bluuebunny/crossref_metadata_2025 huggingface dataset:
Odynophagia after Cardiac Catheterization: A Rare Complication in the Presence of Aberrant Subclavian Artery
Authors: Naidu Moumita , Singh Robby , Zughaib Marcel
Published: December 2020

Background. Vascular complications from transradial cardiac catheterization are uncommon. Mediastinal hematoma is a rare complication with life-threatening potential. We present a case of a patient who underwent cardiac catheterization and subsequently experienced odynophagia from injury to an aberrant subclavian artery that led to a mediastinal hematoma. Case Report. A 59-year-old female with past medical history of coronary artery disease presented with complaints of angina and underwent a transradial cardiac catheterization. Immediately after the procedure, the patient complained of chest pain and odynophagia. EKG and echocardiogram were unremarkable, and a CT scan of the chest demonstrated an ill-defined fluid collection present in the superior mediastinum and an aberrant right subclavian artery. The patient was closely monitored in the Intensive Care Unit, and the patient remained hemodynamically stable throughout the admission. The patient was subsequently discharged home in good condition and did well on outpatient follow-up. Conclusion. Vascular injuries associated with delivery of standard radial catheters in the subclavian artery are rare, with very few cases reported in the literature. We presented the case of a patient who had a previously unidentified right aberrant subclavian artery with a retroesophageal course which precipitated the hematoma and subsequently resulted in odynophagia despite an uncomplicated catheterization. This rare complication of a commonplace procedure necessitates prompt recognition, appropriate hemodynamic management, and possible repair of the injured vessel to appropriately manage a potentially life-threatening condition.
Antiamylase, Antilipase, Antimicrobial, and Cytotoxic Activity of Nonea obtusifolia (Willd.) DC. from Palestine
Authors: Jaradat Nidal , Abualhasan Murad N. , Qadi Mohammad , Issa Linda , Mousa Ahmad , Allan Fathia , Hindi Mohammad , Alhrezat Zaid
Published: December 2020

Background. Medicinal plants are widely used in many cultures, traditions, and civilizations worldwide. Plants with high contents of the valuable biological compounds can efficiently cure many diseases. This study is aimed at assessing, for the first time, the anti‐α‐amylase, antilipase, antimicrobial, and cytotoxic activities of Nonea obtusifolia (Willd.) DC. of five extracts from Palestine. Methods. The antimicrobial activity was estimated using well diffusion method for N. obtusifolia plant of five extracts against eight ATCC (American Type Culture Collection) and clinical isolates. The cytotoxic effects for these extracts were evaluated against HeLa (cervical) carcinoma cells using MTS (3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium) assay. Moreover, the lipase and α‐amylase inhibitory properties were determined using standard biomedical assays. Results. The acetone extract of N. obtusifolia plant showed a more potent α‐amylase inhibitory compared with acarbose with IC50 values of 25.7 ± 0.08 and 28.18 ± 1.22 μg/ml, respectively. Additionally, the acetone and methanol extracts revealed moderate antilipase activity compared to orlistat with IC50 values of 30.19 ± 0.11, 33.11 ± 0.13, and 12.3 ± 0.35 μg/ml, respectively. The methylene chloride extract was found to inhibit the growth of all the tested bacterial and fungal strains and also found to have potential cytotoxic effect against HeLa cancer cell line. Conclusion. This research work reports for the first time the biological activity of N. obtusifolia from Palestine, and the results were promising indicating that N. obtusifolia extracts contain valuable bioactive molecules that have a potential anti‐α‐amylase, antilipase, antibacterial, and antifungal cytotoxic potentials. Therefore, N. obtusifolia could have a medical significance in the future.
Impurities in Drug Vials Intended for Intravitreal Medication
Authors: Pohl Lisa , Strudel Lisa , Dimopoulos Spyridon , Ziemssen Focke
Published: December 2020

Sterility is an important prerequisite for minimizing the risk of severe vision loss due to endophthalmitis after intravitreal injections. We describe three cases series of incidents where an unclear contamination of the drug solution or syringe caused the injection process to stop and continue with a new preparation. During a period of 12 months with 30,502 intravitreal injections at a tertiary center, wherein 7,076 were of the drug Aflibercept drawn up from a glass vial, three cases of the critical incident reporting system relating to intravitreal injections were identified: (1) After a typical contact with the filter cannula, the glass of an Aflibercept vial was no longer intact. (2) In the course of another injection, there was a clear deposition of debris on the outer edge of the syringe when removing the attached filter cannula. (3) After inserting the syringe into the rubber top of the vial, a whitish particle of unclear origin was identified within the drug solution. Later, this contamination/particle was identified as part of the greyish rubber that was punched out with the cannula, according to the analyses of the material sent in and the manufacturer’s investigations. Thus, even in busy clinics, visual inspection of the injection solution and materials used for impurities, preferably before and after pulling them out of a vial, must be an essential part of the injection process. Even when using ready-to-use prefilled syringes (PFS), vigilance must be kept high, knowing the risk of potential contamination.
Three‐Dimensional Numerical Modeling and Roof Deformation Analysis of Yuanjue Cave Based on Point Cloud Data
Authors: Meng Zhigang , He Manchao , Tao Zhigang , Li Bin , Zhao Gang , Xiao Mingru
Published: December 2020

