bluuebunny/crossref_metadata_2025 huggingface dataset:
ASP5878, a Novel Inhibitor of FGFR1, 2, 3, and 4, Inhibits the Growth of FGF19-Expressing Hepatocellular Carcinoma
Authors: Futami Takashi , Okada Hidetsugu , Kihara Rumi , Kawase Tatsuya , Nakayama Ayako , Suzuki Tomoyuki , Kameda Minoru , Shindoh Nobuaki , Terasaka Tadashi , Hirano Masaaki , Kuromitsu Sadao
Published: November 2016

Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19–expressing hepatocellular carcinoma cell lines Hep3B2.1-7, HuH-7, and JHH-7. In the Hep3B2.1-7 cell line, ASP5878 inhibited the phosphorylation of fibroblast growth factor receptor 4 and its downstream signaling molecules as well as induced apoptosis. Oral administration of ASP5878 at 3 mg/kg induced sustained tumor regression in a subcutaneous xenograft mouse model using Hep3B2.1-7. In HuH-7, an orthotopic xenograft mouse model, ASP5878 induced complete tumor regression and dramatically extended the survival of the mice. These results suggest that ASP5878 is a potentially effective therapeutic agent for hepatocellular carcinoma patients with tumors expressing fibroblast growth factor 19. Mol Cancer Ther; 16(1); 68–75. ©2016 AACR.
Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma
Authors: Haak Andrew J. , Appleton Kathryn M. , Lisabeth Erika M. , Misek Sean A. , Ji Yajing , Wade Susan M. , Bell Jessica L. , Rockwell Cheryl E. , Airik Merlin , Krook Melanie A. , Larsen Scott D. , Verhaegen Monique , Lawlor Elizabeth R. , Neubig Richard R.
Published: November 2016

Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971–mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC–expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics. Mol Cancer Ther; 16(1); 193–204. ©2016 AACR.
Abstract A10: A Cdk4-dependent phosphorylation threshold regulates the cell cycle entry decision
Authors: Kaulich Manuel , Dowdy Steven
Published: November 2016

Cyclin-dependent kinases (Cdk's) are major cell cycle regulators and uncontrolled cell cycle entry is a hallmark of cancer. Cyclin D, the regulatory subunit of Cdk4, is misregulated in about 75% of human malignancies, leading to hyperactive Cdk4 and uncontrolled cell cycle entry. In sharp contrast, the total loss of Cyclin D-mediated activity results in permanent cell cycle arrest. Several functions of Cdk4 during cell cycle entry have been identified; however, the underlying mechanism for cell cycle arrest upon its inactivation remains unanswered. Here we employed CRISPR/Cas9 and rAAV-mediated gene editing to visualize Restriction Point passage in highly synchronized single cells and find that cyclin D:Cdk4/6 complexes perform a critical switch-like function that results in activation of cyclin E:Cdk2 complexes. Taken together, our data indicate that while cyclin E:Cdk2 is the rate-limiting step for transition across the Restriction Point, it is dependent on cyclin D:Cdk4/6 phosphorylation of an as of yet unknown molecule.

Citation Format: Manuel Kaulich, Steven Dowdy. A Cdk4-dependent phosphorylation threshold regulates the cell cycle entry decision. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A10.
Abstract A13: A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation
Authors: Parker Danitra , Mitra Kasturi
Published: November 2016

Cyclin E is indispensable for release from quiescence. However, the regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynamin related protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-cell-density environments elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events. Ref. JCS,(2015), 128, 4171-4182.

Citation Format: Danitra Parker, Kasturi Mitra. A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A13.
Abstract A18: G1 cell cycle arrest is required for invasive behavior
Authors: Kohrman Abraham Q. , Chandhok Mana , Zhang Wan , Matus David Q.
Published: November 2016

