assay and serotonin release assay testing between January 1, 2011, and August 1, 2014.

Interventions: None.

Measurements And Main Results: A total of 135 patients had 4Ts, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, and serotonin release assay scores. A total of 11 patients (8.1%) had positive serotonin release assay and 80 patients had positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay; 10 patients were identified as heparin-induced thrombocytopenia positive. Positive serotonin release assay was noted in nine of 11 patients (81.8%) with antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density greater than or equal to 2.0, compared with one of 22 patients (4.5%) with optical density values of 0.85-1.99, and one of 102 patients (1.0%) with optical density values of 0-0.84. Out of 135 patients, 29 patients (21.5%) received treatment with argatroban, lepirudin, or fondaparinux: 10 of 10 heparin-induced thrombocytopenia-positive patients (100%) compared with 19 of 125 heparin-induced thrombocytopenia-negative patients (15%).

Conclusions: Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold.
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http://dx.doi.org/10.1097/CCM.0000000000002002DOI Listing
January 2017

High-value care in the surgical intensive care unit: effect on ancillary resources.

Authors:
Ara Ko Jason S Murry David M Hoang Megan Y Harada Lia Aquino Charles Coffey Harry C Sax Rodrigo F Alban

J Surg Res 2016 05 23;202(2):455-60. Epub 2016 Feb 23.

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Changes in health care policies have influenced transformations in hospital systems to be cost-efficient while maintaining robust outcomes. This is particularly important in intensive care units where significant resources are used to care for critically ill patients. We sought to determine whether high-value care processes (HVCp) implemented in a surgical intensive care unit (SICU) have an impact on commonly used ancillary tests.

Materials And Methods: An implementation phase using a Lean Six Sigma approach was performed in October 2014 at a 24-bed large academic center SICU with aims to decrease orders of excessive daily laboratory tests and X-rays. The HVCp implemented included use of daily checklists, staff education, and visual reminders emphasizing the importance of appropriate laboratory tests and chest X-rays. Preintervention (July 2014-October 2014) and post-intervention (November 2014-June 2015) phases were compared.

Results: Average SICU census, case mix index (4.3 versus 4.4, P = 0.57), all patient refined severity of illness (3.2 versus 3.2, P = 0.91), and SICU mortality (7.1% versus 5.1%, P = 0.18) were similar in both phases. A significant reduction of excessive laboratory tests was evident after the implementation period. Eight hundred sixty-five arterial blood gases/mo were obtained in the preintervention phase compared with 420 arterial blood gases/mo after intervention (P = 0.004), representing a 51.4% reduction. Similar results were obtained with complete blood counts, basic metabolic profiles, coagulation profiles, and chest X-rays (12%, 17.8%, 30.2%, and 20.3% reductions, respectively), a total estimated cost savings of $59,137/mo and prevention of excess phlebotomy of approximately 4 L of blood/mo.

Conclusions: By implementing an HVCp including a checklist, visual reminders, and provider education, we significantly reduced the use of commonly ordered ancillary tests in the SICU without affecting outcomes, resulting in an annual cost savings of $710,000.
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http://dx.doi.org/10.1016/j.jss.2016.01.040DOI Listing
May 2016

Body mass index strongly impacts the diagnosis and incidence of heparin-induced thrombocytopenia in the surgical intensive care unit.

Authors:
Matthew B Bloom Andrea A Zaw David M Hoang Russell Mason Rodrigo F Alban Rex Chung Nicolas Melo Oksana Volod Eric J Ley Daniel R Margulies

J Trauma Acute Care Surg 2016 Mar;80(3):398-403; discussion 403-4

From the Division of Trauma and Critical Care (M.B.B., A.A.Z., D.M.H., R.F.A., R.C., N.M., E.J.L., D.R.M.), Department of Surgery, Department of Pharmacy (R.M.), and Division of Coagulation Service (O.V.), Department of Hematology, Cedars-Sinai Medical Center, Los Angeles, California.

Background: The obese state has been linked to several immune-mediated conditions. Our objective was to examine the association of body mass index (BMI) with the diagnosis of heparin-induced thrombocytopenia (HIT).

