bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA03: Targeting the DNA damage response to generate new medicines for cancer treatment
Authors: O'Connor Mark J.
Published: April 2017

Cancers are characterized by high levels of genomic instability and endogenous DNA damage. Traditional cancer therapies include radiotherapy and DNA-damaging chemotherapy, but these treatments are associated with significant damage to normal tissue. These unwanted side effects may be reduced by using targeted treatment approaches that preferentially affect tumor cells with specific mutations. The DNA damage response (DDR) in cancer cells differs in at least three aspects to those of normal cells, namely the loss of one or more DDR pathway or capability, increased levels of replication stress and higher levels of endogenous DNA damage. In addition, an analysis of DDR associated genes suggests that there are more than 450 gene products involved in various aspects of DDR, many of which are performing enzymatic activities that could be targeted by small molecule inhibitors. DDR therefore represents both a hallmark of cancer and a weakness that can be exploited for new cancer therapies. Both the opportunities and challenges associated with translating inhibitors of DDR into new medicines for cancer patients will be presented.

Citation Format: Mark J. O'Connor. Targeting the DNA damage response to generate new medicines for cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA03.
Abstract IA08: Synthetic viability due to BRCA2 and PARP1 loss
Authors: Sharan Shyam K.
Published: April 2017

It is very well established that BRCA1 and BRCA2 deficient cells are hypersensitive to PARP inhibitors (PARPi) due to synthetic lethality. Because Parp1 parylates proteins involved in a wide range of biological processes, we hypothesized that inhibiting PARP activity may have detrimental effect on cells that are HR proficient and do not undergo synthetic lethality. We have demonstrated that although Brca2 null ES cells are not viable, they can survive after ES cells expressing a conditional allele of Brca2 are treated with olaparib prior to Cre-mediated deletion of the conditional allele. We also found that while Parp1 loss does not rescue the HR defect, surprisingly, it rescues the MRE11-mediated degradation of stalled replication forks associated with BRCA2 loss. Interestingly, we found that reducing MRE11 activity/levels also rescues the lethality of Brca2ko/ko ES cells. Similar to the ES cells, we observe fork protection in mouse B-cells deficient in Parp1 and Brca2 as well as in human MCF10A cells.

This unexpected functional interaction between BRCA2 and PARP1 that results in synthetic viability can have profound clinical implications: use of PARP inhibitors for cancer prevention in BRCA-mutation carriers is being explored based on the assumption that PARPi would be innocuous in normal cells. Our findings raise concerns that when patients are treated with PARPi, not only are the tumor cells killed, but normal cells can also be affected. In BRCA-mutation carriers, the majority of the cells that lose the wild-type allele undergo cell cycle arrest or apoptosis unless they acquire additional mutations in genes (the identity of which are unknown) that bypass such a response. Our work provides strong evidence that Parp1 inhibition contributes to the viability of BRCA2 deficient cells, a key step in the transformation of a normal cell to pre-neoplastic state. We have genetic evidence to show that Parp1 deficiency can contribute to tumorigenesis in mice. We found a significant increase in tumorigenesis in Brca2 conditional knockout mice (cko/cko) with K14Cre on a Parp1 heterozygous background compared to those on a Parp1 wild-type background.

Citation Format: Shyam K. Sharan. Synthetic viability due to BRCA2 and PARP1 loss [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA08.
Abstract IA09: Replication fork stability confers chemoresistance in BRCA-deficient cells
Authors: Chaudhuri Arnab Ray , Callen Elsa , Ding Xia , Gogola Ewa , Duarte Alexandra A. , Lee Ji-Eun , Wong Nancy , Lafarga Vanessa , Calvo Jennifer A. , Panzarino Nicholas J. , John Sam , Day Amanda , Crespo Anna Vidal , Shen Binghui , Starnes Linda M. , Ruiter Julian R. de , Daniel Jeremy A. , Konstantinopoulos Panagiotis A. , Cortez David , Cantor Sharon B. , Fernandez-Capetillo Oscar , Ge Kai , Jonkers Jos , Rottenberg Sven , Sharan Shyam K. , Nussenzweig André
Published: April 2017

Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein PTIP protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn, protects nascent DNA strands from extensive degradation. More generally, acquisition of PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2-reversion mutations. Disruption of multiple proteins including PARP1 and CHD4 leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance.

