bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-polynomial Worst-Case Analysis of Recursive Programs
Authors: Chatterjee Krishnendu , Fu Hongfei , Goharshady Amir Kafshdar 
Published: October 2019

We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of non-recursive programs. First, we apply ranking functions to recursion, resulting in measure functions. We show that measure functions provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in non-polynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas Lemma, and Handelman’s Theorem using linear programming. While previous methods obtain polynomial worst-case bounds, our approach can synthesize bounds of various forms including O(
n
log
n
) and O(
n

r

), where
r
is not an integer. We present experimental results to demonstrate that our approach can efficiently obtain worst-case bounds of classical recursive algorithms such as (i) Merge sort, Heap sort, and the divide-and-conquer algorithm for the Closest Pair problem, where we obtain O(
n
log
n
) worst-case bound, and (ii) Karatsuba’s algorithm for polynomial multiplication and Strassen’s algorithm for matrix multiplication, for which we obtain O(
n

r

) bounds such that
r
is not an integer and is close to the best-known bound for the respective algorithm. Besides the ability to synthesize non-polynomial bounds, we also show that our approach is equally capable of obtaining polynomial worst-case bounds for classical programs such as Quick sort and the dynamic programming algorithm for computing Fibonacci numbers.
Radiation Drives the Evolution of Orthotopic Xenografts Initiated from Glioblastoma Stem–like Cells
Authors: McAbee Joseph H. , Rath Barbara H. , Valdez Kristin , Young Dejauwne L. , Wu Xiaolin , Shankavaram Uma T. , Camphausen Kevin , Tofilon Philip J. 
Published: October 2019

Abstract

A consequence of the intratumor heterogeneity (ITH) of glioblastoma (GBM) is the susceptibility to treatment-driven evolution. To determine the potential of radiotherapy to influence GBM evolution, we used orthotopic xenografts initiated from CD133+ GBM stem–like cells (GSC). Toward this end, orthotopic xenografts grown in nude mice were exposed to a fractionated radiation protocol, which resulted in a significant increase in animal survival. Brain tumors from control and irradiated mice were then collected at morbidity and compared in terms of growth pattern, clonal diversity, and genomic architecture. In mice that received fractionated radiation, tumors were less invasive, with more clearly demarcated borders and tumor core hypercellularity as compared with controls, suggesting a fundamental change in tumor biology. Viral integration site analysis indicated a reduction in clonal diversity in the irradiated tumors, implying a decrease in ITH. Changes in clonal diversity were not detected after irradiation of GSCs in vitro, suggesting that the radiation-induced reduction in ITH was dependent on the brain microenvironment. Whole-exome sequencing revealed differences in mutation patterns between control and irradiated tumors, which included modifications in the presence and clonality of driver mutations associated with GBM. Moreover, changes in the distribution of mutations as a function of subpopulation size between control and irradiated tumors were consistent with subclone expansion and contraction, that is, subpopulation evolution. Taken together, these results indicate that radiation drives the evolution of the GSC-initiated orthotopic xenografts and suggest that radiation-driven evolution may have therapeutic implications for recurrent GBM.

Significance:
Radiation drives the evolution of glioblastoma orthotopic xenografts; when translated to the clinic, this may have therapeutic implications for recurrent tumors.
Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome
Authors: Wischhusen Jonathan W. , Ukaegbu Chinedu , Dhingra Tara G. , Uno Hajime , Kastrinos Fay , Syngal Sapna , Yurgelun Matthew B. 
Published: October 2019

Abstract

Background:
Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). It is unknown how to determine which Lynch syndrome carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among Lynch syndrome carriers.

Methods:
The study population was a cohort of 52,758 consecutively ascertained individuals undergoing Lynch syndrome testing at a commercial laboratory. Clinical data were obtained from test request forms completed by the ordering provider. Univariate analysis and multivariate logistic regression were performed to identify factors associated with UTC among Lynch syndrome carriers.

