bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-sided expansions of monoids
Authors: Kudryavtseva Ganna 
Published: July 2019

We initiate the study of expansions of monoids in the class of two-sided restriction monoids and show that generalizations of the Birget–Rhodes prefix group expansion, despite the absence of involution, have rich structure close to that of relatively free inverse monoids. For a monoid [Formula: see text] and a class of partial actions of [Formula: see text], determined by a set, [Formula: see text], of identities, we define [Formula: see text] to be the universal [Formula: see text]-generated two-sided restriction monoid with respect to partial actions of [Formula: see text] determined by [Formula: see text]. This is an [Formula: see text]-restriction monoid which (for a certain [Formula: see text]) generalizes the Birget–Rhodes prefix expansion [Formula: see text] of a group [Formula: see text]. Our main result provides a coordinatization of [Formula: see text] via a partial action product of the idempotent semilattice [Formula: see text] of a similarly defined inverse monoid, partially acted upon by [Formula: see text]. The result by Fountain, Gomes and Gould on the structure of the free two-sided restriction monoid is recovered as a special case of our result. We show that some properties of [Formula: see text] agree well with suitable properties of [Formula: see text], such as being cancellative or embeddable into a group. We observe that if [Formula: see text] is an inverse monoid, then [Formula: see text], the free inverse monoid with respect to strong premorphisms, is isomorphic to the Lawson–Margolis–Steinberg generalized prefix expansion [Formula: see text]. This gives a presentation of [Formula: see text] and leads to a model for [Formula: see text] in terms of the known model for [Formula: see text].
Linear capabilities for fully abstract compilation of separation-logic-verified code
Authors: Van Strydonck Thomas , Piessens Frank , Devriese Dominique 
Published: July 2019

Separation logic is a powerful program logic for the static modular verification of imperative programs. However, dynamic checking of separation logic contracts on the boundaries between verified and untrusted modules is hard, because it requires one to enforce (among other things) that outcalls from a verified to an untrusted module do not access memory resources currently owned by the verified module.
This paper proposes an approach to dynamic contract checking by relying on support for capabilities, a well-studied form of unforgeable memory pointers that enables fine-grained, efficient memory access control. More specifically, we rely on a form of capabilities called linear capabilities for which the hardware enforces that they cannot be copied.
We formalize our approach as a fully abstract compiler from a statically verified source language to an unverified target language with support for linear capabilities. The key insight behind our compiler is that memory resources described by spatial separation logic predicates can be represented at run time by linear capabilities. The compiler is separation-logic-proof-directed: it uses the separation logic proof of the source program to determine how memory accesses in the source program should be compiled to linear capability accesses in the target program.
The full abstraction property of the compiler essentially guarantees that compiled verified modules can interact with untrusted target language modules as if they were compiled from verified code as well.
Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer
Authors: Shang Stephen , Yang Jiekun , Jazaeri Amir A. , Duval Alexander James , Tufan Turan , Lopes Fischer Natasha , Benamar Mouadh , Guessous Fadila , Lee Inyoung , Campbell Robert M. , Ebert Philip J. , Abbas Tarek , Landen Charles N. , Difeo Analisa , Scacheri Peter C. , Adli Mazhar 
Published: July 2019

AbstractChemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers.Significance:Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.
Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia
Authors: Hosseini Mohsen , Rezvani Hamid Reza , Aroua Nesrine , Bosc Claudie , Farge Thomas , Saland Estelle , Guyonnet-Dupérat Véronique , Zaghdoudi Sonia , Jarrou Latifa , Larrue Clément , Sabatier Marie , Mouchel Pierre Luc , Gotanègre Mathilde , Piechaczyk Marc , Bossis Guillaume , Récher Christian , Sarry Jean-Emmanuel 
Published: July 2019

Abstract

Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance.

Significance:
These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.
Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States
Authors: Mahal Brandon A. , Catalano Paul J. , Haddad Robert I. , Hanna Glenn J. , Kass Jason I. , Schoenfeld Jonathan D. , Tishler Roy B. , Margalit Danielle N. 
Published: July 2019

Abstract

Background:
Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed.

Methods:
The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and “other pharynx”), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality.

Results:
From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51–4.73] versus 1.82 (95% CI, 1.75–1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58–0.66) versus 1.38 (95% CI, 1.32–1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P &lt; 0.001], but not non-OPSCC (aHR, 1.08; P = 0.81), Pinteraction = 0.002.

Conclusions:
The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx.