The ability for a cell to breach the surrounding basement membrane and adopt an invasive phenotype is a critical, but poorly understood step in the progression of cancer. Like many aspects of cancer cell behavior, the genetic programs that regulate invasive behavior are likely shared with normal cell biological processes, as invasion occurs during embryonic development and immune surveillance. Due to difficulties of studying this dynamic behavior in vivo, elucidating the genetic and epigenetic controls of cell invasive activity has been difficult. Our laboratory uses a unique in vivo model to examine cell invasion that combines functional genomic and genetic tools with single-cell high resolution visual analyses. We examine anchor cell (AC) invasion into the vulval epithelium during the larval development of the model roundworm, C. elegans. Our data functionally links G1 cell cycle arrest to acquisition of invasive behavior. Previously we have identified that a single transcription factor, the conserved nuclear hormone receptor nhr-67 (NR2E1/TLX) is required in the AC to prevent the invasive AC from entering the cell cycle. NHR-67 maintains the AC in G1 cell cycle arrest, in part through upregulation of the cyclin-dependent kinase inhibitor cki-1 (p21CIP1/p27Kip1). Loss of nhr-67 results in non-invasive mitotic ACs that fail to express matrix metalloproteinases (MMPs) and actin regulators or form invadopodia, F-actin rich membrane-localized protrusions that are required for invasion. Strikingly, AC invasion can be rescued through induction of G1 arrest, preventing cell division and promoting differentiation. Downstream of G1 arrest, the AC requires the activity of the conserved histone deacetylase HDA-1, a key regulator of cell differentiation, to regulate the expression of pro-invasive genes and localize invadopodia. Through loss-of-function RNA interference (RNAi) screening, we have identified new cell cycle regulatory components (lin-35/RB, skr-2/SKP1, cdc-14/CDC14A, cul-1/ Cullin-1 and cul-4/ Cullin-4B) and epigenetic modifiers (let-418/Mi-2/CHD3 and Swi/snf-components) that function with cki-1 and hda-1, respectively, to maintain G1 cell cycle arrest and differentiate the invasive phenotype. Together our results suggest that the acquisition of the invasive phenotype is a post-mitotic differentiated state, which may help explain the paradoxical reports that the invasive fronts of many metastatic cancers are non-proliferative.

Citation Format: Abraham Q. Kohrman, Mana Chandhok, Wan Zhang, David Q. Matus. G1 cell cycle arrest is required for invasive behavior. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr A18.
Abstract B24: Ataxia-telangiectasia and Rad3-related (ATR) phosphorylation as a pharmacodynamic biomarker of ATR activation in solid tumor tissue models
Authors: Wilsker Deborah , Marrero Allison M. , Dull Angie , Pfister Thomas D. , Lawrence Scott M. , Carter John , Gottholm-Ahalt Michelle , Hollingshead Melinda , Doroshow James , Parchment Ralph E. , Kinders Robert J.
Published: November 2016

Inhibitors of checkpoint kinases, such as ATR, Chk1 or Wee1, in combination with cytotoxic agents could enhance therapeutic efficacy compared to monotherapy, and these combination approaches are currently being extensively explored. The presence of replicative stress or deregulated S-phase in cancer has been recognized as a rationale for the use of ATR and Chk1 inhibitors with chemotherapy and efforts are underway to define genetic determinants that sensitize cancer cells to ATR inhibition. Pharmacodynamic (PD) biomarkers of drug activity are valuable tools in clinical trials using targeted agents to determine whether each investigational agent is acting upon its intended target, the expected intracellular signaling pathways are modulated, and the dosage regimen and sequencing are optimal. In addition, investigations of the potential effects of cell cycle distribution within the tumor (in animal models) on drug efficacy may point to alternative dosing regimens. The first clinical trials evaluating inhibitors of the ataxia telangiectasia and Rad3-related kinase (ATR) in combination with cytotoxic agents are enrolling patients. The current method for quantifying ATR inhibition used in preclinical in vitro and in vivo models is via indirect measurement of downstream effector proteins, such as phosphorylated Chk1, rather than measurement of direct target engagement. We propose that an immunofluorescence microscopy assay of ATR autophosphorylation status as a biomarker of DNA damage activation combined with measurement of the downstream effector proteins will reveal more specific information about target engagement and intended PD effect than would be obtained from a single-biomarker assay. Here we propose that the measurement of ATR pT1989, Chk1 pS345 and γH2AX by validated quantitative immunofluorescence assays will be useful in PD evaluation of tumor responses in clinical trials as a biomarker for ATR pathway activation or inhibition. In addition, evaluation of the variability of expression of activated ATR in tumor models of different histologies may provide valuable insight into tumor types likely to be sensitive to ATR inhibitors.