Results:
Compared with noncarriers, Lynch syndrome carriers were significantly more likely to have had UTC (4.1% vs. 1.2%; P &lt; 0.0001). Lynch syndrome–associated UTC was independently associated with male sex [OR 1.95; 95% confidence interval (CI), 1.38–2.76], increased age (OR 2.44 per 10 years; 95% CI, 2.11–2.82), familial burden of UTC (OR 2.69 per first-/second-degree relative with UTC; 95% CI, 1.99–3.63), and pathogenic EPCAM/MSH2 variants (OR 4.01; 95% CI, 2.39–6.72) but not MLH1 variants (OR 1.17; 95% CI, 0.63–2.17), race, or history of other Lynch syndrome–associated malignancy. A total of 143 of 158 (90.5%) Lynch syndrome carriers with UTC had ≥1 of the following characteristics: male sex, EPCAM/MSH2 variants, or family history of UTC; 1,236 of 1,251 (98.8%) Lynch syndrome carriers lacking all of these characteristics had no history of UTC.

Conclusions:
Specific clinical factors can reliably identify Lynch syndrome carriers most likely to be at risk for UTC.

Impact:
A predictable subset of Lynch syndrome carriers may be most likely to benefit from UTC surveillance/prevention.
Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker
Authors: Parada Carolina A. , Osbun Joshua W. , Busald Tina , Karasozen Yigit , Kaur Sumanpreet , Shi Min , Barber Jason , Adidharma Widya , Cimino Patrick J. , Pan Catherine , Gonzalez-Cuyar Luis F. , Rostomily Robert , Born Donald E. , Zhang Jing , Ferreira Manuel 
Published: October 2019

Abstract

Purpose:
Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.

Experimental Design:
Mass spectrometry (MS)–based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.

Results:
The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.

Conclusions:
RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.
Epigenetic Profiling Identifies LIF as a Super-enhancer-Controlled Regulator of Stem Cell–like Properties in Osteosarcoma
Authors: Lu Bing , He Yangyang , He Jincan , Wang Li , Liu Zhenguo , Yang Jiayan , Gao Zhuoxing , Lu Guohao , Zou Changye , Zhao Wei 
Published: October 2019

Abstract

Osteosarcoma is an aggressive malignancy with poor prognosis. Super-enhancers (SE) have been highlighted as critical oncogenic elements required for maintaining the cancer cell characteristics. However, the regulatory role of SEs in osteosarcoma properties has not yet been elucidated. In the current study, we found that osteosarcoma cells and clinical specimens shared a significant fraction of SEs. Moreover, leukemia-inhibitory factor (LIF) was identified as an essential factor under the control of osteosarcoma-specific SE. The expression of LIF was positively correlated with the stem cell core factor genes in osteosarcoma. Furthermore, LIF recombinant protein–treated osteosarcoma cells displayed enhanced stem cell–like characteristics, such as increased sphere-forming potential, stimulated self-renewal, upregulated metastasis ability, and increased stemness-related gene expression. Notably, the histone 3 lysine 27 tri-methylation (H3K27me3) demethylase UTX was found as a key activator of LIF transcription in osteosarcoma. The UTX inhibitor, GSK-J4, induced H3K27me3 accumulation and impaired histone 3 lysine 27 acetylation (H3K27ac) at LIF gene locus, leading to LIF signaling pathway inhibition. GSK-J4 treatment resulted in profound defects in stem cell-like characteristics and stemness-related gene activation in osteosarcoma by modulating the H3K27ac of NOTCH1 signaling pathway gene loci. The NOTCH1 inhibitor Crenigacestat (TargetMol, T3633) repressed LIF-mediated activation of the stemness-related genes in osteosarcoma patient-derived primary tissues.

