bluuebunny/crossref_metadata_2025 huggingface dataset:
What Is the Price of Science?
Authors: Alwine James C. , Enquist Lynn W. , Dermody Terence S. , Goodrum Felicia
Published: March 2021

The peer-reviewed scientific literature is the bedrock of science. However, scientific publishing is undergoing dramatic changes, which include the expansion of open access, an increased number of for-profit publication houses, and ready availability of preprint manuscripts that have not been peer reviewed. In this opinion article, we discuss the inequities and concerns that these changes have wrought.
Dysbiosis in Metabolic Genes of the Gut Microbiomes of Patients with an Ileo-anal Pouch Resembles That Observed in Crohn's Disease
Authors: Dubinsky Vadim , Reshef Leah , Rabinowitz Keren , Yadgar Karin , Godny Lihi , Zonensain Keren , Wasserberg Nir , Dotan Iris , Gophna Uri
Published: March 2021

Crohn's disease (CD), ulcerative colitis (UC), and pouchitis are chronic inflammatory conditions of the bowel. Pouchitis develops in former UC patients after proctocolectomy and ileal-pouch-anal anastomosis and is characterized by inflammation of the previously normal small intestine comprising the pouch.
Takayasu’s arteritis and secondary membranous nephropathy: an exceptional association
Authors: Enos Daniel , Labarca Gonzalo , Hernandez Mariel , Mendez Gonzalo P
Published: March 2021

The association between Takayasu’s arteritis and membranous nephropathy is uncommon. We present the case of a 46-year-old man with Takayasu’s arteritis treated over 10 years by a multidisciplinary medical team. He had an atrophic left kidney due to arterial stenosis, with a basal creatinine of 1.59 mg/dL (140.55 µmol/l). Three years ago, he presented with full nephrotic syndrome, uncontrolled blood pressure, creatinine increases to 4.5 mg/dL (basal: 1.59 mg/dL), severe hypoalbuminaemia (1.4 g/dL) and albuminuria of 24.6 g per day. He underwent percutaneous biopsy of the right kidney that showed membranous nephropathy with negative PLA2R1 and positive IgG 1, 3 and 4 subclasses. After therapy with oral prednisone and cyclophosphamide, the patient’s kidney function improved, without recurrence of disease after 3 years of follow-up. Here, we present this extremely uncommon association of Takayasu’s arteritis and membranous nephropathy.
How does hormone transition in transgender women change body composition, muscle strength and haemoglobin? Systematic review with a focus on the implications for sport participation
Authors: Harper Joanna , O'Donnell Emma , Sorouri Khorashad Behzad , McDermott Hilary , Witcomb Gemma L
Published: March 2021

Objectives

We systemically reviewed the literature to assess how long-term testosterone suppressing gender-affirming hormone therapy influenced lean body mass (LBM), muscular area, muscular strength and haemoglobin (Hgb)/haematocrit (HCT).

Design

Systematic review.

Data sources

Four databases (BioMed Central, PubMed, Scopus and Web of Science) were searched in April 2020 for papers from 1999 to 2020.

Eligibility criteria for selecting studies

Eligible studies were those that measured at least one of the variables of interest, included transwomen and were written in English.

Results

Twenty-four studies were identified and reviewed. Transwomen experienced significant decreases in all parameters measured, with different time courses noted. After 4 months of hormone therapy, transwomen have Hgb/HCT levels equivalent to those of cisgender women. After 12 months of hormone therapy, significant decreases in measures of strength, LBM and muscle area are observed. The effects of longer duration therapy (36 months) in eliciting further decrements in these measures are unclear due to paucity of data. Notwithstanding, values for strength, LBM and muscle area in transwomen remain above those of cisgender women, even after 36 months of hormone therapy.

Conclusion

In transwomen, hormone therapy rapidly reduces Hgb to levels seen in cisgender women. In contrast, hormone therapy decreases strength, LBM and muscle area, yet values remain above that observed in cisgender women, even after 36 months. These findings suggest that strength may be well preserved in transwomen during the first 3 years of hormone therapy.
Parental assessment of disease severity in febrile children under 5 years of age: a qualitative study
Authors: Kuijpers Dora L , Peeters Daphne , Boom Nina C , van de Maat Josephine , Oostenbrink Rianne , Driessen Gertjan J A
Published: March 2021

Objective

To explore how parents judge disease severity of their febrile child and to identify symptoms they associate with serious illness, minor illness or health.

Design

Semistructured interviews were conducted. Interviews were audio taped, transcribed verbatim and analysed thematically.

Participants

Parents of children aged 0–5 years with a febrile illness.

Setting

Participants were recruited at the paediatric ward and the emergency department.