Yuanjue Cave is the core exquisite cultural relic of the Dazu Stone Carvings World Cultural Heritage Site. For hundreds of years, with the continuous effect of natural forces and the erosion of various deterioration factors, the sidewall and roof rock mass of Yuanjue Cave were eroded, some parts of supporting rock mass were fragmented, and the boundary conditions of the rock mass have deteriorated, which have seriously endangered the Yuanjue Cave; once the roof collapses, the national treasure in the cave will be destroyed. In order to preevaluate the stability characteristics of the Yuanjue Cave rock mass and provide key parameters for the preventive protection of the Yuanjue Cave, this paper firstly established a refined database of key parameters of Yuanjue Cave and adjacent areas (geometry, geology, physical properties) based on three‐dimensional laser point cloud scanning, a fine survey of adjacent areas, engineering geophysical prospecting, and indoor multifactor coupling tests. Then, based on FLAC3D finite difference numerical simulation technology, an accurate three‐dimensional numerical calculation model of Yuanjue Cave was constructed. Finally, the model was used to analyze the roof stability of Yuanjue Cavern, revealing the deformation laws of the Yuanjue Cave roof under static load conditions, and the numerical calculation results were compared with the on‐site measured results, verifying the feasibility of the high‐precision modeling method, and the reliability of the numerical calculation results provided a reference for the preventive protection of the cultural relics of the cave temple.
Knowledge and Use of Caries Detection Methods among Dental Students and Dental Practitioners in Riyadh, Saudi Arabia
Authors: Radwan Waseem , AlNasser Abeer A. , Aloqab Hesah , Al-Saggaf Khalid , Almuhtab Nora A. , Alnasyan Bothinah
Published: December 2020

Aim. Accurate detection and diagnosis of dental caries is an integral part of achieving adequate comprehensive dental care. Furthermore, the high prevalence of caries and generally poor oral health in Saudi Arabia is a public health concern. In addition to necessary preventive programs and awareness initiatives, understanding diagnostic practices plays an important role in garnering broad background knowledge regarding the routine diagnostic means utilized by our targeted respondents. Therefore, this study aimed to assess the methods of caries detection among dental students and dental practitioners in Riyadh using a cross-sectional observational study design. Methods. The sample comprised 496 dental students, interns, postgraduate residents, general dental practitioners, specialists, and consultants from the Riyadh region of Saudi Arabia. A survey was designed to assess caries detection methods, risk assessment practices, and knowledge of advanced diagnostic methods. The responses were correlated with demographic and educational variables. Regression models were used to predict associations. Results. 42.3% and 32.7% use sharp explorers in diagnosing caries always and most of the time, respectively. When conducting caries risk assessment practices, 64.4% was very likely to review the patient’s medical history and lifestyle. In terms of knowledge of advanced diagnostic methods, 47.8% know “much” to “very much” about FOTI. The knowledge of advanced caries diagnostic methods and practices of advanced diagnostic methods were significantly positively correlated (r = 0.388,

P
<
0.001

). Linear regression analysis indicated that higher experience (10+ years) was associated with higher knowledge regarding advanced caries diagnostic methods (

β

 = 0.27,

P
=
0.009

). The mean rank for risk assessment practices was significantly lower in GPs compared to consultants

P
<
0.05

. Conclusions. The use of traditional and invasive methods of caries detection is prevalent among our respondents, while the usage of advanced diagnostic methods is for the most part low. Therefore, we advocate for more minimally invasive approaches and as such encourage the practice and availability of advanced diagnostic methods.
A Novel Approach to Supply the Water Reservoir Demand Based on a Hybrid Whale Optimization Algorithm
Authors: Donyaii Alireza , Sarraf Amirpouya , Ahmadi Hassan
Published: December 2020

Managing water resources requires the optimum operation of dam reservoirs. To satisfy the downstream water demand in the operational optimization of Boostan dam reservoir, the improved whale optimization algorithm (IWOA) performance was compared in the present study with that of its constituents (i.e., the whale optimization and differential evolution) based on GAMS nonlinear programming results. The model evaluative indicators and an objective function were used to select the optimal algorithm. The findings suggested that IWOA resulted in the lowest computational duration and fastest convergence rate compared to the other algorithms. Additionally, the average water demand and discharge volume of IWOA were 3.21 × 106 m3 and 3.03 × 106 m3, respectively. In contrast, the other algorithms yielded lower water release volumes. IWOA enhanced the WOA performance by 21.7% through reducing the variation coefficient by 78% in optimizing the objective function. The water demand was therefore more effectively satisfied by the IWOA compared to the other algorithms. Furthermore, the IWOA resulted in a lower amount of errors. The hybrid algorithm performance increased in terms of all the evaluative indicators. Developing multicriteria decision-making models using TOPSIS and the Shannon entropy also suggested the IWOA excels the other algorithms in optimizing the reservoir operational problem.
Spectrum-Effect Relationships of Flavonoids in Glycyrrhiza uralensis Fisch.
Authors: Li Tingting , Hua Shiyao , Ma Jiahua , Dong Lin , Xu Fang , Fu Xueyan
Published: December 2020