Citation Format: Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A. Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A. Calvo, Nicholas J. Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M. Starnes, Julian R. de Ruiter, Jeremy A. Daniel, Panagiotis A. Konstantinopoulos, David Cortez, Sharon B. Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K. Sharan, André Nussenzweig. Replication fork stability confers chemoresistance in BRCA-deficient cells [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA09.
Abstract IA20: Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2
Authors: Powell Simon N.
Published: April 2017

There is genetic evidence that Chk2, BRCA1 and BRCA2 are functioning in the same pathway of DNA repair, but the links between the proteins are poorly understood. We have previously shown that BRCA1's regulation of homologous recombination (HR) is dependent on Chk2-mediated phosphorylation of BRCA1 at serine 988 (BRCA1-S988). We also found that BRCA1 regulates BRCA2 recruitment in response to DNA damage, which is also dependent on the phosphorylation of BRCA1 at Serine-988. Furthermore, in HCT116/Chk2-/- cells and in MCF7 cells with depleted Chk2, the same effects on HR and BRCA2 recruitment has been found as found in cells expressing the BRCA1-S988A protein. However, in both cases, BRCA1 is recruited to chromatin and into nuclear foci, so the effect of Chk2 is not affecting the recruitment of BRCA1. BRCA1-S988A shows a defect in RPA phosphorylation in response to replication stress and DNA damage. After global DNA damage with X-rays, MRE11 foci form at double-strand breaks, and in S and G2 phases of the cell cycle, an association with CTIP is observed transiently. In the presence of BRCA1-S988A, MRE11 co-localized with CTIP persists for much longer, and results in reduced single-stranded DNA bound by RPA. In response to a site-specific DSB induced by I-SceI nuclease, BRCA1-S988A can localize to the vicinity of the break, but not directly at the broken end, as observed by chromatin immuno-precipitation. A physical assay of resection, which distinguishes single-stranded DNA from double-stranded DNA by its susceptibility to restriction enzyme digestion, shows that BRCA1-S988A expressing cells have an initiation of resection, but a failure to extend resection up to 2 kb observed in wild-type cells. The recruitment of Exo1 is being investigated. Therefore, these results demonstrate that BRCA1-S988 plays key role in regulating the extent of resection, which in turn impedes the recruitment of BRCA2 to sites of resected DSB. Chk2 inhibition may exacerbate the defect in HR, particularly in cells with a partial or mild HR-deficiency, which is found quite commonly in human tumor cells, suggesting that combination of Chk2 and PARP inhibitors may be a useful combination DNA repair based therapy.

Citation Format: Simon N. Powell. Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA20.
Abstract IA22: The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy
Authors: Kirsch David
Published: April 2017

Fibroblasts isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation and mice lacking the gene mutated in ataxia telangiectasia (ATM) are sensitive to total-body irradiation. Kinase inhibitors of ATM can sensitize tumor cells to radiation, but these inhibitors may also sensitize normal tissues to radiation toxicity. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but whether endothelial cell death plays an important role in tumor response to radiation therapy has remained unclear. To clarify the role of endothelial cells in the response of cancer to radiation therapy, we employed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm. Deletion of Atm in proliferating tumor endothelial cells increased endothelial cell death after radiation therapy and enhanced the response of primary sarcomas to radiation as measured by tumor growth delay. However, deletion of Atm from endothelial cells failed to enhance sarcoma eradication as no difference was observed when a higher radiation dose was utilized with local control as the endpoint. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Interestingly, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. However, in mice lacking p53 in endothelial cells, which are sensitized to radiation-induced injury to the heart, deletion of ATM in addition to p53 further enhanced radiation sensitivity following whole-heart irradiation. Taken together, these genetic experiments suggest that targeting ATM during radiotherapy may provide a therapeutic gain for tumors lacking p53 function particularly when the tumor is located at an anatomic site where the adjacent normal tissue is quiescent. To test this model in mice using a pharmacological approach, we treated mice with BEZ235, which is a small molecule inhibitor of several PI3-kinase family kinases including ATM. BEZ235 sensitized primary sarcomas to radiation therapy, but only enhanced radiation-induced heart disease when p53 was deleted from endothelial cells. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

Citation Format: David Kirsch. The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA22.
Abstract PR01: Mechanisms of regulation of the tumor suppressor PALB2
Authors: Couturier Anthony , Buisson Rémi , Pauty Joris , Rodrigue Amélie , Joshi Niraj , Caron Marie-Christine , Coulombe Yan , Zou Lee , Masson Jean-Yves
Published: April 2017

One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9 fold. PALB2 was identified BRCA2 interacting protein, essential for BRCA2 anchorage to nuclear structures and for its function in double-strand break repair. Inherited mutations in PALB2 are associated with a predisposition for ovarian, breast and pancreatic cancers. The basis of the tumorigenic potential of PALB2 is thought to be related to functions in homologous recombination.

Therefore, the regulation of PALB2 during the DNA damage response and the effect of cancer-causing mutation is of high interest. Two mechanisms of regulation of PALB2 will be presented. The first mechanism regulates PALB2 localization to DNA damage sites in S-phase through ATR-mediated phosphorylation. We have found specific phosphorylated residues in PALB2 that promote BRCA1-PALB2 interaction after DNA damage.

To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different aggressive phenotypes. We performed a structure-function analysis of PALB2 using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a second PALB2 regulation mechanism. Our data explains the tumorigenesis associated with some PALB2 mutations, a concept that also applies to other WD40-containing proteins.

This abstract is also being presented as Poster B11.

