bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Polyploidy by Histone Deacetylase Inhibitor: A Pathway for Antitumor Effects
Authors: Xu Wei-Sheng , Perez Gisela , Ngo Lang , Gui Chang-Yun , Marks Paul A. 
Published: July 2017

Abstract
Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21WAF1−/− or HCT116 p53−/− cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21WAF1 or p53 genes.
Lysosomes as Targets for Cancer Therapy
Authors: Fehrenbacher Nicole , Jäättelä Marja 
Published: July 2017

Abstract
Tumor invasion and metastasis are associated with altered lysosomal trafficking and increased expression of the lysosomal proteases termed cathepsins. Emerging experimental evidence suggests that such alterations in lysosomes may form an “Achilles heel” for cancer cells by sensitizing them to death pathways involving lysosomal membrane permeabilization and the release of cathepsins into the cytosol. Here, we highlight recent results on cancer-related changes in the composition and function of lysosomes, focusing on possible implications for the development of novel cancer therapeutics that target tumor cell lysosomes.
Cancer Chemotherapy by Deoxynucleotide Depletion and E2F-1 Elevation
Authors: Wang Ajin , Li Chiang J. , Reddy Prem V. , Pardee Arthur B. 
Published: July 2017

Abstract
We propose that the lethality of commonly used anticancer drugs, e.g., methotrexate and cis-platinum are due, at least in part, to an increase of the E2F-1–mediated apoptotic cascade. The drugs directly or indirectly decrease deoxynucleoside triphosphates. The E2F family acts to provide control of S phase by transcribing genes required for deoxynucleoside triphosphate and DNA synthesis. Thus, a mechanism for control of E2F-1 is essential, a signal safeguarding against aberrant or uncontrolled cell proliferation. We have proposed a feedback control by NTPs that down-regulates E2F-1. Here, we provide evidence in support of this hypothesis.
HYAL1 Hyaluronidase in Prostate Cancer: A Tumor Promoter and Suppressor
Authors: Lokeshwar Vinata B. , Cerwinka Wolfgang H. , Isoyama Tadahiro , Lokeshwar Bal L. 
Published: July 2017

Abstract
Hyaluronidases degrade hyaluronic acid, which promotes metastasis. HYAL1 type hyaluronidase is an independent prognostic indicator of prostate cancer progression and a biomarker for bladder cancer. However, it is controversial whether hyaluronidase (e.g., HYAL1) functions as a tumor promoter or as a suppressor. We stably transfected prostate cancer cells, DU145 and PC-3 ML, with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector DNA. HYAL1-AS transfectants were not generated for PC-3 ML because it expresses little HYAL1. HYAL1-S transfectants produced ≤42 milliunits (moderate overproducers) or ≥80 milliunits hyaluronidase activity (high producers). HYAL1-AS transfectants produced &lt;10% hyaluronidase activity when compared with vector transfectants (18-24 milliunits). Both blocking HYAL1 expression and high HYAL1 production resulted in a 4- to 5-fold decrease in prostate cancer cell proliferation. HYAL1-AS transfectants had a G2-M block due to decreased cyclin B1, cdc25c, and cdc2/p34 expression and cdc2/p34 kinase activity. High HYAL1 producers had a 3-fold increase in apoptotic activity and mitochondrial depolarization when compared with vector transfectants and expressed activated proapoptotic protein WOX1. Blocking HYAL1 expression inhibited tumor growth by 4- to 7-fold, whereas high HYAL1 producing transfectants either did not form tumors (DU145) or grew 3.5-fold slower (PC-3 ML). Whereas vector and moderate HYAL1 producers generated muscle and blood vessel infiltrating tumors, HYAL1-AS tumors were benign and contained smaller capillaries. Specimens of high HYAL1 producers were 99% free of tumor cells. This study shows that, depending on the concentration, HYAL1 functions as a tumor promoter and as a suppressor and provides a basis for anti-hyaluronidase and high-hyaluronidase treatments for cancer.
Identification of Novel p53 Target Genes in Ionizing Radiation Response
Authors: Jen Kuang-Yu , Cheung Vivian G. 
Published: July 2017