Results

Twenty-six interviews were conducted, in which 37 parents participated. Parents described disease severity of their child mainly in terms of changes in their child’s normal characteristics (behaviour and physical features). They found it harder to describe specific disease symptoms such as dyspnoea or dehydration. Their child being active, eating and drinking well, and smiling were perceived as reassuring, whereas high fever, moving very little and uncertainty about the type of infections were mentioned as alarming symptoms. Previous experience with febrile illnesses in their children was of great influence on the number and accuracy of symptoms they reported.

Conclusion

Parents used the normal behaviour and physical features of their child as a reference frame for judging disease severity. With a larger deviation from the child’s normal characteristics, parents considered the illness more serious. They were less able to describe specific symptoms of disease such as dyspnoea or dehydration. This knowledge is important for clinicians in their communication with parents of children with febrile illness.
ANalgesic Efficacy and safety of MOrphiNe versus methoxyflurane in patients with acute myocardial infarction: the rationale and design of the ANEMON-SIRIO 3 study: a multicentre, open-label, phase II, randomised clinical trial
Authors: Kubica Aldona , Kosobucka Agata , Niezgoda Piotr , Adamski Piotr , Buszko Katarzyna , Lesiak Maciej , Wojakowski Wojciech , Gasior Mariusz , Gorący Jarosław , Kleinrok Andrzej , Nadolny Klaudiusz , Navarese Eliano , Kubica Jacek
Published: March 2021

Introduction

The unfavourable influence of morphine on the pharmacokinetics of ticagrelor resulting in weaker and retarded antiplatelet effect in patients with acute coronary syndrome (ACS) has been previously shown. Replacing morphine with methoxyflurane, a potent, non-opioid analgesic agent, that does not weaken or delay the effect of antiplatelet agents may improve the clinical efficacy of treatment of patients with ACS.

Methods

The ANEMON-SIRIO 3 study was designed as a multicentre, open-label, phase II, randomised clinical trial aimed to test the analgesic efficacy and safety of methoxyflurane in patients with ACS. The study population will comprise patients with ST-elevation myocardial infarction or non-ST-elevation ACS admitted to the study centres with typical chest pain requiring analgesic treatment. Before percutaneous coronary intervention (PCI) for the patients with index ACS will be randomly assigned in 1:1 ratio to receive methoxyflurane administered by inhalation, or to obtain morphine administered intravenously. Analgesic treatment will be followed by 300 mg loading dose of aspirin and 180 mg loading dose of ticagrelor. Patients will be assessed with regard to pain intensity according to the Numeric Pain Rating Scale at baseline, 3 min after study drug administration and immediately after PCI. Moreover, patients will be actively monitored with regard to the occurrence of side effects of evaluated therapies, as well as adverse events that may be related to insufficient platelet inhibition (no-reflow phenomenon assessed immediately after PCI, administration of GPIIb/IIIa inhibitors during PCI, acute stent thrombosis).

Ethics and dissemination

The study will be conducted in six Polish clinical centres from the beginning of in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Trial registration details

ClinicalTrials.gov,NCT04476173.
Palivizumab reimbursement criteria and neonatal RSV hospitalisation: a regional retrospective review
Authors: Belleudi Valeria , Marchetti Federico , Finocchietti Marco , Davoli Marina , Addis Antonio
Published: March 2021

In Italy, reimbursement restrictions regarding palivizumab prophylaxis approved in 2016 have been revoked in 2017, restoring use in infants with Gestational Age (GA) >29 weeks. Respiratory Syncytial Virus (RSV) hospitalisations and prevalence of palivizumab use in infants aged <6 months during five seasons (2014–2019), were considered according to different GA. Although RSV hospitalisations rate showed no significant changes, during different seasons in all GA, lower prevalence of palivizumab use in 2016 (0.8% vs 0.3%), returned to a higher level following the revoke of restrictions. Changes in reimbursement criteria were not associated with neonatal RSV hospitalisations rate but with a significant impact on palivizumab use.
Real classical geometry with arbitrary deficit parameter(s) $$\alpha (_{I})$$ in deformed Jackiw–Teitelboim gravity
Authors: Momeni Davood
Published: March 2021

An interesting deformation of Jackiw–Teitelboim (JT) gravity has been proposed by Witten by adding a potential term $$U(\phi )$$

U
(
ϕ
)

as a self-coupling of the scalar dilaton field. During calculating the path integral over fields, a constraint comes from integration over $$\phi $$
ϕ
as $$R(x)+2=2\alpha \delta (\vec {x}-\vec {x}')$$

R

(
x
)

+
2
=
2
α
δ

(

x
→

-

x
→

′

)