Citation Format: Anthony Couturier, Rémi Buisson, Joris Pauty, Amélie Rodrigue, Niraj Joshi, Marie-Christine Caron, Yan Coulombe, Lee Zou, Jean-Yves Masson. Mechanisms of regulation of the tumor suppressor PALB2 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR01.
Abstract PR07: Identifying factors mediating response and resistance to chemotherapy through a chemical-genetic interaction map
Authors: Hu Hsien-Ming , Bandyopadhyay Sourav
Published: April 2017

Nearly every cancer patient, especially those with highly lethal and aggressive tumor types, is treated with cytotoxic chemotherapy. Currently, the selection of chemotherapy is based on average responses over a large number of patients. This belies our understanding of DNA repair that has demonstrated that the inability of a tumor cell to properly repair particular types of DNA damage has a dramatic influence on cell survival. Here, we report the generation of a quantitative chemical-genetic interaction map to chart the influence of knockdown of 625 genes on sensitivity to 30 FDA approved chemotherapeutic agents in breast epithelial cells. The resulting map highlights key genes which, when mutated or deleted in tumor cells, can dramatically induce sensitivity or resistance to particular DNA damaging agents. Interrogation of this map reveals new DNA repair factors that are recurrently deleted in breast and ovarian cancers, provides a platform for prediction of cancer cell line responses from genomic data and provides the basis for the prioritization of new drug combinations. Our data reveal that the loss of ARID1A, a key component of the SWI/SNF chromatin remodeling complex, drives resistance to cisplatin as well as PARP inhibition. Mechanistically, we uncover that ARID1A functions as a suppressor of DNA repair by homologous recombination (HR) and that its loss via mutation or deletion rescues HR in a BRCA1 independent fashion. Together, our data indicates a plethora of potential biomarkers for chemotherapy response and provides an opportunity for computational integration of chemical-genetic networks with patient genomic data to predict optimal chemotherapeutic regimes.

This abstract is also being presented as Poster A14.

Citation Format: Hsien-Ming Hu, Sourav Bandyopadhyay. Identifying factors mediating response and resistance to chemotherapy through a chemical-genetic interaction map [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR07.
Abstract PR18: Somatic ERCC2 mutations, nucleotide excision repair (NER) function, and cisplatin response in muscle-invasive bladder cancer (MIBC)
Authors: Mouw Kent , Lazaro Jean-Bernard , Damish Alexis , Reznichenko Elizaveta , Frazier Zoe , Liu David , Kim Jaegil , Polak Paz , Garraway Levi , Getz Gad , Rosenberg Jonathan , Allen Eliezer Van , D'Andrea Alan
Published: April 2017

ERCC2 is a core member of the nucleotide excision repair (NER) pathway, a highly conserved and remarkably versatile DNA repair pathway responsible for repairing intrastrand DNA adducts created by genotoxic agents such as UV irradiation and platinum-based chemotherapies. Recent large-scale genomic efforts have shown that somatic ERCC2 missense mutations are present in approximately 20% of all primary muscle-invasive bladder cancers (MIBC). We previously showed that ERCC2 mutations are associated with treatment response and overall survival in MIBC patients treated with cisplatin-based chemotherapy. Initial functional studies on a subset of the observed ERCC2 mutations suggest that the mutations confer loss of normal cellular NER capacity. However, sequencing of additional MIBC cohorts has revealed that mutations occur across the ERCC2 gene, and the functional effects of the majority of these mutations remain unknown. In order to understand the functional landscape of ERCC2 mutations in MIBC, we have developed a high-throughput fluorescence-based assay to test the functional consequences of mutations in ERCC2 and other NER genes on cellular NER capacity. We apply this approach to all observed ERCC2 mutations across three published MIBC cohorts and find that the majority of ERCC2 mutations result in complete or near-complete loss of cellular NER. In addition, by correlating our functional results with available clinical data, we find interesting examples of cases in which ERCC2 status and cisplatin response are decoupled, highlighting the importance of using functional data to complement genomic and clinical endpoints in the search for reliable predictive biomarkers.

This abstract is also being presented as Poster A29.

Citation Format: Kent Mouw, Jean-Bernard Lazaro, Alexis Damish, Elizaveta Reznichenko, Zoe Frazier, David Liu, Jaegil Kim, Paz Polak, Levi Garraway, Gad Getz, Jonathan Rosenberg, Eliezer Van Allen, Alan D'Andrea. Somatic ERCC2 mutations, nucleotide excision repair (NER) function, and cisplatin response in muscle-invasive bladder cancer (MIBC) [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR18.
Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in Ipilimumab-Treated Advanced Melanoma Patients
Authors: Garcia-Neuer Marlene , Marmarelis Melina E. , Jangi Sushrut R. , Luke Jason J. , Ibrahim Nageatte , Davis Meredith , Weinberg Janice , Donahue Hilary , Bailey Nancy , Hodi F. Stephen , Buchbinder Elizabeth L. , Ott Patrick A.
Published: April 2017