Implications:
This study reveals osteosarcoma SE profiles and uncovers a distinct tumor–stemness epigenetic regulatory mechanism in which an osteosarcoma-specific SE-mediated factor, LIF, promotes osteosarcoma stemness gene activation via NOTCH1 signaling pathway.
Comparison of Functional Outcomes between Functional Jejunal Interposition and Conventional Roux-en-Y Esophagojejunostomy after Total Gastrectomy for Gastric Cancer
Authors: Yun Li , Zhiwei Jiang , Junsheng Peng , Xiaobin Wu , Cancan Xia , Jieshou Li 
Published: October 2019

<b><i>Background:</i></b> The reconstruction of digestive tract after total gastrectomy is associated with various postoperative complications. We aimed to investigate the differences in functional outcomes of 2 reconstruction techniques following total gastrectomy: functional jejunal interposition (FJI) versus Roux-en-Y esophagojejunostomy. <b><i>Methods:</i></b> Sixty patients were enrolled and divided into FJI and Roux-en-Y groups. Nutritional parameters and incidences of reconstruction-related symptoms were evaluated. Oral glucose tolerance test and endoscopy examination were carried out. <b><i>Results:</i></b> The postoperative prognostic nutritional index scores and postoperative/preoperative body weight, meal intake, serum albumin level ratio were significantly higher in the FJI group than in the Roux-en-Y group. At 3, 6, and 12 months postoperatively, the elevations of plasma glucose level after glucose intake were more significant in the FJI group than in the Roux-en-Y group. The incidence of postoperative stasis symptoms in the Roux-en-Y group was significantly higher than in the FJI group, but no obvious difference was observed regarding dumping and reflux symptoms. The incidence rates of severe esophageal mucosa injury and severe anastomotic stricture were also similar between the 2 groups. <b><i>Conclusion:</i></b> FJI reconstruction might accelerate the recovery of nutritional status and reduce the occurrence of stasis symptoms postoperatively as compared with Roux-en-Y esophagojejunostomy, which may have an advantage over FJI in stabilizing body glycometabolism after surgery. These 2 types of reconstruction may have a similar anti-reflux function to prevent severe reflux esophagitis and anastomotic stenosis.
Genera of orders Actiniaria and Corallimorpharia (Cnidaria, Anthozoa, Hexacorallia), and their type species*
Authors: FAUTIN DAPHNE GAIL , ZELENCHUK TARAS , RAVEENDRAN DINESH 
Published: October 2019

We determined the type species, if any, for the 425 genera of the order Actiniaria and for the 19 genera of order Corallimorpharia. In Actiniaria, 393 genera have a clear type species; 46 generic names are homonyms, 17 of which are senior, 26 of which are junior (six have been replaced), and three are both junior and senior. Of the 18 available genera of Corallimorpharia, there are no junior homonyms, and one senior homonym.
Phylum Nematoda*
Authors: HODDA MIKE 
Published: October 2019

The systematics of nematodes is reviewed, including: an overview of the general biology, ecology, scientific and economic importance of the group; a history of classification; evolutionary affinities and origins of nematodes; and the current diagnosis of the group. Alternative classifications within the Phylum Nematoda are discussed, and a classification to family level incorporating the latest molecular, developmental and morphological research is presented. This classification reflects the current views on evolution within the phylum, as well as significant areas of uncertainty, particularly related to the early evolution of nematodes. It includes 5 classes, 9 subclasses, 23 superorders, 39 orders, 52 suborders, 89 superfamilies and 241 families. There are few changes at the superfamily and family levels.
QT interval prolongation in patients with acute ischemic stroke: a report in northwest China
Authors: Wu Jine , Nizhamuding Dilimulati , Liu Peng , Jiang Yongrong , Qiang Hua , Sun Chaofeng , Dai Chongliang , Yin Yanrong 
Published: October 2019