Glycyrrhiza uralensis Fisch. is used in large quantities in traditional Chinese medicine. It contains flavonoids, saponins, and polysaccharides, with flavonoids being the main active ingredients. In this study, flavonoids were isolated from the roots of Glycyrrhiza uralensis Fisch. grown in 21 areas in China by water extraction, alcohol precipitation, polyamide resin separation, and other methods. Fingerprints were established by high performance liquid chromatography (HPLC). There were 15 common peaks in the fingerprints by similarity evaluations of the chromatographic fingerprints. The spectrum-effect relationships between the HPLC fingerprints and pharmacological activities of flavonoids in G. uralensis Fisch., including the heat clearing, detoxifying effects, cough relief, and phlegm elimination effects, were assessed by gray relational analysis and partial least squares regression. After HPLC-quadrupole time-of-flight mass spectrometry and standard comparison, these five identified compounds (liquiritin apioside, neoisoliquiritin, licochalcone A, licochalcone B, and licochalcone C) could be used to evaluate licorice quality with regard to its efficacy. This research provides a scientific basis for improving licorice quality and also establishes a model for modernization of traditional Chinese medicines.
Gas Displacement Engineering Test by Combination of Low and Medium Pressure Injection with Liquid CO2 in High Gas and Low Permeability Coal Seam
Authors: Wen Hu , Liu Mingyang , Wei Gaoming , Zhai Xiaowei , Fan Shixing , Cheng Xiaojiao , Wang Hu , Hao Jianchi
Published: December 2020

Mining high-gas coal seams in China has the characteristics mining of deep, high storage and low permeability, and low drainage efficiency, which seriously restrict the efficient prevention and control of mine gas disasters. Based on the characteristics of low viscosity and permeability, phase change pressurization, and strong adsorption potential energy of liquid CO2, the technology system of liquid CO2 displacement for high-gas and low-permeability coal seam was developed, and field industrial of low-pressure (0.5~2.5 MPa) and medium-pressure (2.5~15.0 MPa) combined injection test was carried out. In this test, the mode of injection followed by drainage was adopted, and the gas drainage effect was investigated for 30 days. The test results show that the effective influence radius of CO2 in this test is 20 m, and the liquid seepage radius is 5 to 7 m. After the injection of liquid CO2 into coal seam, the average gas drainage concentration and drainage purity of all drainage holes were increased by 3.2 and 3.4 times, respectively, and the gas promotion effect was significant. Taking the liquid CO2 low-medium-pressure displacement gas test area as the calculation unit, from the comprehensive benefit analysis, compared with the original drainage mode, the liquid CO2-combined pressure injection process can save 34.7% of the engineering cost and shorten the gas drainage standard time by 45.9%. Therefore, the application of this technology has important technical support and reference significance for the efficient management of gas in the same type of mine.
Sorptive Removal of Color Dye Safranin O by Fibrous Clay Minerals and Zeolites
Authors: Sieren Ben , Baker Jessica , Wang Xisen , Rozzoni Samuel J. , Carlson Kristen , McBain Alyssa , Kerstan Daniel , Allen Lori , Liao Libing , Li Zhaohui
Published: December 2020

The increased use of color dyes in industry imposes a great threat to the environment. As such, developing cost‐effective techniques for dye removal from wastewater attracted great attention. Earth materials, particularly those with large specific surface area (SSA) and high cation exchange capacity (CEC), were evaluated for their potential use for wastewater treatment. In this study, palygorskite, sepiolite, and clinoptilolite were evaluated for their removal of cationic dyes using safranin O (SO+) as a model compound. The CEC values of the materials played a key role in SO+ removal while other physicochemical conditions, such as temperature, equilibrium solution pH, and ionic strength, had less influence on SO+ removal. Sorbed SO+ cations were limited to the external surfaces of the minerals, as their channel sizes are less than the size of SO+ cation. Molecular dynamic simulations showed dense monolayer SO+ uptake on palygorskite due to its relatively large CEC value. In contrast, loosely packed monomer SO+ uptake was adopted on sepiolite for its large SSA and low CEC. Dense multilayers or admicelles of SO+ formed on zeolite surfaces. As such, for the best SO removal, palygorskite is better than sepiolite, though both are fibrous clay minerals.
Polymorphisms in the 3

′

UTR Region of ESR2 and CYP19A1 Genes and Its Influence on Allele-Specific Gene Expression in Endometriosis
Authors: Smolarz Beata , Szaflik Tomasz , Romanowicz Hanna , Szyłło Krzysztof
Published: December 2020

