bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-04-04: Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines
Authors: Kaul R , Risinger AL , Mooberry SL
Published: February 2018

Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While these drugs were classically identified as only antimitotic agents, recent evidence demonstrates that the ability of MTAs to disrupt key signaling components in interphase cells likely contributes to their anticancer actions. Yoshida and colleagues demonstrated that eribulin reverses TGF-β-induced epithelial-to-mesenchymal transition (EMT) in preclinical models of triple negative breast cancer (TNBC) within 7days. To gain a deeper understanding of the interphase effects of eribulin in comparison with other MTAs on the TGF-β signaling pathway, we tested the hypothesis that a short-term, 2 h treatment of TNBC cells with MTAs would disrupt TGF- β signaling. The effects of the microtubule destabilizers eribulin and vinorelbine and the microtubule stabilizers paclitaxel and ixabepilone on downstream targets of the TGF-β pathway were evaluated in two TNBC cell lines. In the mesenchymal type BT-549 cells, eribulin and vinorelbine significantly inhibited TGF-β induced expression of Snail and Slug, while the microtubule stabilizers had no effect on their expression. In the basal-like 1 type HCC1937 cells, the microtubule destabilizers inhibited the expression of Snail when compared to vehicle and stabilizer-treated cells, but caused increased expression of Slug. These data suggest that MTAs have different effects on the TGF-β signaling pathway in distinct molecular contexts. Our efforts are directed towards deciphering the effects of eribulin and other MTAs on the TGF- β pathway and how this contributes to differential sensitivity. Preliminary data suggest that eribulin initiated inhibition of Snail and Slug in BT-549 cells is mediated by the scaffold protein NEDD9 and we are testing whether the differential levels of expression of NEDD9 help explain the differences in the effects of eribulin in BT-549 and HCC1937 cells. These results will begin to decipher differences among MTAs in different molecular contexts and might help identify biomarkers for optimal therapies. Funding for this work was provided by Eisai Inc.

Citation Format: Kaul R, Risinger AL, Mooberry SL. Eribulin differentially disrupts TGF-β signaling pathway in BT-549 and HCC1937 breast cancer cell lines [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-04-04.
Abstract P5-08-03: Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens
Authors: O'Neill HA , Tinder TT , Maher V , Rosenow M , Richards M , Santhanam R , Wei X , Domenyuk V , Miglarese MR , Spetzler D
Published: February 2018

We have previously described the ADAPT Biotargeting System™as a novel platform for highly multiplexed poly-ligand profiling of complex phenotypes such as drug response. Here we report extended capabilities of the this platform for target identification directly from formalin-fixed-paraffin embedded (FFPE) tissues using aptamer libraries enriched toward HER2+ breast cancer. Standard mass spectrometry-based biomarker and drug target discovery from FFPE tissues can be challenging due to limited amounts of tissue, harsh conditions of fixation and extraction and the general problem of masking by highly abundant proteins. A single stranded-oligodeoxynucleotide aptamer library was enriched on HER2+ FFPE breast cancer specimens and conjugated with biotin as well as a label transfer reagent, Sulfo-NHS-SS-Diazirine (Sulfo-SDAD). The biotinylated-SDAD conjugated library (B-SDAD-EL) was applied to HER2+ FFPE tissues and photocrosslinked to cognate binding partners within the FFPE sample in order to preserve aptamer-protein interactions under harsh denaturing conditions required for protein extraction and sample preparation. Aptamer-protein complexes were affinity purified and the label was transferred from bound aptamers to their binding partners under reducing conditions that enable proteomic digestion and high resolution mass spectrometry detection. An open database search was performed where the precursor ion tolerance was set to ± 500 Da for database searching, which enabled identification of peptides containing the transferred label as well as additional unknown variable modifications induced by the tissue fixation process. We identified proteins with known roles in HER2+ breast cancer along with several potentially drugable targets not previously associated with HER2 positivity. Differential expression of candidate targets was orthogonally confirmed by immunohistochemistry. By nature of its extreme molecular complexity and its ability to be enriched or “trained,” toward phenotypes of interest, the ADAPT Biotargeting SystemTM can be deployed to advance precision medicine by identifying predictive biomarkers and drug targets with novel associations to complex interactomes.

Citation Format: O'Neill HA, Tinder TT, Maher V, Rosenow M, Richards M, Santhanam R, Wei X, Domenyuk V, Miglarese MR, Spetzler D. Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-08-03.
Abstract P5-22-08: Not presented
Authors: Kumar C , Srivastava A , Ranjan P , Kataria K , Dhar A , Qaiser D , Mathur S
Published: February 2018

This abstract was not presented at the symposium.
Abstract P5-23-03: Gene expression profiling in male breast cancer
Authors: Dubrovsky E , Raymond S , Chun J , Schnabel F
Published: February 2018

Background:

Tumor gene expression profiling tests are widely used to quantify risk of recurrence of breast cancer and guide systemic therapy in early stage breast cancer. These assays have not been well validated in a male cohort. The purpose of this study was to determine the current rates of genomic testing in male breast cancer (MBC), the distribution of risk of recurrence scores (RRS) in early stage MBC, and the effect of RRS on systemic treatment patterns.

