bluuebunny/crossref_metadata_2025 huggingface dataset:
Contextual equivalence for a probabilistic language with continuous random variables and recursion
Authors: Wand Mitchell , Culpepper Ryan , Giannakopoulos Theophilos , Cobb Andrew
Published: July 2018

We present a complete reasoning principle for contextual equivalence in an untyped probabilistic language. The language includes continuous (real-valued) random variables, conditionals, and scoring. It also includes recursion, since the standard call-by-value fixpoint combinator is expressible.

We demonstrate the usability of our characterization by proving several equivalence schemas, including familiar facts from lambda calculus as well as results specific to probabilistic programming. In particular, we use it to prove that reordering the random draws in a probabilistic program preserves contextual equivalence. This allows us to show, for example, that

(let x =
e
1
in let y =
e
2
in
e
0
) =

ctx

(let y =
e
2
in let x =
e
1
in
e
0
)

(provided
x
does not occur free in
e
2
and
y
does not occur free in
e
1
) despite the fact that
e
1
and
e
2
may have sampling and scoring effects.
Ready, set, verify! applying hs-to-coq to real-world Haskell code (experience report)
Authors: Breitner Joachim , Spector-Zabusky Antal , Li Yao , Rizkallah Christine , Wiegley John , Weirich Stephanie
Published: July 2018

Good tools can bring mechanical verification to programs written in mainstream functional languages. We use hs-to-coq to translate significant portions of Haskell’s containers library into Coq, and verify it against specifications that we derive from a variety of sources including type class laws, the library’s test suite, and interfaces from Coq’s standard library. Our work shows that it is feasible to verify mature, widely-used, highly optimized, and unmodified Haskell code. We also learn more about the theory of weight-balanced trees, extend hs-to-coq to handle partiality, and – since we found no bugs – attest to the superb quality of well-tested functional code.
Prototyping a functional language using higher-order logic programming: a functional pearl on learning the ways of λProlog/Makam
Authors: Stampoulis Antonis , Chlipala Adam
Published: July 2018

We demonstrate how the framework of
higher-order logic programming
, as exemplified in the λProlog language design, is a prime vehicle for rapid prototyping of implementations for programming languages with sophisticated type systems. We present the literate development of a type checker for a language with a number of complicated features, culminating in a standard ML-style core with algebraic datatypes and type generalization, extended with staging constructs that are generic over a separately defined language of terms. We add each new feature in sequence, with little to no changes to existing code. Scaling the higher-order logic programming approach to this setting required us to develop approaches to challenges like complex variable binding patterns in object languages and performing generic structural traversals of code, making use of novel constructions in the setting of λProlog, such as GADTs and generic programming. For our development, we make use of Makam, a new implementation of λProlog, which we introduce in tutorial style as part of our (quasi-)literate development.
Merlin: a language server for OCaml (experience report)
Authors: Bour Frédéric , Refis Thomas , Scherer Gabriel
Published: July 2018

We report on the experience of developing Merlin, a language server for the OCaml programming language in development since 2013. Merlin is a daemon that connects to your favourite text editor and provides services that require a fine-grained understanding of the programming language syntax and static semantics: instant feedback on warnings and errors, autocompletion, "type of the code under the cursor", "go to definition", etc.

Language servers need to handle incomplete and partially-incorrect programs, and try to be incremental to minimize recomputation after small editing actions. Merlin was built by carefully adapting the existing tools (the OCamllex lexer and Menhir parser generators) to better support incrementality, incompleteness and error handling. These extensions are elegant and general, as demonstrated by the interesting, unplanned uses that the OCaml community found for them. They could be adapted to other frontends -- in any language.

Besides incrementality, we discuss the way Merlin communicates with editors, describe the design decisions that went into some demanding features and report on some of the non-apparent difficulties in building good editor support, emerging from expressive programming languages or frustrating tooling ecosystems.

We expect this experience report to be of interest to authors of interactive language tooling for any programming language; many design choices may be reused, and some hard-won lessons can serve as warnings.
Generic zero-cost reuse for dependent types
Authors: Diehl Larry , Firsov Denis , Stump Aaron
Published: July 2018

Dependently typed languages are well known for having a problem with code reuse. Traditional non-indexed algebraic datatypes (e.g. lists) appear alongside a plethora of indexed variations (e.g. vectors). Functions are often rewritten for both non-indexed and indexed versions of essentially the same datatype, which is a source of code duplication.