Citation Format: Deborah Wilsker, Allison M. Marrero, Angie Dull, Thomas D. Pfister, Scott M. Lawrence, John Carter, Michelle Gottholm-Ahalt, Melinda Hollingshead, James Doroshow, Ralph E. Parchment, Robert J. Kinders. Ataxia-telangiectasia and Rad3-related (ATR) phosphorylation as a pharmacodynamic biomarker of ATR activation in solid tumor tissue models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B24.
Abstract B31: Sulindac inhibition of tumor cell transformation
Authors: Liang Zhipin , Feng Xiangling , Chang Hong , Yi Bin , Ma Ruixia , Xi Yaguang
Published: November 2016

Cell transformation is the process in which normal cells acquire the properties of cancer. Sulindac Sulfide (SS) is one of non-steroidal anti-inflammatory drugs (NSAIDs), and its anticancer activity in prevention of tumor occurrence and progression has been documented in various human cancers. In this study, we observed the anti-transformative activity of SS in NIH/3T3 cells by using a two-stage transformation assay induced by the carcinogens, 3-methylcholanthrene (MCA) and 2-O-tetradecanoylphorbol-13-acetate (TPA) in which foci formation is used to characterize the transformed cells. We found that SS could inhibit foci formation by attenuation of TPA's promotive effect. K-Ras was upregulated in the transformed cells, while SS treatment could selectively inhibit the growth of transformed cell in which K-Ras was suppressed significantly. Loss-of-function study demonstrated that knockdown of K-Ras in NIH/3T3 cells could significantly reduce foci formation, which support that K-Ras might be one of the key targets involved in SS inhibiting tumor cell transformation. When studying the mechanism by which SS regulates K-Ras, we triggered two tumor suppressor miRNAs, let-7b and let-7g, which were previously reported to target K-Ras and repress its expression through the post-transcriptional or translational modulation. We found that let-7b and let-7g could be upregulated in the transformed cells by SS treatment. However, the inhibitory effect of SS on foci formation was significantly attenuated when let-7b and let-7g were knocked down by CRISPR/cas9. In parallel, K-Ras maintained static expression in the transformed cells, regardless of SS treatment. These results suggest that upregulation of let-7b and let-7g is the key step for SS to inhibit tumor transformation. In addition, we demonstrated that SS could suppress the expression of Lin28 that interacts with let-7 through a documented feedback loop. Given our previous studies reporting that SS was able to inhibit the transcriptional activity of NF-kappaB that is involved in regulation of Lin28 expression, our study demonstrates that the NF-kappaB/Lin28/Let-7/K-Ras axis addresses a new mechanism responsible for anti-transformative activity of SS. These results will provide novel insights into understanding the mechanisms involved in tumorigenesis and benefiting identification of new targets for drug development in prevention of tumor progression. This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC).

Citation Format: Zhipin Liang, Xiangling Feng, Hong Chang, Bin Yi, Ruixia Ma, Yaguang Xi. Sulindac inhibition of tumor cell transformation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B31.
Abstract B32: Oncogenic role of snoRD93 in breast cancer cells
Authors: Ma Ruixia , Zhao Hongyou , Patterson Dillon , Borchert Glen , Xi Yaguang
Published: November 2016

Noncoding RNAs (ncRNAs) play key roles in many essential processes of human diseases through regulating gene expression. Small nucleolar RNA (snoRNA) is a relatively large group of ncRNAs with diversified functions in mammalian cells, although many of them have not been well-characterized. Recent studies have revealed the alterations of different snoRNAs in prostate, breast, and lung malignancies; however, their mechanistic roles in tumorigenesis and progression have not been well-studied yet. In this study, we compared the transcriptome profiles of human breast cancer cell lines, MCF-7 and MDA-MB-231, by using the next generation sequencing (NGS). MCF-7 cells were derived from the primary breast tumor, while MDA-MB-231 cells are highly metastatic. Our sequencing results showed that 13 snoRNAs was significantly overexpressed in MDA-MB-231 cells versus MCF-7 cells. In particular, we are interested in snoRD93, given its expression showing 27-time higher in MDA-MB-231 cells than MCF-7 cells. We further studied the oncogenic role of snoRD93 in MDA-MB-231 cells by using loss-of-function strategy. By employing cell viability assay, we found that the repression of snoRD93 by transfection of the antisense inhibitors could significantly inhibit the tumor cell growth. In addition, downregulation of snoRD93 could result in relatively low motility of MDA-MB-231 cells as shown in the matrigel invasion assay. Therefore, our data support the oncogenic role of snoRD93 in breast cancer cells and suggest that snoRD93 can be triggered a potential target for development of new anticancer drugs.