Colitis can be a life-threatening toxicity for patients treated with immune checkpoint blockade antibodies. With the anticipated widespread use of these reagents, the timely and accurate diagnosis of immune-related colitis becomes increasingly important. To better understand the clinical presentation of colitis from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a diagnostic tool, we retrospectively analyzed patients with advanced melanoma who received ipilimumab at our institution. Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis. Cancer Immunol Res; 5(4); 286–91. ©2017 AACR.
Masterful Antibodies: Checkpoint Blockade
Authors: Lonberg Nils , Korman Alan J.
Published: April 2017

Cancer therapeutics that target the immune system rather than the cancer cell itself are becoming standard of care in a growing number of different malignancies. Although cancer immunotherapy is not a new concept, the potential importance of this class of drugs was probably not fully appreciated as recently as a decade ago when much of the focus of cancer drug discovery was on cancer cell–targeted medicines. The authors were lucky enough to be able to witness and participate in the discovery and development of ipilimumab and nivolumab, two relatively early examples of immune system–targeted drugs. The challenges associated with discovering and developing these molecules may be of historical interest and instructive for moving cancer immunotherapy forward for greater numbers of patients. Cancer Immunol Res; 5(4); 275–81. ©2017 AACR.
Tumors Presenting as Multiple Cranial Nerve Palsies
Authors: Kumar Kishore , Ahmed Rafeeq , Bajantri Bharat , Singh Amandeep , Abbas Hafsa , Dejesus Eddy , Khan Rana Raheel , Niazi Masooma , Chilimuri Sridhar
Published: April 2017

Cranial nerve palsy could be one of the presenting features of underlying benign or malignant tumors of the head and neck. The tumor can involve the cranial nerves by local compression, direct infiltration or by paraneoplastic process. Cranial nerve involvement depends on the anatomical course of the cranial nerve and the site of the tumor. Patients may present with single or multiple cranial nerve palsies. Multiple cranial nerve involvement could be sequential or discrete, unilateral or bilateral, painless or painful. The presentation could be acute, subacute or recurrent. Anatomic localization is the first step in the evaluation of these patients. The lesion could be in the brain stem, meninges, base of skull, extracranial or systemic disease itself. We present 3 cases of underlying neoplasms presenting as cranial nerve palsies: a case of glomus tumor presenting as cochlear, glossopharyngeal, vagus and hypoglossal nerve palsies, clivus tumor presenting as abducens nerve palsy, and diffuse large B-cell lymphoma presenting as oculomotor, trochlear, trigeminal and abducens nerve palsies due to paraneoplastic involvement. History and physical examination, imaging, autoantibodies and biopsy if feasible are useful for the diagnosis. Management outcomes depend on the treatment of the underlying tumor.
French Medical-Administrative Database for Epidemiology and Safety in Ophthalmology (EPISAFE): The EPISAFE Collaboration Program in Cataract Surgery
Authors: Daien Vincent , Korobelnik Jean-Francois , Delcourt Cécile , Cougnard-Gregoire Audrey , Delyfer Marie Noelle , Bron Alain M. , Carrière Isabelle , Villain Max , Daures Jean Pierre , Lacombe Sandy , Mariet Anne Sophie , Quantin Catherine , Creuzot-Garcher Catherine
Published: April 2017

Medical-administrative databases are an important source of big data to assess the epidemiology of diseases and interventions, compare drugs, and investigate rare adverse events. We describe the French national health insurance system databases and the Epidemiology and Safety (EPISAFE) collaboration program in ophthalmology and illustrate the paper with recent studies that used the databases to investigate cataract surgery. The Système national d'information inter-régime de l'assurance maladie (SNIIR-AM) is one of the largest databases of medical and administrative data for a general population, covering nearly 65 million people. The SNIIR-AM database links data for all outpatient-reimbursed health expenditures, hospitalization in all 1,546 French private or public healthcare facilities, and date of death. The use of this database provides information at the scale of the entire country, allowing measurement of the impact of changes in practices and new guidelines. Between 2009 and 2012, a total of 2,717,203 eyes in 1,817,865 patients underwent cataract surgery in France, and the incidence of cataract surgery increased from 9.86 to 11.08/1,000 person-years. The 4-year cumulative risk of retinal detachment was 0.99%, and patients <60 years of age were at higher risk of retinal detachment. The incidence of pseudophakic cystoid macular edema was 0.95%. From 2005 to 2014, from data including more than 6 million procedures, the incidence of endophthalmitis after cataract surgery decreased from 0.15 to 0.05%. The EPISAFE collaboration program encompasses the key issues facing ophthalmology, including public health and public policy concerning disease incidence and prevalence, safety and adverse event monitoring, and clinical guidelines.
Discontinuation/Dose Reduction of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers during Acute Decompensated Heart Failure in African-American Patients with Reduced Left-Ventricular Ejection Fraction
Authors: Kane Jesse A. , Kim Joseph K. , Haidry Syed Abbas , Salciccioli Louis , Lazar Jason
Published: April 2017

