bluuebunny/crossref_metadata_2025 huggingface dataset:
CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis
Authors: Winters Christopher J. , Koval Olha , Murthy Shubha , Allamargot Chantal , Sebag Sara C. , Paschke John D. , Jaffer Omar A. , Carter A. Brent , Grumbach Isabella M.
Published: November 2015

The calcium and calmodulin-dependent kinase II (CaMKII) translates increases in intracellular Ca2+into downstream signaling events. Its function in pulmonary pathologies remains largely unknown. CaMKII is a well-known mediator of apoptosis and regulator of endoplasmic reticulum (ER) Ca2+. ER stress and apoptosis of type II pneumocytes lead to aberrant tissue repair and progressive collagen deposition in pulmonary fibrosis. Thus we hypothesized that CaMKII inhibition alleviates fibrosis in response to bleomycin by attenuating apoptosis and ER stress of type II pneumocytes. We first established that CaMKII was strongly expressed in the distal respiratory epithelium, in particular in surfactant protein-C-positive type II pneumocytes, and activated after bleomycin instillation. We generated a novel transgenic model of inducible expression of the CaMKII inhibitor peptide AC3-I limited to type II pneumocytes (Tg SPC-AC3-I). Tg SPC-AC3-I mice were protected from development of pulmonary fibrosis after bleomycin exposure compared with wild-type mice. CaMKII inhibition also provided protection from apoptosis in type II pneumocytes in vitro and in vivo. Moreover, intracellular Ca2+levels and ER stress were increased by bleomycin and significantly blunted with CaMKII inhibition in vitro. These data demonstrate that CaMKII inhibition prevents type II pneumocyte apoptosis and development of pulmonary fibrosis in response to bleomycin. CaMKII inhibition may therefore be a promising approach to prevent or ameliorate the progression of pulmonary fibrosis.
Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness
Authors: McGovern Toby K. , Chen Michael , Allard Benoit , Larsson Kjell , Martin James G. , Adner Mikael
Published: November 2015

Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways.
N-cadherin coordinates AMP kinase-mediated lung vascular repair
Authors: Jian Ming-Yuan , Liu Yanping , Li Qian , Wolkowicz Paul , Alexeyev Mikhail , Zmijewski Jaroslaw , Creighton Judy
Published: November 2015

Injury to the pulmonary circulation compromises endothelial barrier function and increases lung edema. Resolution of lung damage involves restoring barrier integrity, a process requiring reestablishment of endothelial cell-cell adhesions. However, mechanisms underlying repair in lung endothelium are poorly understood. In pulmonary microvascular endothelium, AMP kinase α1 (AMPKα1) stimulation enhances recovery of the endothelial barrier after LPS-induced vascular damage. AMPKα1 colocalizes to a discrete membrane compartment with the adhesion protein neuronal cadherin (N-cadherin). This study sought to determine N-cadherin's role in the repair process. Short-hairpin RNA against full-length N-cadherin or a C-terminally truncated N-cadherin, designed to disrupt the cadherin's interactions with intracellular proteins, were expressed in lung endothelium. Disruption of N-cadherin's intracellular domain caused translocation of AMPK away from the membrane and attenuated AMPK-mediated restoration of barrier function in LPS-treated endothelium. AMPK activity measurements indicated that lower basal AMPK activity in cells expressing the truncated N-cadherin compared with controls. Moreover, the AMPK stimulator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to increase AMPK activity in cells expressing the modified N-cadherin, indicating uncoupling of a functional association between AMPK and the cadherin. Isolated lung studies confirmed a physiologic role for this pathway in vivo. AMPK activation reversed LPS-induced increase in permeability, whereas N-cadherin inhibition hindered AMPK-mediated repair. Thus N-cadherin coordinates the vascular protective actions of AMPK through a functional link with the kinase. This study provides insight into intrinsic repair mechanisms in the lung and supports AMPK stimulation as a modality for treating vascular disease.
The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia
Authors: Turner Mark J. , Matthes Elizabeth , Billet Arnaud , Ferguson Amy J. , Thomas David Y. , Randell Scott H. , Ostrowski Lawrence E. , Abbott-Banner Kathy , Hanrahan John W.
Published: November 2015

Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/ F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.
A GWAS Meta-analysis and Replication Study Identifies a Novel Locus withinCLPTM1L/TERTAssociated with Nasopharyngeal Carcinoma in Individuals of Chinese Ancestry
Authors: Bei Jin-Xin , Su Wen-Hui , Ng Ching-Ching , Yu Kai , Chin Yoon-Ming , Lou Pei-Jen , Hsu Wan-Lun , McKay James D. , Chen Chien-Jen , Chang Yu-Sun , Chen Li-Zhen , Chen Ming-Yuan , Cui Qian , Feng Fu-Tuo , Feng Qi-Shen , Guo Yun-Miao , Jia Wei-Hua , Khoo Alan Soo-Beng , Liu Wen-Sheng , Mo Hao-Yuan , Pua Kin-Choo , Teo Soo-Hwang , Tse Ka-Po , Xia Yun-Fei , Zhang Hongxin , Zhou Gang-Qiao , Liu Jian-Jun , Zeng Yi-Xin , Hildesheim Allan
Published: November 2015

Background: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied.

Methods: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case–control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed.

Results: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10−13). Our results also provide support for associations reported from published NPC GWAS—rs6774494 (P = 1.5 × 10−12; located in the MECOM gene region), rs9510787 (P = 5.0 × 10−10; located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10−8, P = 7.0 × 10−7, and P = 8.4 × 10−7, respectively; located in the CDKN2A/B gene region).

Conclusions: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity.

Impact: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis. Cancer Epidemiol Biomarkers Prev; 25(1); 188–92. ©2015 AACR.
Body Mass Index at Diagnosis and Breast Cancer Survival Prognosis in Clinical Trial Populations from NRG Oncology/NSABP B-30, B-31, B-34, and B-38
Authors: Cecchini Reena S. , Swain Sandra M. , Costantino Joseph P. , Rastogi Priya , Jeong Jong-Hyeon , Anderson Stewart J. , Tang Gong , Geyer Charles E. , Lembersky Barry C. , Romond Edward H. , Paterson Alexander H.G. , Wolmark Norman
Published: November 2015

Background: Body mass index (BMI) has been associated with breast cancer outcomes. However, few studies used clinical trial settings where treatments and outcomes are consistently evaluated and documented. There are also limited data assessing how patient/disease characteristics and treatment may alter the BMI–breast cancer association.

Methods: We evaluated 15,538 breast cancer participants from four NSABP protocols. B-34 studied early-stage breast cancer patients (N = 3,311); B-30 and B-38 included node-positive breast cancer patients (N = 5,265 and 4,860); and B-31 studied node-positive and HER2-positive breast cancer patients (N = 2,102). We used Cox proportional hazards regression to calculate adjusted hazards ratios (HR) for risk of death and recurrence, and conducted separate analyses by estrogen receptor (ER) status and treatment group.

Results: In B-30, increased BMI was significantly related to survival. Compared with BMI < 25, HRs were 1.04 for BMI 25 to 29.9 and 1.18 for BMI ≥ 30 (P = 0.02). Separate analyses indicated the significant relationship was only in ER-positive disease (P = 0.002) and the subgroup treated with doxorubicin/cyclophosphamide (P = 0.005). There were no significant trends across BMI for the other three trials. Similar results were found for recurrence. Increased BMI was significantly related to recurrence in B-30 (P = 0.03); and the significant relationship was only in ER-positive breast cancers (P = 0.001). Recurrence was also significant among ER-positive disease in B-38 (P = 0.03).

Conclusions: In our investigation, we did not find a consistent relationship between BMI at diagnosis and breast cancer recurrence or death.