Abstract
The tumor suppressor p53 plays an essential role in cellular adaptation to stress. In response to ionizing radiation, p53 regulates the transcription of genes in a diverse set of pathways including DNA repair, cell cycle arrest, and apoptosis. Previously, we identified by microarray analysis a set of genes that are transcriptionally activated or repressed in response to radiation exposure. In this study, we use computational methods and molecular techniques, including location analysis (ChIP-on-chip assay), to identify ionizing radiation–responsive genes that are directly regulated by p53. Among the 489 ionizing radiation–responsive genes examined, 38 genes were found to be p53 targets. Some of these genes are previously known to be directly regulated by p53 whereas others are novel p53 targets. We further showed that the novel p53 target genes are transcriptionally regulated by p53. The binding of p53 to promoters of target genes correlated with increased transcript levels of these genes in cells with functional p53. However, p53 binding and subsequent transcriptional activation of these target genes were significantly diminished in cells with mutant p53 and in cells from patients with ataxia telangiectasia, which have impaired p53 activation following ionizing radiation exposure. Identification and characterization of ionizing radiation–responsive p53 target genes extend our knowledge of the diverse role that p53 plays in the DNA damage response.
Mice Lacking the Amplified in Breast Cancer 1/Steroid Receptor Coactivator-3 Are Resistant to Chemical Carcinogen–Induced Mammary Tumorigenesis
Authors: Kuang Shao-Qing , Liao Lan , Wang Shu , Medina Daniel , O'Malley Bert W. , Xu Jianming 
Published: July 2017

Abstract
Amplified in breast cancer 1 (AIB1; steroid receptor coactivator-3, p/CIP, RAC3, ACTR, TRAM-1, or NCoA-3) is a transcriptional coactivator for nuclear receptors and certain other transcription factors and is a newly defined oncogene overexpressed in human breast cancer. Although the role and molecular mechanism of AIB1 in normal physiology and in breast cancer are currently under intensive investigation, the role of AIB1 in determination of the susceptibility of mammary gland to chemical carcinogens remains uncharacterized. In this study, we used back-crossed FVB wild-type (WT) and AIB1 mutant mice to assess the role of AIB1 in mammary gland development and in carcinogen-induced tumorigenesis. We show that mammary ductal growth was delayed in AIB1−/− mice with FVB strain background, and mammary ductal outgrowths emanating from the AIB1−/− mammary epithelial transplants in WT mice also were attenuated, indicating that the role of AIB1 in mammary ductal growth is a mammary epithelial autonomous function. In mice treated with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), AIB1 deficiency protected the mammary gland, but not the skin, from tumorigenesis. AIB1 deficiency suppressed the up-regulation of the insulin receptor substrate (IRS)-1 and IRS-2 and thereby inhibited the activation of Akt, expression of cyclin D1, and cell proliferation. The suppression of these components for insulin-like growth factor-I signaling might be partially responsible for the decreased DMBA-induced mammary tumor initiation and progression in AIB1−/− mice. Our results suggest that AIB1 may serve as a potential target for prevention of carcinogen-induced breast cancer initiation and for treatment of breast cancer progression.
In vivo Inhibition of Lung Cancer by GRN163L: A Novel Human Telomerase Inhibitor
Authors: Dikmen Z. Gunnur , Gellert Ginelle C. , Jackson Shalmica , Gryaznov Sergei , Tressler Robert , Dogan Pakize , Wright Woodring E. , Shay Jerry W. 
Published: July 2017

Abstract
Differential regulation of telomerase activity in normal and tumor cells provides a rationale for the design of new classes of telomerase inhibitors. The telomerase enzyme complex presents multiple potential sites for the development of inhibitors. GRN163L, a telomerase enzyme antagonist, is a lipid-modified 13-mer oligonucleotide N3′ → P5′-thio-phosphoramidate, complementary to the template region of telomerase RNA (hTR). We evaluated both the in vitro and in vivo effects of GRN163L using A549-luciferase (A549-Luc) human lung cancer cells expressing a luciferase reporter. GRN163L (1 μmol/L) effectively inhibits telomerase activity of A549-Luc cells, resulting in progressive telomere shortening. GRN163L treatment also reduces colony formation in soft agar assays. Surprisingly, after only 1 week of treatment with GRN163L, A549-Luc cells were unable to form robust colonies in the clonal efficiency assay, whereas the mismatch control compound had no effect. Finally, we show that in vivo treatment with GRN163L is effective in preventing lung metastases in xenograft animal models. These in vitro and in vivo data support the development of GRN163L as a therapeutic for the treatment of cancer.
Lack of Telomerase Gene Expression in Alternative Lengthening of Telomere Cells Is Associated with Chromatin Remodeling of the hTR and hTERT Gene Promoters
Authors: Atkinson Stuart P. , Hoare Stacey F. , Glasspool Rosalind M. , Keith W. Nicol 
Published: July 2017