Methods:

The National Cancer Database was queried and found to include 6,227 cases of pathologic T1/T2 and N0/N1 MBC from 2008-2014 with known genomic testing status. Of the 1478 (23.74%) male patients who had gene expression profiling performed, variables of interest included age at diagnosis, stage, estrogen receptor status (ER), RRS, and treatment. We compared the treatment patterns of the 1,343 patients who had RRS available and the 4,527 patients who were not tested. A similar analysis was performed in female breast cancer (FBC) patients to serve as a point of reference. Statistical analysis included multivariate logistic regression and Pearson's chi-square test.

Results:

Of the 1,478 (23.74%) cases of MBC who had gene expression profiling, the most significant variables included: younger age, non-Black race, diagnosis after 2010, tumor Grade II, Estrogen Receptor (ER) positivity, and N0 or N1mi disease. Of those who had results, the distribution of RRS was 59.3% low, 27.4% intermediate, and 13.3% high. A similar distribution was found in 154,705 women who were tested during the same study period. Risk scores in men were significantly associated with tumor grade and size, but not nodal status. 83.4% of men with a low RRS were treated with hormone therapy alone, with an adjusted odds ratio (AOR) of 7.18 (CI 5.78-8.91, p<0.001). Also, 61.8% of men with a high RRS received combination chemotherapy and hormone therapy, with an AOR of 5.16 (CI 3.60-740, p<0.001).

Conclusion:

Although there is limited literature supporting the use of genomic assays in MBC, our study found similar rates of testing in men and women with early stage breast cancer. Treatment patterns varied significantly based on risk stratification, implying that physicians are using gene profiling assays to help guide treatment in MBC. Understanding the role for genomic profiling in MBC is particularly important as these results will be incorporated into the new AJCC 8th edition staging system. Long term follow up is needed to determine whether these tests accurately predict prognosis and recurrence in a male cohort.

Citation Format: Dubrovsky E, Raymond S, Chun J, Schnabel F. Gene expression profiling in male breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-03.
Abstract P6-06-04: Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach
Authors: Rajamanickam S , Park JH , Bates K , Timilsina S , Eedunuri VK , Onyeagucha B , Subbarayalu P , Abdelfattah N , Jung KH , Favours E , Mohammad TA , Chen H-IH , Vadlamudi RK , Chen Y , Kaipparettu BA , Arbiser JL , Rao MK
Published: February 2018

Triple-negative breast cancers (TNBCs) represent aggressive heterogeneous subtype of breast cancer with poor clinical outcome. TNBCs have been reported to have high levels of replication stress due to i) various oncogene activations (C-myc or EGFR) ii) germline BRCA mutations iii) “BRCAness” in the absence of BRCA mutations in sporadic TNBCs. Replication stress is known to cause genomic instability, promote tumorigenesis and plays a critical role in therapy resistance in TNBCs. Therefore, targeting replication stress has emerged as an effective approach for better TNBC treatment through further downregulation of the remaining checkpoints to induce catastrophic failure of TNBC cells proliferation. Herein, we evaluated the anticancer efficacy of Carbazole Blue (CB), a synthetic analogue of Carbazole, on TNBC cells growth and progression. Our results demonstrated that CB inhibits short and long term viability of TNBC (MDA-MB-231, MDA-MB-468 and BT549) cells in a dose dependent manner without affecting normal mammary epithelial (MCF-10A) cells. In addition, CB treatment significantly reduced proliferation of TNBC cells, as evidenced by the BrdU proliferation assay. Consistent with this, our results further demonstrated that CB treatment induced G1/S cell cycle arrest and apoptosis in TNBCs. Importantly, systemic delivery of CB using nanoparticle-based delivery approach suppressed breast cancer growth without inducing toxicity, in preclinical orthotopic xenograft and PDX mouse models of TNBC. Furthermore, our gene microarray analysis revealed that CB treatment modulates the expression and activity of several genes known to be involved in DNA replication (CDC6, CDT1, MCMs, Claspin, POLE and PCNA) and associated DNA repair machinery such as (XRCC3, Exo1 and RAD51), which play pivotal roles in replication stress. Our results for the first time highlight the potential use of CB as a novel and potent therapeutic agent for treating TNBCs. As exploiting replication stress to treat cancer is gaining major interest, compound/s that may induce replication stress and inhibit DNA repair ability of cancer cells, has immense translational potential.