Methods: Prospectively collected data on patients in the surgical and cardiac intensive care unit suspected of having HIT between January 2007 and August 2014 were analyzed. Patients were categorized into five discrete BMI (kg/m) groups and compared. Data collected included Warkentin 4-T scores, antiplatelet factor 4 (anti-PF4OD) values, serotonin release assay values, and thromboembolic diseases. HIT positivity was defined as serotonin release assay value greater than 20%.

Results: Of 304 patients meeting inclusion criteria, mean (SD) age was 62.1 (16.5) years, 59% were male, and mean (SD) BMI was 27 (6) kg/m. Thirty-six (12%) were positive for HIT. Incidence of HIT increased progressively with BMI (0%, 8%, 11%, 19%, 36%; p < 0.001). Compared with patients with normal BMI, patients with a BMI of 30 kg/m to 39.9 kg/m had a 200% increase in the odds for HIT (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.20-7.54; p = 0.019), while patients with a BMI of 40 kg/m or greater had a 600% increase (OR, 6.98; 95% CI, 1.59-28.2; p = 0.012). After regression analysis, BMI remained an independent predictor of the development of HIT (adjusted OR per kg/m, 1.08; 95% CI, 1.02-1.14; p = 0.010). Anti-PF4OD values greater than or equal to 2.0 also increased with BMI (p < 0.001). In-hospital mortality increased significantly with BMI above normal (p = 0.026). Warkentin 4-T scores, deep venous thrombosis, pulmonary embolism, and stroke incidence did not correlate with changes in BMI.

Conclusion: Increasing BMI seems to be strongly associated with increased rates of HIT in intensive care unit patients. Obesity is an important new clinical variable for estimating the pretest probability of HIT, and patient "thickness" could be considered a fifth "T" of the 4-T scoring system. Additional biochemical work is indicated to decipher the role of obesity in this immune-mediated condition.

Level Of Evidence: Prognostic/epidemiologic study, level III.
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http://dx.doi.org/10.1097/TA.0000000000000952DOI Listing
March 2016

CT Chest with IV Contrast Compared with CT Angiography after Blunt Trauma.

Authors:
Andrea A Zaw Donovan Stewart Jason S Murry David M Hoang Beatrice Sun Sogol Ashrafian Heidi Hotz Rex Chung Daniel R Margulies Eric J Ley

Am Surg 2016 Jan;82(1):41-5

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Blunt aortic injury (BAI) after chest trauma is a potentially lethal condition. Rapid diagnosis is important to appropriately treat patients. The purpose of this study was to compare CT with intravenous contrast (CTI) to CT with angiography (CTA) in the initial evaluation of blunt chest trauma patients. This was a retrospective review of all blunt trauma patients who received a CTI or CTA during the initial evaluation at an urban Level I trauma center from January 1, 2010 to December 31, 2013. Two-hundred and eighty-one trauma patients met inclusion criteria. Most, 167/281 (59%) received CTI and 114/281 (41%) received CTA. There were no differences between cohorts in age, gender, initial heart rate, systolic blood pressure, and Glasgow Coma Scale in emergency department. Mortality rates were similar for CTI and CTA (4% vs 8%, P = 0.20). CTI identified an injury in 54 per cent compared with 46 per cent in CTA (P = 0.05). Overall, 2 per cent of patients had BAI with similar rates in CTI and CTA (2% vs 2%, P = 0.80). BAI was not missed using either CTI or CTA. Trauma patients studied with CTI had similar diagnostic findings as CTA. CTI may be preferable to CTA during the initial assessment for possible BAI because of a single contrast injection for whole body CT.
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January 2016

CT Chest with IV Contrast Compared with CT Angiography after Blunt Trauma.

Authors:
Andrea A Zaw Donovan Stewart Jason S Murry David M Hoang Beatrice Sun Sogol Ashrafian Heidi Hotz Rex Chung Daniel R Margulies Eric J Ley

Am Surg 2015 Oct;81(10):1080-3

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Blunt aortic injury (BAI) after chest trauma is a potentially lethal condition that requires rapid diagnosis for appropriate treatment. We compared CT with IV contrast (CTI) with CT with angiography (CTA) during the initial phase of care at an urban Level I trauma center from January 1, 2010 to December 31, 2013. Overall, 281 patients met inclusion criteria with 167 (59%) CTI and 114 (41%) CTA. There were no differences between cohorts in age, gender, initial heart rate, systolic blood pressure, and Glasgow Coma Scale. Mortality rates were similar for CTI and CTA (4% vs 8%, P = 0.20). CTI identified any chest injury in 54 per cent of patients compared with 46 per cent with CTA (P = 0.05). The rate of BAI was similar with CTI and CTA (2% vs 2%, P = 0.80), and neither modality was falsely negative. We conclude that CTI and CTA are similar at evaluating trauma patients for BAI, although CTI may be preferable during the initial assessment phase because the contrast injection may be combined with abdominal scanning and image time is reduced when whole-body CT is required.
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October 2015

Selective Nonoperative Management of Abdominal Stab Wounds.