Citation Format: Ruixia Ma, Hongyou Zhao, Dillon Patterson, Glen Borchert, Yaguang Xi. Oncogenic role of snoRD93 in breast cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B32.
Abstract B33: The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473
Authors: Jiao Xuanmao , Chen Ke , Xu Shaohua , Ju Xiaoming , Ertel Adam , Tian Lifeng , Yu Zuoren , Sante Gabriele Di , Wang Min , Li Zhiping , Pestell Timothy , Casimiro Mathew , Shen Duanwen , Achilefu Samuel , Pestell Richard
Published: November 2016

The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, growth and cellular migration. Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates pRb, to promote cell cycle progression and functions as a nuclear collaborative oncogene. Herein, genetic deletion of cyclin D1 reduced and overexpression induced Akt1 activity in tissue culture and in vivo. Endogenous cyclin D1 augmented both the rate of onset and maximal cellular Akt1 activity. The cytoplasmic membrane-associated pool of cyclin D1, augmented Akt1 kinase activity, to thereby induce cell cycle progression, cellular migration, proliferation and contact independent growth. The induction of Akt1 kinase activity, via Ser 473, was dependent upon a single residue of cyclin D1 (K112) in vitro, and in vivo in mammary epithelial cell targets tissue specific transgenic mice. Distinct subcellular compartments of cell cycle proteins convey distinct functions to augment cellular growth.

Our data identified the function of the membrane associated cyclin D1 pool is to phosphorylate and activate AKT1, thereby, inducing cell cycle progression, contact independent growth and cellular migration. Membrane mounted cyclin D1 is a novel targetable vulnerability aberrant growth control.

Citation Format: Xuanmao Jiao, Ke Chen, Shaohua Xu, Xiaoming Ju, Adam Ertel, Lifeng Tian, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy Pestell, Mathew Casimiro, Duanwen Shen, Samuel Achilefu, Richard Pestell. The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B33.
Abstract IA07: Targeting the cyclin D-CDK4/6 pathway for cancer therapy
Authors: Abraham Robert T.
Published: November 2016

The cyclin D-CDK4/6 kinase complex plays a pivotal role in the stimulation of cellular proliferation through phosphorylation and functional inactivation of the retinoblastoma protein (pRb), which leads to commitment of G1-phase cells to enter S phase, and ultimately to complete the mitotic cell cycle. Cancer cells frequently escape normal constraints on cell proliferation via persistent inactivation of pRb, through dysregulation of cyclin D-CDK4/6 kinase activity or loss of pRb expression. Interestingly, estrogen-positive (ER+) breast cancer cells rarely show loss of pRb, and hence rely on inappropriate activation of cyclin D-CDK4/6 to drive malignant proliferation. ER+ breast cancer therefore represents an enriched patient population in which to test the efficacy of cyclin D-CDK4/6 inhibition as a therapeutic strategy. Palbociclib, a selective cyclin D-CDK4/6 inhibitor, was approved by the FDA in 2015 for the treatment of women with advanced ER+/HER2- breast cancer. The drug is administered in combination with an anti-hormonal agent, which underscores the critical, collaborative roles of dysregulated estrogen receptor and cyclin D-CDK4/6 activities in driving tumor growth in this breast cancer subtype. This presentation will review the cellular pharmacology of palbociclib, with a particular emphasis on the phenotypic outcomes of combined estrogen receptor and cyclin D-CDK4/6 inhibition in human breast cancer cell lines. In addition, we will provide an update on the clinical activities of palbociclib in breast cancer, as well as prospects for therapeutic targeting of cyclin D-CDK4/6 activity in other cancer subtypes.

Citation Format: Robert T. Abraham. Targeting the cyclin D-CDK4/6 pathway for cancer therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA07.
Abstract IA09: A drug delivery method selective for senescent cells
Authors: Serrano Manuel
Published: November 2016

The accumulation of senescent cells occurs in multiple human degenerative pathologies and are also present within tumors. Senescent cells, although not proliferating, are very active in secreting cytokines that may fuel the growth of tumor cells. Therefore, the selective elimination of senescent cells may bring benefits to the treatment of many diseases, including cancer. I will present a strategy to selective deliver drugs to senescent cells in vivo.