Objectives: Patients with heart failure (HF) and reduced left-ventricular ejection fraction (LVEF) benefit from angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) therapy. While dose reduction/discontinuation (r/d) of β-blockers (BB) and furosemide in acute decompensated HF (ADHF) worsen outcomes, data on ACEI/ARB are lacking. Methods: To determine the frequency and reasons for ACEI/ARB therapy r/d in ADHF patients, we studied 174 patients with LVEF <40% on ACEI/ARB and BB therapy upon admission over 1 year. Results: ACEI/ARB doses were r/d in 17.2% because of acute kidney injury (56.7%), hypotension (23.3%), and hyperkalemia (10%). Clinical characteristics were similar between patients with r/d and continued therapy. Admission and discharge creatinine (Cr) levels were higher in the r/d group. On multivariate analysis, admission Cr and admission systolic blood pressures were independent predictors of r/d. Among patients with renal dysfunction cited as the r/d reason, Cr did not significantly rise in 23.5%. The r/d group had a longer length of stay (LOS). Conclusions: ACEI/ARB dose is reduced and/or discontinued in nearly one-fifth of all ADHF admissions, and LOS is longer in the ACEI/ARB r/d group. While impaired renal function is the most frequently cited reason, nearly one-fourth of the patients had stable renal function. ACEI/ARB r/d therapy in the setting of ADHF merits further study.
The Role of O-GlcNAcylation in Perivascular Adipose Tissue Dysfunction of Offspring of High-Fat Diet-Fed Rats
Authors: Zaborska Karolina E. , Edwards Gillian , Austin Clare , Wareing Mark
Published: April 2017

Perivascular adipose tissue (PVAT), which reduces vascular contractility, is dysfunctional in the male offspring of rats fed a high-fat diet (HFD), partially due to a reduced NO bioavailability. O-GlcNAcylation of eNOS decreases its activity, thus we investigated the role of O-GlcNAcylation in the prenatal programming of PVAT dysfunction. Female Sprague-Dawley rats were fed either a control (10% fat) or an obesogenic HFD (45% fat) diet for 12 weeks prior to mating, and throughout pregnancy and lactation. Offspring were weaned onto the control diet and were killed at 12 and 24 weeks of age. Mesenteric arteries from the 12-week-old offspring of HFD dams (HFDO) contracted less to U46619; these effects were mimicked by glucosamine in control arteries. PVAT from 12- and 24-week-old controls, but not from HFDO, exerted an anticontractile effect. Glucosamine attenuated the anticontractile effect of PVAT in the vessels from controls but not from HFDO. AMP-activated protein kinase (AMPK) activation (with A769662) partially restored an anticontractile effect in glucosamine-treated controls and HFDO PVAT. Glucosamine decreased AMPK activity and expression in HFDO PVAT, although phosphorylated eNOS expression was only reduced in that from males. The loss of anticontractile effect of HFDO PVAT is likely to result from increased O-GlcNAcylation, which decreased AMPK activity and, in males, decreased NO bioavailability.
Hypomethylation of the Angiotensin II Type I Receptor (AGTR1) Gene Along with Environmental Factors Increases the Risk for Essential Hypertension
Authors: Lin Jiabing , Lin Shaowei , Wu Yihai , Wang Xiaoxia , Wu Siying , Li Huangyuan
Published: April 2017

Objectives: The present study aimed to evaluate the hypertension status of community residents, analyze environmental and epigenetic factors, and propose prevention measures for hypertension. Methods: In our study, different methylation levels were distinguished utilizing melting temperature (Tm) values in both the case and the control group. Multiple logistic regression analysis was used to estimate the risk of having essential hypertension (EH) between hypertensive and nonhypertensive participants. A receiver-operating characteristic curve was used to analyze Tm cutoff levels of methylation. Results: The average DNA Tm was 71.784 with a standard deviation of 0.210. The Tm value of community residents (Fujian, China) was inversely correlated with systolic and diastolic blood pressure. Student t test analysis showed a clear separation in Tm expression levels between the hypertensive and the control group (p < 0.05). The Tm value was lower in the hypertension group than in the normotensive group. Multivariate regression analysis showed that high levels of DNA methylation were a protective factor in hypertension with adjustment of demographic and environmental factors, whereas when the Tm value increased by 0.1 units, the risk of hypertension was reduced by 0.652 times. Patients that smoked and consumed an irregular diet demonstrated a lower degree of methylation in the presence of hypertension. Conclusions: DNA methylation affects the risk for the development of hypertension; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH.
Gender Differences in Verbal and Visuospatial Working Memory Tasks in Patients with Mild Cognitive Impairment and Alzheimer Disease
Authors: Elosúa M. Rosa , Ciudad María José , Contreras María José
Published: April 2017