. The resulting Euclidean metric suffered from a conical singularity at $$\vec {x}=\vec {x}'$$

x
→

=

x
→

′

. A possible geometry is modeled locally in polar coordinates $$(r,\varphi )$$

(
r
,
φ
)

by $$\mathrm{d}s^2=\mathrm{d}r^2+r^2\mathrm{d}\varphi ^2,\varphi \cong \varphi +2\pi -\alpha $$

d

s
2

=
d

r
2

+

r
2

d

φ
2

,
φ
≅
φ
+
2
π
-
α

. In this letter we show that there exists another family of ”exact” geometries for arbitrary values of the $$\alpha $$
α
. A pair of exact solutions are found for the case of $$\alpha =0$$

α
=
0

. One represents the static patch of the AdS and the other one is the non-static patch of the AdS metric. These solutions were used to construct the Green function for the inhomogeneous model with $$\alpha \ne 0$$

α
≠
0

. We address a type of phase transition between different patches of the AdS in theory because of the discontinuity in the first derivative of the metric at $$x=x'$$

x
=

x
′

. We extended the study to the exact space of metrics satisfying the constraint $$R(x)+2=2\sum _{i=1}^{k}\alpha _i\delta ^{(2)}(x-x'_i)$$

R

(
x
)

+
2
=
2

∑

i
=
1

k

α
i

δ

(
2
)

(
x
-

x
i
′

)

as a modulus diffeomorphisms for an arbitrary set of deficit parameters $$(\alpha _1,\alpha _2,\ldots ,\alpha _k)$$

(

α
1

,

α
2

,
…
,

α
k

)

. The space is the moduli space of Riemann surfaces of genus g with k conical singularities located at $$x'_k$$

x
k
′

, denoted by $$\mathcal {M}_{g,k}$$

M

g
,
k

.
Spin-dependence of gravity-mediated dark matter in warped extra-dimensions
Authors: Folgado Miguel G. , Donini Andrea , Rius Nuria
Published: March 2021

We study the possibility that Dark Matter (DM) particles of spin 0, 1/2 or 1 may interact gravitationally with Standard Model (SM) particles within the framework of a warped Randall–Sundrum (RS) model. Both the Dark Matter and the Standard Model particles are assumed to be confined to the infra-red (IR) brane and only interchange Kaluza–Klein excitations of the graviton and the radion (adopting the Goldberger–Wise mechanism to stabilize the size of the extra-dimension). We analyze the different DM annihilation channels and find that the presently observed Dark Matter relic abundance, $$\Omega _{\mathrm{DM}}$$

Ω
DM

, can be obtained within the freeze-out mechanism for DM particles of all considered spins. This extends our first work concerning scalar DM in RS scenarios (Folgado et al., in JHEP 01:161. 10.1007/JHEP01(2020)161, 2020) and put it on equal footing with our second work in which we studied DM particles of spin 0, 1/2 and 1 in the framework of the Clockwork/Linear Dilaton (CW/LD) model (Folgado et al., in JHEP 20:036. 10.1007/JHEP04(2020)036, 2020). We study the region of the model parameter space for which $$\Omega _{\mathrm{DM}}$$

Ω
DM

is achieved and compare it with the different experimental and theoretical bounds. We find that, for DM particles mass $$m_{\mathrm{DM}} \in [1,15]$$

m
DM

∈

[
1
,
15
]

TeV, most of the parameter space is excluded by the current constraints or will be excluded by the LHC Run III or by the LHC upgrade, the HL-LHC. The observed DM relic abundance can still be achieved for DM masses $$m_{\mathrm{DM}} \in [4,15]$$

m
DM

∈

[
4
,
15
]

TeV and $$m_{G_1} < 10$$

m

G
1

<
10

TeV for scalar and vector boson Dark Matter. On the other hand, for spin 1/2 fermion Dark Matter, only a tiny region with $$m_{\mathrm{DM }} \in [4, 15]$$

m
DM

∈

[
4
,
15
]

TeV, $$m_{G_1} \in [5,10]$$

m

G
1

∈

[
5
,
10
]

TeV and $$\Lambda > m_{G_1}$$

Λ
>

m

G
1

is compatible with theoretical and experimental bounds. We have also studied the impact of the radion in the phenomenology, finding that it does not modify significantly the allowed region for DM particles of any spin (differently from the CW/LD case, where its impact was quite significant in the case of scalar DM). We, eventually, briefly compare results in RS with those obtained in the CW/LD model.
Baicalein Inhibits Gastric Cancer Cell Proliferation and Migration through a FAK Interaction via AKT/mTOR Signaling
Authors: Qiao Dan , Jin Jingchun , Xing Jian , Zhang Yingying , Jia Nailing , Ren Xiangshan , Lin Zhenhua , Jin Ningyi , Chen Liyan , Piao Yingshi
Published: March 2021

