bluuebunny/crossref_metadata_2025 huggingface dataset:
Despeckling method of ultrasound images using closed-form shrinkage function based on cauchy distribution in wavelet domain
Authors: Kim Kyong-Il , Bahng Soon-Ic , Choe Ryong-Nam
Published: March 2020

Speckle suppression and elimination are very important to improve the visual quality of ultrasound image and the diagnostic ability of the diseases. An effective technique of image denoising based on discrete wavelet transform is to employ a Bayesian maximum a posteriori (MAP) estimator. To suppress and remove the speckle noise using MAP estimator effectively, it must assign correctly the shrinkage function based on appropriate probability density functions (PDFs) for the wavelet coefficients of logarithmically transformed noise-free ultrasound image and speckle noise. In this paper, we introduce a new closed-form shrinkage function that is an analytical solution of a Bayesian MAP estimator for despeckling of the ultrasound images effectively in wavelet domain. We employ a Cauchy prior and Gaussian PDF to model the wavelet coefficients of logarithmically transformed noise-free ultrasound image and speckle noise, respectively. Firstly, we derive the CauchyShrinkGMAP that is a closed-form shrinkage function. In addition, we estimate the noise variance and parameter of MAP estimator. Next, we evaluate the despeckling performance of wavelet image denoising method using the CauchyShrinkGMAP compared to various despeckling method using median and Wiener filters, hard and soft thresholding and GaussShrinkGMAP and MCMAP3N shrinkage function. The experiment results show that PSNR of new closed-form shrinkage function is highest, MSE is smallest, and the correlation coefficient ([Formula: see text]) and SSIM are closer to one than the other existing image denoising methods for noisy synthetic ultrasound images at different speckle noise levels. Also, experiment results show that ENL of new closed-form shrinkage function is highest and that of EN and SD is smallest than the other existing image denoising methods for noisy real ultrasound image.
Thermodynamics of squared speed of sound parametrizations
Authors: Jawad Abdul , Butt Sadaf , Majeed Aneesa
Published: March 2020

In this work, an attempt is made to study the thermodynamical analysis at the apparent horizon in the framework of fractal universe. We consider the Bekenstein entropy to examine validity of the generalized second law of thermodynamics (GSLT) and thermal equilibrium for the four different cases which are developed with the utilization of different forms of squared speed of sound. In each case, we explore the behavior of total entropy through the graphical variation of its first- and second-order derivatives with respect to redshift parameter ([Formula: see text]). It is found that generalized second law of thermodynamics holds for Cases 1 and 2 for [Formula: see text] and [Formula: see text], respectively and it holds in late times as well. However, for Cases [Formula: see text] and [Formula: see text], this law is satisfied in early, present and future epochs. Furthermore, for Cases 1 and 2, instability of thermodynamic equilibrium is observed, but for Cases 3 and 4, it holds in the specific intervals [Formula: see text] and [Formula: see text], respectively.
Remarks on η-parallel real hypersurfaces in ℂP2 and ℂH2
Authors: Wang Yaning
Published: March 2020

Let [Formula: see text] be a three-dimensional real hypersurface in a nonflat complex space form of complex dimension two. In this paper, we prove that [Formula: see text] is [Formula: see text]-parallel with two distinct principal curvatures at each point if and only if it is locally congruent to a geodesic sphere in [Formula: see text] or a horosphere, a geodesic sphere or a tube over totally geodesic complex hyperbolic plane in [Formula: see text]. Moreover, [Formula: see text]-parallel real hypersurfaces in [Formula: see text] and [Formula: see text] under some other conditions are classified and these results extend Suh’s in [Characterizations of real hypersurfaces in complex space forms in terms of Weingarten map, Nihonkai Math. J. 6 (1995) 63–79] and Kon–Loo’s in [On characterizations of real hypersurfaces in a complex space form with [Formula: see text]-parallel shape operator, Canad. Math. Bull. 55 (2012) 114–126].
A study on timelike circular surfaces in Minkowski 3-space
Authors: Abdel-Baky Rashad A. , Alluhaibi Nadia , Ali Akram , Mofarreh Fatemah
Published: March 2020

This paper studies a smooth one-parameter family of standard Lorentzian circles with fixed radius. Such a surface is called a timelike circular surface with constant radius. We call each circle a generating circle. A new type of timelike circular surfaces was identified and coined as the timelike tangent circular surface. The new timelike tangent circular surface has the property of all generating circles being lines of curvature and its Gaussian and mean curvatures being independent of the geodesic curvature of the spherical indicatrix.
The possibility of a stable flat dark energy-dominated Swiss-cheese brane-world universe
Authors: Ahmed Nasr , Bamba Kazuharu , Salama F.
Published: March 2020