Objectives. Endometriosis is supported by hormonal, immunological, and environmental factors. No specific marker for endometriosis has yet been identified. ESR2 and CYP19A1 genes play a major role in the hormonal control of endometriosis women, the development of which largely depends on steroid hormones. Aim. An analysis of ESR2 and CYP19A1 allele-specific gene expressions in the context of the risk for endometriosis occurrence. Methods. The study material included paraffin-embedded tissue specimens, collected from patients (

n
=
100

) with endometriosis. Blood samples from age-matched, endometriosis-free women (

n
=
100

) served as a control. the RT-PCR technique was performed to observe the expression of ESR2 and CYP19A1 genes. Moreover, Sanger’s sequencing method was applied for polymorphism analysis. Results. A set of 4 single-nucleotide polymorphisms (SNPs) was determined; all of them most significantly associated with endometriosis: rs4986938 (G>A)(chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15). There were no differences in the distribution of genotypes and alleles in the studied groups, taking into account ESR2 and CYP19A1 gene expressions. Conclusion. The ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility. Further analysis is needed to specify the role of these polymorphisms in the pathogenesis of endometriosis.
Elliptic Equation of Plastic Area Boundary around the Circular Laneway in Nonuniform Stress Field
Authors: Guo Xiaofei , Guo Linfeng
Published: December 2020

In order to obtain the analytical solution of the plastic area boundary of circular laneway surrounding rock in nonuniform stress field, we studied the evolution of the plastic area shapes of the circular laneway surrounding rock from circular to elliptical and derived the analytical solutions of the boundary radii in the elliptical shape. The results show that (1) with the increase of the confining pressure ratio from 1, the major axis radius of the plastic area increases gradually, the minor axis radius decreases gradually, and the shape of the plastic area gradually evolves from circular to elliptical; (2) on the basis of the Mohr–Coulomb strength criterion, the analytical expressions of major axis and minor axis radii of the elliptical plastic area are derived, and the elliptic equation of the plastic area boundary of circular laneway in nonuniform stress field is established; and (3) the confining pressure ratio is the key factor affecting the shape of the plastic area. When the confining pressure ratio is less than 1.6, the plastic area of the circular laneway surrounding rock is elliptical, and the elliptic boundary equation is applicable. When the confining pressure ratio is greater than 1.6, the plastic area is butterfly shaped, and the elliptic boundary equation is no longer applicable.
Estimation of Generated and Retained Gas Volume of the Besa River Formation in Liard Basin through 3-Dimensional Static Geochemical Modeling
Authors: Kim Kwang Hyun , Hong Sung Kyung , Choi Jiyoung , Lee Kyungbook , Mort Andy , Lee Hyun Suk
Published: December 2020

The Besa River Formation mainly comprises argillaceous sediments, and the upper shale bed of the Formation has been considered as a prospective shale gas reservoir. The maturity and quantity of organic matter found in source rock are considered as factors for evaluating resource value. Original hydrogen index (HIo) and total organic carbon (TOCo) are considered as properties to estimate generated gas volume in shale gas reservoirs. Generally, TOCo and HIo are determined via geochemical analysis of organic matter and calculated from well-log data like density, sonic data, and resistivity. In this study, these properties were measured or calculated by using geological analysis data and bulk-density log, and then the prospective area from the geochemical perspective in Liard Basin is defined by realizing a 3-dimensional static geochemical model. To validate the static model, the gas-in-place (GIP) (496 Bcf/section) of the production well in this study area was compared with GIP (262 Bcf/section) in the static model. Expulsion efficiency was considered as 0.6. The result implies that this model has a method of informative assessment with regard to undeveloped shale gas resources. The static model provides spatial information for generated and retained gas volume in the Besa River Formation, Liard Basin.
Study on the Origin and Fluid Identification of Low-Resistance Gas Reservoirs
Authors: Yuhui Zhou , Qingxiong Hu , Wentao Liu , Zhiqi Wu , Yule Yan , Jialing Ma
Published: December 2020

The Wu 2 section of the Ke017 well block is a low-resistance gas reservoir with ultralow porosity and low permeability. The comprehensive analysis of rock lithology, physical properties, sedimentary characteristics, and gas content demonstrated that the development of micropores in illite/smectite dominated clay minerals together with the resulted additional conductivity capability and complex reservoir pore structures, as well as the enrichment of self-generating conductivity minerals like zeolites and pyrite which were the formation mechanisms of low-resistance gas layers in the Wu 2 section. A low-resistance gas reservoir has poor physical property, and it is difficult to distinguish the oil layer from the dry, gas, or water layers. In this paper, based on well/mud logging data and laboratory data, by taking advantages of the “excavation effect” of neutron gas and the dual-lateral resistivity difference between different depths, we successfully established a set of low-contrast log response methods for the identification and evaluation of oil layer and formation fluids. For a gas layer, the difference between neutron porosity and acoustic (or density) porosity is smaller than 0 and the difference in dual-lateral resistivity is greater than 0. For a water layer, the neutron porosity is similar to the acoustic (or density) porosity and the dual-lateral resistivity difference will be less than 0. While for a dry layer or a layer with both gas and water, the difference in porosity as well as dual-lateral resistivity is very small. The proposed method effectively solves the technical problem of oil layer and formation fluid identification in low-resistance gas reservoirs.
Analysis of Resistance Characteristics of a 37 Rod Fuel Bundle under Low Reynolds Number
Authors: Li Yonghua , Li Meijun , Guo Yangyang
Published: December 2020