Gastric cancer is a common malignancy worldwide and is associated with high morbidity and mortality rates. However, very little is known about the underlying mechanism in human gastric cancer cells. Baicalein (BAI), a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. Here, we investigated the molecular mechanisms underlying BAI action on gastric cancer cell proliferation and migration. The results showed that BAI can expressively inhibit cell proliferation, colony-forming ability and migration ability in a dose-dependent manner, while in the meantime inducing cell apoptosis. Additionally, we found that BAI can suppress FAK and the phosphorylation of PI3K, AKT and mTOR in a dose-dependent manner. Furthermore, BAI significantly inhibited tumor growth in a xenograft model. Also, BAI can inhibit the proliferation and migration of gastric cancer cells and the expression of the pathway by downregulating the expression of FAK. In short, we demonstrated that BAI inhibited gastric cancer cell proliferation and migration through FAK interaction via downregulation in AKT/mTOR signaling, which signifies that BAI may be a latent therapeutic factor for the treatment of gastric cancer patients and that FAK might be a hopeful therapy target for the disease.
CHARACTERIZATION OF BEHAVIORAL COMPLEXITY IN MARINE TRACE FOSSILS AND ITS PALEOENVIRONMENTAL SIGNIFICANCE: A CASE STUDY OF ZOOPHYCOS
Authors: SONG HUIBO , NIE SHASHA , JIN YI , ZHANG XIANGYU , AN HONGLIANG
Published: March 2021

The paleoenvironment influences trace-making behavior significantly, and progressively more evidence shows that this behavior follows scale-invariance properties. In this study, we focused on the definition of behavioral complexity in the trace fossil Zoophycos to explore its paleoenvironmental significance. Firstly, the fractal topography in Zoophycos was established by introducing virtual tertiary lamellae. Next, a fractal dimension ([Formula: see text]) model was proposed and the spatio-temporal evolution trend of the complexity of the trace-making behavior was established. In application, the correlation of [Formula: see text] to the paleo-water depth and substrate consistency of the paleoenvironment was analyzed with the aid of variations of [Formula: see text]C and lamellae deformations in Zoophycos from the Carboniferous-Permian Taiyuan Formation of North China. The results show that [Formula: see text] increases with paleo-water depth, although it decreases when the degree of substrate consistency increases. Our investigation indicates that fractal topography not only provides an essential explanation for the complexity of trace-making behavior but also plays a reliable and significant role in paleoenvironmental interpretation. Most importantly, this work may shed some light on the subject of fractal ichnology and provide a mathematical framework toward studies in quantitative ichnology.
A RIGID PENDULUM IN A MICROGRAVITY: SOME SPECIAL PROPERTIES AND A TWO-SCALE FRACTAL MODEL
Authors: YAO SHAO-WEN
Published: March 2021

Under a microgravity condition, the microgravity-induced motion of a rigid pendulum has many special properties, which cannot be successfully revealed by any known theory. This work suggests a new fractal model for this purpose to describe the microgravity-induced motion by using the fractal derivative, and its variational principle is successfully established according to the semi-inverse method. The variational principle is very helpful to construct conservation laws and to suggest solution structures of the new fractal model. The approximate analytical solution of the model is gained by the two-scale transform method and the homotopy perturbation method.
Spectra of bowtie product of graphs
Authors: Pavithra R. , Rajkumar R.
Published: March 2021

In this paper, we introduce a new graph product, namely, bowtie product. We determine the generalized characteristic polynomial of the bowtie product of graphs and consequently, we obtain the characteristic polynomial of the adjacency martix, the Laplacian matrix, the signless Laplacian matrix and the normalized Laplacian matrix of this graph. Also, from these results, we obtain the [Formula: see text]-spectra of some families of bowtie product of graphs. As an application, we obtain infinite pairs of [Formula: see text]-cospectral graphs and construct infinite number of [Formula: see text]-integral graphs.
Stenopterygiids from the lower Toarcian of Beaujolais and a chemostratigraphic context for ichthyosaur preservation during the Toarcian Oceanic Anoxic Event
Authors: Martin Jeremy E. , Suan Guillaume , Suchéras-Marx Baptiste , Rulleau Louis , Schlögl Jan , Janneau Kevin , Williams Matt , Léna Alex , Grosjean Anne-Sabine , Sarroca Estel , Perrier Vincent , Fernandez Vincent , Charruault Anne-Lise , Maxwell Erin E. , Vincent Peggy
Published: March 2021

