bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finite element analysis on tooth and periodontal stress under simulated occlusal loads
Authors: Zhang H. , Cui J.‐W. , Lu X. L. , Wang M.‐Q. 
Published: April 2017

SummaryThe tooth stress elicited by occluding contact represents critical biomechanical information about dental health during chewing. Effects of occlusal contact on tooth stress remain obscure. In this study, a mandibular first molar finite element model was built from CT images. The effects of area size, location and direction of occlusal loading on both tooth and periodontal stresses were analysed. Results showed tooth and periodontal stress had drastically different patterns. Tooth stress value was much higher than periodontal stress value under the same task. Tooth stress concentration area and its value decreased from outside to inside. The Maximum Tooth Stress (MTS) always occurred at the loading site and a larger loading area elicited a smaller MTS value. The variation of MTS was larger when the fossa bottoms were inclined loaded than when the cusp tips were inclined loaded, larger when lingually loaded than when buccally loaded and larger when mesially loaded than when distally loaded. Distal loadings generally induced smaller Maximum Periodontal Stress (MPS) variations than the mesial loadings. These findings indicated exposure of the rational site(s) to occlusal contact should be helpful to achieve proper tooth and periodontal stress, thus to diminish loading associated structure problems.
Top‐down approach is possible strategy for predicting breakthrough fUTIs and renal scars in infants
Authors: Kawai Shina , Kanai Takahiro , Hyuga Taiju , Nakamura Shigeru , Aoyagi Jun , Ito Takane , Saito Takashi , Odaka Jun , Furukawa Rieko , Aihara Toshinori , Nakai Hideo 
Published: April 2017

AbstractBackgroundAcute‐phase technetium‐99 m dimercaptosuccinic acid (DMSA) scintigraphy is recommended for initial imaging in children with febrile urinary tract infection (fUTI). Recently, the importance of identifying patients at risk of recurrent fUTI (r‐fUTI) has been emphasized. To clarify the effectiveness of DMSA scintigraphy for predicting r‐fUTI in infants, we investigated the relationship between defects on DMSA scintigraphy and r‐fUTI.MethodsSeventy‐nine consecutive infants (male: female, 60:19) with fUTI were enrolled in this study. DMSA scintigraphy was performed in the acute phase, and patients with defect underwent voiding cystourethrography and chronic‐phase (6 months later) DMSA scintigraphy. Patients were followed on continuous antibiotic prophylaxis (CAP).ResultsDefects on acute‐phase DMSA scintigraphy were observed in 32 children (40.5%) of 79. The mean follow‐up observation period was 17.0 ± 10.1 months. Four patients had r‐fUTI (5%). Two of them had defects on DMSA scintigraphy in both the acute phase and chronic phase, and had bilateral vesicoureteral reflux (VUR) grade IV. Two others had r‐fUTI without defects on DMSA and did not have VUR. Twelve patients had defect on chronic‐phase DMSA scintigraphy and four of them had no VUR.ConclusionsThe top‐down approach is a possible method for predicting r‐fUTI in infants and does not miss clinically significant VUR. Also, given that the prevalence of r‐fUTI was 5% regardless of the presence of defects on acute‐phase DMSA, then, in conjunction with genital hygiene and CAP, acute‐phase DMSA might be unnecessary if chronic‐phase DMSA is performed for all patients to detect renal scar.
Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate
Authors: Salih M. A. M. , Fakiola M. , Lyons P. A. , Younis B. M. , Musa A. M. , Elhassan A. M. , Anderson D. , Syn G. , Ibrahim M. E. , Blackwell J. M. , Mohamed H. S. 
Published: April 2017