Authors:
Jason S Murry David M Hoang Sogol Ashragian Doug Z Liou Galinos Barmparas Rex Chung Rodrigo F Alban Daniel R Margulies Eric J Ley

Am Surg 2015 Oct;81(10):1034-8

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Stab wounds (SW) to the abdomen traditionally require urgent exploration when associated with shock, evisceration, or peritonitis. Hemodynamically stable patients without evisceration may benefit from serial exams even with peritonitis. We compared patients taken directly to the operating room with abdominal SWs (ED-OR) to those admitted for serial exams (ADMIT). We retrospectively reviewed hemodynamically stable patients presenting with any abdominal SW between January 2000 and December 2012. Exclusions included evidence of evisceration, systolic blood pressure ≤110 mm Hg, or blood transfusion. NON-THER was defined as abdominal exploration without identification of intra-abdominal injury requiring repair. Of 142 patients included, 104 were ED-OR and 38 were ADMIT. When ED-OR was compared with ADMIT, abdominal Abbreviated Injury Score was higher (2.4 vs 2.1; P = 0.01) and hospital length of stay was longer (4.8 vs 3.3 days; P = 0.04). Incidence of NON-THER was higher in ED-OR cohort (71% vs 13%; P ≤ 0.001). In a regression model, ED-OR was a predictor of NON-THER (adjusted odds ratio 16.6; P < 0.001). One patient from ED-OR expired after complications from NON-THER. There were no deaths in the ADMIT group. For those patients with abdominal SWs who present with systolic blood pressure ≥110 mm Hg, no blood product transfusion in the emergency department and lacking evisceration, admission for serial abdominal exams may be preferred regardless of abdominal exam.
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October 2015

Epidural Analgesia after Rib Fractures.

Authors:
Andrea A Zaw Jason Murry David Hoang Kevin Chen Charles Louy Matthew B Bloom Nicolas Melo Rodrigo F Alban Daniel R Margulies Eric J Ley

Am Surg 2015 Oct;81(10):950-4

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Pain associated with rib fractures impairs respiratory function and increases pulmonary morbidity. The purpose of this study was to determine how epidural catheters alter mortality and complications in trauma patients. We performed a retrospective study involving adult blunt trauma patients with moderate-to-severe injuries from January 1, 2004 to December 31, 2013. During the 10-year period, 526 patients met the inclusion criteria; 43/526 (8%) patients had a catheter placed. Mean age of patients with epidural catheter (CATH) was higher compared with patients without epidural catheter (NOCATH) (54 vs 48 years, P = 0.021), Injury Severity Score was similar (26 CATH vs 27 NOCATH, P = 0.84), and CATH had higher mean rib fractures (7.4 vs 4.1, P < 0.001). Mortality was lower in CATH (0% vs 13%, P = 0.006). Deep vein thrombosis (DVT) rate was higher in CATH (12% vs. 5%, P = 0.036). After regression analysis, we found catheter placement to be a predictor for DVT (adjusted odds ratios 2.80, P = 0.036). Our center noted increased use of epidural catheters in patients who present with moderate-to-severe injuries. Patients with catheters were older and had a mean of 7.4 ribs fractured. The epidural cohort had longer hospital LOS and decreased mortality. In contrast to other studies, DVT rates were increased in patients who received epidural catheters.
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October 2015

Activation of Massive Transfusion for Elderly Trauma Patients.