Citation Format: Rajamanickam S, Park JH, Bates K, Timilsina S, Eedunuri VK, Onyeagucha B, Subbarayalu P, Abdelfattah N, Jung KH, Favours E, Mohammad TA, Chen H-IH, Vadlamudi RK, Chen Y, Kaipparettu BA, Arbiser JL, Rao MK. Targeting replication stress in triple negative breast cancer treatment regimen: An emerging approach [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-04.
Abstract P6-08-23: Not presented
Authors: Ho PJ , Liu J , Miao H , Hartman M
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-13-04: IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer
Authors: Soliman H , Rehmus E , Shah V , Srkalovic G , Mahtani R , Levine E , Mavromatis B , Srinivasiah J , Kassar M , Gabordi R , Yoder E , Qamar R , Audeh W ,   IMPACt Investigators Group I
Published: February 2018

Background: IMPACt is a prospective, case-only study to measure the effect of MammaPrint (MP) and BluePrint (BP) on treatment decisions in breast cancer patients. Here, we report the results of the primary objective in women aged ≥18 years with histologically proven invasive stage I-II, hormone receptor (HR) positive, and HER2-negative breast cancer. Methods: The study included 369 women from 18 US institutions. The recommended treatment plan was captured before and after receiving results for MP and BP. Treatment was started after obtaining results. In addition to the effect of results on physician treatment decisions involving chemotherapy (CT) and physician confidence, the distribution of MP High Risk (HR) and Low Risk (LR) patients was also evaluated. Results: MP classified patients to 62% (n=228) LR and 38% (n=141) HR. Treatment decisions were changed for 25% (n=92) of women after receiving MP and BP results. Of the LR patients initially prescribed CT, 68% (45/66) had CT removed from their treatment recommendation. Of the HR patients who initially were not prescribed CT, 66% (42/64) had CT added. Overall, 89% (202/228) of LR patients did not receive CT, and likewise 84% (119/141) of HR patients did receive CT after receiving MP. Among those who did not change treatment (n=277), 68% of physicians reported having greater confidence in their prescribed therapy. Conclusions: The IMPACt trial shows MP generates a 25% overall treatment change in clinical practice. The highest impact is for women with LR results, where 68% are spared chemotherapy in favor of endocrine therapy alone. Additionally, 73% of physicians report having higher confidence in treatment decisions for their patient after MP.

Table 1: Treatment changesTreatment Decision Pre- to Post-MPMP HRMP LRTotalCT to CT772198no CT tp CT42547CT to no CT04545no CT to no CT22157179Total141228369

Citation Format: Soliman H, Rehmus E, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, Srinivasiah J, Kassar M, Gabordi R, Yoder E, Qamar R, Audeh W, IMPACt Investigators Group I. IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-04.
Abstract PD7-13: Molecular characterization and mortality from breast cancer in men
Authors: Massarweh SA , Sledge GW , Miller DP , McCullough D , Petkov VI , Shak S
Published: February 2018

Background: Limited data exist on the molecular biology, treatment, and outcomes of breast cancer in men and much of our understanding in this area remains largely an extrapolation from data in women with breast cancer.

Methods: We studied men and women with hormone receptor (HR)-positive breast cancer and 21-gene test (RS) results. Patients with negative nodes, micrometastasis, and 1-3 positive nodes were included. Differences in clinical characteristics and gene expression were determined and distribution of RS results was analyzed and correlated with 5-year breast cancer specific survival (BCSS) and overall survival (OS).

Results: There were 3806 men and 571115 women. Men were older than women (mean age 64.2 vs. 59.1 years, p<0.001). RS <18 predominated in both genders, but RS ≥31 was more frequent in men (12.4% vs. 7.4%, p<0.001) as were very low scores (RS <11) (33.8% vs. 22.1%, p<0.001). Mean gene expression was higher in men for the ER, proliferation, and invasion groups. ER was lowest and PR highest in women <50 years, with a progressive increase in ER with age. Men <50 years had slightly lower ER and PR compared to older men. Survival data was available from SEER for 322 men and 55842 women. 5-year estimates for BCSS differed significantly between RS groups for both men (p=0.003) and women (p<0.001). For men, the 5-year BCSS was 99.0% and 95.9% with RS <18 and RS 18-30, respectively, and for women it was 99.5% and 98.6%, regardless of nodal status. RS ≥31 was associated with a 5-year BCSS of 81.0% in men and 94.9% in women. The prognostic utility of RS was evident in both men and women, despite the progressive increase in adjuvant chemotherapy use with higher RS results. 5-year BCSS and OS were overall lower in men than in women.

Conclusion: This large genomic study reveals some distinctive biologic features of breast cancer in men and an important prognostic role for 21-gene testing in both men and women, regardless of nodal status. Future adjuvant trials in ER-positive breast cancer should focus on targeting endocrine-resistance in those patients with RS ≥31, and need to consider the weight of competing causes of mortality when investigating the value of any additional treatment beyond endocrine therapy.