SummaryVisceral leishmaniasis (VL) in Sudan caused by Leishmania donovani is fatal in susceptible individuals if untreated. Treatment with sodium stibogluconate (SSG) leads to post‐kala‐azar dermal leishmaniasis (PKDL) in 58% of patients. Here, Affymetrix microarrays were used to identify genes differentially expressed in lymph nodes (N=9 paired samples) pre‐ and post‐treatment with SSG. Using the Bioconductor package limma, 438 genes from 28 869 post‐quality‐control probe sets were differentially expressed (Pnominal≤.02) post‐ vs pretreatment. Canonical pathway analysis using Ingenuity Pathway Analysis™ identified “role of nuclear factor of activated T‐cell in regulation of immune response” (Pnominal=1.35×10−5; PBH‐adjusted=4.79×10−3), “B‐cell development” (Pnominal=2.04×10−4; PBH‐adjusted=.024), “Fcγ receptor‐mediated phagocytosis in macrophages and monocytes” (Pnominal=2.04×10−4; PBH‐adjusted=.024) and “OX40 signalling” (Pnominal=2.82×10−4; PBH‐adjusted=.025) as pathways differentially regulated post‐ vs pretreatment. Major network hub genes included TP53, FN1, MYC, BCL2, JUN, SYK, RUNX2, MMP1 and ACTA2. Top endogenous upstream regulators included IL‐7 (P=2.28×10−6), TNF (P=4.26×10−6), Amyloid Precursor Protein (P=4.23×10−5) and SPI1/PI.1 (P=1.17×10−7). Top predicted chemical drug regulators included the flavonoid genistein (P=4.56×10−7) and the quinoline alkaloid camptothecin (P=5.14×10−5). These results contribute to our understanding of immunopathology associated with VL and response to SSG treatment. Further replication could identify novel therapeutic strategies that improve on SSG treatment and reduce the likelihood of progression to PKDL.
Expression of kit ligand and insulin‐like growth factor binding protein 3 during in vivo or in vitro development of ovarian follicles in sheep
Authors: Srividya D , Praveen Chakravarthi V , Kona SSR , Siva Kumar AVN , Brahmaiah KV , Rao VH 
Published: April 2017

ContentsExpression of Kit ligand (KL) and insulin‐like growth factor binding protein (IGFBP3) genes was studied at different in vivo and corresponding in vitro stages of development of the ovarian follicles in sheep. The expression of both KL and IGFBP3 was significantly higher in the primordial follicles relative to any other stage of development. Compared to the other stages, the KL expression in the cumulus cells from in vivo grown large antral follicles and that of IGFBP3 in COCs’ isolated from large antral follicles matured in vitro for 24 hr were significantly higher. In the oocytes from in vivo grown ovarian follicles, the expression of KL was the same at all the stages of development. Insulin‐like growth factor binding protein 3 expression was also the same in the oocytes at all the stages of the development except for a significantly lower expression in those from antral follicles. The expression of KL in the cumulus cells decreased significantly in the in vitro grown early antral follicles but did not change further as the development progressed. The expression of IGFBP3 in the cumulus cells from in vitro grown ovarian follicles appeared to increase as the development progressed although the increase was not significant between any two consecutive stages of development. In the oocytes in in vitro grown ovarian follicles, the expression levels of KL and IGFBP3 genes did not change with development. It is concluded that (i) KL and IGFBP3 genes follow specific patterns of expression during ovarian folliculogenesis and (ii) in vitro culture of preantral follicles compromises the development potential through alterations in the stage‐specific patterns of expression of these and other developmentally important genes.
EXPERT OPINIONS AND LOGARITHMIC UTILITY MAXIMIZATION FOR MULTIVARIATE STOCK RETURNS WITH GAUSSIAN DRIFT
Authors: SASS JÖRN , WESTPHAL DOROTHEE , WUNDERLICH RALF 
Published: April 2017