Citation Format: Manuel Serrano. A drug delivery method selective for senescent cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA09.
Abstract IA16: Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer
Authors: Leone Gustavo W.
Published: November 2016

E2F transcriptional activators and repressors regulate cell cycle-dependent gene expression. Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output we show that mouse development is relatively insensitive to alterations in E2F levels and composition. However, modest increases in E2F output resulted in spontaneous hepatocellular carcinoma (HCC) without additional organ involvement, whereas decreases protected against HCC. Cell type- and temporal-specific gene ablation strategies defined a cell-autonomous oncogenic role for E2F1/3B and a tumor suppressor role for E2F7/8 in hepatocytes. Genetic, biochemical and profiling studies suggest a mechanism involving E2F1/3B-mediated activation and E2F7/8-mediated repression of a common set of targets during early post-natal liver development, which are associated with HCC progression. Thus, while overall development is sufficiently robust, the liver is uniquely sensitive to perturbations in E2Fs. In summary, we identified the critical network components in immature hepatocytes that control E2F output and foster a cancer-free life span.

Citation Format: Gustavo W. Leone. Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA16.
Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women
Authors: Thurston Rebecca C. , Chang Yuefang , Barinas-Mitchell Emma , Jennings J. Richard , Landsittel Doug P. , Santoro Nanette , von Känel Roland , Matthews Karen A.
Published: November 2016

Background and Purpose—

There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations.

Methods—

A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of intima media thickness and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol.

Results—

More frequent physiologic hot flashes were associated with higher carotid intima media thickness (for each additional hot flash: β [SE]=0.004 [0.001];
P
=0.0001; reported hot flash: β [SE]=0.008 [0.002];
P
=0.002, multivariable) and plaque (eg, for each additional hot flash, odds ratio [95% confidence interval] plaque index ≥2=1.07 [1.003–1.14];
P
=0.04, relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors.

Conclusions—

Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman’s vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women.
Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times)
Authors: Ganesh Aravind , Al-Ajlan Fahad S. , Sabiq Farahna , Assis Zarina , Rempel Jeremy L. , Butcher Kenneth , Thornton John , Kelly Peter , Roy Daniel , Poppe Alexandre Y. , Jovin Tudor G. , Devlin Thomas , Baxter Blaise W. , Krings Timo , Casaubon Leanne K. , Frei Donald F. , Choe Hana , Tampieri Donatella , Teitelbaum Jeanne , Lum Cheemun , Mandzia Jennifer , Phillips Stephen J. , Bang Oh Young , Almekhlafi Mohammed A. , Coutts Shelagh B. , Barber Philip A. , Sajobi Tolulope , Demchuk Andrew M. , Eesa Muneer , Hill Michael D. , Goyal Mayank , Menon Bijoy K.
Published: November 2016

Background and Purpose—

Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

Methods—

The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I–III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days.

Results—

From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [
P
=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11–0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09–0.74; adjusted for age, type of treatment, and follow-up scan).

Conclusions—

INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01778335.
The “Bolotnoe Affair” and the Implementation of the Right to Freedom of Assembly in the Russian Federation
Authors: Riekkinen Mariya
Published: November 2016

A series of protests across Russia, triggered by procedural violations during the 2011 parliamentary elections and results of the 2012 presidential elections, culminated on 6 May 2012 with a demonstration at Bolotnaia Square in Moscow. That demonstration led to violent clashes between protesters and the police. The dispersal of this demonstration and the subsequent criminal and administrative trials conducted against some of the protesters, as well as the controversy regarding the severity of some of the penalties imposed by the courts, became known as the Bolotnoe Affair. The Bolotnoe Affair is analyzed from the perspective of implementing the right to freedom of assembly in Russia. The main goal is to conduct a contextual legal analysis clarifying whether the right to freedom of assembly is adequately implemented in the legal order of the Russian Federation, in order to illustrate whether the protesters in the Bolotnoe Affair were able to express their opinions with regard to the procedure and results of the elections. The leading court cases relevant to the participatory rights of the protesters as exemplified by the appellate decisions of the Moscow City Court will also be examined. In particular, twelve decisions of the Moscow City Court during the period 2012–2014 (full texts of which are reproduced in publicly available legal databases) are reviewed, as well as two recent judgments in European Court of Human Rights (ECtHR) cases closely related to these earlier cases. Analyzing the Moscow City Court decisions vis-à-vis the judgments of the ECtHR, the author concludes that the Moscow City Court’s rulings did not conform with the provisions of the European Convention on Human Rights (echr) regarding the right to freedom of assembly and the right to liberty.
Exercise and Time Perception: An Exploration of the Impact of High Intensity Cardio Exercise (Zumba) on Human Timing
Authors: Pillai Jeevita S. , McLoughlin Aoife
Published: November 2016