Impact: This work demonstrates that the heterogeneity of breast cancer between different breast cancer populations and the different therapies used to treat them may modify any association that exists between BMI and breast cancer outcome. Cancer Epidemiol Biomarkers Prev; 25(1); 51–59. ©2015 AACR.
Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus
Authors: Yu Ming , O'Leary Rachele M. , Kaz Andrew M. , Morris Shelli M. , Carter Kelly T. , Chak Amitabh , Chandar Apoorva , Willis Joseph E. , Moinova Helen R. , Markowitz Sanford D. , Brenner Dean E. , Anandabapasathy Sharmila , Westerhoff Maria , Wong Chao-Jen , Shaheen Nicholas J. , Chen Yanwen , Barnholtz-Sloan Jill S. , Grady William M.
Published: November 2015

Background: Barrett's esophagus (BE) is a preneoplastic condition in which normal esophageal squamous epithelium (SQ) is replaced by specialized intestinal metaplasia. It is the presumed precursor for esophageal adenocarcinoma (EAC) as well as the strongest risk factor for this cancer. Unfortunately, many patients with BE go undiagnosed under the current BE screening guidelines. The development of noninvasive and accurate BE detection assays could potentially identify many of these undiagnosed BE patients.

Methods: DNA methylation is a common epigenetic alteration in BE. Therefore, we conducted a genome-wide methylation screen to identify potential BE biomarkers. Samples from SQ (N = 12), stomach (N = 28), and BE (N = 29) were analyzed and methylation levels at over 485,000 CpG sites were compared. Pyrosequencing assays were used to validate the results and MethyLight assays were developed to detect the methylated alleles in endoscopic brushings.

Results: We discovered two genes, B3GAT2 and ZNF793, that are aberrantly methylated in BE. Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median = 32.5% and 33.1%, respectively) than in control tissues (median = 2.29% and 2.52%, respectively; P < 0.0001 for both genes). Furthermore, gene-specific MethyLight assays could accurately detect BE (P < 0.0001 for both) in endoscopic brushing samples.

Conclusion: B3GAT2 and ZNF793 are hypermethylated in BE, and the methylation status of these genes can be used to detect BE in tissue samples.

Impact: These findings support the development of methylated B3GAT2 and ZNF793 as biomarkers for noninvasive assays for the detection of BE. Cancer Epidemiol Biomarkers Prev; 24(12); 1890–7. ©2015 AACR.
Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen
Authors: Nyante Sarah J. , Sherman Mark E. , Pfeiffer Ruth M. , de Gonzalez Amy Berrington , Brinton Louise A. , Bowles Erin J. Aiello , Hoover Robert N. , Glass Andrew , Gierach Gretchen L.
Published: November 2015

Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)–positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and ≤50 years (N = 6) or >50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and >50 years), tamoxifen duration (<4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction < 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines. Cancer Epidemiol Biomarkers Prev; 25(1); 212–6. ©2015 AACR.
Partnership Status and Socioeconomic Factors in Relation to Health Behavior Changes after a Diagnosis of Ductal Carcinoma In Situ
Authors: Khadanga Sherrie , Lakoski Susan G. , Hart Vicki , Sprague Brian L. , Ba Yi , Hampton John M. , Higgins Stephen T. , Ades Philip A. , Newcomb Polly A. , Trentham-Dietz Amy
Published: November 2015

Background: Change in health behaviors can occur among women newly diagnosed with ductal carcinoma in situ (DCIS). We sought to understand whether partnership status and socioeconomic status (SES) affected behavioral changes in body weight, physical activity, alcohol consumption, and smoking.

Methods: The Wisconsin In Situ Cohort (WISC) study comprises 1,382 women diagnosed with DCIS with information on demographics, SES factors, and pre- and post-DCIS diagnosis health-related behaviors. Logistic regression models were used to determine the association between partnership status, education, and income with change in behavior variables.

Results: Higher educational attainment was associated with lower likelihood of stopping physical activity [OR, 0.45; 95% confidence interval (CI), 0.32–0.63; college vs. high school degree], or starting to drink alcohol (OR, 0.34; 95% CI, 0.15–0.80). Results suggested that higher family income was associated with lower likelihood of gaining >5% body mass index (P = 0.07) or stopping physical activity (P = 0.09). Living with a partner was not strongly associated with behavior changes.