Citation Format: Massarweh SA, Sledge GW, Miller DP, McCullough D, Petkov VI, Shak S. Molecular characterization and mortality from breast cancer in men [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-13.
Abstract PD8-12: Mutational processes, genome evolution and outcome in metastatic breast cancers
Authors: Patsouris A , Filleron T , Jacquet A , Goncalves A , Bonnefoi H , Letourneau C , Bachelot T , Jimenez M , Andre F
Published: February 2018

Background: to determine the distribution and evolution of mutational processes in metastatic breast cancers (mBC), together with their clinical relevance Methods: Whole exome sequencing (Hi-Seq, Illumina) and determination of copy number alterations (CNA) (CGH array / SNP6.0) were performed in 240 and 692 metastatic breast cancers respectively. Mutational processes were defined according to Alexandrov (Nature, 2013). Homologous Recombination Deficiency (HRD) was determined by genome wide assessment of loss-of-heteroygosity (LOH) on SNP6.0 (n = 210). Finally, genomic instability was assessed by the % of genome altered assessed by CGH / SNP6.0 Results: Whole exome sequencing showed that HR+/Her2- metastatic breast cancer presented an increased contribution of APOBEC-related signatures, as compared to early breast cancer (TCGA) (58% of the mutations vs 31%, p < 0.0001). Twelve percent of the HR+/Her2- mBC acquired an hypermutator genotype ( > 200 non-synonymous mutations). This acquisition of an hypermutator genotype was confirmed in five paired primary-metastatic samples. An operational APOBEC-related signature 13 was associated with a poor outcome in a multivariate analysis (HR: 1.75, 95%CI: 1.1-2.7, p = 0.017). High LOH score (HRD) was observed in 30% of HR+/Her2- mBC as compared to 13% of early HR+/Her2- early BC (p < 0.0001). The opposite was observed in TNBC (43% in mTNBC versus 58% in early TNBC ,p = 0.032). High LOH score was associated with a trend for poor outcome in HR+/Her2- mBC (multivariate 1.67, 95%CI: 0.949-2.951, p = 0.075).The % of genome altered was associated with a poor outcome in multivariate analyses both in the overall and HR+/Her2- mBC (HR / 10 increase:1.144, 95%CI:1.038-1.261, p = 0.007 and HR:1.18, 95%CI:1.037-1.344, p = 0.012 respectively). Copy number analyses identified 143 genes that are more frequently amplified as compared to early breast cancers (FDR < 0.01) Conclusions: metastatic HR+/Her2- metastatic breast cancer present an increased in APOBEC-related mutational burden and in LOH score as compared to early breast cancers. APOBEC-related signature 13 and genome instability are associated with a poor outcome and could be used in the future to better stratify metastatic breast cancer patients.

Citation Format: Patsouris A, Filleron T, Jacquet A, Goncalves A, Bonnefoi H, Letourneau C, Bachelot T, Jimenez M, Andre F. Mutational processes, genome evolution and outcome in metastatic breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-12.
Grenzstrahlung bei refraktärer aktinischer Porokeratose: eine verträgliche und effektive Therapieoption
Authors: Schilling Bastian
Published: February 2018

Background: Disseminated superficial actinic porokeratosis (DSAP) is a rare keratinization disorder with potential malignant transformation, for which present treatment strategies show limited success. Aim: To evaluate the response of DSAP lesions to grenz ray radiotherapy (RTx). Methods: Data of patients treated with RTx at University Hospital Zurich, Switzerland, between 2004 and 2015, were reviewed. Patients with DSAP, who received at least 1 RTx treatment session and who had been followed up for at least 4 weeks were included in the further data analysis. Results: The study cohort consisted of 8 patients with a median age of 73 years (range 54-84). All were treated with grenz rays for DSAP. Most (7/8) patients showed complete clinical clearing of the lesions. All patients experienced temporary side effects of RTx, which resolved within 4 weeks after the last irradiation. Conclusion: We suggest radiotherapy with grenz rays as a treatment option for DSAP.
K101-03 bei Onychomykose und Nagelpsoriasis - alter Wein in neuen Schläuchen?
Authors: Gerber Peter Arne
Published: February 2018

Introduction: Onychomycosis and nail psoriasis can be embarrassing to patients, so improving the appearance of affected nails should be one of the key short-term goals of treatment. Methods: An 8-week open-label multicenter study was conducted to assess whether K101-03, a marketed topical treatment containing propylene glycol, glycerol, urea, and lactic acid, could produce rapid cosmetic improvements in affected nails. Adult patients with a big toenail or thumbnail (the «target» nail) affected by onychomycosis (n = 72) or psoriasis (n = 34) or both (n = 1) applied K101-03 to their affected nails once a day for 8 weeks. During and after treatment, patients rated the overall appearance of their target nail on a 4-point scale. They also assessed whether thickening, discoloration, brittleness, and softness of the target nail had improved since baseline. Adverse events (AEs) that occurred between the first application of K101-03 and the end of treatment were recorded and categorized according to severity and relationship to K101-03. Results: After 8 weeks of K101-03 treatment, 92,2% of patients (95% confidence interval [CI] 87,06-97,40) reported at least some improvement in the target nail. After 1 week of treatment, 78,3% of patients with onychomycosis (95% CI 68,53-87,99) reported at least some improvement in the target nail, and 55,1% of them reported that discoloration of their target nail had improved. Three patients reported a total of 5 AEs, none of which were judged to be related to K101-03. Conclusions: In summary, K101-03 was well tolerated in patients with onychomycosis or nail psoriasis and rapidly improved their nails.
Mycosis fungoides: Therapieerfolg im Frühstadium mit UV-A1-Therapie
Authors: Lehmann Percy
Published: February 2018