Background/Aims: To date, there are few studies on gender differences in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). In the present study, the existence of differences between sexes in verbal and visuospatial working memory tasks in the evolution of cognitive and pathological aging was examined. Method: Ninety participants took part in this study: 30 AD, 30 MCI, and 30 healthy elderly participants (50% men and 50% women). Results: There were no significant differences between men and women with AD in visuospatial tasks, whereas these differences were found within the MCI group, with the average of men achieving significantly higher results than women. In verbal tasks, there were no differences between sexes for any of the groups. Conclusion: Execution in visuospatial tasks tends to depend on gender, whereas this does not occur for verbal tasks.
Japanese Historic “Timescapes”: An Anthropological Approach
Authors: Steger Brigitte
Published: April 2017

In this article, I propose a methodology to investigate “timescapes” in Japanese history from an anthropological perspective by analyzing historical sources on social activities, more specifically on sleeping and napping. Such an analysis provides the methodological basis for a research project on premodern Japanese “timescapes” at the University of Cambridge. Rather than studying the social use of the clock to investigate the extent to which various time structures have penetrated people’s private lives, I approach these questions by paying attention to how sleep and other social activities have been organized on a socio-temporal level—in other words, how people have been “doing time.” I argue that this focus makes abstract notions of time tangible. Issues discussed are time-use priorities, time measurement, appropriateness of performing certain tasks at specific times, regulating time as a tool of power, disciplining bodies through scheduling and early rising, as well as monochronic and polychronic time use.
Type specimens and type localities of birds (Aves) collected during F. J. F. Meyen’s circumnavigation in 1830–1832
Authors: MLÍKOVSKÝ JIŘÍ , FRAHNERT SYLKE
Published: April 2017

At least 32 bird species were described as new to science on the basis of material collected by Franz Meyen during his circumnavigation in 1830–1832. We identified the type specimens and determined the type localities of these species, which are currently housed in the Museum für Naturkunde, Berlin, Germany. Ardea longicollis Meyen, 1834, is identified as a senior synonym of Egretta eulophotes (Swinhoe, 1860), but is set aside as a nomen oblitum. The name of a Neotropical dove is corrected from Metriopelia ceciliae zimmeri (Peters, 1937) to Metriopelia ceciliae gymnops (Chubb, 1917). A lectotype is designated for Nectarinia philippensis Meyen, 1834a.
Two new troglobiont Pygmarrhopalites species of the principalis group (Collembola: Arrhopalitidae) from the West Caucasus
Authors: VARGOVITSH ROBERT S.
Published: April 2017

Springtails of the principalis-group of the genus Pygmarrhopalites from the W Caucasian caves in Abkhazia are described: Pygmarrhopalites dbari sp. nov. from Psyrtskha Cave in Novy Afon and Pygmarrhopalites kovali sp. nov. from caves of Tsebelda Karst Massif. They differ from epigean relatives mainly by troglomorphies: reduced pigmentation, elongated appendages and modified foot complex. These new species as well as a great portion of endemic Caucasian speleofauna have highly restricted distribution and require protection. A new record of Arrhopalites abchasicus Vargovitsh, 2013 in Novoafonskaya Cave is added.
Diaphanosoma Fischer, 1850 (Crustacea: Cladocera: Sididae) of Lake Turkana (East Africa), with the description of a new species of the genus
Authors: KOROVCHINSKY NIKOLAI M. , WALSH ELIZABETH J. , SMOLAK RADOSLAV
Published: April 2017

Diaphanosoma turkanae sp. nov. is described from Lake Turkana (Kenya, East Africa). This species is the second Afrotropical endemic in the order Ctenopoda. It is characterized by a distinctive feature, the presence of an unusually small number of setae on the upper two-segmented antennal branch (exopodite); the proximal segment of the branch always bears three setae while the distal segment bears either six or seven setae. Morphologically the new species is most similar to D. orghidani Negrea, also occurring in Africa and presumably sharing an evolutionary affinity. D. turkanae sp. nov. co-occurs with two other species of the genus, D. lacustris Kořinek and D. excisum Sars, which are briefly described here. Temperate-subtropical species of the genus Diaphanosoma penetrate far south along the Nile River system up to the equatorial and Ethiopian lakes and further southwards, often forming multi-species assemblages.
Leptobotia micra, a new species of loach (Teleostei: Botiidae) from Guilin, southern China
Authors: BOHLEN JÖRG , ŠLECHTOVÁ VENDULA
Published: April 2017

Leptobotia micra, new species, is described from the upper Li River (Pearl River basin) around Guilin in Guangxi province, southern China. The new species is evidently the smallest species of Leptobotia, with females of 45‒46 mm SL bearing oocytes. It can be distinguished from all other species of Leptobotia by a combination of the following characters: no dark bars or dorsal saddles on body, a row of white dots along dorsal midline, 4+34 vertebrae, a predorsal distance of 58.1‒59.0% SL, eye diameter 1.8‒2.0 % SL, pelvic fins not reaching anus, an emarginated caudal fin (length of median rays 1.3‒1.4 times in length of lower lobe) and the anus positioned distinctly closer to anal-fin origin than to pelvic-fin base.
Invariance of the Double-Moment Normalized Raindrop Size Distribution through 3D Spatial Displacement in Stratiform Rain
Authors: Raupach Timothy H. , Berne Alexis
Published: April 2017