Authors:
Jason S Murry Andrea A Zaw David M Hoang Devorah Mehrzadi Danielle Tran Miriam Nuno Matthew Bloom Nicolas Melo Daniel R Margulies Eric J Ley

Am Surg 2015 Oct;81(10):945-9

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Massive transfusion protocol (MTP) is used to resuscitate patients in hemorrhagic shock. Our goal was to review MTP use in the elderly. All trauma patients who required activation of MTP at an urban Level I trauma center from January 1, 2011 to December 31, 2013 were reviewed retrospectively. Elderly was defined as age ≥ 60 years. Sixty-six patients had MTP activated: 52 nonelderly (NE) and 14 elderly (E). There were no statistically significant differences between the two cohorts for gender, injury severity score, head abbreviated injury scale, emergency department Glasgow Coma Scale, initial hematocrit, intensive care unit length of stay, or hospital length of stay. Mean age for NE was 35 years and 73 years for E (P < 0.01). Less than half (43%) of E patients with activation of MTP received 10 or more units of blood products compared with 69 per cent of the NE (P = 0.07). Mortality rates were similar in the NE and the E (53%vs 50%, P = 0.80). After multivariate analysis with Glasgow Coma Scale, injury severity score, and blunt versus penetrating trauma, elderly age was not a predictor of mortality after MTP (P = 0.35). When MTP is activated, survival to discharge in elderly trauma patients is comparable to younger patients.
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October 2015

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer.

Authors:
Pooja G Talati Lei Gu Elyse M Ellsworth Melanie A Girondo Marco Trerotola David T Hoang Benjamin Leiby Ayush Dagvadorj Peter A McCue Costas D Lallas Edouard J Trabulsi Leonard Gomella Andrew E Aplin Lucia Languino Alessandro Fatatis Hallgeir Rui Marja T Nevalainen

Am J Pathol 2015 Sep;185(9):2505-22

Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Urology, Thomas Jefferson University, Philadelphia, Pennsylvania; Prostate Cancer Discovery and Development Program, Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/b-induced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells.
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http://dx.doi.org/10.1016/j.ajpath.2015.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597281PMC
September 2015

Prospective evaluation of early propranolol after traumatic brain injury.

Authors:
Jason S Murry David M Hoang Galinos Barmparas Megan Y Harada Marko Bukur Matthew B Bloom Kenji Inaba Daniel R Margulies Ali Salim Eric J Ley

J Surg Res 2016 Jan 25;200(1):221-6. Epub 2015 Jun 25.

Division of Trauma and Critical Care, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Although beta-adrenergic receptor blockade may improve outcomes after traumatic brain injury (TBI), its early use is not routine. We hypothesize that judicious early low-dose propranolol after TBI (EPAT) will improve outcomes without altering bradycardia or hypotensive events.

Methods: We conducted a prospective, observational study on all patients who presented with moderate-to-severe TBI from March 2010-August 2013. Ten initial patients did not receive propranolol (control). Subsequent patients received propranolol at 1-mg intravenous every 6 h starting within 12 h of intensive care unit (ICU) admission (EPAT) for a minimum of 48 h. Heart rate and blood pressure were recorded hourly for the first 72 h. Bradycardia and hypotensive events, mortality, and length of stay (LOS) were compared between cohorts to determine significant differences.

Results: Thirty-eight patients were enrolled; 10 control and 28 EPAT. The two cohorts were similar when compared by gender, emergency department (ED) systolic blood pressure, ED heart rate, and mortality. ED Glasgow coma scale was lower (4.2 versus 10.7, P < 0.01) and injury severity score higher in control. EPAT patients received a mean of 10 ± 14 doses of propranolol. Hypotensive events were similar between cohorts, whereas bradycardia events were higher in control (5.8 versus 1.6, P = 0.05). ICU LOS (15.4 versus 30.4 d, P = 0.02) and hospital LOS (10 versus 19.1 d, P = 0.05) were lower in EPAT. Mortality rates were similar between groups (10% versus 10.7%, P = 0.9). The administration of propranolol led to no recorded complications.

Conclusions: Although bradycardia and hypotensive events occur early after TBI, low-dose intravenous propranolol does not increase their number or severity. Early use of propranolol after TBI appears to be safe and may be associated with decreased ICU and hospital LOS.
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http://dx.doi.org/10.1016/j.jss.2015.06.045DOI Listing
January 2016

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.