This paper investigates optimal trading strategies in a financial market with multidimensional stock returns, where the drift is an unobservable multivariate Ornstein–Uhlenbeck process. Information about the drift is obtained by observing stock returns and expert opinions which provide unbiased estimates on the current state of the drift. The optimal trading strategy of investors maximizing expected logarithmic utility of terminal wealth depends on the filter which is the conditional expectation of the drift given the available information. We state filtering equations to describe its dynamics for different information settings. At information dates, the expert opinions lead to an update of the filter which causes a decrease in the conditional covariance matrix. We investigate properties of these conditional covariance matrices. First, we consider the asymptotic behavior of the covariance matrices for an increasing number of expert opinions on a finite time horizon. Second, we state conditions for convergence in infinite time with regularly-arriving expert opinions. Finally, we derive the optimal trading strategy of an investor. The optimal expected logarithmic utility of terminal wealth, the value function, is a functional of the conditional covariance matrices. Hence, our analysis of the covariance matrices allows us to deduce properties of the value function.
Abstract A20: Synthetic lethality induced by pharmacological inhibition of ATM and PARP1
Authors: Mak Joyce Pui Ying , Poon Randy Yat Choi 
Published: April 2017

Abstract
DNA double-stranded breaks (DSBs) are highly deleterious and need to be repaired for maintaining genomic stability and viability. Cells resolve DSBs via non-homologous end-joining or homologous recombination repair (HRR). The simultaneous downregulation of both repair mechanisms induces synthetic lethality. Accordingly, PARP1 inhibitors (PARPi) are being used to target cancers with defective HRR such as cancers with BRCA1/2 mutations. Similar to BRCA1/2, ATM is involved in HRR; and ATM deficiency enhances sensitivity towards PARPi. But unlike BRCA1/2, ATM can be targeted using various small-molecule inhibitors (ATMi) in cancers containing wild type ATM. Using nasopharyngeal carcinoma cell lines as models, we found that the combined treatment of PARPi and ATMi led to the accumulation of DSBs, activation of the G2 DNA damage checkpoint, reduced mitotic entry, and diminished cell proliferation. Co-inhibition of ATM and PARP1 induced robust DNA damage responses without triggering mitotic catastrophe. In agreement with this, PARPi induced more DNA damage in ATM-knockout cells than wild type cells. Conversely, ATMi promoted more DNA damage when PARP1 was ablated. Although it is believed that PARPi exerts its effects by both inhibiting PARP1 catalytic activities and trapping PARP1 at DNA breaks, we found that the synergism between ATMi and PARPi did not require PARP1 trapping. These results provide insights on developing combined treatment of PARPi and ATMi into anti-cancer therapies for cancers without HRR or NHEJ deficiencies.
Citation Format: Joyce Pui Ying Mak, Randy Yat Choi Poon. Synthetic lethality induced by pharmacological inhibition of ATM and PARP1 [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 A20.
Abstract B07: Learning from human tumors: Modeling of Mre11 complex patient mutations in yeast
Authors: Hohl Marcel , Inagaki Akiko , Petrini John H.J. 
Published: April 2017

Abstract
The Mre11 complex plays a central role in the eukaryotic DNA damage response (DDR) in which it acts as a sensor of DNA double strand breaks (DSBs), and thereby governs DNA damage signaling as well as DSB repair. The complex is comprised of Mre11, Rad50, and Nbs1 (or Xrs2 in budding yeast), with dimers of Rad50 and Mre11 forming its core and a Nbs1/Xrs2 protomer binding to each Mre11. The Mre11 complex globular domain harbors all enzymatic and DNA binding functions of the Mre11 complex and is a very dynamic domain regulated by conformational changes induced by Rad50 ATP binding and hydrolysis cycles. It was suggested that the ATP-bound closed form of the complex promotes Mre11 complex role in ATM/Te1l signaling, whereas ATP hydrolysis opens the globular domain, and renders the Mre11 nuclease domain accessible to the DNA substrate to promote its role in DSB repair. We have recently shown that Mre11 complex role in ATM/Te1l signaling and DSB repair are genetically separable. The curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy was promoted in part by the simultaneous inhibition of both the ATR and the ATM axes of the DDR, as the tumor harbored a missense mutation within the Rad50 ATPase D-loop domain attenuating ATM signaling. To date, targeted tumor sequencing identified more than 800 missense mutations within Mre11 complex genes spanning various types of tumors, with some mutations occurring in highly conserved residues in several patients. Modeling of these alleles in yeast revealed a strong bias towards attenuating Mre11 complex's role in Tel1/ATM signaling, while leaving its DSB repair function intact. Using a combination of yeast and mouse genetic studies along with biochemical analysis, we aim to get mechanistic insights into Mre11 complex-ATM/Tel1 signaling. Learning from tumor samples deficient in Mre11 complex ATM signaling could not only be valuable for guiding treatment decisions in a synthetic lethal approach with ATR inhibitors, but also potentiate the design of drugs that specifically block Mre11 complex ATM signaling.
Citation Format: Marcel Hohl, Akiko Inagaki, John H.J. Petrini. Learning from human tumors: Modeling of Mre11 complex patient mutations in yeast [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 B07.
Abstract B27: Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors
Authors: Packer Matthew , Saleh Ali , Katyal Sachin 
Published: April 2017