Time is an important aspect of people’s lives and how it is perceived has a great impact on how we function, which includes whether we engage in activities such as exercise that are beneficial for our health. These activities can also have impact on our experience of time. The current study aims to investigate human interval timing after completion of one of two tasks: listening to an audiobook, or engaging in a Zumba workout. Participants in this study completed two temporal bisection tasks (pre and post intervention). Bisection points (point of subjective equality) and Weber’s ratios (sensitivity to time) were examined. It was hypothesised that individuals in the Zumba condition would experience a distortion in their timing post workout consistent with an increase in pacemaker speed. Unexpectedly there appeared to be no significant difference in bisection points across or within (pre/post) the conditions, suggesting that neither intervention had an impact on an internal pacemaker. However, there were significant differences in sensitivity to timing after Zumba Fitness suggesting a potential attentional focus post workout. Implications and future directions are also discussed.
Temporal Expectation Indexed by Pupillary Response
Authors: Akdoğan Başak , Balcı Fuat , van Rijn Hedderik
Published: November 2016

Forming temporal expectations plays an instrumental role for the optimization of behavior and allocation of attentional resources. Although the effects of temporal expectations on visual attention are well-established, the question of whether temporal predictions modulate the behavioral outputs of the autonomic nervous system such as the pupillary response remains unanswered. Therefore, this study aimed to obtain an online measure of pupil size while human participants were asked to differentiate between visual targets presented after varying time intervals since trial onset. Specifically, we manipulated temporal predictability in the presentation of target stimuli consisting of letters which appeared after either a short or long delay duration (1.5 vs. 3 s) in the majority of trials (75%) within different test blocks. In the remaining trials (25%), no target stimulus was present to investigate the trajectory of preparatory pupillary response under a low level of temporal uncertainty. The results revealed that the rate of preparatory pupillary response was contingent upon the time of target appearance such that pupils dilated at a higher rate when the targets were expected to appear after a shorter as compared to a longer delay period irrespective of target presence. The finding that pupil size can track temporal regularities and exhibit differential preparatory response between different delay conditions points to the existence of a distributed neural network subserving temporal information processing which is crucial for cognitive functioning and goal-directed behavior.
Moist Formulations of the Eliassen–Palm Flux and Their Connection to the Surface Westerlies
Authors: Dwyer John G. , O’Gorman Paul A.
Published: November 2016

The Eliassen–Palm (EP) flux is an important diagnostic for wave propagation and wave–mean flow interaction in the atmosphere. Here, two moist formulations of the EP flux are compared with the traditional dry EP flux, and their links to the surface westerlies are analyzed using reanalysis data and simulations with GCMs. The first moist formulation of the EP flux modifies only the static stability to account for latent heat release by eddies, while the second moist formulation simply replaces all potential temperatures with equivalent potential temperatures. For reanalysis data, the peak upward EP flux in the lower troposphere is farther equatorward and stronger when the moist formulations are used, with greater changes for the second moist formulation. The moist formulations have the advantage of giving a closer relationship over the seasonal cycle between the latitudes of the peak surface westerlies and the peak upward EP flux. In simulations with a comprehensive GCM, the dry and moist upward EP fluxes shift poleward by a similar amount as the climate warms. In simulations over a wider range of climates with an idealized GCM, the surface westerlies can shift both poleward and equatorward with warming, and they are influenced by an anomalous region of dry EP flux divergence near the subtropical jet. Using moist EP fluxes weakens this anomalous divergence in the idealized GCM simulations, and the shifts in the surface westerlies can then be understood through changes in the preference for equatorward or poleward wave propagation.
Influence of the Ocean and Greenhouse Gases on Severe Drought Likelihood in the Central United States in 2012
Authors: Rupp David E. , Li Sihan , Mote Philip W. , Massey Neil , Sparrow Sarah N. , Wallom David C. H.
Published: November 2016