Authors:
Zhiyong Liao Lei Gu Jenny Vergalli Samanta A Mariani Marco De Dominici Ravi K Lokareddy Ayush Dagvadorj Puranik Purushottamachar Peter A McCue Edouard Trabulsi Costas D Lallas Shilpa Gupta Elyse Ellsworth Shauna Blackmon Adam Ertel Paolo Fortina Benjamin Leiby Guanjun Xia Hallgeir Rui David T Hoang Leonard G Gomella Gino Cingolani Vincent Njar Nagarajan Pattabiraman Bruno Calabretta Marja T Nevalainen

Mol Cancer Ther 2015 Aug 29;14(8):1777-93. Epub 2015 May 29.

Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547362PMC
August 2015

Abdominal Injuries in the "Found Down": Is Imaging Indicated?

Authors:
Ara Ko Andrea A Zaw Galinos Barmparas David M Hoang Jason S Murry Tong Li Sogol Ashrafian Nathan J McNeil Daniel R Margulies Eric J Ley

J Am Coll Surg 2015 Jul 24;221(1):17-24. Epub 2015 Mar 24.

Department of Surgery, Division of Trauma and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA. Electronic address:

Background: We sought to investigate the incidence of abdominal injuries in "found down" trauma patients to better understand the value of emergency department (ED) imaging. Found down patients are at high risk for injuries to the head or neck and low risk to the abdomen or pelvis, so imaging with CT of the abdomen/pelvis (AP) or Focused Assessment with Sonography for Trauma (FAST) is of questionable value.

Study Design: The trauma registry was queried over a 10-year period ending December 2013 for found down patients. Demographics, CT AP, FAST scans, and injuries were abstracted from the trauma registry and then through a confirmatory chart review. The primary outcome was significant abdominal or pelvis injury, defined as abdomen/pelvis Abbreviated Injury Scale (AIS) ≥ 3 or an abdominal injury that required operative intervention. The secondary outcome was mortality due to abdominal injury.

Results: Of the 342 patients who met inclusion criteria, mean Glasgow Coma Scale (GCS) was 11.0, and 189 (60%) of those tested for alcohol were intoxicated. Abdominal imaging included: CT AP only, 88 (57%); FAST only, 37 (24%); and CT AP and FAST, 29 (19%). Neither CT AP nor FAST scan led to a change in treatment and no patient had abdomen/pelvis AIS ≥ 3. Overall mortality was 33 (10%).The 24 trauma deaths were attributed to serious head trauma (n = 16) or traumatic arrest in the ED (n = 8); the 9 medical deaths were due to cerebral vascular accident (n = 5) or sepsis (n = 4).

Conclusions: Although patients found down have a high mortality, abdominal injuries identified by imaging are highly unlikely. Efforts should focus on rapidly identifying and treating other causes of mortality, especially trauma to the head and neck, or medical diagnoses such as cerebral vascular accident or sepsis.
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http://dx.doi.org/10.1016/j.jamcollsurg.2015.03.025DOI Listing
July 2015

Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer.

Authors:
David T Hoang Lei Gu Zhiyong Liao Feng Shen Pooja G Talati Mateusz Koptyra Shyh-Han Tan Elyse Ellsworth Shilpa Gupta Heather Montie Ayush Dagvadorj Saija Savolainen Benjamin Leiby Tuomas Mirtti Diane E Merry Marja T Nevalainen

Mol Cancer Ther 2015 Mar 31;14(3):713-26. Epub 2014 Dec 31.

Deparment of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance the signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, bicalutamide, flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors, and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the prostate-specific antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456253PMC
March 2015

Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation.

Authors:
Lei Gu Pooja Talati Paraskevi Vogiatzi Ana L Romero-Weaver Junaid Abdulghani Zhiyong Liao Benjamin Leiby David T Hoang Tuomas Mirtti Kalle Alanen Michael Zinda Dennis Huszar Marja T Nevalainen

Mol Cancer Ther 2014 May 27;13(5):1246-58. Epub 2014 Feb 27.

Authors' Affiliations: Departments of Cancer Biology, Urology, and Medical Oncology, Kimmel Cancer Center; Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania; Oncology iMED, AstraZeneca R&D Boston, Waltham, Massachusetts; Department of Pathology, Haartman Institute; Institute of Molecular Medicine, University of Helsinki, Helsinki; and Department of Pathology, Institute of Biomedicine, University of Turku, Turku, Finland.

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013199PMC
May 2014

Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer.