Background: Phototherapy has been the mainstay of therapies for early mycosis fungoides (MF). The beneficial role of ultraviolet (UV) light on MF is suggested by the observation that lesions occur on non-sun-exposed areas. Therapeutic light sources that are available today are broadband UVB, psoralen and UVA, narrowband UVB, and long-wave UV (UVA1). Current literature provides increasing evidence on the use of UVA1 to treat MF. Aim: To investigate the treatment responses of early MF patients treated with fixed 30 J/cm2 doses of UVA1 phototherapy. Material and Methods: Nineteen patients with early MF, stage IA-IIA of the TNM staging system, received fixed 30 J/cm2 doses of UVA1, given 5 times weekly over 5 weeks. Therapeutic effectiveness was assessed by clinical examination and was confirmed by histological evaluation. Results: Of the 19 patients, complete responses were achieved in 12 (63%) and partial responses were achieved in 7 (37%) patients after UVA1 radiation exposures. During the study, UVA1 therapy was well tolerated. During the follow-up, 7 (58%) of the 12 patients with complete response relapsed within 3 months of the UVA1 therapy. Conclusion: The current study provides clinical and histological evidence for the effectiveness of UVA1 (30 J/cm2 5 times a week for 5 weeks) as a skin-directed therapy in the treatment of early MF; however, such a treatment failed to maintain a long and sustained response. Thus, studies to identify the optimal dosing protocol regarding the therapeutic efficacy, the factors affecting relapse time/rate, and the necessity of maintenance treatment are needed.
Expression of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Human Epicardial and Intramyocardial Coronary Arteries of Male Patients Undergoing Coronary Artery Bypass Grafting
Authors: Synetos Andreas , Karanasos Antonios , Spyropoulos Stauros , Gazouli Maria , Latsios George , Toutouzas Konstantinos , Perrea Despina , Tousoulis Dimitrios , Chloroyiannis Ioannis A.
Published: February 2018

Objectives: Atherosclerosis is almost absent in intramyocardial coronary arteries, while epicardial coronary arteries may show extensive occlusive disease. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression has been implicated in atherogenesis. We aimed to investigate differences in arterial wall LOX-1 expression between human epicardial and intramyocardial coronary arteries. Methods: Epicardial and intramyocardial total artery wall specimens were obtained from 13 male patients (aged 61.9 ± 10.3 years) undergoing coronary artery bypass graft surgery due to 3-vessel coronary artery disease. LOX-1 expression was examined by reverse transcription-polymerase chain reaction. Results: LOX-1 expression was significantly higher in the arterial wall of epicardial coronary arteries compared to intramyocardial coronary arteries. The LOX-1/GAPDH ratio was 0.48 ± 0.07 vs. 0.35 ± 0.03 (p < 0.001). Conclusions: Our findings may partially explain the atheroprotective effect of the intramyocardial course since arterial wall LOX-1 expression was lower in intramyocardial arteries and higher in epicardial coronary arteries.
Nonbacterial Thrombotic Endocarditis Presenting with Leg Pain and a Left Atrial Mass Lesion
Authors: Abouarab Ahmed A. , Elmously Adham , Leonard Jeremy R. , Arisha Mohammed J. , Gaudino Mario , Narula Naveent , Salemi Arash
Published: February 2018

Systemic lupus erythematosus (SLE) is a major cause of nonbacterial thrombotic endocarditis (NBTE) associated with intracardiac sterile vegetations. It is rare for vegetations to present as an atrial tumor. This report describes a 48-year-old female with SLE and antiphospholipid syndrome complicated by recurrent thrombosis on anticoagulation. A large left atrial mass lesion was detected on echocardiography during a work-up for leg burning. Infective endocarditis could not be confirmed, and hence left atrial mass lesion was the most likely diagnosis. The patient was managed surgically and the pathology report revealed fibrin networks in a pattern similar to that of thrombosis, characteristic of NBTE.
Multiloculated Cavitary Primary Pulmonary Hodgkin Lymphoma: Case Series
Authors: Aljehani Yasser , Al-Saif Hind , Al-Osail Aisha , Al-Osail Emad
Published: February 2018

Primary pulmonary Hodgkin lymphoma (PPHL) is very rare and typically involves the superior portion of the lung. Pulmonary involvement is observed in 15–40% of Hodgkin lymphoma patients. Three such patients who presented with an unusual form of PPHL in radiological studies, i.e., multiloculated cavitary lesions, were admitted to our hospital. These lesions represent a new pathological and radiological feature of PPHL.
A Report of a Case Involving Body Lateropulsion with Numbness of the Ipsilesional Fingers Caused by a Small Infarction in the Dorsal Part of the Middle Medulla
Authors: Yamaoka Yumiko , Kishishita Sadahiro , Takayama Yohei , Okubo Seiji
Published: February 2018