We work in a Curry-style dependent type theory, where the same untyped term may be classified as both the non-indexed and indexed versions of a datatype. Many solutions have been proposed for the problem of dependently typed reuse, but we exploit Curry-style type theory in our solution to not only reuse data and programs, but do so at zero-cost (without a runtime penalty). Our work is an exercise in dependently typed generic programming, and internalizes the process of zero-cost reuse as the identity function in a Curry-style theory.
Following OCDE recommendations on digital government: open innovation and data science
Authors: Jimenez-Gomez Carlos E.
Published: July 2018

This introduction presents the two pieces written by Dr. Gasco-Hernandez and Dr. Luna-Reyes, for the fourth issue of the Association for Computing Machinery, Special Interest Groups on Computers and Society (SIGCAS) Newsletter. We introduce the articles through their main topics (open innovation and the data scientist) as linked elements to the OCDE strategies recommended for Digital Government and, specifically, to collaboration and openness as social-enablers.
How to make decisions with algorithms
Authors: Persson Anders , Kavathatzopoulos Iordanis
Published: July 2018

The use of automated decision-making support, such as algorithms within predictive analytics, will inevitably be more and more relevant and will be affecting society. Sometimes it is good, and sometimes there seems to be negative effect, such as with discrimination. The solution focused on in this paper is how humans and algorithms, or ICT, could interact within ethical decision-making. What predictive analytics can produce is, arguably, mostly implicit knowledge, so what a human decision-maker could, possibly, help with is the explicit thought processes. This could be one way to conceptualize an interactive effect between humans and algorithms that could be fruitful. Presently there does not seem to be very much research regarding predictive analytics and ethical decisions, concerning this human-algorithm interaction. Rather it is often a focus on pure technological solutions, or with laws and regulation.
Opening up attendance at HotNets
Authors: Mogul Jeffrey C. , Davie Bruce , Balakrishnan Hari , Govindan Ramesh
Published: July 2018

HotNets has historically been invitation-only. The SIGCOMM community has recently encouraged HotNets to allow broader participation. This note reports on a HotNets 2015 experiment with a more open attendance policy, and on the results of a post-workshop survey of the attendees. Based on this experiment and the survey, the HotNets Steering Committee believes it is possible for the workshop to support broader attendance, while preserving an atmosphere that encourages free-flowing discussions.
The student mentoring column
Authors: Akella Aditya
Published: July 2018

In this edition of the student mentoring column, we will cover three topics: the importance of journal and workshop papers, questions pertaining to giving/listening to talks, and two specific questions about jobs in networking.
Ouabain Does Not Induce Selective Spiral Ganglion Cell Degeneration in Guinea Pigs
Authors: Schomann Timo , Ramekers Dyan , de Groot John C. M. J. , van der Ploeg Carola H. , Hendriksen Ferry G. J. , Böhringer Stefan , Klis Sjaak F. L. , Frijns Johan H. M. , Huisman Margriet A.
Published: July 2018

Round window membrane (RWM) application of ouabain is known to selectively destroy type I spiral ganglion cells (SGCs) in cochleas of several rodent species, while leaving hair cells intact. This protocol has been used in rats and Mongolian gerbils, but observations in the guinea pig are conflicting. This is why we reinvestigated the effect of ouabain on the guinea pig cochlea. Ouabain solutions of different concentrations were placed, in a piece of gelfoam, upon the RWM of the right cochleas. Auditory function was assessed using acoustically evoked auditory brainstem responses (aABR). Finally, cochleas were fixed and processed for histological examination. Due to variability within treatment groups, histological data was pooled and three categories based upon general histological observations were defined: cochleas without outer hair cell (OHC) and SGC loss (Category 1), cochleas with OHC loss only (Category 2), and cochleas with OHC and SGC loss (Category 3). Animals treated with 1 mM or 10 mM ouabain showed shifts in hearing thresholds, corresponding with varying histological changes in their cochleas. Most cochleas exhibited complete outer hair cell loss in the basal and middle turns, while some had no changes, together with either moderate or near-complete loss of SGCs. Neither loss of inner hair cells nor histological changes of the stria vascularis were observed in any of the animals. Cochleas in Category 1 had normal aABRs and morphology. On average, in Category 2 OHC loss was 46.0±5.7%, SGC loss was below threshold, ABR threshold shift was 44.9±2.7 dB, and ABR wave II amplitude was decreased by 17.1±3.8 dB. In Category 3 OHC loss was 68.3±6.9%, SGC loss was 49.4±4.3%, ABR threshold shift was 39.0±2.4 dB, and ABR amplitude was decreased by 15.8±1.6 dB. Our results show that ouabain does not solely destroy type I SGCs in the guinea pig cochlea.
Anomalously Faster Deterioration of LiNi0.8Co0.15Al0.05O2/Graphite High-Energy 18650 Cells at 1.5 C than 2.0 C
Authors: Cui Dawei , Wang Jinlong , Sun Ailing , Song Hongmei , Wei Wenqing
Published: July 2018