Aims QT interval prolongation is common in patients with stroke and increases the risk of malignant arrhythmia and sudden death. Our aim was to analyze differences in the QT interval and electrocardiogram abnormalities between acute ischemic stroke patients and controls. Methods We retrospectively collected data from 273 patients with acute ischemic stroke from the neurological intensive care unit and 495 controls from other departments. A standard 12-lead electrocardiogram was recorded within 24 hours of hospitalization. Clinical information, the QT interval corrected for heart rate (QTc), and the incidence of electrocardiogram abnormalities were compared between groups. Results There was no difference in age, sex, or the prevalence of hypertension or diabetes mellitus between the acute ischemic stroke group and controls. Acute ischemic stroke patients showed a significantly longer QTc and a higher incidence of both sinus bradycardia and ST-T changes compared with controls. We also showed that the changes in electrocardiogram results observed in acute ischemic stroke might be transient. Conclusion Acute ischemic stroke patients may have a longer QT interval and a higher incidence of electrocardiogram abnormalities. In clinical practice, careful attention should be paid to acute ischemic stroke patients to prevent malignant arrhythmia.
Physical activity may drive healthy microvascular ageing via downregulation of p66Shc
Authors: Streese Lukas , Khan Abdul W , Deiseroth Arne , Hussain Shafaat , Suades Rosa , Tiaden Andre , Kyburz Diego , Hanssen Henner , Cosentino Francesco 
Published: October 2019

Background Narrower retinal arterioles and wider venules are linked to adverse cardiovascular outcomes. The mitochondrial adaptor p66Shc is a major source of ageing-induced generation of reactive oxygen species. Promoter DNA methylation inhibits p66Shc gene transcription. This cross-sectional study was designed to investigate the link between physical activity, retinal vessel diameters and p66Shc expression in active and sedentary ageing subjects. Design/methods Altogether 158 subjects were included in the study (mean age 59.4 ± 7.0 years). Thirty-eight subjects were healthy active, 36 were healthy sedentary and 84 were sedentary with ≥2 cardiovascular risk factors. Retinal arteriolar and venular diameters were measured by means of a retinal vessel analyser. As a marker of oxidative stress, plasma 3-nitrotyrosine was determined by enzyme-linked immunosorbent assay. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and methylated-DNA capture (MethylMiner Enrichment kit) coupled with quantitative polymerase chain reaction, respectively. Results Wider retinal arterioles (179 ± 14 vs 172 ± 11 and 171 ± 14 µm; p < 0.05 and narrower venules (204 ± 17 vs 209 ± 11 and 218 ± 16 µm; p < 0.001) were observed in healthy active subjects compared with healthy sedentary subjects and sedentary subjects with ≥2 cardiovascular risk factors, respectively. Furthermore, healthy active subjects had blunted p66Shc expression and lower 3-nitrotyrosine plasma levels compared with healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors. Accordingly, hypomethylation of p66Shc promoter observed in healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors was not found in healthy active subjects. Conclusion Long-term physical activity-induced DNA methylation of p66Shc may represent a putative mechanistic link whereby active lifestyle promotes healthy microvascular ageing.
Chinese version of the Rotator Cuff Quality of Life questionnaire: Cross-cultural adaptation and validation in rotator cuff-impaired patients in Hong Kong
Authors: Li Ho-ming , Chau Jackie YM , Woo SB , Lai J , Chan WL 
Published: October 2019

Purpose: To adapt the Rotator Cuff Quality of Life (RC-QOL) questionnaire into traditional Chinese (Chi-RC-QOL) and to evaluate the validity and reliability in patients suffering from rotator cuff pathologies in Hong Kong. Methods: The Chi-RC-QOL will be constructed using the forward-translation followed by the backward-translation method. Thirty consecutive patients with clinically and radiologically confirmed rotator cuff pathology were recruited. Descriptive statistics will be followed by validity assessment using comparison with the Constant Shoulder (CS) score, University of California Los Angeles (UCLA) Shoulder Rating Scale, and Western Ontario Rotator Cuff (WORC) score. Parametric data will be tested using Pearson’s correlation coefficient for the total scores. Reliability was assessed using a test–retest interval of 30 min. The Cronbach’s α and intraclass correlation coefficient were calculated. Results: Cronbach’s α and internal consistency scores were high for all parts of the Chi-RC-QOL, with Cronbach’s α ranging between 0.89 and 0.98. Internal consistency scores range from 0.82 to 0.92, which can be regarded as an excellent correlation. Test–retest reliability was excellent for all parts of the Chi-RC-QOL with good absolute reliability. Chi-RC-QOL correlates well with the CS score, UCLA Shoulder Rating Scale, and the WORC score, with all being statistically significant. Conclusions: The current study adapted the RC-QOL to traditional Chinese version. The analysis confirmed the validity and reliability of the Chi-RC-QOL questionnaire. Level of Evidence: III.
Inherited Disorders of the Ras-MAPK Pathway
Authors: Kratz Christian P. , Zenker Martin 
Published: October 2019