Conclusion: Higher educational attainment and higher income, but not living with a partner, were associated with positive health behaviors after a DCIS diagnosis.

Impact: The associations between higher educational attainment and, to a lesser extent, higher income with positive health behaviors underscore the importance of considering SES when identifying those at risk for negative behavioral change after DCIS diagnosis. Cancer Epidemiol Biomarkers Prev; 25(1); 76–82. ©2015 AACR.
Association of Parity and Time since Last Birth with Breast Cancer Prognosis by Intrinsic Subtype
Authors: Sun Xuezheng , Nichols Hazel B. , Tse Chiu-Kit , Bell Mary B. , Robinson Whitney R. , Sherman Mark E. , Olshan Andrew F. , Troester Melissa A.
Published: November 2015

Background: Parity and time since last birth influence breast cancer risk and vary by intrinsic tumor subtype, but the independent effects of these factors on prognosis have received limited attention.

Methods: Study participants were 1,140 invasive breast cancer patients from phases I and II of the population-based Carolina Breast Cancer Study, with tissue blocks available for subtyping using immunohistochemical markers. Breast cancer risk factors, including pregnancy history, were collected via in-person interviews administered shortly after diagnosis. Vital status was determined using the National Death Index. The association of parity and birth recency with breast cancer–specific and overall survival was assessed using Cox proportional hazards models.

Results: During follow-up (median = 13.5 years), 450 patients died, 61% due to breast cancer (n = 276). High parity (3+ births) and recent birth (<5 years before diagnosis) were positively associated with breast cancer–specific mortality, independent of age, race, and selected socioeconomic factors [parity, reference = nulliparous, adjusted HR = 1.76; 95% confidence interval (CI) = 1.13–2.73; birth recency, reference = 10+ years, adjusted HR = 1.29; 95% CI, 0.79–2.11]. The associations were stronger among patients with luminal tumors and those surviving longer than 5 years.

Conclusions: Parity and recent birth are associated with worse survival among breast cancer patients, particularly among luminal breast cancers and long-term survivors.

Impact: The biologic effects of parity and birth recency may extend from etiology to tumor promotion and progression. Cancer Epidemiol Biomarkers Prev; 25(1); 60–67. ©2015 AACR.
Combination of Photodynamic Therapy and Specific Immunotherapy Efficiently Eradicates Established Tumors
Authors: Kleinovink Jan Willem , van Driel Pieter B. , Snoeks Thomas J. , Prokopi Natasa , Fransen Marieke F. , Cruz Luis J. , Mezzanotte Laura , Chan Alan , Löwik Clemens W. , Ossendorp Ferry
Published: November 2015

Purpose: The efficacy of immunotherapy against advanced cancer may be improved by combination strategies. Photodynamic therapy (PDT) is a local tumor ablation method based on localized activation of a photosensitizer, leading to oxygen radical-induced tumor cell death. PDT can enhance antitumor immune responses by release of antigen and danger signals, supporting combination protocols of PDT with immunotherapy.

Experimental Design: We investigated the local and systemic immune effects of PDT after treatment of established tumors. In two independent aggressive mouse tumor models, TC-1 and RMA, we combined PDT with therapeutic vaccination using synthetic long peptides (SLP) containing epitopes from tumor antigens.

Results: PDT of established tumors using the photosensitizer Bremachlorin resulted in significant delay of tumor outgrowth. Combination treatment of PDT with therapeutic SLP vaccination cured one third of mice. Importantly, all cured mice were fully protected against subsequent tumor rechallenge, and combination treatment of primary tumors led to eradication of distant secondary tumors, indicating the induction of a systemic antitumor immune response. Indeed, PDT by itself induced a significant CD8+ T-cell response against the tumor, which was increased when combined with SLP vaccination and essential for the therapeutic effect of combination therapy.