We report new ichthyosaur material excavated in lower Toarcian levels of the LafargeHolcim Val d'Azergues quarry in Beaujolais, SE France. A partially articulated skull and a smaller, unprepared but likely subcomplete skeleton preserved in a carbonate concretion are identified as stenopterygiids, a family of wide European distribution during the Early Jurassic. These specimens are among the finest preserved Toarcian exemplars known from Europe and, in one of them, soft tissue preservation is suspected. Their state of preservation is attributed to the combination of prolonged anoxic conditions near the water–sediment interface and early carbonate cementation resulting from the activity of sulfate-reducing bacteria. We also present carbon and strontium isotope values obtained from the study site that allow detailed temporal comparisons with other Toarcian vertebrate-yielding sites and environmental perturbations associated with the Toarcian Oceanic Anoxic Event (T-OAE). These comparisons suggest that the relatively high abundance and good preservation state of Toarcian vertebrates was favoured by a prolonged period of low bottom water oxygenation and accumulation rates. The environmental conditions that prevailed during the T-OAE were probably responsible for the extensive nature of Lagerstätte-type deposits with exceptional preservation of marine organisms. Testing whether the T-OAE had a biological impact on marine vertebrates requires a precise chemostratigraphic context of the fossil record spanning the Pliensbachian–Toarcian interval.
Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies
Authors: Jacobsen Elizabeth A. , Jackson David J. , Heffler Enrico , Mathur Sameer K. , Bredenoord Albert J. , Pavord Ian D. , Akuthota Praveen , Roufosse Florence , Rothenberg Marc E.
Published: March 2021

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.
Knowledge of Preconception Healthcare and Associated Factors: A Study among Mothers in Jinka Town, Southern Region, Ethiopia
Authors: Tesema Kassahun Fikadu , Cheneka Tamirat , Alemu Alemayehu , Feyissa Mekonen , Birkaye Birhanu , Mohammed Hafiza , Kidu Eleni , Wegaso Getahun , Wasihun Biresaw
Published: March 2021

Background. Preconception healthcare is promising to improve the reproductive health status of women and couples if they receive care three months to two years before conception. In the current context of Ethiopia, however, preconception healthcare is overlooked in the continuum of care. Therefore, this study aimed to assess the knowledge of preconception healthcare and associated factors: a study among mothers in Jinka town, southern region, Ethiopia. Methods. A community-based cross-sectional study was employed among 522 randomly selected women of childbearing age who are living in Jinka town from March to April 2018. The study considers all the kebeles in the town. Study subjects were determined using proportionate-to-population size allocation. Then, a systematic random sampling technique was applied. Data were collected using a semistructured and pretested questionnaire. Descriptive summary data and binary logistic regression analysis were carried out to identify factors with the 95% confidence level and apvalue of less than 0.05. Results. A total of 513 study subjects participated in this study. The overall preconception healthcare knowledge score of women in Jinka town was 51.1%. In the multivariable analysis, housewives (AOR = 2.93; 95% CI: 1.38–6.19), an education level of at least college (AOR = 3.79; 95% CI: 1.75–8.23), no history of neonatal death (AOR = 4.13; 95% CI = 1.39–12.25), and the use of family planning methods (AOR = 2.38; 95% CI: 1.49–3.79) increased the probability of preconception healthcare knowledge compared to the counterparts. Conclusion. In this study, women’s knowledge of preconception healthcare was found borderline. The identified factors were housewife, education level of at least college, no history of neonatal death, and using family planning methods. Therefore, emphasizing these factors for the enhancement of women’s knowledge of preconception healthcare is a necessary step.
Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models
Authors: Galicia-Moreno Marina , Silva-Gomez Jorge A , Lucano-Landeros Silvia , Santos Arturo , Monroy-Ramirez Hugo C , Armendariz-Borunda Juan
Published: March 2021

Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-β-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.
Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
Authors: Tasaki Yoshihiko , Suzuki Miho , Katsushima Keisuke , Shinjo Keiko , Iijima Kenta , Murofushi Yoshiteru , Naiki-Ito Aya , Hayashi Kazuki , Qiu Chenjie , Takahashi Akiko , Tanaka Yoko , Kawaguchi Tokuichi , Sugawara Minoru , Kataoka Tomoya , Naito Mitsuru , Miyata Kanjiro , Kataoka Kazunori , Noda Tetsuo , Gao Wentao , Kataoka Hiromi , Takahashi Satoru , Kimura Kazunori , Kondo Yutaka
Published: March 2021

Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU–based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-FU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy.

Significance:

Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.
Shaping Functional Avidity of CAR T Cells: Affinity, Avidity, and Antigen Density That Regulate Response
Authors: Greenman Raanan , Pizem Yoav , Haus-Cohen Maya , Goor Alona , Horev Guy , Denkberg Galit , Sinik Keren , Elbaz Yael , Bronner Vered , Levin Anat Globerson , Horn Galit , Shen-Orr Shai , Reiter Yoram
Published: March 2021

Chimeric antigen receptors (CARs) are immunoreceptors that redirect T cells to selectively kill tumor cells. Given their clinical successes in hematologic malignancies, there is a strong aspiration to advance this immunotherapy for solid cancers; hence, molecular CAR design and careful target choice are crucial for their function. To evaluate the functional significance of the biophysical properties of CAR binding (i.e., affinity, avidity, and antigen density), we generated an experimental system in which these properties are controllable. We constructed and characterized a series of CARs, which target the melanoma tumor–associated antigen Tyr/HLA-A2, and in which the affinity of the single-chain Fv binding domains ranged in KD from 4 to 400 nmol/L. These CARs were transduced into T cells, and each CAR T-cell population was sorted by the level of receptor expression. Finally, the various CAR T cells were encountered with target cells that present different levels of the target antigen. We detected nonmonotonic behaviors of affinity and antigen density, and an interrelation between avidity and antigen density. Antitumor activity measurements in vitro and in vivo corroborated these observations. Our study contributes to the understanding of CAR T-cell function and regulation, having the potential to improve therapies by the rational design of CAR T cells.