Discharge rate is a key parameter affecting the cycle life of lithium-ion batteries (LIB). Normally, lithium-ion batteries deteriorate more severely at a higher discharge rate. In this paper, we report that the cycle performance of LiNi0.8Co0.15Al0.05O2/graphite high-energy 2.8 Ah 18650 cells is abnormally worse at a 1.5 C discharge rate than at a 2.0 C discharge rate. Combining macromethods with micromethods, the capacity/rate performance, electrochemical impedance spectroscopy (EIS), and scanning electron microscope (SEM) morphology of the electrodes are systematically investigated. We have found that the impedance of the negative electrodes after 2.0 C aged is smaller than that after 1.5 C aged, through EIS analysis, and the discharge rate performance of the negative electrodes after 2.0 C aged is better than that after 1.5 C aged through coin cell analysis. In addition, some special microcracks in the negative electrodes of aged cells are observed through SEM analysis, which can accelerate the side reaction between active and electrolyte and form the thicker SEI which will hinder the Li+ insertion and cause resistance increase. In short, the LiNi0.8Co0.15Al0.05O2/graphite-based lithium-ion batteries show better cycle life at a 2.0 C discharge rate than at a 1.5 C discharge rate which indicates that the negative electrodes contribute more than the positive electrodes.
Punicalagin Decreases Serum Glucose Levels and Increases PON1 Activity and HDL Anti‐Inflammatory Values in Balb/c Mice Fed a High‐Fat Diet
Authors: Atrahimovich Dana , Samson Abraham O. , Khattib Ali , Vaya Jacob , Khatib Soliman
Published: July 2018

Polyphenols are consumed daily in the human diet and are associated with reduced risk of a number of chronic diseases, including cancer, cardiovascular disease, and diabetes. Traditionally, the health benefits of polyphenols have been attributed to their antioxidant activity, but many studies might be hampered by oral administration and insignificant bioavailability. Rather than exerting a direct antioxidant effect, the mechanisms by which polyphenols express their beneficial effect seem to involve their interaction with proteins. The present study is aimed at broadening and confirming our recently published in vitro results showing that polyphenols may reduce atherosclerosis risk via interaction with proteins and lipoproteins related to atherosclerosis. The biological functions of punicalagin and quercetin in relation to glucose and lipid levels, paraoxonase 1 (PON1) activity, and inflammation were examined in vivo. Mice were fed a high‐fat diet (HFD) for 12 weeks, and during the last 4 weeks, they received subcutaneous treatments via implanted minipumps, which released physiological concentrations of punicalagin, quercetin, or atorvastatin (as a positive control) daily into the serum. The HFD reduced serum PON1 activity, whereas punicalagin administration restored PON1 activity to the level of mice fed a normal diet. In addition, punicalagin significantly reduced glucose levels in HFD mice and improved HDL anti‐inflammatory properties. In conclusion, beyond antioxidant activity, the mechanisms by which polyphenols exert their beneficial properties appear to involve their interaction with serum proteins that mediate HDL function and lipid‐glucose state in the circulation.
Gray Relational Optimization of the Surface Performance of Splines Formed by Cold Roll-Beating
Authors: Cui Fengkui , Su Yongxiang
Published: July 2018

Surface roughness, residual stress, and work hardening are the key parameters characterizing the mechanical properties of a spline surface after undergoing cold roll-beating. A comprehensive optimization of the mechanical properties of such surfaces has not been previously reported. To improve the performance of the spline surface, gray theory is used to study the relationships between the surface roughness, residual stress, and work hardening in the pitch diameter of spline teeth. This method addresses the surface performance optimization of an involute spline as influenced by the cold roll-beating speed and feed rate as the main parameters during the cold roll-beating process. The results show that the surface roughness and hardening degree of the splines increase with an increasing feed rate but decrease with an increasing cold roll-beating speed; the residual stress of the spline decreases with an increasing feed rate and increases with an increasing cold roll-beating speed. The results also show that the feed rate has a strong influence on the surface performance of splines produced by cold roll-beating. The optimal process parameters in terms of the spline surface performance are a cold roll-beating speed of 1428 r/min and a feed rate of 42 mm/min. The results of the present work emphasize the significance of improving the surface performance of the cold roll-beating spline-forming process and determining the optimal process parameters.
In-Motion Iterative Fine Alignment Algorithm for On-Board Vehicular Odometer-Aided SINS
Authors: Gong Baichun , He Chenglong , Wang Xiaoyue , Li Xin
Published: July 2018

This research proposes a novel in-motion fine alignment algorithm for vehicular dead reckoning (DR) with odometer-aided strapdown inertial navigation system (SINS) while the map matching result is used for a group of landmark points to estimate misalignment angles. The proposed algorithm is designed based on principle of similarity, that is, trajectory of DR is similar to the true trajectory that the main difference between these two trajectories is rotation and scale. Further, the results from map matching are introduced as a group of landmark points to estimate the residual of azimuth error angle after coarse alignment and the scale factor error of the odometer. It is theoretically proved that the alignment effectiveness based on the results from map matching is equivalent to that on single zero error landmark point. Finally, digital simulations are conducted to verify the presented algorithm and test the performance.
Curcumin Attenuates Testicular Injury in Rats with Streptozotocin-Induced Diabetes
Authors: Zha Wenliang , Bai Yuting , Xu Ling , Liu Yuning , Yang Zhen , Gao Hui , Li Jun
Published: July 2018