Conclusions: We show that immunotherapy can be efficiently combined with PDT to eradicate established tumors, based on strong local tumor ablation and the induction of a robust systemic immune response. These results suggest combination of active immunotherapy with tumor ablation by PDT as a feasible novel treatment strategy for advanced cancer. Clin Cancer Res; 22(6); 1459–68. ©2015 AACR.
Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers
Authors: Aparicio Ana M. , Shen Li , Tapia Elsa Li Ning , Lu Jing-Fang , Chen Hsiang-Chun , Zhang Jiexin , Wu Guanglin , Wang Xuemei , Troncoso Patricia , Corn Paul , Thompson Timothy C. , Broom Bradley , Baggerly Keith , Maity Sankar N. , Logothetis Christopher J.
Published: November 2015

Purpose: Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, “aggressive variant prostate cancer (AVPC)” also share molecular features with SCPC.

Experimental Design: Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC.

Results: Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.

Conclusions: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN. Clin Cancer Res; 22(6); 1520–30. ©2015 AACR.
An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib
Authors: Danial Christina , Sarin Kavita Y. , Oro Anthony E. , Chang Anne Lynn S.
Published: November 2015

Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).

Experimental Design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.

Results: The median duration of treatment with sonidegib was 6 weeks (range, 3–58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.

Conclusions: Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors. Clin Cancer Res; 22(6); 1325–9. ©2015 AACR.
mTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer
Authors: Mo Wei , Liu Qingxin , Lin Curtis Chun-Jen , Dai Hui , Peng Yang , Liang Yulong , Peng Guang , Meric-Bernstam Funda , Mills Gordon B. , Li Kaiyi , Lin Shiaw-Yih
Published: November 2015

Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2. Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC.

Experimental Design: We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action.

Results: We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs.

Conclusions: Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients. Clin Cancer Res; 22(7); 1699–712. ©2015 AACR.
MECP2Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy
Authors: Neupane Manish , Clark Allison P. , Landini Serena , Birkbak Nicolai J. , Eklund Aron C. , Lim Elgene , Culhane Aedin C. , Barry William T. , Schumacher Steven E. , Beroukhim Rameen , Szallasi Zoltan , Vidal Marc , Hill David E. , Silver Daniel P.
Published: November 2015

An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.

Significance: MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45–58. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1
Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer
Authors: Russo Mariangela , Misale Sandra , Wei Ge , Siravegna Giulia , Crisafulli Giovanni , Lazzari Luca , Corti Giorgio , Rospo Giuseppe , Novara Luca , Mussolin Benedetta , Bartolini Alice , Cam Nicholas , Patel Roopal , Yan Shunqi , Shoemaker Robert , Wild Robert , Di Nicolantonio Federica , Bianchi Andrea Sartore , Li Gang , Siena Salvatore , Bardelli Alberto
Published: November 2015

Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA–NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.

Significance: We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1); 36–44. ©2015 AACR.

See related commentary by Okimoto and Bivona, p. 14.

This article is highlighted in the In This Issue feature, p. 1
Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer
Authors: Mulligan Anna Marie , Pinnaduwage Dushanthi , Tchatchou Sandrine , Bull Shelley B. , Andrulis Irene L.
Published: November 2015

We previously observed T-bet+ lymphocytes to be associated with a good prognosis in a cohort of women with familial breast cancer. To validate this finding, we evaluated lymphocyte T-bet expression in an independent unselected prospectively accrued series of women with lymph node–negative breast carcinoma. T-bet and clinicopathologic data were available for 614 women. Hormone receptors, HER2, Ki-67, CK5, EGFR, p53, and T-bet status were determined using IHC and/or biochemical methods. Tumors were assigned to luminal A, luminal B, HER2, and basal subtypes based on the expression of IHC markers. Multiple cutpoints were examined in a univariate penalized Cox model to stratify tumors into T-bet+/high and T-bet−/low. Fisher exact test was used to analyze T-bet associations with clinicopathologic variables, IHC markers, and molecular subtype. Survival analyses were by the Cox proportional hazards model. All tests were two sided. A test with a P value < 0.05 was considered statistically significant. T-bet+/high tumor status was significantly associated with large tumor size, high grade, hormone receptor negativity, CK5, EGFR and p53 positivity, high Ki-67, and basal subtype. With a median follow-up of 96.5 months, T-bet−/low tumor status was associated with a reduced disease-free survival compared with T-bet+/high tumor status in multivariate analysis (P = 0.0027; relative risk = 5.62; 95% confidence intervals, 1.48–50.19). Despite being associated with adverse clinicopathologic characteristics, T-bet+ tumor-infiltrating lymphoid cells are associated with a favorable outcome. This supports their role in Th1-mediated antitumor activity and may provide insight for the development of new therapeutic strategies. Cancer Immunol Res; 4(1); 41–48. ©2015 AACR.
Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model
Authors: Reardon David A. , Gokhale Prafulla C. , Klein Sarah R. , Ligon Keith L. , Rodig Scott J. , Ramkissoon Shakti H. , Jones Kristen L. , Conway Amy Saur , Liao Xiaoyun , Zhou Jun , Wen Patrick Y. , Van Den Abbeele Annick D. , Hodi F. Stephen , Qin Lei , Kohl Nancy E. , Sharpe Arlene H. , Dranoff Glenn , Freeman Gordon J.
Published: November 2015

Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti–CTLA-4 plus anti–PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8+ and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124–35. ©2015 AACR.
Epicardial Catheter Ablation Using High-Intensity Ultrasound
Authors: Nazer Babak , Salgaonkar Vasant , Diederich Chris J. , Jones Peter D. , Duggirala Srikant , Tanaka Yasuaki , Ng Bennett , Sievers Richard , Gerstenfeld Edward P.
Published: November 2015

Background—

Epicardial radiofrequency catheter ablation of ventricular tachycardia remains challenging because of the presence of deep myocardial scar and adjacent cardiac structures, such as the coronary arteries, phrenic nerve, and epicardial fat that limit delivery of radiofrequency energy. High-intensity ultrasound (HIU) is an acoustic energy source able to deliver deep lesions through fat, while sparing superficial structures. We developed and tested an epicardial HIU ablation catheter in a closed chest, in vivo swine model.

Methods and Results—

The HIU catheter is an internally cooled, 14-French, side-facing catheter, integrated with A-mode ultrasound guidance. Swine underwent percutaneous subxyphoid epicardial access and ablation with HIU (n=10 swine) at 15, 20, and 30 W. Compared with irrigated radiofrequency lesions in control swine (n = 5), HIU demonstrated increased lesion depth (HIU 11.6±3.2 mm versus radiofrequency 4.7±1.6 mm; mean±SD) and epicardial sparing (HIU 2.9±2.1 mm versus radiofrequency 0.1±0.2 mm) at all HIU powers, and increased lesion volume at HIU 20 and 30 W (
P
<0.0001 for all comparisons). HIU ablation over coronary arteries and surrounding epicardial fat resulted in deep lesions with normal angiographic flow. Histological disruption of coronary adventitia, but not media or intima, was noted in 44% of lesions.

Conclusions—

Compared with radiofrequency, HIU ablation in vivo demonstrates significantly deeper and larger lesions with greater epicardial sparing in a dose-dependent manner. Further development of this catheter may lead to a promising alternative to epicardial radiofrequency ablation.
Efficacy of Various Percutaneous Interventions for In-Stent Restenosis
Authors: Sethi Ankur , Malhotra Gurveen , Singh Sukhchain , Singh Param P. , Khosla Sandeep
Published: November 2015

Background—

In-stent restenosis (ISR) remains a difficult problem in interventional cardiology. The relative efficacy and safety of available interventions is not clear. We aimed to perform a network meta-analysis using both direct evidence and indirect evidence to compare all available interventions.