The impacts of sea surface temperature (SST) anomalies and anthropogenic greenhouse gases on the likelihood of extreme drought occurring in the central United States in the year 2012 were investigated using large-ensemble simulations from a global atmospheric climate model. Two sets of experiments were conducted. In the first, the simulated hydroclimate of 2012 was compared to a baseline period (1986–2014) to investigate the impact of SSTs. In the second, the hydroclimate in a world with 2012-level anthropogenic forcing was compared to five “counterfactual” versions of a 2012 world under preindustrial forcing. SST anomalies in 2012 increased the simulated likelihood of an extreme summer precipitation deficit (e.g., the deficit with a 2% exceedance probability) by a factor of 5. The likelihood of an extreme summer soil moisture deficit increased by a similar amount, due in great part to a large spring soil moisture deficit carrying over into summer. An anthropogenic impact on precipitation was detectable in the simulations, doubling the likelihood of what would have been a rainfall deficit with a 2% exceedance probability under preindustrial-level forcings. Despite this reduction in rainfall, summer soil moisture during extreme drought was essentially unaffected by anthropogenic forcing because of 1) evapotranspiration declining roughly one-to-one with a decrease in precipitation due to severe water supply constraint and despite higher evaporative demand and 2) a decrease in stomatal conductance, and therefore a decrease in potential transpiration, with higher atmospheric CO2 concentrations.
In attesa di riscontro: Postille a Scotellaro
Authors: Manica Raffaele
Published: November 2016

Il saggio indaga nell'ottica di ciò che rimane di Scotellaro anche in rapporto al vicinato tra “cugini” socialisti e comunisti, dove emerge prioritariamente una componente psicologica. Sembra che il progetto letterario di Scotellaro abbia funzionato meglio nella sua prosa e torna emblematico il giudizio di Amelia Rosselli su Contadini del Sud. Partendo da un'indicazione di Pasolini sulla lingua, in verità frettolosa, vengono proposte notazioni puntuali. Penetrante l'indagine circa la presenza scotellariana nelle antologie e specie in “Quarta Generazione”.
Critical Essay: Meta-analysis: A critical realist critique and alternative
Authors: Brannan Matthew J , Fleetwood Steve , O’Mahoney Joe , Vincent Steve
Published: November 2016

Meta-analysis has proved increasingly popular in management and organization studies as a way of combining existing empirical quantitative research to generate a statistical estimate of how strongly variables are associated. Whilst a number of studies identify technical, procedural and practical limitations of meta-analyses, none have yet tackled the meta-theoretical flaws in this approach. We deploy critical realist meta-theory to argue that the individual quantitative studies, upon which meta-analysis relies, lack explanatory power because they are rooted in quasi-empiricist meta-theory. This problem, we argue, is carried over in meta-analyses. We then propose a ‘critical realist synthesis’ as a potential alternative to the use of meta-analysis in organization studies and social science more widely.
The Complexity of Immigrant Generations: Implications for Assessing the Socioeconomic Integration of Hispanics and Asians
Authors: Duncan Brian , Trejo Stephen J.
Published: November 2016

Because of data limitations, virtually all studies of later-generation descendants of immigrants rely on subjective measures of ethnic self-identification rather than arguably more objective measures based on the countries of birth of the respondent and his ancestors. In this context, biases can arise from “ethnic attrition” (e.g., U.S.-born individuals who do not self-identify as Hispanic despite having ancestors who were immigrants from a Spanish-speaking country). Analyzing 2003–2013 data from the Current Population Survey (CPS), the authors show that such ethnic attrition is sizeable and selective for the second- and third-generation populations of key Hispanic and Asian national origin groups. In addition, the results indicate that ethnic attrition generates measurement biases that vary across groups in direction as well as magnitude, and that correcting for these biases is likely to raise the socioeconomic standing of the U.S.-born descendants of Hispanic immigrants relative to their Asian counterparts.
Food insecurity and social work: A comprehensive literature review
Authors: Burgess Danielle , Shier Micheal L
Published: November 2016