Authors:
Lei Gu Zhiyong Liao David T Hoang Ayush Dagvadorj Shilpa Gupta Shauna Blackmon Elyse Ellsworth Pooja Talati Benjamin Leiby Michael Zinda Costas D Lallas Edouard J Trabulsi Peter McCue Leonard Gomella Dennis Huszar Marja T Nevalainen

Clin Cancer Res 2013 Oct 13;19(20):5658-74. Epub 2013 Aug 13.

Authors' Affiliations: Departments of Cancer Biology, Urology, Pathology, and Medical Oncology, Kimmel Cancer Center; Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania; and Oncology iMED, AstraZeneca R&D Boston, Waltham, Massachusetts.

Purpose: Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer.

Experimental Design: Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480.

Results: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate-resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b.

Conclusions: We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021137PMC
October 2013

STAT5A/B gene locus undergoes amplification during human prostate cancer progression.

Authors:
Bassem R Haddad Lei Gu Tuomas Mirtti Ayush Dagvadorj Paraskevi Vogiatzi David T Hoang Renu Bajaj Benjamin Leiby Elyse Ellsworth Shauna Blackmon Christian Ruiz Mark Curtis Paolo Fortina Adam Ertel Chengbao Liu Hallgeir Rui Tapio Visakorpi Lukas Bubendorf Costas D Lallas Edouard J Trabulsi Peter McCue Leonard Gomella Marja T Nevalainen

Am J Pathol 2013 Jun 7;182(6):2264-75. Epub 2013 May 7.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.

The molecular mechanisms underlying progression of prostate cancer (PCa) to castrate-resistant (CR) and metastatic disease are poorly understood. Our previous mechanistic work shows that inhibition of transcription factor Stat5 by multiple alternative methods induces extensive rapid apoptotic death of Stat5-positive PCa cells in vitro and inhibits PCa xenograft tumor growth in nude mice. Furthermore, STAT5A/B induces invasive behavior of PCa cells in vitro and in vivo, suggesting involvement of STAT5A/B in PCa progression. Nuclear STAT5A/B protein levels are increased in high-grade PCas, CR PCas, and distant metastases, and high nuclear STAT5A/B expression predicts early disease recurrence and PCa-specific death in clinical PCas. Based on these findings, STAT5A/B represents a therapeutic target protein for advanced PCa. The mechanisms underlying increased Stat5 protein levels in PCa are unclear. Herein, we demonstrate amplification at the STAT5A/B gene locus in a significant fraction of clinical PCa specimens. STAT5A/B gene amplification was more frequently found in PCas of high histologic grades and in CR distant metastases. Quantitative in situ analysis revealed that STAT5A/B gene amplification was associated with increased STAT5A/B protein expression in PCa. Functional studies showed that increased STAT5A/B copy numbers conferred growth advantage in PCa cells in vitro and as xenograft tumors in vivo. The work presented herein provides the first evidence of somatic STAT5A/B gene amplification in clinical PCas.
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http://dx.doi.org/10.1016/j.ajpath.2013.02.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668029PMC
June 2013

Statewide ban on recreational fires resulted in a significant decrease in campfire-related summer burn center admissions.

Authors:
David Manh Hoang Dixie Reid Christopher William Lentz

J Burn Care Res 2013 Jan-Feb;34(1):74-7

University of New Mexico Health Sciences Center, Albuquerque, NM, USA.