Abstract
Purpose: Current methods to treat glioblastoma multiforme (GBM) are highly invasive, lead to poor quality-of-life and an abysmal patient survival rate thus making GBMs one of the most difficult-to-treat and deadliest form of all primary CNS malignancies. The targeted use of Topoisomerase-1 (Top1) poisons/inhibitors to sensitize or augment tumor cell killing is a long-standing and powerful tool in cancer therapy. A number of trials utilizing Top1 inhibitors to manage GBM have shown promise.
We have uncovered a novel functional requirement for ATM (Mutated in Ataxia Telangiectasia) in resolving oxidative DNA breaks and Topoisomerase 1-DNA covalent complexes (Top1cc), a DNA-protein intermediate that can generate DNA breaks upon collision with the transcriptional machinery or DNA replication forks. These data have identified Top1cc as the first specific endogenous pathogenic neural DNA lesion associated with loss of ATM and heritable pediatric neurodegenerative disease. Furthermore, biochemical and genetic studies identified collaboration of ATM and TDP1 (Tyrosyl-DNA Phosphodiesterase 1) in the resolution of Top1cc during neurodevelopment.
We hypothesize that co-inhibition of ATM and TDP1 will sensitize brain tumors to Top1-dependent chemotherapy by augmenting Top1cc levels and anti-tumor success.
Methods: Genetic and biochemical methods to co-inhibit ATM and TDP1 and improve the efficacy of Top1 poisons include novel high-throughput cell-based DNA damage repair and viability assays and in vivo brain tumor regression assays using mouse xenograft models.
Results: We have found that brain tumor cell killing via Top1-dependent inhibition is greatly enhanced through an ATM and TDP1 co-inhibition strategy. Induced genotoxic cell death occurs at lower chemotherapeutic drug doses as a result of sensitization to Top1cc. We are presently validating these results and performing in vivo studies.
Conclusions: ATM and TDP1 co-inhibition represents an effective two-pronged approach to chemoradiosensitize CNS tumors. As TDP1 antagonizes Top1cc formation and efficacy of Top1 poisons such as the camptothecin (CPT) cohort of drugs, our findings will improve existing Top1-mediated anti-cancer strategies by enhancing tumor cell killing while reducing clinical doses and patient side-effects. Furthermore, these findings also suggest an alternative avenue in the clinical management of GBM.
Citation Format: Matthew Packer, Ali Saleh, Sachin Katyal. Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors [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 B27.
Abstract IA17: Non-canonical aspects of ATM and p53 signaling pathways
Authors: Kastan Michael B. , Scarbrough Peter , Chen Jing , Brown Adam , Crutchley John , Fleenor Donald 
Published: April 2017