Oxidative damage, inflammation, and apoptosis are the primary features of diabetic testicular damage. Curcumin protects against diabetic testicular injury, but the underlying mechanisms remain obscure. This study examined the effect of curcumin on type 2 diabetes mellitus- (T2DM-) induced testicular injury, oxidative stress, and apoptotic changes. T2DM rats were intraperitoneally injected with 40 mg/kg STZ after being fed a high-fat diet for 8 weeks. One week after STZ injection, 100 or 200 mg/kg curcumin was administered orally to the diabetic rats for 16 weeks. Histological changes in the testes were determined by HE staining. Serum testosterone was measured. Markers of superoxide levels, such as SOD activity and MDA content, and markers of cell death, including the expression of Bax, Bcl-2, and MAPK family members, were measured by molecular biology or immunohistochemical techniques. Degeneration and disruption of seminiferous tubule structure were observed in diabetic rats. Serum testosterone levels were markedly lower in diabetic rats than in control rats. Moreover, testicular apoptosis and Bax expression were much higher in diabetic rats than in control rats. Superoxide generation, the NADP+/NADPH ratio, and NADPH oxidase subunit expression, including expression of the gp91phox, p47phox, and p67phox subunits, increased, while antioxidant enzyme levels decreased in diabetic rats. Furthermore, the MAPK signaling pathway was activated in diabetic rats. Curcumin partially prevented diabetes-induced microstructural abnormalities and significantly increased serum testosterone levels compared to untreated T2DM rats. Additionally, curcumin reduced testicular apoptosis by regulating apoptotic proteins and markedly inhibited oxidative stress levels by downregulating MDA expression, decreasing NADPH activity, and restoring antioxidant enzymes. Remarkably, curcumin treatment also suppressed MAPK activation. Thus, curcumin may have therapeutic value in the treatment of diabetes-induced testicular injury due to its prevention of testicular apoptosis and attenuation of oxidative stress.
Are Downhill Varices an Overlooked Entity of Upper Gastrointestinal Bleedings?
Authors: Ayvaz M. A. , Rakici H. , Allescher H. D.
Published: July 2018

Aim. Downhill varices are not so safe as thought and can lead to life-threating or mortal bleeding complication, even if rare. In order to draw attention to this topic, we analysed 129 patients. Materials and Methods. We evaluated the electronic endoscopy data records of all patients undergoing upper gastrointestinal endoscopy over a nine-year period from January 2004 till December 2012, within a retrospective approach. The primary endpoints, incidence, causes, kind of resulting upper gastrointestinal bleeding, and the severity of the bleeding were evaluated. Secondary endpoints were the evaluation of the size of downhill varices and a comparison of the risk of bleeding between downhill varices and uphill varices. Results. Downhill varices were identified, described, and/or documented in 129 patients of 25,680 upper gastrointestinal endoscopies. 26 patients had central venous catheter or port implantation, 22 patients had a history of an implantation of a cardiac pacemaker, 7 patients had severe pulmonary artery embolism, and 4 patients had severe chronic obstructive pulmonary disease. Two patients had mediastinal tumors, and one patient had a large retrosternal goiter as a possible cause of the vena cava syndrome. Altogether, 62 patients were related to a vena cava superior syndrome; 67 were not. Conclusions. Downhill varices can be seen with an incidence of 0.5%. Therapeutic means are the banding therapy as a safe and effective option. Severe bleedings associated with downhill varices can be mortal. Severe forms of downhill varices should be examined in relation to the origin in order to start a specific therapy.
Heritability Analysis and Phenotypic Characterization of Spider Plant (Cleome gynandra L.) for Yield
Authors: Kangai Munene Ann , Nzuve Felister , Ambuko Jane , Odeny Damaris
Published: July 2018

Knowledge on phenotypic diversity among existing spider plant accessions is a milestone in the improvement of spider plant, which is a highly nutritious indigenous vegetable in Kenya. A study involving agronomic and morphological characterization of 49 spider plant accessions assembled from East and South Africa was carried out at the University of Nairobi Field Station for two seasons in a randomized complete block design with three replications. Phenotypic data was collected on growth habit, flower, petiole, leaf and stem colour, petiole, leaf and stem hairiness, number of leaves per plant, plant height, number of primary branches, leaf length and width, single leaf area, and chlorophyll content according to FAO descriptors with modifications. Data was analyzed using both DARwin software V6 and Genstat Version 14. We observed significant differences among the traits implying great genetic variability among the evaluated spider plant accessions. The high genetic variation was further validated using the Unweighted Pair Group Method with Arithmetic mean (UPGMA) clustering method with stem and flower colour as key traits. The 49-spider plant accessions were clustered into 2 major groups, each consisting of Kenyan and South African accessions. Stepwise regression revealed that plant height had the most influence on yield in terms of number of leaves per plant. We also observed high heritability for several traits including days to flowering (91%), number of leaves per plant (99%), plant height (99%), number of primary branches (94%), chlorophyll content (94%), and single leaf area (87%). Our results reveal the high genetic variation between different spider plant accessions, especially from different regions of Africa that could be further exploited to improve productivity in the plant. The high heritability of most of the yield related traits is promising for improving yield in the crop through direct selection.
Renal Transplantation with Simultaneous Aortoiliac Reconstruction Using a Polytetrafluoroethylene Vascular Graft for Severe Atherosclerosis
Authors: Anan Go , Nanmoku Koji , Shimbo Masaki , Nagahama Masahiko , Kimura Takaaki , Sakuma Yasunaru , Endo Fumiyasu , Komatsu Yasuhiro , Hattori Kazunori , Yagisawa Takashi
Published: July 2018