Every summer, there is an increase in the number of burn injuries caused by accidents around campfires. Because of the prevalence of drought, high winds, and uncontrolled wild fires, a statewide ban on recreational fires was instituted in New Mexico from June to July 2011. We hypothesized that this legislation would have a significant impact on burn admissions caused by campfire-related injuries. A retrospective review of summer admissions to a state burn center was conducted to assess the effect of this ban on recreational fire injuries, and these data were compared with that of the previous summer when no ban was in effect. All burn admissions to a state burn center were reviewed from Memorial Day to Labor Day in 2010 and 2011. Data collected included cause, % TBSA, age, days of hospitalization, intensive care unit days, and total surface area grafted. Nonparametric statistical analysis was performed with Fisher exact test for dichotomous data and Mann-Whitney test for continuous data with significance at P < .05. There were 164 burn center admissions between Memorial Day and Labor Day in 2010 (n = 82) and 2011 (n = 82). Compared with all summer burn center admissions, patients injured by campfires were younger (18 vs 37 years; P = .002) with smaller total surface area burns (3.2 vs 6.2%; P = .41) and had shorter lengths of stay (10-11 vs 6-7 days; P = .62). There was more than a 3-fold decrease in burn admissions due to recreational fires during the study period (n = 14 [17%] in 2010 and 4 [5%] in 2011; P = .02). This resulted in a decrease in the number of patient-days from 91 in 2010 to 25 in 2011. Half of the camp fire admissions required skin grafts to definitively close the wounds (6/14 in 2010 and 2/4 in 2011). Recreational fire bans targeted at controlling wildfires during conditions favoring rapid spread were associated with a 3- to 4-fold decrease in campfire-related burn admissions. Compared with a summer when no fire ban was in effect, the number of patient-days decreased from 91 to 25.
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http://dx.doi.org/10.1097/BCR.0b013e3182676cabDOI Listing
June 2013

Prolactin regulation of the prostate gland: a female player in a male game.

Authors:
Vincent Goffin David T Hoang Roman L Bogorad Marja T Nevalainen

Nat Rev Urol 2011 Oct 4;8(11):597-607. Epub 2011 Oct 4.

Inserm, Unit 845, Research Center Growth and Signaling, Prolactin/GH Pathophysiology Laboratory, University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Necker site, Paris F-75015, France.

Prolactin is best known for its actions on the mammary gland. However, circulating prolactin is also detected in males and its receptor (PRLR) is expressed in the prostate, suggesting that the prostate is a target of prolactin. Germline knockout of prolactin or its receptor has failed to reveal a key role for prolactin signaling in mouse prostate physiology. However, several studies involving rodent models and human prostate cell lines and specimens have supported the contribution of the canonical PRLR-Jak2-Stat5a/b pathway to prostate cancer tumorigenesis and progression. Increased expression of prolactin in the prostate itself (rather than changes in circulating prolactin levels) and crosstalk with androgen receptor (AR) signaling are potential mechanisms for increased Stat5a/b signaling in prostate cancer. In the mouse prostate, prolactin overexpression results in disorganized expansion of the basal/stem cell compartment, which has been proposed to house putative prostate tumor-initiating cells. These findings provide new insight into the molecular and cellular targets by which locally produced prolactin could contribute to prostate cancer initiation and progression. A number of pharmacological inhibitors targeting various levels of the PRLR-Jak2-Stat5a/b pathway have been developed and are entering clinical trials for advanced prostate cancer.
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http://dx.doi.org/10.1038/nrurol.2011.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035044PMC
October 2011

mTOR is a selective effector of the radiation therapy response in androgen receptor-positive prostate cancer.

Authors:
Matthew J Schiewer Robert Den David T Hoang Michael A Augello Yaacov R Lawrence Adam P Dicker Karen E Knudsen

Endocr Relat Cancer 2012 Feb 9;19(1):1-12. Epub 2012 Jan 9.

Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Ionizing radiation (IR) is used frequently in the management of multiple tumor types, including both organ-confined and locally advanced prostate cancer (PCa). Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mammalian target of rapamycin (mTOR) inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy (HT)-sensitive and castration-resistant PCa (CRPC) cell proliferation as single agents and have a profound radiosensitization effect when used in combination with IR. Importantly, the observed radiosensitization was influenced by the treatment schedule, in which adjuvant administration of mTOR inhibitors was most effective in limiting PCa cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Finally, adjuvant administration of either mTOR inhibitor tested after IR significantly decreased clonogenic cell survival of both HT-sensitive and CRPC cells compared with IR alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment.
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http://dx.doi.org/10.1530/ERC-11-0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253653PMC
February 2012

Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors.

Authors:
Dolores López-Terrada Preethi H Gunaratne Adekunle M Adesina Joseph Pulliam David M Hoang Yummy Nguyen Toni-Ann Mistretta Judith Margolin Milton J Finegold

Hum Pathol 2009 Jun 5;40(6):783-94. Epub 2009 Feb 5.

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.