Impact:
This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.
Urinary Metabolites Diagnostic and Prognostic of Intrahepatic Cholangiocarcinoma
Authors: Haznadar Majda , Diehl Christopher M. , Parker Amelia L. , Krausz Kristopher W. , Bowman Elise D. , Rabibhadana Siritida , Forgues Marshonna , Bhudhisawasdi Vajarabhongsa , Gonzalez Frank J. , Mahidol Chulabhorn , Budhu Anuradha , Wang Xin W. , Ruchirawat Mathuros , Harris Curtis C. 
Published: July 2019

Abstract

Background:
Liver cancer is the second leading cause of cancer-related deaths worldwide. With a predicted 2.4-fold rise in liver cancer incidence by 2020, there is an urgent need for early, inexpensive diagnostic biomarkers to deploy in the clinic.

Methods:
We employed ultraperformance liquid chromatography tandem mass-spectrometry (UPLC/MS-MS) for the quantitation of four metabolites, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate, and a lipid molecule designated as 561+, in urine samples from the NCI-MD cohort comprising 98 hepatocellular carcinoma (HCC) cases, 101 high-risk subjects, and 95 controls. Validation was carried out in the TIGER-LC cohort [n = 370 HCC and intrahepatic cholangiocarcinoma (ICC) cases, 471 high-risk subjects, 251 controls], where ICC, the second most common primary hepatic malignancy, is highly prevalent. Metabolite quantitation was also conducted in TIGER-LC tissue samples (n = 48 ICC; n = 51 HCC).

Results:
All profiled metabolites were significantly increased in liver cancer when compared with high-risk subjects and controls in the NCI-MD study. In the TIGER-LC cohort, the four-metabolite profile was superior at classifying ICC than a clinically utilized marker, CA19-9, and their combination led to a significantly improved model (AUC = 0.88, P = 4E-8). Metabolites CR and NANA were significantly elevated in ICC when compared with HCC cases in both urine and tissue samples. High levels of CR were associated with poorer prognosis in ICC.

Conclusions:
Four metabolites are significantly increased in HCC and ICC and are robust at classifying ICC in combination with the clinically utilized marker CA19-9.

Impact:
Noninvasive urinary metabolite biomarkers hold promise for diagnostic and prognostic evaluation of ICC.
Safety, Clinical Activity, and Biological Correlates of Response in Patients with Metastatic Melanoma: Results from a Phase I Trial of Atezolizumab
Authors: Hamid Omid , Molinero Luciana , Bolen Christopher R. , Sosman Jeffrey A. , Muñoz-Couselo Eva , Kluger Harriet M. , McDermott David F. , Powderly John D. , Sarkar Indrani , Ballinger Marcus , Fassò Marcella , O'Hear Carol , Chen Daniel S. , Hegde Priti S. , Hodi F. Stephen 
Published: July 2019

Abstract

Purpose:
Atezolizumab [anti–programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842).

Patients and Methods:
Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored.

Results:
Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35–not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9–66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival.

Conclusions:
Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.
The Covalent CDK7 Inhibitor THZ1 Potently Induces Apoptosis in Multiple Myeloma Cells In Vitro and In Vivo
Authors: Zhang Yu , Zhou Liang , Bandyopadhyay Dipankar , Sharma Kanika , Allen Alexander Joseph , Kmieciak Maciej , Grant Steven 
Published: July 2019

Abstract

Purpose:
The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models.

Experimental Design:
Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model.

Results:
THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2–M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138−/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation.

Conclusions:
THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.
Circulating Tumor Cell Clusters in Patients with Metastatic Breast Cancer: a SWOG S0500 Translational Medicine Study
Authors: Paoletti Costanza , Miao Jieling , Dolce Emily M. , Darga Elizabeth P. , Repollet Madeline I. , Doyle Gerald V. , Gralow Julie R. , Hortobagyi Gabriel N. , Smerage Jeffrey B. , Barlow William E. , Hayes Daniel F. 
Published: July 2019

Abstract

Purpose:
Metastasis requires malignant cell circulation from the primary to a distant tissue. Elevated levels of circulating tumor cells (CTC) portend a poor prognosis in breast and other cancers. Recent studies have suggested that CTC clusters may be a factor in the metastatic process. We conducted a prospective retrospective study of the SWOG0500 clinical trial to test whether CTC clusters are associated with poorer prognosis.

Experimental Design:
CTC CellSearch galleries from SWOG0500 trial were reread using prespecified criteria for CTC clusters, doublets, and enumeration. Survival analysis methods include Kaplan–Meier plots and log-rank tests.