Studies on aortoiliac reconstruction for severe atherosclerosis with renal transplantation are limited. Here, we report a rare experience of the simultaneous reconstruction of the external iliac artery caused by severe atherosclerosis with polytetrafluoroethylene vascular graft and renal transplantation in a 55-year-old female; she was unable to undergo standard renal artery anastomosis to the right external iliac artery because of severe atherosclerosis, which would result in complete occlusion. Next, we directly anastomosed the donor renal artery to the polytetrafluoroethylene graft. After transplantation, delayed graft function occurred; therefore, the patient had to undergo hemodialysis. On day 7 after transplantation, her creatine level started to decrease. She was discharged from the hospital on the 14th day after transplantation. After 1 month, her serum creatinine level reduced to 1.12 mg/dL. After 3 years of transplantation, her serum creatinine level was 1.2 mg/dL. The simultaneous implantation of the polytetrafluoroethylene graft and renal transplantation was feasible as well as safe, with no infectious complications and stable renal function noted on long time follow-up. Although our case was rare, it emphasizes the need for transplant surgeons to gain surgical skills for vascular surgery using vascular grafts.
Mucin-1 Gene Mutation and the Kidney: The Link between Autosomal Dominant Tubulointerstitial Kidney Disease and Focal and Segmental Glomerulosclerosis
Authors: Trimarchi H. , Paulero M. , Rengel T. , González-Hoyos I. , Forrester M. , Lombi F. , Pomeranz V. , Iriarte R. , Iotti A.
Published: July 2018

Glomerular diseases are one of the most frequent causes of chronic kidney disease, focal and segmental glomerulosclerosis being one of the commonest glomerulopathies. However, the etiology of this glomerular entity, which merely depicts a morphologic pattern of disease, is often not established and, in most of the patients, remains unknown. Nephrologists tend to assume focal and segmental glomerulosclerosis as a definitive diagnosis. However, despite the increasing knowledge developed in the field, genetic causes of glomerular diseases are currently identified in fewer than 10% of chronic kidney disease subjects. Moreover, unexplained familial clustering among dialysis patients suggests that genetic causes may be underrecognized. Secondary focal and segmental glomerulosclerosis due to genetic mutations mainly located in the podocyte and slit diaphragm can occur from childbirth to adulthood with different clinical presentations, ranging from mild proteinuria and normal renal function to nephrotic syndrome and renal failure. However, this histopathological pattern can also be due to primary defects outside the glomerulus. The present report illustrates an adult case of secondary focal and segmental glomerulosclerosis with a dominant tubulointerstitial damage that led to the pursue of its cause at the tubular level. In this patient with an undiagnosed family history of adult kidney disease, a genetic study unraveled a mutation in the mucin-1 gene and a final diagnosis of adult dominant tubular kidney disease-MUC1 was made.
Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells
Authors: Zhao Chengzhu , Ikeya Makoto
Published: July 2018

Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.
Anomalous Left Main Coronary Artery Arising from the Right Sinus of Valsalva in a Young Man Presenting with Recurrent Syncope and Myocardial Infarction
Authors: Khalighi Koroush , Sharma Munish , Toor Amit , Toor Rubinder S. , Costacurta Gary
Published: July 2018

A 19-year-old man with the left main coronary artery (LMCA) arising from the right sinus of Valsalva presented with recurrent episodes of syncope and myocardial infarction (MI). Anomalous aortic origin of a coronary artery (AAOCA) is an uncommon but extremely important differential diagnosis that should not be missed in patients presenting with syncope, MI, ventricular arrhythmias, or cardiac arrest. A definitive diagnosis with coronary angiography and prompt surgical intervention is imperative in such symptomatic patients.
Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer
Authors: Ubellacker Jessalyn M. , Baryawno Ninib , Severe Nicolas , DeCristo Molly J. , Sceneay Jaclyn , Hutchinson John N. , Haider Marie-Therese , Rhee Catherine S. , Qin Yuanbo , Gregory Walter M. , Garrido-Castro Ana C. , Holen Ingunn , Brown Janet E. , Coleman Robert E. , Scadden David T. , McAllister Sandra S.
Published: July 2018

The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiologic, pathologic, and therapeutic conditions impact hematopoiesis, it remains unclear whether targeting hematopoiesis presents opportunities for limiting bone metastasis. Using preclinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at randomization revealed that women with high-plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence.