Double-moment normalization of the drop size distribution (DSD) summarizes the DSD in a compact way, using two of its statistical moments and a “generic” double-moment normalized DSD function. Results are presented of an investigation into the invariance of the double-moment normalized DSD through horizontal and vertical displacement in space, using data from disdrometers, vertically pointing K-band Micro Rain Radars, and an X-band polarimetric weather radar. The invariance of the double-moment normalized DSD is tested over a vertical range of up to 1.8 km and a horizontal range of up to approximately 100 km. The results suggest that for practical use, with well-chosen input moments, the double-moment normalized DSD can be assumed invariant in space in stratiform rain. The choice of moments used to characterize the DSD affects the amount of DSD variability captured by the normalization. It is shown that in stratiform rain, it is possible to capture more than 85% of the variability in DSD moments zero to seven using the technique. Most DSD variability in stratiform rain can thus be explained through the variability of two of its statistical moments. The results suggest similar behavior exists in transition and convective rain, but the limited data samples available do not allow for robust conclusions for these rain types. The results have implications for practical uses of double-moment DSD normalization, including the study of DSD variability and microphysics, DSD-retrieval algorithms, and DSD models used in rainfall retrieval.
Spatial Patterns and Intensity of the Surface Storm Tracks in CMIP5 Models
Authors: Booth James F. , Kwon Young-Oh , Ko Stanley , Small R. Justin , Msadek Rym
Published: April 2017

To improve the understanding of storm tracks and western boundary current (WBC) interactions, surface storm tracks in 12 CMIP5 models are examined against ERA-Interim. All models capture an equatorward displacement toward the WBCs in the locations of the surface storm tracks’ maxima relative to those at 850 hPa. An estimated storm-track metric is developed to analyze the location of the surface storm track. It shows that the equatorward shift is influenced by both the lower-tropospheric instability and the baroclinicity. Basin-scale spatial correlations between models and ERA-Interim for the storm tracks, near-surface stability, SST gradient, and baroclinicity are calculated to test the ability of the GCMs’ match reanalysis. An intermodel comparison of the spatial correlations suggests that differences (relative to ERA-Interim) in the position of the storm track aloft have the strongest influence on differences in the surface storm-track position. However, in the North Atlantic, biases in the surface storm track north of the Gulf Stream are related to biases in the SST. An analysis of the strength of the storm tracks shows that most models generate a weaker storm track at the surface than 850 hPa, consistent with observations, although some outliers are found. A linear relationship exists among the models between storm-track amplitudes at 500 and 850 hPa, but not between 850 hPa and the surface. In total, the work reveals a dual role in forcing the surface storm track from aloft and from the ocean surface in CMIP5 models, with the atmosphere having the larger relative influence.
The North Atlantic Eddy Heat Transport and Its Relation with the Vertical Tilting of the Gulf Stream Axis
Authors: Treguier A. M. , Lique C. , Deshayes J. , Molines J. M.
Published: April 2017

Correlations between temperature and velocity fluctuations are a significant contribution to the North Atlantic meridional heat transport, especially at the northern boundary of the subtropical gyre. In satellite observations and in a numerical model at ⅞° resolution, a localized pattern of positive eddy heat flux is found northwest of the Gulf Stream, downstream of its separation at Cape Hatteras. It is confined to the upper 500 m. A simple kinematic model of a meandering jet can explain the surface eddy flux, taking into account a spatial shift between the maximum velocity of the jet and the maximum cross-jet temperature gradient. In the Gulf Stream such a spatial shift results from the nonlinear temperature profile and the vertical tilting of the velocity profile with depth. The numerical model suggests that the meandering of the Gulf Stream could account, at least in part, for the large eddy heat transport (of order 0.3 PW) near 36°N in the North Atlantic and for its compensation by the mean flow.
Observations and Modeling of Typhoon Waves in the South China Sea
Authors: Xu Yao , He Hailun , Song Jinbao , Hou Yijun , Li Funing
Published: April 2017