Abstract
The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys4 H3. Methylation of Lys20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.
Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III
Authors: Finlay-Schultz Jessica , Gillen Austin E. , Brechbuhl Heather M. , Ivie Joshua J. , Matthews Shawna B. , Jacobsen Britta M. , Bentley David L. , Kabos Peter , Sartorius Carol A. 
Published: July 2017

Abstract
Greater than 50% of estrogen receptor (ER)–positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, &lt;25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, &gt;50% of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III–transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNAs and mature tRNAs with PR and POLR3A colocalized at their promoters were relatively decreased in estrogen + progestin–treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth. Cancer Res; 77(18); 4934–46. ©2017 AACR.
Trans-Atlantic Connections between North African Dust Flux and Tree Growth in the Florida Keys, United States
Authors: Harley Grant L. , King James , Maxwell Justin T. 
Published: July 2017

Abstract
Atmospheric mineral aerosols include multiple, interrelated processes and feedbacks within the context of land–atmosphere interactions and thus are poorly understood. As the largest dust source in the world, North Africa supplies mineral dust aerosols each year to the Caribbean region and southeastern United States that alter cloud processes, ocean productivity, soil development, and the radiation budget. This study uses a suite of Earth Observation and ground-based analyses to reveal a potential novel effect of atmospheric aerosols on Pinus elliottii var. densa cambial growth during the 2010 CE growing season from the Florida Keys. Over the Florida Keys region, the Earth Observation products captured increased aerosol optical thickness with a clear geographical connection to mineral dust aerosols transported from northern Africa. The MODIS Terra and Aqua products corroborated increased Ozone Monitoring Instrument (OMI) aerosol optical thickness values. Anomalously high Aerosol Robotic Network aerosol optical depth data corresponding with low Ångstrom coefficients confirm the presence of transported mineral dust aerosols during the period circa 4–20 July 2010. The fraction of photosynthetically absorbed radiation over the region during July 2010 experienced an anomalous decrease, concurrent with reduced incoming total and direct solar radiation resulting in a reduced growth response in P. elliottii. The authors pose one of the primary mechanisms responsible for triggering growth anomalies in P. elliottii is the reduction of total photosynthetically active radiation due to a dust-derived increase in aerosol optical depth. As a rare long-lived conifer (300+ years) in a subtropical location, P. elliottii could represent a novel proxy with which to reconstruct annual or seasonal mineral dust aerosol fluxes over the Caribbean region.
Effect of adjunctive ranitidine for antipsychotic-induced weight gain: A systematic review of randomized placebo-controlled trials
Authors: Gu Xiao-Jing , Chen Rui , Sun Chen-Hui , Zheng Wei , Yang Xin-Hu , Wang Shi-Bin , Ungvari Gabor S. , Ng Chee H. , Golenkov Andrei , Lok Grace K.I. , Li Lu , Chow Ines H.I. , Wang Fei , Xiang Yu-Tao 
Published: July 2017

This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735
Understanding Predisposition to Schizophrenia: Toward Intervention and Prevention
Authors: Tsuang Ming T , Stone William S , Faraone Stephen V 
Published: July 2017

Objective: Early intervention to prevent schizophrenia is one of the most important goals of schizophrenia research. However, the field is not yet ready to initiate trials to prevent prodromal or psychotic symptoms in people who are at risk for developing the disorder. In this paper, we consider some of the major obstacles that must be studied before prevention strategies become feasible. Method and Results: One of the most important hurdles is the identification of a syndrome or set of traits that reflects a predisposition to schizophrenia and that might provide potential targets for intervention. In a recent reformulation of Paul Meehl's concept of schizotaxia, we integrate research findings obtained over the last 4 decades to propose a syndrome with meaningful clinical manifestations. We review the conceptualization of this syndrome and consider its multidimensional clinical expression. We then describe preliminary research diagnostic criteria for use in adult, nonpsychotic, first-degree relatives of patients diagnosed with schizophrenia, based on negative symptoms and neuropsychological deficits. We follow this with evidence supporting the validity of the proposed syndrome, which mainly includes social dysfunction and response to a low dosage of one of the newer antipsychotic medications. Conclusions: Continued progress toward the eventual initiation of prevention strategies for schizophrenia will include sustained efforts to validate the traits reflecting a predisposition to develop the disorder (for example, schizotaxia), follow-up studies to confirm initial findings, and the identification of potentially useful preventive interventions.
Diabetes, Tardive Dyskinesia, Parkinsonism, and Akathisia in Schizophrenia: A Retrospective Study Applying 1998 Diabetes Health Care Guidelines to Antipsychotic Use
Authors: Lévy Emmanuelle , Margolese Howard C , Annable Lawrence , Chouinard Guy 
Published: July 2017