See related article on p. 946
The Discovery of a Novel Antimetastatic Bcl3 Inhibitor
Authors: Soukupová Jitka , Bordoni Cinzia , Turnham Daniel J. , Yang William W. , Seaton Gillian , Gruca Aleksandra , French Rhiannon , Lee Kok Yung , Varnava Athina , Piggott Luke , Clarkson Richard W.E. , Westwell Andrew D. , Brancale Andrea
Published: March 2021

The development of antimetastatic drugs is an urgent healthcare priority for patients with cancer, because metastasis is thought to account for around 90% of cancer deaths. Current antimetastatic treatment options are limited and often associated with poor long-term survival and systemic toxicities. Bcl3, a facilitator protein of the NF-κB family, is associated with poor prognosis in a range of tumor types. Bcl3 has been directly implicated in the metastasis of tumor cells, yet is well tolerated when constitutively deleted in murine models, making it a promising therapeutic target. Here, we describe the identification and characterization of the first small-molecule Bcl3 inhibitor, by using a virtual drug design and screening approach against a computational model of the Bcl3-NF-kB1(p50) protein–protein interaction. From selected virtual screening hits, one compound (JS6) showed potent intracellular Bcl3-inhibitory activity. JS6 treatment led to reductions in Bcl3-NF-kB1 binding, tumor colony formation, and cancer cell migration in vitro; and tumor stasis and antimetastatic activity in vivo, while being devoid of overt systemic toxicity. These results represent a successful application of in silico screening in the identification of protein–protein inhibitors for novel intracellular targets, and confirm Bcl3 as a potential antimetastatic target.
Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer
Authors: Branch Jonathan R. , Bush Tammy L. , Pande Vineet , Connolly Peter J. , Zhang Zhuming , Hickson Ian , Ondrus Janine , Jaensch Steffen , Bischoff James R. , Habineza Georges , Van Hecke Geert , Meerpoel Lieven , Packman Kathryn , Parrett Christopher J. , Chong Yolanda T. , Gottardis Marco M. , Bignan Gilles
Published: March 2021

Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.
Abstract LT017: ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology
Authors: Rejniak Katarzyna A. , Poonja Sharan , Mathur Shreya , Kingsley Jessica , Bui Marilyn
Published: March 2021

Progression from a ductal carcinoma in situ (DCIS) to an invasive tumor is a major step initiating a devastating and often lethal metastatic cascade. One sentinel event that initiate this process is the development of ductal microinvasions, i.e., small cohorts of tumor cells that breach the basement membrane surrounding the duct and migrate through the extracellular matrix (ECM) leading to irreversible changes in tumor and stromal architecture. We used a combination of advanced image analysis techniques applied to patients’ histology data to extract features which identify specific properties of individual tumor cells inside the duct and on the invasive front. By integrating these histology-based data with a hybrid agent-based mathematical model, we investigated the biomechanical interactions between the cells and the ECM fiber architecture, and microenvironmental physical and metabolic features that define tumor niche prone to microinvasions. The identified physical properties of the matrix elucidate conditions that can facilitate or prevent the progression of such microinvasions. The presented method provides also a tool for quantifying morphological and immunohistochemical properties of individual cells within the mammary ducts and ductal microinvasion, as well as for testing biomechanical hypotheses of tumor cell-tumor matrix interactions. These findings can be compared to the patient histology samples and help define criteria for identification of changes in tumor architecture and future development of new diagnostic methods.

Citation Format: Katarzyna A. Rejniak, Sharan Poonja, Shreya Mathur, Jessica Kingsley, Marilyn Bui. ECM mechanical and metabolic architecture during early ductal invasions: integrating in silico modeling, histology-based machine learning and mechanobiology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT017.
Abstract PO040: Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy
Authors: Voss Jorine J.L.P. , Damalanka Vishnu , Mahoney Matthew , Klampfer Lidija , Janetka James W.
Published: March 2021