Hepatoblastoma is characterized by a diversity of differentiation patterns, some resembling stages of liver development, and occasionally associated with clinical behavior. Our hypothesis is that histologic microheterogeneity in hepatoblastoma correlates with molecular heterogeneity and reflects different stages of developmental arrest. We studied the activation status of the Wnt and Notch pathways and the differential expression of hepatocyte nuclear factor 4alpha, EGFR, and IGF2 genes, relevant to liver development and malignant transformation in histologic variants of hepatoblastoma. Eighty-seven percent of 32 hepatoblastoma cases studied carried CTNNB1 mutations within the ubiquitination domain. Large deletions were seen only in pure fetal cases, also characterized by CCND1 and GLUL (GS) overexpression. Hepatoblastomas with small-cell type appeared clearly distinct and were the only ones with negative GLUL expression. HES1 expression and HES1/AXIN2 used to measure Notch versus Wnt activation ratio were particularly elevated in pure fetal cases and were lowest in hepatoblastomas with small-cell component. Hepatocyte nuclear factor 4alpha was relatively elevated only in embryonal hepatoblastomas. DLK1, DKK, AXIN2, IGF2, and EGFR were increased in all subtypes. Our results support the hypothesis that hepatoblastoma microheterogeneity correlates with molecular heterogeneity. DLK1, a marker of bipotential oval cells, is consistently up-regulated in hepatoblastoma. Therefore, we speculate that hepatoblastomas may arise from a proliferating bipotential precursor. Wnt activation is prevalent in hepatoblastomas, most significantly in predominantly embryonal and mixed types, whereas Notch activation, needed for cholangiocytic differentiation at a more differentiated state, is highest in pure fetal hepatoblastomas. The relative Wnt versus Notch activation appears useful in stratifying different subtypes.
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http://dx.doi.org/10.1016/j.humpath.2008.07.022DOI Listing
June 2009

MicroRNAs can regulate human APP levels.

Authors:
Neha Patel David Hoang Nathan Miller Sara Ansaloni Qihong Huang Jack T Rogers Jeremy C Lee Aleister J Saunders

Mol Neurodegener 2008 Aug 6;3:10. Epub 2008 Aug 6.

Department of Bioscience & Biotechnology, Drexel University, Philadelphia, PA, USA.

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs.
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http://dx.doi.org/10.1186/1750-1326-3-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2529281PMC
August 2008

Novel microRNA candidates and miRNA-mRNA pairs in embryonic stem (ES) cells.

Authors:
Peili Gu Jeffrey G Reid Xiaolian Gao Chad A Shaw Chad Creighton Peter L Tran Xiaochuan Zhou Rafal B Drabek David L Steffen David M Hoang Michelle K Weiss Arash O Naghavi Jad El-daye Mahjabeen F Khan Glen B Legge David A Wheeler Richard A Gibbs Jonathan N Miller Austin J Cooney Preethi H Gunaratne

PLoS One 2008 Jul 2;3(7):e2548. Epub 2008 Jul 2.

Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

Background: MicroRNAS (miRNAS: a class of short non-coding RNAs) are emerging as important agents of post transcriptional gene regulation and integral components of gene networks. MiRNAs have been strongly linked to stem cells, which have a remarkable dual role in development. They can either continuously replenish themselves (self-renewal), or differentiate into cells that execute a limited number of specific actions (pluripotence).

Methodology/principal Findings: In order to identify novel miRNAs from narrow windows of development we carried out an in silico search for micro-conserved elements (MCE) in adult tissue progenitor transcript sequences. A plethora of previously unknown miRNA candidates were revealed including 545 small RNAs that are enriched in embryonic stem (ES) cells over adult cells. Approximately 20% of these novel candidates are down-regulated in ES (Dicer(-/-)) ES cells that are impaired in miRNA maturation. The ES-enriched miRNA candidates exhibit distinct and opposite expression trends from mmu-mirs (an abundant class in adult tissues) during retinoic acid (RA)-induced ES cell differentiation. Significant perturbation of trends is found in both miRNAs and novel candidates in ES (GCNF(-/-)) cells, which display loss of repression of pluripotence genes upon differentiation.

Conclusion/significance: Combining expression profile information with miRNA target prediction, we identified miRNA-mRNA pairs that correlate with ES cell pluripotence and differentiation. Perturbation of these pairs in the ES (GCNF(-/-)) mutant suggests a role for miRNAs in the core regulatory networks underlying ES cell self-renewal, pluripotence and differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002548PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2481296PMC
July 2008