Abstract
The ATM protein kinase and p53 protein are both central mediators of many aspects of DNA damage and cellular stress signaling. While there is a clear, direct relationship between ATM and p53, ATM has numerous substrates in addition to p53 and, conversely, p53 can be activated by selected stresses without ATM. We have identified novel aspects of stress response signaling independently involving either ATM or p53. Though ATM plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in the cancer-prone disorder, Ataxia-telangiectasia (A-T), are difficult to attribute directly to alterations in DNA damage signaling, such as neurodegeneration (primarily cerebellar), immunodeficiency, insulin resistance, progressive lung disease, and telangiectasia development. Our recent data demonstrate that, in addition to its DNA damage signaling functions, the ATM protein kinase has critical, p53-independent, non-canonical roles in modulating mitochondrial function and affecting metabolic stress signaling. It is intriguing that one gene product seems to be at a nexus of DNA damage signaling and metabolic signaling, but perhaps it should not be surprising that these pathways would be linked and that a protein with a PI-3K domain and a protein in the mTOR kinase family would provide such a link. These insights suggest that Ataxia-telangiectasia should be considered, at least in part, as a mitochondrial dysfunction disease and provide links between cancer-related DNA damage signaling, general metabolic signaling pathways, and cancer development. We have also identified novel aspects of p53 regulation by DNA damage involving ATM-independent regulation of RNA splicing, a process which affects splicing of p53 and other gene products and modulates cellular outcome after DNA damage. This DNA damage-induced alternative splicing pathway expands the repertoire of gene products that modulate cellular stress responses.
Citation Format: Michael B. Kastan, Peter Scarbrough, Jing Chen, Adam Brown, John Crutchley, Donald Fleenor. Non-canonical aspects of ATM and p53 signaling pathways [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 IA17.
It Takes a Village to Unmask HSTL
Authors: Yoshida Noriaki , Weinstock David M. 
Published: April 2017

Abstract
Summary: In this issue of Cancer Discovery, McKinney and colleagues describe the genetics of hepatosplenic T-cell lymphoma, a rare subtype of T-cell lymphoma with unique clinical characteristics. The findings, specifically frequent mutations of STAT5B, PIK3CD, and the histone methyltransferase SETD2, may help guide translational efforts to target this deadly disease. Cancer Discov; 7(4); 352–3. ©2017 AACR.
See related article by McKinney et al., p. 369.
Secondary Eyewall Formation in Tropical Cyclones by Outflow–Jet Interaction
Authors: Dai Yi , Majumdar Sharanya J. , Nolan David S. 
Published: April 2017

Abstract
This study uses idealized numerical simulations to show that the interaction between tropical cyclones and a midlatitude jet can result in secondary eyewall formation. It is argued that the eddy activity by the outflow–jet interaction can enhance the upper-level outflow, thereby creating an asymmetric stratiform region outside of the primary eyewall. Numerous long-lasting deep convective cells are able to form in the stratiform cloud, creating forcing necessary for the secondary eyewall. The low-level inflow and the TC’s primary circulation advect the deep convective cells inward and cyclonically. The secondary eyewall forms after the deep convection has surrounded the TC. In contrast, numerical simulations without the jet do not show secondary eyewall formation. For moderately strong jets of wind speed 15–30 m s−1, there is little sensitivity to the jet strength. There is sensitivity to the distance between the jet and the TC, with secondary eyewall formation evident when their separation is 15° latitude but not when the separation exceeds 20°.
Upper-Ocean Contribution to Short-Term Regional Coastal Sea Level Variability along the United States
Authors: Nieves Veronica , Marcos Marta , Willis Josh K. 
Published: April 2017

Abstract
The upper ocean thermal structure is largely influenced by natural internal variability, and it modulates global surface temperature as well as regional sea level anomalies over decadal time scales. The internal variability of some important oceanographic processes, such as the Pacific decadal oscillation, can cause differences of 10 to 20 cm relative to the global mean in many coastal locations. These differences are sufficient to alter decisions between soft and/or large protective measures on every coast. Yet, current indicators of sea level changes are based on either surface variables or subsurface ocean measurements through the entire water column. There is also a lack of focus on short-term predictions of sea level change and concrete applications of these predictions at regional scale, which clouds local decision-making. The results herein confirm that the information contained within the top 300 m of the ocean is essential to capture decadal, regional relative sea level variability, whereas depths well below the thermocline do not appear to be closely tied to these large oscillations. Hence, the authors propose a regionally scoped indicator based on upper-ocean temperature as a first step toward identifying trend changes in short-term sea level rise over large coastal regions of the United States. The proposed indicator is a promising new tool that could help close the gaps mentioned above and improve the utility of existing local sea level records.