Buoy-based observations of surface waves during three typhoons in the South China Sea were used to obtain the wave characteristics. With the local wind speeds kept below 35 m s−1, the surface waves over an area with a radius 5 times that of the area in which the maximum sustained wind was found were mainly dominated by wind-wave components, and the wave energy distribution was consistent with fetch-limited waves. Swells dominated the surface waves at the front of and outside the central typhoon region. Next, the dynamics of the typhoon waves were studied numerically using a state-of-the-art third-generation wave model. Wind forcing errors made a negligible contribution to the surface wave results obtained using hindcasting. Near-realistic wind fields were constructed by correcting the idealized wind vortex using in situ observational data. If the different sets of source terms were further considered for the forcing stage of the typhoon, which was defined as the half inertial period before and after the typhoon arrival time, the best model performance had mean relative biases and root-mean-square errors of −0.7% and 0.76 m, respectively, for the significant wave height, and −3.4% and 1.115 s, respectively, for the peak wave period. Different sets of source terms for wind inputs and whitecapping breaking dissipation were also used and the results compared. Finally, twin numerical experiments were performed to investigate the importance of nonlinear wave–wave interactions on the spectrum formed. There was evidence that nonlinear wave–wave interactions efficiently transfer wave energy from high frequencies to low frequencies and prevent double-peak structures occurring in the frequency-based spectrum.
Bulk versus Spectral Wave Parameters: Implications on Stokes Drift Estimates, Regional Wave Modeling, and HF Radars Applications
Authors: Kumar Nirnimesh , Cahl Douglas L. , Crosby Sean C. , Voulgaris George
Published: April 2017

Accurate estimates of Stokes drift are necessary to quantify Lagrangian transport and upper-ocean mixing. These can be estimated from directional wave spectra. Here, a methodology for the reconstruction of such spectra is developed using partitioned bulk wave parameters provided by global wave models. These reconstructed spectra agree well with global wave model–simulated full spectra. Regional wave model simulations with reconstructed spectra as open boundary conditions lead to more accurate estimates of bulk wave parameters in the coastal ocean. Furthermore, the reconstructed directional spectra can be used to improve high-frequency (HF) radar–derived surface Lagrangian current estimates. Stokes drift vertical profiles from complete directional spectra are more accurate, and therefore coupled ocean circulation and wave models should incorporate spectral estimates for wave–current interaction studies. Based on model simulations conducted here, it is recommended that regional wave modeling studies use partitioned rather than bulk wave parameter products from global wave simulations to reconstruct complete directional spectra for open boundary conditions. Finally, this study shows that inclusion of the peak spectral energy for each partition improves the ability to reconstruct more accurately directional spectra and surface Stokes drift. It is recommended that the global wave model hindcast/forecast include this additional bulk parameter.
Turbulence Measurements from Compliant Moorings. Part I: Motion Characterization
Authors: Harding Samuel , Kilcher Levi , Thomson Jim
Published: April 2017

High-fidelity measurements of turbulence in the ocean have long been challenging to collect, in particular in the middle of the water column. In response, a measurement technique has been developed to deploy an acoustic Doppler velocimeter (ADV) to midwater locations on a compliant mooring. A variety of instrumentation platforms have been deployed as part of this work with a range of dynamic motion characteristics. The platforms discussed herein include the streamlined StableMoor buoy (SMB), the Tidal Turbulence Mooring (TTM) system based on a conventional 0.9-m spherical buoy, and a 100-lb sounding weight suspended from the stern of a research vessel. The ADV head motion is computed from inertial motion sensors integrated into an ADV, and the spectra of these signals are investigated to quantify the motion of each platform. The SMB with a single ADV head mounted on the nose provided the most stable platform for the measurement of tidal turbulence in the inertial subrange for flow speeds exceeding 1.0 m s−1. The modification of the SMB with a transverse wing configuration for multiple ADVs showed a similar frequency response to the nose configuration in the horizontal plane but with large contamination in the vertical direction as a result of platform roll. While the ADV motion on the TTM was significant in the horizontal directions, the vertical motion of this configuration was the most stable of all configurations tested. The sounding weight measurements showed the greatest motion at the ADV head but are likely to be influenced by both prop-wash and vessel motion.
A Prospective Comparison of Transcutaneous and Serum Bilirubin Within Brief Time Intervals
Authors: Jones Denise F. , McRea Abigail R. , Knowles James D. , Lin Feng-Chang , Burnette Erin , Reller Lara A. , Lohr Jacob A.
Published: April 2017

The American Academy of Pediatrics recommends screening newborns ≥35 weeks’ gestation with total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) to detect hyperbilirubinemia. Retrospective studies show TcB measurements strongly correlate with TSB; however, few prospective trials document this relationship. Furthermore, Dräger’s newest TcB instrument, JM-105, remains unstudied in the United States. We measure TcB on foreheads and sternums of newborns using JM-105 and Bilichek devices within 30 minutes of TSB measurement. We find best overall TcB/TSB correlation with JM-105 on the sternum (mean TcB-TSB difference: −0.21 ± 1.15 mg/dL). Correlations between paired measurements for TcB on the sternum using JM-105 were 0.93 for all TSB levels (n = 178), 0.82 for TSB > 10 (n = 19), 0.69 for TSB > 12 (n = 11), and 0.52 for TSB > 15 (n = 6). TcB accuracy via JM-105 on the sternum significantly differed among races ( P < .001). For 5% of paired measurements, TcB with JM-105 on the sternum underestimated TSB by ≥2 mg/dL, and for <1% by ≥3 mg/dL.