Significance: Bone marrow myeloid/osteoclast progenitor cell lineage potential has a profound impact on breast cancer bone metastasis and can be modulated by G-CSF and bone-targeting agents. Cancer Res; 78(18); 5300–14. ©2018 AACR.
Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma
Authors: Toker Aras , Nguyen Linh T. , Stone Simone C. , Yang S.Y. Cindy , Katz Sarah Rachel , Shaw Patricia A. , Clarke Blaise A. , Ghazarian Danny , Al-Habeeb Ayman , Easson Alexandra , Leong Wey L. , McCready David R. , Reedijk Michael , Guidos Cynthia J. , Pugh Trevor J. , Bernardini Marcus Q. , Ohashi Pamela S.
Published: July 2018

Purpose: Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell–associated molecules that can be targeted by tumor immunotherapies.

Experimental Design: The phenotype of intratumoral and circulating Treg cells was analyzed by multicolor flow cytometry, mass cytometry, RNA-seq, and functional assays.

Results: Treg cells isolated from ovarian tumors displayed a distinct cell surface phenotype with increased expression of a number of receptors associated with TCR engagement, including PD-1, 4-1BB, and ICOS. Higher PD-1 and 4-1BB expression was associated with increased responsiveness to further TCR stimulation and increased suppressive capacity, respectively. Transcriptomic and mass cytometry analyses revealed the presence of Treg cell subpopulations and further supported a highly activated state specifically in ovarian tumors. In comparison, Treg cells infiltrating melanomas displayed lower FOXP3, PD-1, 4-1BB, and ICOS expression and were less potent suppressors of CD8 T-cell proliferation.

Conclusions: The highly activated phenotype of ovarian tumor-infiltrating Treg cells may be a key component of an immunosuppressive tumor microenvironment. Receptors that are expressed by tumor-infiltrating Treg cells could be exploited for the design of novel combination tumor immunotherapies. Clin Cancer Res; 24(22); 5685–96. ©2018 AACR.
Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models
Authors: Jiang Hongmei , Xu Mai , Li Lin , Grierson Patrick , Dodhiawala Paarth , Highkin Maureen , Zhang Daoxiang , Li Qiong , Wang-Gillam Andrea , Lim Kian-Huat
Published: July 2018

Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF–MEK–ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K–AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients. Mol Cancer Ther; 17(10); 2144–55. ©2018 AACR.
Auranofin Enhances Ibrutinib's Anticancer Activity in EGFR-Mutant Lung Adenocarcinoma
Authors: Hu Jing , Zhang Huijuan , Cao Mengru , Wang Li , Wu Shuhong , Fang Bingliang
Published: July 2018

We previously found that ibrutinib has anticancer activity in EGFR-mutant non–small cell lung cancer (NSCLC). One of our recent studies showed that auranofin, a gold complex that has been used to treat rheumatoid arthritis, inhibited the PI3K/AKT/mTOR pathway and promoted apoptosis in some NSCLC cells. Because the PI3K/AKT/mTOR pathway is one of the major downstream pathways of EGFR, we hypothesized that ibrutinib's activity might be enhanced by combination therapy with auranofin in NSCLC cells. To this end, we examined ibrutinib's dose responses in EGFR-mutant H1975, PC9, and H1650 cells and in EGFR wild-type Calu3 and H460 cells in the presence or absence of auranofin. Although low concentrations of auranofin alone demonstrated mild anticancer activities, its presence dramatically enhanced ibrutinib's activity in H1975, PC9, and H1650 cells (IC50 value reduced 10- to 100-fold), but had only mild effect on Calu3 and H460 cells, demonstrating that ibrutinib's anti-EGFR activity is enhanced when it is combined with auranofin. A mechanistic analysis revealed that ibrutinib alone induced dramatic inhibition of the MEK/ERK pathway in both H1975 and H1650 cells, whereas auranofin alone inhibited the AKT/mTOR pathway. The combination of ibrutinib and auranofin led to a dramatically enhanced inhibition of the expression or phosphorylation of multiple key nodes in the AKT/mTOR and MEK/ERK pathways in both cell lines. In mice, the combination of ibrutinib and auranofin significantly suppressed the growth of H1975 xenografted tumors without inducing obvious toxic effects. Our results demonstrate the feasibility of improving ibrutinib's anti-EGFR activity for NSCLC using combination therapy with auranofin. Mol Cancer Ther; 17(10); 2156–63. ©2018 AACR.
Accuracy of Acid-Base Diagnoses Using the Central Venous Blood Gas in the Medical Intensive Care Unit
Authors: Schrauben Sarah J. , Negoianu Dan , Costa Cristiana , Cohen Raphael M. , Goldfarb Stanley , Fuchs Barry D. , Berns Jeffrey S.
Published: July 2018