During the working period of decay heat removal system, the flow rate of liquid sodium in wire-wrapped fuel assembly is very low, generally

Re
<
1000

. In the present study, both experimental methods and numerical simulation methods are applied. First, water experiment of 37-pin wire-wrapped rod bundle was carried out. Then, the numerical simulation study was carried out, the experimental data and the numerical simulation results were compared and analyzed, and a suitable turbulence model was selected to simulate the liquid sodium medium. Finally, numerical simulations under different boundary conditions were performed. Results indicate that except for the low Reynolds number

k

-

ε

turbulence model, other turbulence models have little difference with the experimental results. The results of realizable

k

-

ε

turbulence model are the most close to the experimental results. Compared with the friction factor obtained by using water medium and liquid sodium medium, the calculation results of water medium and sodium medium under the same condition are basically consistent, with the deviation within 1%. The reason is that the velocity of water is higher than sodium medium at the same Reynolds number, and the transverse disturbance caused by helical wire is larger.
Irreducibility of a Polynomial Shifted by a Power of Another Polynomial
Authors: Dubickas Artūras
Published: December 2020

In this note, we show that, for any

f
∈
ℤ

x

and any prime number

p

, there exists

g
∈
ℤ

x

for which the polynomial

f

x

−
g

x

p

is irreducible over

ℚ

. For composite

p
≥
2

, this assertion is not true in general. However, it holds for any integer

p
≥
2

if

f

is not of the form

a
h

x

k

, where

a
≠
0

and

k
≥
2

are integers and

h
∈
ℤ

x

.
Abstract IA14: Increasing viral mimicry with vitamin C
Authors: Jones Peter A.
Published: December 2020

Responses of MDS patients to DNA methylation inhibitors (DNMTis) is due in part to the induction of expression of transposable elements, particularly endogenous retroviruses (ERVs). Induction of these transcripts leads to an innate immune response which may be responsible for the clinical efficacy of the drugs and we have called this “viral mimicry”. We investigated whether physiological concentrations of vitamin C given simultaneously with treatment with DNMTis would increase the expression of ERVs. The rationale being that the TET enzymes require vitamin C for their maximum activities, and we hypothesized that the induction of 5-hydroxymethylcytosine would stimulate the expression of these retroviruses. Experiments in culture showed that addition of vitamin C, strongly increases the expression of ERVs and increases the formation of 5-hydroxymethylcytosine during treatment. This is important since culture medium is mostly not supplemented with vitamin C. In more recent patient trials we have shown that responses to DNMTis may indeed be partially due to the induction of ERVs. Because we and others have shown that many patients in hematology clinics are severely vitamin C deficient, we are now exploring whether restoration of vitamin C levels to normal may potentiate the activities of the DNMTis. Preliminary data shows that oral administration of vitamin C increases the expression of ERVs and also the quantity of 5-hydroxymethylcytosine in the DNA of circulating cells. We have now designed a prospective clinical trial to test these hypothesis and preliminary data will be presented.

Citation Format: Peter A. Jones. Increasing viral mimicry with vitamin C [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA14.
Abstract PO-003: Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2
Authors: Greenberg Inbal , Klein Anat , Grossman Rachel , Sokol Ethan , Yeini Eilam , Ofek Paula , Satchi-Fainaro Ronit , Reuveni Hadas , Rubinek Tami , Wolf Ido
Published: December 2020

Brain metastases (BMs) from colorectal cancer (CRC) are currently the fourths leading cause of BMs, and their incidence is on the rise. Yet, mechanisms mediating the formation of BMs from CRC are unknown. We aimed to explore genomic drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms facilitating the process. We analyzed FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence was noted in the insulin receptor substrate 2 (IRS2) gene, which was significantly amplified in BMs relative to primary tumors and other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is known to be involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BMs. Next, we created an in-vitro system mimicking the brain microenvironment using human astrocytes or their conditioned media (CM). Under these conditions, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres. IRS2-silenced CRC cells showed a mirror image. Furthermore, IRS2-overexpressed CRC cells generated larger brain lesions in an intracranial CRC BMs mice model. Interestingly, a transcriptomic analysis revealed significant enrichment of the AKT and β-catenin pathways by IRS2. Indeed, IRS2-amplified cells showed enhanced AKT phosphorylation and inhibition of PI3K or AKT using Alpelisib or Akt1/2 kinase inhibitor, respectively, effectively decreased their proliferation in CM. Importantly, IRS2-amplified cells had increased expression and transcriptional activity of the β-catenin, and AKT pathway inhibitors or IRS2 inhibitor (NT-219) had a more pronounced effect on the activity of β-catenin on those cells. These data indicate, for the first time, the unique genomic profile of CRC BMs and imply the IRS2 role in promoting CRC BMs. These effects may be mediated, at least in part, by modulation of the AKT and β-catenin pathway. These findings may pave the way for the development of novel therapeutic strategies to prevent BMs formation.