Overproduction of Hepatocyte Growth Factor (HGF) in the tumor microenvironment by tumor-associated fibroblasts or cancer cells is associated with poor patient outcomes and is a common cause of therapeutic resistance. HGF signals via the MET receptor, which results in the activation of downstream signaling pathways that promote cell survival, proliferation, migration, scattering, and invasion of cancer cells. HGF is secreted as an inactive precursor, pro-HGF, and proteolytic processing into its active form by one of the serine proteases, matriptase, hepsin, or HGF Activator (HGFA), is the rate-limiting step in HGF/MET signaling. The expression of these proteases is upregulated in cancer, whereas the activity of endogenous inhibitors of HGF-activating proteases, HGF-Activation Inhibitors (HAI-1/HAI-2), is reduced in cancer. We have developed small-molecule inhibitors of the three HGF-activating proteases, matriptase, hepsin, and HGFA. We refer to these inhibitors as synthetic HGF-Activation Inhibitors (sHAI), because they mimic the activity of HAI-1/HAI-2. The activity of sHAI was tested in in vitro models of therapeutic resistance and in in vivo models of HGF-driven lung cancer progression. ZFH7116 and VD2173, two lead SHAI compounds, are both potent inhibitors of the HGF-activating proteases and have good drug-like pharmacokinetic (PK) properties. We demonstrated that ZFH7116 and VD2173 inhibit proteolytic activation of pro-HGF to its active form. Both compounds overcome HGF-mediated resistance to EGFR and MET-targeted therapy in lung and colon cancer models of therapeutic resistance. Furthermore, ZFH7116 and VD2173 inhibit HGF-dependent growth of lung cancer cells in mice. Overall, our data demonstrate that inhibitors of HGF activation, such as ZFH7116 and VD2173, prevent HGF-dependent tumor growth, and overcome HGF-mediated resistance to targeted anti-cancer therapy. As such, they represent a unique way of inhibiting oncogenic HGF/MET signaling.

Citation Format: Jorine J.L.P. Voss, Vishnu Damalanka, Matthew Mahoney, Lidija Klampfer, James W. Janetka. Protease inhibitors of HGF activation prevent HGF-dependent tumor progression and overcome resistance to anti-cancer therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO040.
Abstract PO041: Hyaluronan processing and function in the progression of breast cancer
Authors: Witschen Patrice M. , Chaffee Thomas S. , Brady Nicholas J. , Knutson Todd P. , LaRue Rebecca S. , Munro Sarah , Tiegs Lyubov , McCarthy James B. , Nelson Andrew C. , Schwertfeger Kathryn L.
Published: March 2021

Hyaluronan (HA) is a large, soluble, glycosaminoglycan of the extracellular matrix that has anti-inflammatory effects under physiologic conditions. However, HA is cleaved into low molecular weight (LMW) fragments under conditions of cellular or organismal stress, acting as a molecular “switch” that promotes inflammation. In breast cancer, a decrease in HA synthesis has been correlated with decreased tumor cell proliferation and migration. However, the roles of HA fragmentation in the progression of breast cancer are unknown. We predict that HA fragmentation increases during this transition, promoting inflammation through LMW HA-CD44 interactions. To test our hypothesis, the presence/absence of HA fragmentation was determined using gel electrophoresis in breast cancer cell lines. Additionally, qRT-PCR was performed to examine gene expression of the three major hyaluronan synthases (Has) 1-3 and the three major hyaluronidases (Hyal) 1, 2, and PH-20. Our data suggest as a cancerous lesion progresses, HMW HA production increases (primarily through Has2), but HA fragmentation does not occur until the tumor acquires a more aggressive phenotype (primarily through Hyal1). Following characterization of HA fragmentation and machinery within our system, we found changes in inflammatory cytokines (such as CCL2) as downstream effects of CD44 and HA synthesis inhibition. We have currently knocked out CD44 in two breast cancer cell lines using the CRISPR/Cas9 method to determine the functional relationship between CD44 and HA using an in vivo mouse model. By targeting HA-CD44 signaling associated with inflammation, new therapeutic approaches can be developed for the treatment of breast cancer.

Citation Format: Patrice M. Witschen, Thomas S. Chaffee, Nicholas J. Brady, Todd P. Knutson, Rebecca S. LaRue, Sarah Munro, Lyubov Tiegs, James B. McCarthy, Andrew C. Nelson, Kathryn L. Schwertfeger. Hyaluronan processing and function in the progression of breast cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO041.
Abstract PO046: Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis
Authors: Hwang-Verslues Wendy W. , Chang Po-Hao
Published: March 2021

Breast cancer is the most common cancer of women worldwide. Although the 5-year survival rate has greatly improved due to early detection and advance in therapeutic strategies, metastasis remains the major cause of breast cancer death. Metastatic cancer cells which formed clusters of circulating tumor cells (CTCs) are particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that Desmoglein2 (DSG2), a cell adhesion molecule involved in desmosome mediated intercellular adhesion, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. Importantly, regulation of DSG2 by hypoxia was a key to this process. Hypoxia-induced DSG2 downregulation led to elevated epithelial-mesenchymal transition (EMT) gene expression allowing cells to detach from the primary tumor and undergo intravasation. Subsequent reactivation of DSG2 expression after release of hypoxic stress in the circulation allowed CTCs to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to activate expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis.