Background: Acid-base disturbances are frequent in critically ill patients. Arterial blood gas (ABG) is the gold standard in the diagnosis of these disturbances, but it is invasive with potential hazards. For patients with a central venous catheter, venous blood gas (VBG) sampling may be an alternative, less-invasive diagnostic tool. However, the accuracy of a central VBG-based acid-base disorder diagnosis compared to an ABG is unknown. The primary objective of this study was to assess the accuracy of a central VBG-based acid-base disorder diagnosis compared to the “gold standard” ABG in critically ill patients. Methods: This was a study of adult patients in a medical intensive care unit that had simultaneously drawn ABG and central VBG samples. Expert acid-base diagnosticians, all nephrologists, diagnosed the acid-base disorder(s) in each blood gas sample. The central VBG diagnostic accuracy was assessed with percent agreement, sensitivity, and specificity compared to the ABG-based diagnosis. Results: The study involved 23 participants. Overall, the central VBG had 100% sensitivity for metabolic acidosis, metabolic alkalosis, and respiratory acidosis, and lower sensitivity (71%) for respiratory alkalosis, and high percent agreement, ranging from 75 to 94%. VBG-based diagnoses in vasopressor-dependent patients (n = 13, 56.5%) performed similarly to the entire sample. Conclusions: In critically ill adult patients, central VBG may be used to detect and diagnose acid-base disturbances with reasonable diagnostic accuracy, even in shock states, compared to the ABG. This study supports the use of central VBG for diagnosis of acid-base disturbances in critically ill patients.
Marshmallow Root Extract for the Treatment of Irritative Cough: Two Surveys on Users' View on Effectiveness and Tolerability
Authors: Fink Careen , Schmidt Mathias , Kraft Karin
Published: July 2018

Background: Cough preparations containing aqueous marshmallow root extracts (Althaea officinalis) have a long history as medicinal products in Germany. The aim of the 2 prospective, non-interventional surveys reported here was to create a better documentation of the users' impression of the effectiveness and tolerability, and user satisfaction. Methods: Consumers (n = 822) buying either lozenges or syrup of the aqueous marshmallow root extract STW42 to treat their dry cough were recruited in pharmacies in 2 independently performed surveys. They were asked to fill in a questionnaire covering a treatment duration of 7 days so that the course of symptoms could be documented, and the overall effectiveness, tolerability and satisfaction assessed. Results: This consumer-reported outcome shows that both preparations showed a good effect with respect to the symptomatic treatment of oral or pharyngeal irritation and associated dry cough with a very rapid onset of effects, in the majority of cases within 10 min. The tolerability was very good (with only 3 minor adverse events for the syrup). Conclusion: The results of the surveys justify the long-established use of both marshmallow preparations for symptomatic treatment of dry cough.
Offene Fragen zur endoskopischen Lungenvolumen- reduktion mit Endobronchialventilen
Authors: Caviedes Iván R. , Labarca Gonzalo , de Oliveira Hugo G. , Herth Felix J.F. , Fernandez-Bussy Sebastián
Published: July 2018

Die endoskopische Lungenvolumenreduktion ist ein minimalinvasiver Eingriff bei Lungenemphysem mit dem Ziel, dass die überblähten Lungenanteile weniger Raum einnehmen. Der Nutzen dieses Verfahrens bei Patientinnen und Patienten mit fortgeschrittener chronisch-obstruktiver Lungenerkrankung und hochgradiger Überblähung ist nachgewiesen. Immer häufiger kommen dabei Endobronchialventile zum Einsatz, und immer häufiger wird auch über unerwünschte Ereignisse berichtet. Als häufigste Komplikationen nach diesem Eingriff treten Pneumothorax, Blutungen und Infektionen auf, und Ventile müssen entfernt werden oder werden ausgestoßen. Wir behandelten kürzlich einen Patienten, bei dem zunächst eine sofortige Atelektase im linken Oberlappen eintrat, dann jedoch am 6. Tag ein Pneumothorax und eine Abknickung des linken Unterlappenbronchus, die beinahe fatal verlaufen wäre. Der Patient erlitt Erstickungsanfälle, vermutlich infolge einer funktionellen linksseitigen Pneumektomie. Diese ungewöhnliche Komplikation sollte künftig bedacht werden, wenn sich der Zustand einer Patientin oder eines Patienten verschlechtert, bei dem zuvor mit einer endoskopischen Lungenvolumenreduktion eine komplette lobäre Atelektase herbeigeführt wurde. Übersetzung aus Respiration 2018;95:269-272 (DOI: 10.1159/000484252)
The Influence of Hyperosmolarity in the Intervertebral Disc on the Proliferation and Chondrogenic Differentiation of Nucleus Pulposus-Derived Mesenchymal Stem Cells
Authors: Li Hao , Wang Jingkai , Li Fangcai , Chen Gang , Chen Qixin
Published: July 2018

Nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) are suitable cell candidates for intervertebral disc (IVD) regeneration. However, little work has been done to determine the proliferation and chondrogenic differentiation of NP-MSCs in the hyperosmotic microenvironment of IVD. This study aimed to investigate the influence of the hyperosmolarity of IVD on the proliferation and chondrogenic differ­entiation of NP-MSCs. NP-MSCs were cultured in media of 300, 400, 430, and 500 mOsm/L, mimicking the osmotic pressures of serious degenerative, moderately degenerative, and healthy IVD. Cell proliferation was measured by CCK-8 assay. The expression of aggrecan, collagen I, and collagen II were measured by gene and protein expression analysis. Alcian blue and dimethylmethylene blue assay were used to investigate the accumulation of sulfate glycosaminoglycan. The regulation role of extracellular signal-regulated kinase (ERK) pathway was also analyzed. The results showed that, compared to 300 mOsm/L, hyperosmolarity of healthy IVD (430 and 500 mOsm/L) inhibited the proliferation and chondrogenic differentiation of NP-MSCs. The relative hypoosmotic condition of moderately degenerative IVD (400 mOsm/L) led to great proliferation and chondrogenic differentiation capacity. The ERK pathway was activated by the hyperosmolarity; inhibition of the ERK pathway abolished the difference in cell proliferation between the 300 mOsm/L and the hyperosmotic conditions, and enhanced chondrogenic differentiation. In conclusion, hyperosmolarity of IVD had a significant impact on the proliferation and chondrogenic differentiation of NP-MSCs. The ERK pathway was involved in the inhibition of proliferation and chondrogenic differentiation of NP-MSCs by the hyperosmolarity of IVD. The relative hypo-osmotic condition prevailing in degenerative discs offers a more permissive microenvironment for NP-MSCs.
Large Nasal Defects with Exposed Cartilage: The Folded Transposition Flap as an Innovative Alternative to the Paramedian Forehead Flap
Authors: Schäfer Kristina , Rudolph Christina , Cotofana Sebastian , Goebeler Matthias , Weyandt Gerhard
Published: July 2018

Background: Skin cancer removal surgery involving the tip or dorsum of the nose often results in large-sized defects with exposure of cartilage. In such cases, the paramedian forehead flap is a frequently used reconstruction technique; however, this method is complex and can result in a cosmetically unsatisfying outcome. Objective: To describe the folded transposition flap as an aesthetically pleasing alternative to the paramedian forehead flap for large nasal defects with exposed cartilage. Methods: The folded transposition flap is a 2-stage surgical modification of the transposition flap. In the first stage, an overlong axial cheek pedicle is used to cover the defect. In the second stage, the flap is thinned and the nasal scars are revised. Results: All 4 patients experienced aesthetically pleasing results. Conclusion: The folded transposition flap is an alternative for reconstructing large surgical defects of the nasal tip or distal dorsum of the nose.
Cancer-Associated Hypercoagulation Increases the Risk of Early Recurrent Stroke in Patients with Active Cancer
Authors: Fujinami Jun , Ohara Tomoyuki , Kitani-Morii Fukiko , Tomii Yasuhiro , Makita Naoki , Yamada Takehiro , Kasai Takashi , Nagakane Yoshinari , Nakagawa Masanori , Mizuno Toshiki
Published: July 2018

Background: This study assessed the incidence and predictors of short-term stroke recurrence in ischemic stroke patients with active cancer, and elucidated whether cancer-associated hypercoagulation is related to early recurrent stroke. Methods: We retrospectively enrolled acute ischemic stroke patients with active cancer admitted to our hospital between 2006 and 2017. Active cancer was defined as diagnosis or treatment for any cancer within 12 months before stroke onset, known recurrent cancer or metastatic disease. The primary clinical outcome was recurrent ischemic stroke within 30 days. Results: One hundred ten acute ischemic stroke patients with active cancer (73 men, age 71.3 ± 10.1 years) were enrolled. Of those, recurrent stroke occurred in 12 patients (11%). When patients with and without recurrent stroke were compared, it was found that those with recurrent stroke had a higher incidence of pancreatic cancer (33 vs. 10%), systemic metastasis (75 vs. 39%), multiple vascular territory infarctions (MVTI; 83 vs. 40%), and higher ­D-dimer levels (16.9 vs. 2.9 µg/mL). Multivariable logistic regression analysis showed that each factor mentioned above was not significantly associated with stroke recurrence independently, but high D-dimer (hDD) levels (≥10.4 µg/mL) and MVTI together were significantly associated with stroke recurrence (OR 6.20, 95% CI 1.42–30.7, p = 0.015). Conclusions: Ischemic stroke patients with active cancer faced a high risk of early recurrent stroke. The concurrence of hDD levels (≥10.4 µg/mL) and MVTI was an independent predictor of early recurrent stroke in active cancer patients. Our findings suggest that cancer-associated hypercoagulation increases the early recurrent stroke risk.