Methods and Results—

We systematically searched electronic databases for randomized trials comparing ≥2 treatments for ISR. A network meta-analysis was performed using a Bayesian approach. Eleven treatments were compared in 31 studies with 8157 patient-years follow-up. Compared with balloon angioplasty, everolimus-eluting stent (hazard ratio [95% credibility interval], 0.13 [0.048–0.35]), paclitaxel-eluting balloon (0.32 [0.20–0.49]), paclitaxel-eluting cutting balloon (0.054 [0.0017–0.5]), paclitaxel-eluting stent (0.39 [0.24–0.62]), and sirolimus-eluting stent (0.32 [0.18–0.50]) are associated with lower target vessel revascularization. Balloon angioplasty is not different from cutting balloon (0.73 [0.31–1.5]), excimer laser (0.89 [0.29–2.7]), rotational atherectomy (0.96 [0.53–1.7]), and vascular brachytherapy (0.60 [0.35–1.0]). In drug-eluting stent ISR, balloon angioplasty was inferior to everolimus-eluting stent (0.19 [0.049–0.76]), paclitaxel-eluting balloon (0.43 [0.18–0.80]), paclitaxel-eluting stent (0.35 [0.13–0.76]), and sirolimus-eluting stent (0.36 [0.11–0.86]) for target vessel revascularization. There was no difference between treatments in probable or definitive stent thrombosis. The results of binary restenosis and target lesion revascularization were similar. Paclitaxel-eluting cutting balloon, everolimus-eluting stent, and paclitaxel-eluting balloon have the highest probability of being in the top 3 treatments based on low target lesion revascularization, but there was no statistical significant difference between them.

Conclusions—

Balloon angioplasty is inferior to all drug-eluting treatments for ISR, including drug-eluting stent ISR. Drug-eluting stent, particularly everolimus-eluting stent, or paclitaxel-eluting cutting balloon and paclitaxel-eluting balloon should be preferred for treating ISR.
Importance of Implantable Cardioverter‐Defibrillator Back‐Up in Cardiac Resynchronization Therapy Recipients: A Systematic Review and Meta‐Analysis
Authors: Barra Sérgio , Providência Rui , Tang Anthony , Heck Patrick , Virdee Munmohan , Agarwal Sharad
Published: November 2015

Background

It remains to be determined whether patients receiving cardiac resynchronization therapy (
CRT
) benefit from the addition of an implantable cardioverter‐defibrillator (
ICD
).

Methods and Results

We performed a literature search looking for studies of patients implanted with
CRT
s. Comparisons were performed between patients receiving
CRT
‐defibrillator (
CRT
‐D) versus
CRT
‐pacemaker (
CRT
‐P). The primary outcome was all‐cause mortality. Data were pooled using a random‐effects model. The relative risk (
RR
) and hazard ratio (
HR
, when available) were used as measurements of treatment effect. Nineteen entries were entitled for inclusion, comprising 12 378 patients (7030 receiving
CRT
‐D and 5348 receiving
CRT
‐P) and 29 799 patient‐years of follow‐up. Those receiving
CRT
‐D were younger, were more often males, had lower
NYHA
class, lower prevalence of atrial fibrillation, higher prevalence of ischemic heart disease, and were more often on beta‐blockers. Ten studies showed significantly lower mortality rates with the
CRT
‐D device, while the remaining 9 were neutral. The pooled data of studies revealed that
CRT
‐D patients had significantly lower mortality rates compared with
CRT
‐P patients (mortality rates:
CRT
‐D 16.6% versus
CRT
‐P 27.1%;
RR
=0.69, 95%
CI
0.62–0.76;
P
<0.00001). The number needed to treat to prevent one death was 10. The observed I
2
values showed moderate heterogeneity among studies (I
2
=48%). The benefit of
CRT
‐D was more pronounced in ischemic cardiomyopathy (
HR
=0.70, 95%
CI
0.59–0.83,
P
<0.001, I
2
=0%), but a trend for benefit, albeit of lower magnitude, could also be seen in non‐ischemic dilated cardiomyopathy (
HR
=0.79, 95%
CI
0.61–1.02,
P
=0.07, I
2
=36%).