Abstract
RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaciocutaneous syndrome, and Costello syndrome); (2) Neurofibromatosis type 1 and the related disorders Neurofibromatosis-Noonan syndrome and Legius syndrome; (3) Mosaic RASopathies including a rapidly growing group of mainly (neuro)cutaneous disorders with "oncogenic" mutations in a somatic mosaic state; (4) RAS-MAPK pathway dysregulation without a NS-like phenotype including non-syndromic intellectual disability due to SYNGAP1mutations and capillary malformation-arteriovenous malformation/Parkes-Weber syndrome; (5) RAS-MAPK pathway defects without overactivation such as metachondromatosis. Germline mutations leading to Ras-MAPK dysregulation typically lead to a characteristic pattern of craniofacial anomalies, heart defects, shorts stature, and variable neurodevelopmental deficits as seen in NS and other RASopathies of category 1. Confirmed genes leading to RASopathies from this category include BRAF,CBL, HRAS, KRAS, MAP2K1, MAP2K1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, LZTR1, and PPP1CB. Newer genes include SOS2, MRAS, RRAS, and RASA2. For some individual RASopathy disease entities, specific genotype associations exist, for others, this correlation is not tight. The cancer risk in many patients with RASopathies is only moderately increased, however, for a subgroup of patients the cancer risk is very high. These include patients with Costello syndrome (HRAS) who develop rhabdomyosarcoma, neuroblastoma and bladder cancer, patients with NF1 who develop juvenile myelomonocytic leukemia (JMML), neurofibroma/-fibrosarcoma, and brain tumors, and patients and with CBL syndrome who develop JMML. New clinical studies explore the use of RAS-MAPK Pathway inhibitors in this unique population. Various animal and in vitro models have been described, which (partially) recapitulate the human RASopathy phenotype and phenotypic rescue by manipulating RAS-MAPK signal flow has been demonstrated.

Disclosures
No relevant conflicts of interest to declare.
PKM2 Expression Is Associated with Favorable Outcome in Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Yongqiang , Wei Xiaolei , Song Jialin , Huang Weimin , Zeng Hong , Zheng Jingxia , Wei Qi , Feng Ru 
Published: October 2019

Abstract
Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and thought to contribute to cancer cell metabolic reprogramming. The aim of this study was to evaluate whether PKM2 expression by immunohistochemical was a potential prognostic biomarker in diffuse large B-cell lymphoma (DLBCL) patients. Herein, we explore the expression of PKM2 by immunohistochemistry in all 87 patients diagnosed as de novo DLBCL according to WHO classification. Among all the 87 patients, high expression of PKM2 was observed in 20 cases (23.0%). There was no significant difference in gender, age, B symptoms, performance status, LDH, stage and IPI score between patients with high and low PKM2 expression(P>0.05). Patients with high PKM2 expression showed significant superiorevent-free survival, but only a tendency in overall survival compared with low PKM2 expression patients (p=0.047 and p=0.465, respectively). Multivariate analysis showed that high expression of PKM2, independent of the international prognostic index, implied a favorable event-free survival (HR=0.363; 95% CI=0.109-0.927, p=0.038), but not overall survival (HR=0.646; 95% CI= 0.185-2.254, p=0.493). In conclusion, these data suggest that the expression of PKM2 may implied a good outcome in DLBCL patients treated with R-CHOP.

Disclosures
No relevant conflicts of interest to declare.