Based on the complexity of functional anatomy, a small infarction in the medulla can produce various types of clinical symptoms or signs depending on the location of this infarction. We describe the case of a 46-year-old man who presented with sudden onset of body lateropulsion to the left side and numbness of the ipsilateral fingers. 3-tesla diffusion-weighted magnetic resonance imaging with a section thickness of 2 mm revealed a small infarction in the dorsal part of the left middle medulla. To our knowledge, this is the first case report describing vestibular dysfunction apparent upon otoelectrophysiological examination but without vestibular symptoms or signs except for body lateropulsion.
Microarray Expression Profile of Circular RNAs in Peripheral Blood Mononuclear Cells from Active Tuberculosis Patients
Authors: Huang Zi-Kun , Yao Fang-Yi , Xu Jian-Qing , Deng Zhen , Su Ri-Gu , Peng Yi-Ping , Luo Qing , Li Jun-Ming
Published: February 2018

Background/Aims: Dysregulated expression of circular RNAs (circRNAs) was demonstrated to be implicated in many diseases. Here, we aimed to determine circRNA profile in peripheral blood mononuclear cells (PBMCs) from active tuberculosis (TB) patients to identify novel biomarkers for TB. Methods: Expression profile of circRNAs in PBMCs from 3 active pulmonary TB patients and 3 healthy controls were analyzed by microarray assay. Six circRNAs were selected for validation using real time-quantitative PCR (qRT-PCR) in 40 TB patients and 40 control subjects. Receiver operating characteristic (ROC) curve was constructed to evaluate their values in TB diagnosis. Hsa_circRNA_001937 was chosen for further evaluation in an independent cohort consisting of 115 TB, 40 pneumonia, 40 COPD, 40 lung cancer patients and 90 control subjects. An eight-month follow up was performed in 20 newly diagnosed TB patients to investigate the expression change of hsa_circRNA_001937 after chemotherapy. Results: We revealed and confirmed that a number of circRNAs were dysregulated in TB patients. Of the six studied physio circRNAs, the levels of hsa_circRNA_001937, hsa_circRNA_009024 and hsa_ circRNA_005086 were significantly elevated and hsa_circRNA_102101, hsa_circRNA_104964 and hsa_circRNA_104296 were significantly reduced in PBMCs from TB patients as compared to healthy controls. ROC curve analysis suggested that hsa_circRNA_001937 has the largest area under the curve (AUC = 0.873, P<0.001). Hsa_circRNA_001937 was significantly increased in patients with TB compared with patients with pneumonia, COPD and lung cancer. Hsa_ circRNA_001937 was correlated with TB severity (r = 0.4053, P = 0.010) and its expression significantly decreased after treatment. Conclusion: This study identified a set of deregulated circRNAs in active TB PBMCs, our data also suggest that hsa_circRNA_001937 can be used as a potential diagnostic biomarker of TB.
Lycorine Suppresses Endplate-Chondrocyte Degeneration and Prevents Intervertebral Disc Degeneration by Inhibiting NF-κB Signalling Pathway
Authors: Wang Gangliang , Huang Kangmao , Dong Yangxin , Chen Shuai , Zhang Jianfeng , Wang Jiying , Xie Ziang , Lin Xianfeng , Fang Xiangqiang , Fan Shunwu
Published: February 2018

Background/Aims: Cartilaginous endplate (CEP) degeneration is an important cause for intervertebral disc (IVD) degeneration that leads to low-back pain. The identification of compounds that may prevent CEP degeneration is of interest for the prevention of IVD degeneration. Methods: Catabolic protease expression in the CEP of disc degeneration patients was first assessed. The toxicity, function and underlying mechanism of lycorine (LY) on CEP-derived chondrocytes degeneration were assessed in vitro by flow cytometry analysis and western blotting. The concentration and function of LY in rat-tail disc-degeneration models were also assessed by HPLC (High Performance Liquid Chromatography) quantification and histological analysis. Results: In CEP cells, Interleukin (IL)-1β upregulated the expression of matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 that is critical for the degradation of cartilage extracellular matrix. Interestingly, LY suppressed the expression of these enzymes via the inhibition of nuclear factor-κB (NFκB) signalling and thus prevented IL-1β-induced endplate cell degeneration in vitro. More importantly, LY also reduced the expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in CEP and exerted a protective effect on both CEP and nucleus pulposus (NP) degeneration. In addition to its inhibitory effect on matrix-degrading protease expression, LY treatment also reduced positive regulators of proinflammatory cytokines, such as MIF, which can be secreted by CEP cells and subsequently target NP cells. Conclusion: LY could serve as a potential drug for treating IVD disease.
Altered Long Noncoding RNA and Messenger RNA Expression in Experimental Intracerebral Hemorrhage - a Preliminary Study
Authors: Hanjin Cui , Tao Liu , Pengfei Li , Ali Yang , Huajun Zhou , Jiekun Luo , Yang Wang , Tao Tang
Published: February 2018