Results:
Patients were classified into three prognostic subgroups based on baseline CTC/7.5 mL whole blood (WB): Arm A: &lt;5CTC; Arm B/C: ≥5CTC and then B (&lt;5CTC) and C (≥5CTC)/7.5 mL WB at first follow-up. At baseline, 19% of patients had CTC doublets or clusters, which were more likely in Arm B/C versus Arm A (38% vs. 1.4%; P &lt; 0.0001). Furthermore, doublets or clusters were significantly more common in patients who were ultimately assigned to Arm C versus B (54% vs. 25%; P &lt; 0.0001). In Arm C, doublets and clusters were associated with worse overall survival than only doublets, clusters, or no doublets nor clusters at baseline (P = 0.008) and first follow-up (P = 0.010). When compared with enumeration alone, doublets, clusters, or both were not prognostic in patients who had 5–19 or ≥20 CTC/7.5 mL WB.

Conclusions:
In patients with metastatic breast cancer starting first-line chemotherapy, mortality is independent of the presence of CTC clusters, but rather depends on the number of CTC/7.5 mL WB.
Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity
Authors: Dagogo-Jack Ibiayi , Rooney Marguerite , Lin Jessica J. , Nagy Rebecca J. , Yeap Beow Y. , Hubbeling Harper , Chin Emily , Ackil Jennifer , Farago Anna F. , Hata Aaron N. , Lennerz Jochen K. , Gainor Justin F. , Lanman Richard B. , Shaw Alice T. 
Published: July 2019

Abstract

Purpose:
Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.

Experimental Design:
We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.

Results:
By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with ≥2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new ALK mutations on lorlatinib.

Conclusions:
ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.
Widespread phenotypic hypervariation in the enigmatic anchialine shrimp Barbouria cubensis (Decapoda: Barbouriidae)
Authors: DITTER ROBERT E. , ERDMAN ROBERT B. , GOEBEL ANNA M. , BRACKEN-GRISSOM HEATHER D. 
Published: July 2019

Classification and evolutionary relationships among anchialine shrimp from the family Barbouriidae Christoffersen, 1987, has long been a topic of debate amongst crustacean taxonomists. To date, no study has examined morphological or molecular variation among populations of these enigmatic shrimp. The present study documents and analyzes patterns of widespread morphological variation within populations of Barbouria cubensis von Martens, 1872, from anchialine pools on three Bahamian islands. Such extensive morphological variation confounds identification using classic taxonomical methods. Phenotypic variation is by no means a new topic, but studies of decapods are typically limited to isolated individuals or few morphological characters. Moreover, past studies of B. cubensis do not report extensive morphological variation, however we find that upwards of 90% of individuals are affected. Anomalous phenotypes are described in 54 morphological characters with no detectable pattern associated with geographic distribution. The term phenotypic hypervariation (PhyV) is used to describe morphological variation that greatly deviates from any previous taxonomic descriptions. Analysis of partial sequences of the 16S and COI mitochondrial genes confirm the identity of morphologically variable specimens as B. cubensis without population structure across the tropical western Atlantic. A test for cryptic diversity within B. cubensis suggests PhyV is not correlated with cryptic diversity. Morphological variation at this scale likely depends on recent changes either to their environment or genetic diversity.
An Updated Analysis of Northern Hemisphere Submonthly Retrograde Waves
Authors: Raghunathan Girish Nigamanth , Huang Huei-Ping 
Published: July 2019

Abstract
This study performs an updated analysis of Northern Hemisphere retrograde disturbances that were first identified by classical observational studies as one of the dominating coherent structures in the higher latitudes on the submonthly time scale. Analyzing 8–30-day bandpass-filtered data based on reanalysis, a set of criteria on the phase and amplitude of zonal wave-1 Fourier coefficients of geopotential height anomalies at 250 mb (1 mb = 1 hPa) and 60°N are used to identify strong retrograde-wave events in the spirit of Madden and Speth. The new catalog of retrograde-wave events from 1979 to 2017 is used to extract basic statistics and structures of retrograde waves across all major events. The results broadly agree with those reported in the classical observational studies, reaffirming the robustness of the phenomenon. The new catalog can be used to aid further studies on the mechanisms and predictability of retrograde waves. As an example, an analysis of isentropic potential vorticity over the Pacific sector for selected retrograde-wave events reveals the common occurrence of an extrusion of low-PV air into the higher latitudes, followed by a westward shift of the low-PV patch and vortex shedding. Future directions of research surrounding the retrograde-wave phenomenon are discussed.