This study provides a comprehensive literature review of food insecurity in social work. A search of peer-reviewed scholarly articles yielded 1686 abstracts with relevance to food insecurity. While there has been a rapid increase in the number of articles written on the topic of food insecurity since 1955, there has been a disproportionate interest in the issue in the Global North. The authors found that the literature clustered around five key themes: food access, food insecurity for vulnerable groups, food policy, food systems and interventions. Relevance of these findings to social work practice and recommendations for future research are discussed.
The Role of Pannexin 3 in Bone Biology
Authors: Ishikawa M. , Yamada Y.
Published: November 2016

Cell–cell and cell–matrix communications play important roles in both cell proliferation and differentiation. Gap junction proteins mediate signaling communication by exchanging small molecules and dramatically stimulating intracellular signaling pathways to determine cell fate. Vertebrates have 2 gap junction families: pannexins (Panxs) and connexins (Cxs). Unlike Cxs, the functions of Panxs are not fully understood. In skeletal formation, Panx3 and Cx43 are the most abundantly expressed gap junction proteins from each family. Panx3 is induced in the transient stage from the proliferation and differentiation of chondrocytes and osteoprogenitor cells. Panx3 regulates both chondrocyte and osteoblast differentiation via the activation of intracellular Ca2+ signaling pathways through multiple channel activities: hemichannels, endoplasmic reticulum (ER) Ca2+ channels, and gap junctions. Moreover, Panx3 also inhibits osteoprogenitor cell proliferation and promotes cell cycle exit through the inactivation of Wnt/β-catenin signaling and the activation of p21. Panx3-knockout (KO) mice have more severe skeletal abnormalities than those of Cx43-KO mice. A phenotypic analysis of Panx3-KO mice indicates that Panx3 regulates the terminal differentiation of chondrocytes by promoting vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) 13. Based on the generation of Panx3-/-; Cx43-/- mice, Panx3 is upstream of Cx43 in osteogenesis. Panx3 promotes Cx43 expression by regulating Wnt/β-catenin signaling and osterix expression. Further, although Panx3 can function in 3 ways, Cx43 cannot function through the ER Ca2+ channel, only via the hemichannels and gap junction routes. In this review, we discuss the current knowledge regarding the roles of Panx3 in skeletal formation and address the potential for new therapies in the treatment of diseases and pathologies associated with Panx3, such as osteoarthritis (OA).
An unusual lethal gunshot wound to the head
Authors: Shaqiri Elmas , Xhemali Bledar , Ismaili Zija , Sinamati Admir , Vyshka Gentian
Published: November 2016

Atypical gunshot wounds present a challenge for the forensic expert, and sometimes differentiating these from a blunt trauma can be difficult. A careful crime scene investigation can be helpful in finding additional evidence and clarifying the nature of the injuries. We describe a case of an unusual craniocerebral injury that was initially interpreted as a blow from a wooden object. The appearance of the wound lacked the classical characteristics of entrance and exit bullet wounds, but the investigation showed it was due to the ricocheting of a destabilized bullet. Potentially lethal, craniocerebral gunshot injuries are a common occurrence in developing countries even in non-conflict areas, with very bad outcomes even when treated aggressively in specialized neurosurgical facilities. The authors briefly discuss similar cases and opinions in the relevant literature, emphasizing the importance of a rational approach during the reconstruction of the crime scene.
Pattern of unnatural deaths among children: An autopsy study
Authors: Athani Praveen , Hugar Basappa S , Harish S , Girishchandra YP
Published: November 2016

This study was conducted at the M. S. Ramaiah Medical College, Bangalore, between October 2007 and September 2009 to analyse the age and sex distribution of unnatural deaths in children, patterns and manner of death. Detailed information regarding the circumstances of death was sought from the relatives, friends and police. The scene of occurrence was visited, and photographs of the scene of occurrence were examined in relevant cases. Unnatural deaths in children constituted 6.62% of the total autopsies conducted. The majority of childhood deaths were in the age group of 15–18 years of both sexes constituting 46.88%. Males constituted 55.22% of cases. Suicide accounted for 40.63% of the cases. Most children committed suicide by hanging (82.05%). The main reason was academic failure and some of the cases were accidental (48.96%). Road traffic accidents accounted for 26.04% of the cases, where most children were pedestrians (56%). Drowning accounted for 15.63% of the cases. Most of the children drowned while playing near ponds (83.33%). Homicide accounted for 9.36% of the cases – either killed by their mother as part of a pedicide–suicide event or by the father, and in two cases the children were sexually abused before being killed.