Background/Aims: Functional recovery in the chronic phase is a difficult problem in intracerebral hemorrhage (ICH) treatment. Long noncoding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in post-ICH injury and repair are poorly understood, especially those that may be attributed to long-term neurological deficit. The present study depicted the lncRNA and messenger RNA (mRNA) profile by microarray at late stage after an experimental ICH. Methods: LncRNA and mRNA microarray was used to first identify differentially expressed genes. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine bio-functions and signaling pathways, with which differentially expressed genes are most closely related. Quantitative real-time polymerase chain reaction (PCR) was used to validate the results of microarray. Finally, the lncRNA-mRNA co-expression network was constructed to find the interaction of genes. Results: A total of 625 differentially expressed lncRNAs and 826 expressed mRNAs were identified. Altered genes were enriched in mitochon-drial matrix, G-protein coupled receptor signaling pathway, and olfactory transduction, which may be associated with ICH-induced pathophysiologic changes in the long term. A co-expression network profile based on 5 validated differentially expressed lncRNAs and 205 interacted mRNAs was composed of 210 nodes and 298 connections. Conclusion: Mitochondrial matrix, reduced G-protein coupled receptor activity, and impaired olfactory transduction may be involved in the sequelae following ICH. Further, these dysregulated lncRNAs and mRNAs may be the promising therapeutic targets to overcome obstacles in functional recovery following ICH.
ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation
Authors: Alsina-Sanchís Elisenda , García-Ibáñez Yaiza , Figueiredo Ana M. , Riera-Domingo Carla , Figueras Agnès , Matias-Guiu Xavier , Casanovas Oriol , Botella Luisa M. , Pujana Miquel A. , Riera-Mestre Antoni , Graupera Mariona , Viñals Francesc
Published: February 2018

Objective—

ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-β (transforming growth factor-β) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia—a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia.

Approach and Results—

In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1
+/
−
mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1
+/
−
retinas and in turn normalize the vasculature.

Conclusions—

Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.
Interventional Treatment of Severe Tricuspid Regurgitation
Authors: Lauten Alexander , Figulla Hans R. , Unbehaun Axel , Fam Neil , Schofer Joachim , Doenst Torsten , Hausleiter Joerg , Franz Marcus , Jung Christian , Dreger Henryk , Leistner David , Alushi Brunilda , Stundl Anja , Landmesser Ulf , Falk Volkmar , Stangl Karl , Laule Michael
Published: February 2018

Background—

Transcatheter caval valve implantation is under evaluation as a treatment option for inoperable patients with severe tricuspid regurgitation (TR). The procedure involves the catheter-based implantation of bioprosthetic valves in the inferior vena cava and superior vena cava to treat symptoms associated with TR. This study is the first to evaluate the feasibility, safety, and efficacy of this interventional concept.

Methods and Results—

Twenty-five patients (mean age, 73.9±7.6 years; women, 52.0%) with severe symptomatic TR despite optimal medical treatment deemed unsuitable for surgery were treated with caval valve implantation under a compassionate clinical use program. Technical feasibility defined as procedural success, hemodynamic effect defined as venous pressure reduction, and safety defined as periprocedural adverse events were evaluated, with clinical follow-up at discharge and up to 12 months. The functional impact was evaluated by assessment of New York Heart Association class at the time of hospital discharge. The total number of valves implanted in the caval position was 31. Patients were treated with single (inferior vena cava-only; n=19; 76.0%) or bicaval valve implantation (inferior vena cava+superior vena cava; n=6; 24.0%). Either balloon-expandable valves (Sapien XT/3: n=18; 72.0%) or self-expandable valves (TricValve: n=6; 24.0%; Directflow: n=1; 4.0%) were used. Procedural success was achieved in 96% (n=24). Early and late valve migration requiring surgical intervention occurred in 1 patient each. Thirty-day and in-hospital mortality were 8% (2 of 25) and 16% (4 of 25). Causes of in-hospital mortality included respiratory (n=1) or multiple organ failure (n=3) and were not linked to the procedure. Mean overall survival in the study cohort was 316±453 days (14–1540 days).

Conclusions—

Caval valve implantation for the treatment of severe TR and advanced right ventricular failure is associated with a high procedural success rate and seems safe and feasible in an excessive-risk cohort. The study demonstrates hemodynamic efficacy with consistent elimination of TR-associated venous backflow and initial clinical improvement. These results encourage further trials to determine which patients benefit most from this interventional approach.
Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility
Authors: Mayourian Joshua , Ceholski Delaine K. , Gorski Przemek A. , Mathiyalagan Prabhu , Murphy Jack F. , Salazar Sophia I. , Stillitano Francesca , Hare Joshua M. , Sahoo Susmita , Hajjar Roger J. , Costa Kevin D.
Published: February 2018

Rationale:

The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved.

Objective:

This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies.

Methods and Results:

Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo–mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes.