Background: This study examines the links among diabetes, tardive dyskinesia (TD), and other extrapyramidal symptoms (EPS) in schizophrenia outpatients treated with typical and atypical antipsychotics. Objectives: Using a retrospective chart review, we compared 30 schizophrenia patients with diabetes mellitus (DM) with 30 schizophrenia patients, matched for age and sex, with no DM. We compared prevalence and severity of parkinsonism, akathisia, TD, dystonia, and antipsychotic type (that is, typical vs atypical). Results: We found no statistically significant differences between the DM group and the non-DM group prevalence and severity of EPS, including TD. Conclusion: We did not find DM and TD association to be significant in the era of atypical antipsychotics, possibly because of their antidyskinetic effect.
Defects of Mitochondrial Electron Transport Chain in Bipolar Disorder: Implications for Mood-Stabilizing Treatment
Authors: Wang Jun-Feng 
Published: July 2017

Objective: Converging lines of evidence indicate that defects in the mitochondrial electron transport chain (ETC) are associated with bipolar disorder (BD), and that mood-stabilizing drugs produce neuroprotective effects. Our objective is to review the most recent findings regarding this research. Method: We searched MEDLINE and have reviewed here the most recently published articles. Results: There are deletions, mutation, and decreased expression of mitochondrial ETC complexes in BD. Because ETC is a major source of reactive oxygen species, these factors, along with decreased expression of antioxidant enzymes in BD, suggest the presence of oxidative damage in this disorder. Numerous recent studies have shown that mood-stabilizing drugs produce neuroprotective effects against oxidative damage and increase expression and activities of endogenous antioxidant enzymes in the rat brain. Conclusion: These findings indicate that the process of oxidative damage could be a significant therapeutic target for the treatment of BD with mood-stabilizing drugs.
Molecular Genetics of the Psychosis Phenotype
Authors: DeRosse Pamela , Malhotra Anil K , Lencz Todd 
Published: July 2017

Objective: Relative to recent successes in elucidating the genetic mechanisms associated with complex diseases, including macular degeneration, diabetes mellitus, type 2, heart disease, and cancer, molecular genetic approaches to psychiatric illness have met with more limited success. While factors such as small allelic effects, allelic heterogeneity, and variation in population substructure have received considerable attention in attempt to explain the paucity of significant results in psychiatric genetics, significantly less focus has been directed toward phenotypic factors. Method: Data derived from molecular genetic studies of the psychosis phenotype in patients with a range of psychiatric illnesses are reviewed. Results: Available data suggest that genes do not respect the boundaries of the current diagnostic system but may confer risk for symptom-based phenotypic variation that traverses those boundaries. Conclusions: Molecular genetic studies offer convincing evidence for a relation between genetic variation and symptom-based phenotypic variation within psychiatric illness. These data may provide novel insights into the pathophysiology of schizophrenia and other related disorders. The exploration of relations between genetic variation and symptom variation that traverses traditional diagnostic boundaries may ultimately lead to more refined classification systems that more closely refect the genetic etiology of psychiatric illness.
Public Health and Politics: Using the Tax Code to Expand Advocacy
Authors: Gorovitz Eric 
Published: July 2017

Protecting the public's health has always been an inherently political endeavor. The field of public health, however, is conspicuously and persistently absent from sustained, sophisticated engagement in political processes, particularly elections, that determine policy outcomes. This results, in large part, from widespread misunderstanding of rules governing how, and how much, public advocates working in tax-exempt organizations can participate in public policy development.This article briefly summarizes the rules governing public policy engagement by exempt organizations. It then describes different types of exempt organizations, and how they can work together to expand engagement. Next, it identifies several key mechanisms of policy development that public health advocates could influence. Finally, it suggests some methods of applying the tax rules to increase participation in these arenas.