Citation Format: Inbal Greenberg, Anat Klein, Rachel Grossman, Ethan Sokol, Eilam Yeini, Paula Ofek, Ronit Satchi-Fainaro, Hadas Reuveni, Tami Rubinek, Ido Wolf. Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2 [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-003.
Abstract PO-019: DNA methylation status in a promoter region of the K-RAS gene in patients with Colorectal Cancer
Authors: Herrera-Pulido Jehison Alirio , Ricaurte-Guerrero Orlando , Acosta-Forero Jinneth , Moreno-Acosta Pablo , Sanabria-Salas María Carolina , Arboleda-Granados Humberto , Hernández Gustavo , Serrano-López Martha Lucía
Published: December 2020

Background: DNA methylation plays an important role in colorectal cancer (CRC) carcinogenesis. The mutated K-RAS gene has been reported to be crucial in CRC progression, but it is not known whether the wild-type gene is regulated by methylation and whether or not this mechanism contributes to disease progression. Now, there are not known reports about the methylation status of the distal K-RAS gene promoter in patients diagnosed with CRC. Materials and methods: Fifty-seven formalin-fixed, paraffin-embedded (FFPE) tissue samples from 57 patients diagnosed with CRC, without K-RAS mutation, were analyzed to determine the methylation status of the distal promoter of this gene. The analysis was performed by DNA extraction from laser microdissections, and 2 mm diameter punch, conversion with sodium bisulfite, amplification by nested PCR, and direct sequencing of purified PCR products. Results: Of the 57 cases, in 2 (6.25%) partial methylation was found in island 2 for one of the cases and in islands 1 and 2 for the other. In 30 (93.75%) cases no methylation was found and in the remaining 25 (43.85%) cases methylation could not be determined, probably due to the quantity and quality of DNA extracted from these blocks. Conclusion: The results found from the preliminary analysis of the methylation status of a region of the distal promoter of the K-RAS gene that serves as an anchorage to Sp1, allowed to determine a partial methylation status in 6.25% of the cases studied, concluding that methylation in this region is not a frequent event

Citation Format: Jehison Alirio Herrera-Pulido, Orlando Ricaurte-Guerrero, Jinneth Acosta-Forero, Pablo Moreno-Acosta, María Carolina Sanabria-Salas, Humberto Arboleda-Granados, Gustavo Hernández, Martha Lucía Serrano-López. DNA methylation status in a promoter region of the K-RAS gene in patients with Colorectal Cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-019.
Abstract PO-044: Epigenetic silencing of SLC17A7 promotes osteosarcoma growth
Authors: Nerlakanti Niveditha , McGuire Jeremy , Yu Diana , Reed Damon R. , Lynch Conor C.
Published: December 2020

Osteosarcoma is an orphan disease with only 900 patients diagnosed each year in US. Most patients are adolescents with small number of older patients. The 5-survival rates for those with metastatic disease is only 30%. Frustratingly, there has been little change in treatment options (chemotherapy, surgery and radiotherapy) due to the difficulty of conducting clinical trials in this rare but deadly cancer. To address this, strong pre-clinical trial information is required to motivate clinical trial design. In vitro and in vivo, we identified that the pan-HDAC inhibitor, panobinostat is highly effective in limiting osteosarcoma growth and metastasis. Panobinostat is approved for the treatment of other malignancies but has noted toxicities. Therefore, to identify therapeutic targets, we explored the HDACs responsible for driving osteosarcoma metastasis and the specific genes through which those HDACs mediated their effects. Our data shows that HDAC1 and HDAC2 are key for osteosarcoma survival using siRNA approaches. Use of the HDAC1/2 selective inhibitor romidepsin in vitro and in vivo supported this finding. To identify targets being regulated by HDAC1/2, we performed microarray and proteomics analyses on romidepsin treated osteosarcoma cells. We found and validated independently that, SLC17A7, a metabolic vesicular glutamate transporter to be highly induced in response to romidepsin treatment; >100 fold more than base line in multiple osteosarcoma cell lines. Functionally, SLC17A7 allows entry of glutamate into the synaptic vesicles from cytoplasm and releases the glutamate from the cells via exocytosis. In our studies, we have seen that romidepsin treatment leads to reduced glutamate levels in the conditioned media and cell death indicating key roles for SLC17A7 in driving osteosarcoma progression and metastasis. In conclusion, our data shows that HDAC1/2 suppression of SLC17A7 is a novel means of promoting osteosarcoma progression and metastasis.

Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. Epigenetic silencing of SLC17A7 promotes osteosarcoma growth [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-044.
Abstract A26: Comparison of DNA extraction kits for metagenomic studies in feces
Authors: Takenaka Isabella Kuniko T. , Moda Bruno S. , Bartelli Thaís F. , Amorim Maria G. , Albuquerque Gabriela E. , Thomas Andrew M. , Dias-Neto Emmanuel , Nunes Diana N.
Published: December 2020

DNA extraction is a critical step in metagenomic studies since it requires the proper lysis of cell walls, allowing the recovery of nucleic acids that would represent the total diversity of communities. Recent studies indicated that the use of different DNA extraction methods in the same sample yielded distinct microbial profiles, highlighting the importance of standardization in DNA extraction methodologies to accurately measure the human microbiome. These issues are even more critical when limiting amounts of samples are available, or when studies target communities with reduced abundance, such as fungi, which represents only 0.1% of total gut microbiota, as has been poorly explored. Here we investigated the performance of three commercial kits for DNA extraction from human fecal samples: QIAamp DNA Stool Mini Kit (Qiagen), E.Z.N.A. Stool DNA Kit (Omega), and ZymoBIOMICS DNA Kit (Zymo), all with or without adding an enzymatic extraction with MetaPolyzyme (MAC4L - Sigma), in an attempt to improve the microbiome community profiling. After extraction, DNA-quality and yield were evaluated using Qubit and real-time PCR, V4-V5 16S rRNA and ITS2 followed by DNA sequencing, as well as further analysis using shotgun DNA sequencing. No significant differences were observed in DNA yield as evaluated by Qubit; an average of 40.3 ng/ul of DNA was obtained for all samples and kits. For both fungi and bacteria analysis, the addition of MAC4L in the extraction protocol apparently did not change the alpha diversity (observed and Shannon) for both individuals. Our analysis for samples extracted with different kits, with or without MAC4L, indicated the percentage of reads from bacteria to vary between 85-90%, whereas fungi were between 0.29-0.49%. Human DNA was also found, as expected, and relative amounts varied from 0.1 to 0.3%. qPCR showed that for all kits up to 50ng of DNA/15uL reaction can be safely used, with no significant DNA polymerase inhibition. These results showed similar efficacy for the three kits in representing bacteria and fungi from feces, and maybe because all these kits had a bead-beading step we had no clear benefits from adding extra enzymatic digestion steps with MAC4L. Finally, we decided to use the Omega kit in our lab, since it combines a simple extraction protocol and is reliable and cost-effective.

Citation Format: Isabella Kuniko T. Takenaka, Bruno S. Moda, Thaís F. Bartelli, Maria G. Amorim, Gabriela E. Albuquerque, Andrew M. Thomas, Emmanuel Dias-Neto, Diana N. Nunes. Comparison of DNA extraction kits for metagenomic studies in feces [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A26.
Abstract B16: High-resolution metagenomic profiling revealed gut microbiome features for the response to cancer immunotherapy reproducible among multiple cohorts of patients
Authors: Kim Chan Yeong , Ahn Beung-Chul , Hong Min Hee , Chun Yoo Jin , Kim Hye Ryun , Lee Insuk
Published: December 2020

Cancer immunotherapy is currently standard of treatment showing significant clinical benefits to cancer patients, but the beneficial effects are limited to a relatively small subset of patients. Of various factors that may affect the efficacy of cancer immunotherapy, the gut microbiome is receiving more attention because of its strong correlation with immune regulation. Recently, independent studies based on Western populations have identified several taxa that are differentially abundant between responders and nonresponders. However, the reported taxa associated with anti-PD-1 response differ entirely among these studies. In this study, we performed 1) deep (>100M reads in average) metagenome shotgun sequencing on the fecal sample of 49 Korean non-small cell lung cancer (NSCLC) patients, 2) taxonomic profiling using a highly comprehensive gut microbiome-specific genome database, and 3) gene-level profiling with the gut microbiome specific gene catalog to improve the resolution of metagenomic analysis. With the high-resolution metagenomic profiling, we found several taxonomic and functional signatures associated with the response of anti-PD-1 therapy. Interestingly, we found that some of the signatures were reproduced in five independent datasets regardless of the cancer types (melanoma, NSCLC, and renal cell carcinoma) and the type of immunotherapy (anti-PD-1, anti-CTLA4, and the combination of them). For instance, a responder-enriched taxon in the Korean cohort was more frequently detected in the responders in all cohorts (abundance fold-change > 2) and significantly enriched (p<0.05) in two cohorts. Moreover, when we performed an association analysis with the combined profile, the taxon was identified with the highest significance among the differentially abundant taxa (fold-change=2.41, p=2.5e-06). Consistent with the result of the taxon-level analysis, we found that the genes encoded by the taxon were also enriched in responders in multiple studies. In summary, using high-resolution metagenomic profiling, we identified gut microbiome features for the response to cancer immunotherapy shared across multiple cohorts for the first time, to the best of our knowledge.