Conclusions:

miR-21-5p plays a key role in hMSC-exo–mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.
Childhood Stature and Growth in Relation to First Ischemic Stroke or Intracerebral Hemorrhage
Authors: Gjærde Line Klingen , Truelsen Thomas Clement , Baker Jennifer Lyn
Published: February 2018

Background and Purpose—

Attained height, an indicator of genetic potential and childhood growth environment, is inversely associated with stroke, but the mechanisms are poorly understood. We investigated whether childhood height and growth are associated with ischemic stroke (IS) and intracerebral hemorrhage (ICH).

Methods—

In a cohort of Danish schoolchildren born 1930 to 1989, with measured height from 7 to 13 years, we investigated associations of childhood stature and growth with risks of adult IS and ICH. Cox proportional hazards regressions were performed to estimate hazard ratios (HRs) with CIs separately for women and men.

Results—

Among 311 009 individuals, 10 412 were diagnosed with IS and 2546 with ICH. Height at 7 years was inversely and significantly associated with IS in both sexes (per
z
score, equivalent to ≈5.2 cm in women and 5.1 cm in men; women: HR=0.89 [95% CI: 0.87–0.92]; men: HR=0.90 [95% CI: 0.88–0.92]) and with ICH in men (HR=0.89 [95% CI: 0.84–0.94]) but not in women (HR=0.97 [95% CI: 0.91–1.04]). Associations were similar at older childhood ages and were stable throughout the study period. No statistically significant associations for growth from 7 to 13 years were observed for IS or ICH.

Conclusions—

Short stature at 7 to 13 years is significantly associated with increased risks of IS in both sexes and with ICH in men. Growth during this period of childhood is not significantly associated with either of these stroke subtypes, suggesting that underlying mechanisms linking height with risks of stroke may exert their influence already by early childhood.
Multi-Objectivising Combinatorial Optimisation Problems by Means of Elementary Landscape Decompositions
Authors: Ceberio Josu , Calvo Borja , Mendiburu Alexander , Lozano Jose A.
Published: February 2018

In the last decade, many works in combinatorial optimisation have shown that, due to the advances in multi-objective optimisation, the algorithms from this field could be used for solving single-objective problems as well. In this sense, a number of papers have proposed multi-objectivising single-objective problems in order to use multi-objective algorithms in their optimisation. In this article, we follow up this idea by presenting a methodology for multi-objectivising combinatorial optimisation problems based on elementary landscape decompositions of their objective function. Under this framework, each of the elementary landscapes obtained from the decomposition is considered as an independent objective function to optimise. In order to illustrate this general methodology, we consider four problems from different domains: the quadratic assignment problem and the linear ordering problem (permutation domain), the 0-1 unconstrained quadratic optimisation problem (binary domain), and the frequency assignment problem (integer domain). We implemented two widely known multi-objective algorithms, NSGA-II and SPEA2, and compared their performance with that of a single-objective GA. The experiments conducted on a large benchmark of instances of the four problems show that the multi-objective algorithms clearly outperform the single-objective approaches. Furthermore, a discussion on the results suggests that the multi-objective space generated by this decomposition enhances the exploration ability, thus permitting NSGA-II and SPEA2 to obtain better results in the majority of the tested instances.
Late Pleistocene and Holocene Lithic Variability at Goda Buticha (Southeastern Ethiopia): Implications for the Understanding of the Middle and Late Stone Age of the Horn of Africa
Authors: Leplongeon Alice , Pleurdeau David , Hovers Erella
Published: February 2018

Abstracts

The Late Pleistocene is a key period to understand the shift from the Middle (msa) to the Late Stone Age (lsa) in Africa. More generally, it is also a crucial time for elucidation of changes in the technological behaviours of human populations in Africa after the main Out of Africa event of modern humans ca. 60-50 thousand years ago. However, the archaeological record for this period is relatively poor, particularly for the Horn of Africa. Here we present a detailed analysis of the lithic assemblages from Goda Buticha (gb), a cave in southeastern Ethiopia, which has yielded a long stratigraphic sequence including Late Pleistocene and Holocene levels. This study (1) contributes to a better knowledge of the latemsain the Horn of Africa; (2) documents a late Holocenelsalevel (gb– Complexi); (3) highlights the presence ofmsacharacteristics associated withlsafeatures in the Holocene (gb– Layeriic). This adds to the emerging record of great lithic technological variability during the Late Pleistocene and Holocene in this region.
The Rock Art of Northeast Africa: Methodological Achievements and Perspectives of Further Research
Authors: Varadzinová Lenka
Published: February 2018

There are two essential points in any rock-art research: time and meaning. The former constitutes the basic precondition for an effective study of the evidence, while the understanding of the latter is the ultimate objective of the research. This paper starts with an overview of the methodological achievements of rock-art research in Northeast Africa concerning the dating and understanding of the original meaning of regional rock art. Subsequently, it focuses on theunintentionalsignificance of rock art and discusses several themes worthy of elaboration but little explored so far. All of them unfold from two simple questions – “where” and “who” – with a view to outreaching from the imagery itself to the people who stood behind it to obtain social and other testimonies on the artists and their worlds – testimonies they themselves might have been unaware of or unwilling to give.