Conclusions

The addition of the
ICD
associates with a reduction in the risk of all‐cause mortality in
CRT
patients. This seems to be more pronounced in patients with ischemic cardiomyopathy.
Does Corporate Philanthropy Increase Firm Value? The Moderating Role of Corporate Governance
Authors: Su Weichieh , Sauerwald Steve
Published: November 2015

The link between corporate philanthropy and firm value has been controversial. On one hand, corporate philanthropy is often criticized as an agency cost because it may serve narrow managerial self-interests. On the other hand, corporate philanthropy may enhance firm value because it improves the relationships between firms and their stakeholders. In this study, we argue that this controversy is contingent upon whether corporate governance mechanisms can stimulate the financial benefit of corporate philanthropy. Based on a sample of U.S. firms from 1996 to 2003, we find that CEO long-term pay positively moderates the relationship between corporate philanthropy and firm value while multiboard outside directors negatively moderate this relationship. Contrary to our expectations, we find that the relationship between corporate philanthropy and firm value enhances as CEO tenure increases. Our findings show that corporate governance plays an important moderating role in the relationship between corporate philanthropy and firm value.
Evaluation of Simulated Clinical Breast Exam Motion Patterns Using Marker-Less Video Tracking
Authors: Azari David P. , Pugh Carla M. , Laufer Shlomi , Kwan Calvin , Chen Chia-Hsiung , Yen Thomas Y. , Hu Yu Hen , Radwin Robert G.
Published: November 2015

Objective:

This study investigates using marker-less video tracking to evaluate hands-on clinical skills during simulated clinical breast examinations (CBEs).

Background:

There are currently no standardized and widely accepted CBE screening techniques.

Methods:

Experienced physicians attending a national conference conducted simulated CBEs presenting different pathologies with distinct tumorous lesions. Single hand exam motion was recorded and analyzed using marker-less video tracking. Four kinematic measures were developed to describe temporal (time pressing and time searching) and spatial (area covered and distance explored) patterns.

Results:

Mean differences between time pressing, area covered, and distance explored varied across the simulated lesions. Exams were objectively categorized as either sporadic, localized, thorough, or efficient for both temporal and spatial categories based on spatiotemporal characteristics. The majority of trials were temporally or spatially thorough (78% and 91%), exhibiting proportionally greater time pressing and time searching (temporally thorough) and greater area probed with greater distance explored (spatially thorough). More efficient exams exhibited proportionally more time pressing with less time searching (temporally efficient) and greater area probed with less distance explored (spatially efficient). Just two (5.9 %) of the trials exhibited both high temporal and spatial efficiency.

Conclusions:

Marker-less video tracking was used to discriminate different examination techniques and measure when an exam changes from general searching to specific probing. The majority of participants exhibited more thorough than efficient patterns.

Application:

Marker-less video kinematic tracking may be useful for quantifying clinical skills for training and assessment.
The development of a protocol simulator for active learning
Authors: Pearce David AJ
Published: November 2015

The development of a first-year module in communications protocols is described, employing active learning techniques enabled by a new protocol simulator designed for education. The simulator has a simple graphical user interface and is designed for ease of use, rather than speed or flexibility. Protocols can be programmed in a version of C and run from the graphical user interface with no requirement to use an object-oriented programming language or scripting language. The simulator and the active learning approach has proved popular and robust and allows problem-based learning techniques, whereby students invent and test their own protocols, to be used at an early stage in the degree.
Cost Sharing, Health Care Expenditures, and Utilization
Authors: Perkowski Patryk , Rodberg Leonard
Published: November 2015

Health systems implement cost sharing to help reduce health care expenditure and utilization by discouraging the use of unnecessary health care services. We examine cost sharing in 28 countries in the Organisation for Economic Co-operation and Development from 1999 through 2009 in the areas of medical care, hospital care, and pharmaceuticals. We investigate associations between cost sharing, health care expenditures, and health care utilization and find no significant association between cost sharing and health care expenditures or utilization in these countries.
Black Churches and Mental Health Professionals
Authors: Dempsey Keith , Butler S. Kent , Gaither LaTrece
Published: November 2015

African Americans reportedly have a greater severity of untreated mental health disorders than any other known racial group. History purports that African Americans are more likely to rely on the elders of their churches and their own spiritual beliefs, rather than seek support from mental health professionals. Due to past and present experiences with institutionalized racism in America, Black church leadership and their members have been apprehensive to collaborate with mental health agencies. This article explores how clergy of Black churches and leaders in mental health agencies may collaborate to provide culturally sensitive services for African Americans.