Citation Format: Chan Yeong Kim, Beung-Chul Ahn, Min Hee Hong, Yoo Jin Chun, Hye Ryun Kim, Insuk Lee. High-resolution metagenomic profiling revealed gut microbiome features for the response to cancer immunotherapy reproducible among multiple cohorts of patients [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr B16.
Abstract IA09: The particulars of circulars: Novel RNAs from oncogenic herpesviruses
Authors: Chang Yuan
Published: December 2020

Circular RNAs (circRNA) are formed by backsplicing of linear RNA. Due to their covalently joined cyclized nature, circRNAs are resistant to exonucleases and therefore comparatively more stable than their linear counterparts. Kaposi sarcoma-associated herpesvirus (KSHV/HHV8) and Epstein-Barr virus (EBV/HHV4) have recently been found by RNA sequencing to generate circular RNAs (circRNAs) in infected tissues and cell lines. These molecules represent a novel class of viral RNA that may have a more sustained functional role than linear transcripts. Initial characterization shows that circRNAs are expressed in infection-associated diseases and can be regulated depending on virus life cycle—although the quantity, localization, cell type, and viral life cycle expression of individual circRNAs vary considerably. Some viral circRNAs are incorporated into viral particles for preformed delivery, suggesting a potential function in early infection.

Citation Format: Yuan Chang. The particulars of circulars: Novel RNAs from oncogenic herpesviruses [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA09.
Abstract IA21: Deciphering the human gut microbiome with chemistry
Authors: Balskus Emily P.
Published: December 2020

The human body is colonized by trillions of microorganisms that exert a profound influence on human biology, in part by providing functional capabilities that extend beyond those of host cells. In particular, there is growing evidence linking chemical processes carried out by the human gut microbiome to diseases such as colorectal cancer. However, we still do not understand the vast majority of the molecular mechanisms underlying this phenomenon. Major obstacles faced in surmounting this knowledge gap include the difficulty in linking functions associated with the human gut microbiota to specific microbial enzymes and the challenge of controlling these activities in complex microbial communities. This talk will discuss my lab’s efforts to characterize gut microbial metabolic activities that are linked to colorectal cancer, including a gut microbial genotoxin called colibactin. Gaining a molecular understanding of cancer-associated gut microbial activities will not only help to elucidate the mechanisms by which these organisms contribute to carcinogenesis but should also enable efforts to treat and prevent disease by manipulating this microbial community.

Citation Format: Emily P. Balskus. Deciphering the human gut microbiome with chemistry [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA21.
Abstract IA11: Detecting and targeting cellular heterogeneity of the lymphoid blood malignancies
Authors: Wu Catherine J.
Published: December 2020

Multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens, and have motivated the development of personalized cancer neoantigen targeting approaches. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. Because the immune response has the capacity of addressing multiple tumor neoantigens simultaneously, immune-based therapy has a potential for directly address tumor heterogeneity. As a field, we have now successfully moved beyond the first wave proof-of-concept studies that have demonstrated the safety, feasibility and high immunogenicity of these personalized neoantigen-targeting vaccines. An imperative now is to address the challenges of discovering and optimizing the selection of antigens to target, the delivery approach, and extending this promising approach to a broader array of cancer settings.

Citation Format: Catherine J. Wu. Detecting and targeting cellular heterogeneity of the lymphoid blood malignancies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA11.
Abstract IA18: Genomic evolution of brain metastases: Implications for precision medicine
Authors: Brastianos Priscilla K.
Published: December 2020

Brain metastases are clinically devastating. Up to 25% of cancer patients will develop brain metastases and prognosis in this patient population continues to be poor. The vast majority of clinical trials in the US exclude patients with active brain metastases. Our understanding of how intracranial metastases genetically evolve from primary tumors has historically been limited, which has hampered the development of clinical trials for this patient population. In this presentation, I will present our ongoing work on genomic characterization of central nervous system metastases with a comparison to primary tumors and extracranial sites. Intracranial metastases demonstrate branched evolution, whereby the brain metastases and primary tumors share a common genetic ancestor yet both the primary tumor and brain metastasis continue to evolve independently. We also show that comprehensive genomic characterization of brain metastases, coupled with functional validation in mouse models of metastasis, can lead to the discovery of putative drivers of progression and metastasis. Taken together, our data implies that precision medicine approaches based solely on genetic characterization of extracranial sites tumors may miss potential therapeutic targets from which patients with brain metastases might benefit. Importantly, despite genetic heterogeneity between the brain metastases and extracranial sites, there are common clinically actionable genetic alterations across brain metastases of different histologies. We have translated these findings to clinical trials, including an NCI-sponsored cooperative group genomically-guided clinical trial in patients with progressive brain metastases (Alliance A071701).

Citation Format: Priscilla K. Brastianos. Genomic evolution of brain metastases: Implications for precision medicine [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA18.