Citation Format: Wendy W. Hwang-Verslues, Po-Hao Chang. Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO046.
Abstract PO050: EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival
Authors: Moyano-Galceran Lidia , Turunen Pauliina S. , Sugiyama Nami , von Nandelstadh Pernilla , Gucciardo Erika , Varjosalo Markku , Lehti Kaisa
Published: March 2021

The receptor tyrosine kinase EphA2 is overexpressed in many solid cancers and associated with disease aggressiveness and poor clinical outcome. EphA2 signaling mechanisms are complex, context-dependent and still not completely understood. In several cancers, EphA2-ephrinA1 interaction is associated with cell repulsion and growth suppressive signaling. Yet, this receptor can also be activated in a ligand-independent manner by crosstalk with growth factor receptors and adhesion molecules, and its signaling can be further regulated via proteolytic cleavage by the matrix metalloproteinase MT1-MMP (MMP14). Studying how such proteolytic events, duality in signaling modes and repulsive responses are co-regulated and coexist in cancer could reveal potential therapeutic opportunities. To this goal, we have here used human breast, ovarian and prostate cancer cells grown in 2D and 3D extracellular matrices (ECM), as mono- and co-cultures to mimic the confines provided by the tumor microenvironment. Our results revealed segregation of EphA2 signaling within cancer colonies, including EphA2-MMP14 co-internalization at the cancer cells confronting ephrinA1-expressing cells, in contrast to the stabilization of the receptor and induction of non-canonical signaling in the colonies. This separation of the ligand-mediated and non-canonical EphA2 signaling was dependent on MMP14 and affected platinum chemotherapy-induced apoptosis. By a mass spectroscopy-based screen for EphA2 interacting proteins in the different signaling contexts we identified regulators of proteolysis as well as endocytic pathways with differential interactions upon the ligand-dependent and independent activation states of this receptor. Our studies will help to understand the diverse EphA2 signaling modes and their impact on the regulation of cell-cell and cell-ECM communication affecting cell invasion and survival upon anti-cancer drug treatments.

Citation Format: Lidia Moyano-Galceran, Pauliina S. Turunen, Nami Sugiyama, Pernilla von Nandelstadh, Erika Gucciardo, Markku Varjosalo, Kaisa Lehti. EphA2 signaling segregation and modulation by diverse tumor microenvironment components differentially regulates cancer cell invasion and survival [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO050.
Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions
Authors: Kim Jong Hyuk , Megquier Kate , Thomas Rachael , Sarver Aaron L. , Song Jung Min , Kim Yoon Tae , Cheng Nuojin , Schulte Ashley J. , Linden Michael A. , Murugan Paari , Oseth LeAnn , Forster Colleen L. , Elvers Ingegerd , Swofford Ross , Turner-Maier Jason , Karlsson Elinor K. , Breen Matthew , Lindblad-Toh Kerstin , Modiano Jaime F.
Published: March 2021

Sporadic angiosarcomas are aggressive vascular sarcomas whose rarity and genomic complexity present significant obstacles in deciphering the pathogenic significance of individual genetic alterations. Numerous fusion genes have been identified across multiple types of cancers, but their existence and significance remain unclear in sporadic angiosarcomas. In this study, we leveraged RNA-sequencing data from 13 human angiosarcomas and 76 spontaneous canine hemangiosarcomas to identify fusion genes associated with spontaneous vascular malignancies. Ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in seven of the 13 human tumors, with two tumors showing mutations of TP53. HRAS and NRAS mutations were found in angiosarcomas without fusions or TP53 mutations. We found 15 novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 in 11 of the 76 canine hemangiosarcomas; these fusion genes were seen exclusively in tumors of the angiogenic molecular subtype that contained recurrent mutations in TP53, PIK3CA, PIK3R1, and NRAS. In particular, fusion genes and mutations of TP53 cooccurred in tumors with higher frequency than expected by random chance, and they enriched gene signatures predicting activation of angiogenic pathways. Comparative transcriptomic analysis of human angiosarcomas and canine hemangiosarcomas identified shared molecular signatures associated with activation of PI3K/AKT/mTOR pathways. Our data suggest that genome instability induced by TP53 mutations might create a predisposition for fusion events that may contribute to tumor progression by promoting selection and/or enhancing fitness through activation of convergent angiogenic pathways in this vascular malignancy.

Implications:

This study shows that, while drive events of malignant vasoformative tumors of humans and dogs include diverse mutations and stochastic rearrangements that create novel fusion genes, convergent transcriptional programs govern the highly conserved morphologic organization and biological behavior of these tumors in both species.