In this paper, we study the possibility of obtaining a stable flat dark energy-dominated universe in a good agreement with observations in the framework of Swiss-cheese brane-world cosmology. Two different brane-world cosmologies with black strings have been introduced for any cosmological constant [Formula: see text] using two empirical forms of the scale factor. In both models, we have performed a fine-tuning between the brane tension and the cosmological constant so that the Equation of state (EoS) parameter [Formula: see text] for the current epoch, where the redshift [Formula: see text]. We then used these fine–tuned values to calculate and plot all parameters and energy conditions. The deceleration–acceleration cosmic transition is allowed in both models, and the jerk parameter [Formula: see text] at late-times. Both solutions predict a future dark energy-dominated universe in which [Formula: see text] with no crossing to the phantom divide line. While the pressure in the first solution is always negative, the second solution predicts a better behavior of cosmic pressure where the pressure is negative only in the late-time accelerating era but positive in the early-time decelerating era. Such a positive-to-negative transition in the evolution of pressure helps to explain the cosmic deceleration–acceleration transition. Since black strings have been proved to be unstable by some authors, this instability can actually reflect doubts on the stability of cosmological models with black strings (Swiss-cheese type brane-worlds cosmological models). For this reason, we have carefully investigated the stability through energy conditions and sound speed. Because of the presence of quadratic energy terms in Swiss-cheese type brane-world cosmology, we have tested the new nonlinear energy conditions in addition to the classical energy conditions. We have also found that a negative tension brane is not allowed in both models of the current work as the energy density will no longer be well defined.
A general existence result for isothermal two-phase flows with phase transition
Authors: Hantke Maren , Thein Ferdinand
Published: March 2020

Liquid–vapor flows with phase transitions have a wide range of applications. Isothermal two-phase flows described by a single set of isothermal Euler equations, where the mass transfer is modeled by a kinetic relation, have been investigated analytically in [M. Hantke, W. Dreyer and G. Warnecke, Exact solutions to the Riemann problem for compressible isothermal Euler equations for two-phase flows with and without phase transition, Quart. Appl. Math. 71(3) (2013) 509–540]. This work was restricted to liquid water and its vapor modeled by linear equations of state. The focus of this work lies on the generalization of the primary results to arbitrary substances, arbitrary equations of state and thus a more general kinetic relation. We prove existence and uniqueness results for Riemann problems. In particular, nucleation and cavitation are discussed.
CarePre
Authors: Jin Zhuochen , Cui Shuyuan , Guo Shunan , Gotz David , Sun Jimeng , Cao Nan
Published: March 2020

Clinical decision support systems are widely used to assist with medical decision making. However, clinical decision support systems typically require manually curated rules and other data that are difficult to maintain and keep up to date. Recent systems leverage advanced deep learning techniques and electronic health records to provide a more timely and precise result. Many of these techniques have been developed with a common focus on predicting upcoming medical events. However, although the prediction results from these approaches are promising, their value is limited by their lack of interpretability. To address this challenge, we introduce CarePre, an intelligent clinical decision assistance system. The system extends a state-of-the-art deep learning model to predict upcoming diagnosis events for a focal patient based on his or her historical medical records. The system includes an interactive framework together with intuitive visualizations designed to support diagnosis, treatment outcome analysis, and the interpretation of the analysis results. We demonstrate the effectiveness and usefulness of the CarePre system by reporting results from a quantities evaluation of the prediction algorithm, two case studies, and interviews with senior physicians and pulmonologists.
Permutation Network De-obfuscation
Authors: Guo Zimu , Chowdhury Sreeja , Tehranipoor Mark M. , Forte Domenic
Published: March 2020

Permutation-based obfuscation has been proposed to protect hardware against cloning, overproduction, reverse engineering, and unauthorized operation. To prevent key extraction from memory, the key used by the obfuscation is usually stored in volatile memory. Since the key is erased after the system loses power, this scheme is often considered the best way to prevent a key from being stolen, since many attacks would require power. However, in this article, we propose a new attack where the key is determined by exploring path aging within the permutation network used for obfuscation. Both the theoretical analysis and experimental results are provided. A practical procedure to achieve the proposed attack is also discussed in the context of an attacker’s capabilities and knowledge. The proposed attack is executed in both simulation and hardware. The experimental results show the accuracy of identifying the key is over 80% and more than enough to reduce the number of brute-force combinations required by an attacker. This attack accuracy reaches 100% when the permutation network has experienced sufficient degradations. Besides the attack, we also propose a low-cost countermeasure that sweeps the permutation network configurations. Incorporating this countermeasure, the proposed attack becomes no better than brute-force guessing.
Ancient Plant Genomics in Archaeology, Herbaria, and the Environment
Authors: Kistler Logan , Bieker Vanessa C. , Martin Michael D. , Pedersen Mikkel Winther , Ramos Madrigal Jazmín , Wales Nathan
Published: March 2020

The ancient DNA revolution of the past 35 years has driven an explosion in the breadth, nuance, and diversity of questions that are approachable using ancient biomolecules, and plant research has been a constant, indispensable facet of these developments. Using archaeological, paleontological, and herbarium plant tissues, researchers have probed plant domestication and dispersal, plant evolution and ecology, paleoenvironmental composition and dynamics, and other topics across related disciplines. Here, we review the development of the ancient DNA discipline and the role of plant research in its progress and refinement. We summarize our understanding of long-term plant DNA preservation and the characteristics of degraded DNA. In addition, we discuss challenges in ancient DNA recovery and analysis and the laboratory and bioinformatic strategies used to mitigate them. Finally, we review recent applications of ancient plant genomic research.
Ethanol feeding accelerates pancreatitis progression in CPA1 N256K mutant mice
Authors: Orekhova Anna , Geisz Andrea , Sahin-Tóth Miklós
Published: March 2020

Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here, we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression. To this end, we fed an ethanol-containing diet to CPA1 N256K mice, which carry the human p.N256K CPA1 mutation and develop spontaneous chronic pancreatitis. Inexplicably, CPA1 N256K mice suffered generalized seizures after 2–3 wk of ethanol feeding, which resulted in high mortality and the early termination of the study. Analysis of CPA1 N256K mice euthanized after 3–3.5 wk of ethanol feeding revealed more severe chronic pancreatitis associated with significantly increased Hspa5 [ER chaperone immunoglobulin heavy chain-binding protein (BiP)] mRNA levels when compared with CPA1 N256K mice on a control liquid diet. In contrast, ethanol feeding of C57BL/6N mice for 4 wk increased Hspa5 levels to a lesser degree and caused no pancreatitis. We conclude that ethanol feeding synergizes with the misfolding CPA1 mutant in promoting ER stress and thereby accelerates progression of chronic pancreatitis in CPA1 N256K mice.

NEW & NOTEWORTHY Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. This study demonstrates that alcohol synergizes with digestive enzyme misfolding in promoting endoplasmic reticulum stress and thereby accelerates progression of chronic pancreatitis.
SNX27 regulates DRA activity and mediates its direct recycling by PDZ-interaction in early endosomes at the apical pole of Caco2 cells
Authors: Bannert Karen , Berlin Peggy , Reiner Johannes , Lemcke Heiko , David Robert , Engelmann Robby , Lamprecht Georg
Published: March 2020

DRA (downregulated in adenoma, SLC26A3) and NHE3 (Na+/H+ exchanger 3, SLC9A3) together mediate intestinal electroneutral NaCl absorption. Both transporters contain PDZ (postsynaptic density 95, disc large, zonula occludens 1) binding motifs and interact with PDZ adaptor proteins regulating their activity and recycling. SNX27 (sorting nexin 27) contains a PDZ domain and is involved in the recycling of cargo proteins including NHE3. The interaction of SNX27 with DRA and its potential role for the activity and recycling of DRA have been evaluated in this study. SNX27 specifically interacts with DRA via its PDZ domain. The knockdown (KD) of SNX27 reduced DRA activity by 50% but was not accompanied by a decrease of DRA surface expression. This indicates that DRA is trafficked to specific functional domains in the plasma membrane in which DRA is particularly active. Consistently, the disruption of lipid raft integrity by methyl-β-cyclodextrin has an inhibitory effect on DRA activity that was strongly reduced after SNX27 KD. In differentiated intestinal Caco2 cells, superresolution microscopy and a novel quantitative axial approach revealed that DRA and SNX27 colocalize in rab5-positive early endosomes at the apical pole. SNX27 regulates the activity of DRA in the apical plasma membrane through binding with its PDZ domain. This interaction occurs in rab5-positive early endosomes at the apical pole of differentiated intestinal Caco2 cells. SNX27 is involved in the direct recycling of DRA to the plasma membrane where it is inserted into lipid rafts facilitating increased activity.

NEW & NOTEWORTHY SNX27 has a PDZ domain and is involved in the regulation and recycling of transmembrane proteins. The role of SNX27 on the activity and recycling of the intestinal Cl−/[Formula: see text] exchanger DRA has not yet been studied. This study shows that SNX27 directly interacts with DRA in early endosomes at the apical pole of intestinal Caco2 cells and mediates its direct recycling to facilitate high activity in lipid rafts in the apical plasma membrane.
Systems analysis of benign bladder disorders: insights from omics analysis
Authors: Hashemi Gheinani Ali , Bigger-Allen Alexander , Wacker Amanda , Adam Rosalyn M.
Published: March 2020

The signaling pathways and effectors that drive the response of the bladder to nonmalignant insults or injury are incompletely defined. Interrogation of biological systems has been revolutionized by the ability to generate high-content data sets that capture information on a variety of biomolecules in cells and tissues, from DNA to RNA to proteins. In oncology, such an approach has led to the identification of cancer subtypes, improved prognostic capability, and has provided a basis for precision treatment of patients. In contrast, systematic molecular characterization of benign bladder disorders has lagged behind, such that our ability to uncover novel therapeutic interventions or increase our mechanistic understanding of such conditions is limited. Here, we discuss existing literature on the application of omics approaches, including transcriptomics and proteomics, to urinary tract conditions characterized by pathological tissue remodeling. We discuss molecular pathways implicated in remodeling, challenges in the field, and aspirations for omics-based research in the future.
Numerical Simulation of the Tar Mist and Dust Movement Process in a Low-Temperature Dry Distillation Furnace
Authors: Zhang Qiuli , Hui Xiangrong , Yan Long , Luo Min , Feng Wenru , Zhou Jun , Lan Xinzhe
Published: March 2020

In the low-temperature dry distillation of low-rank coal, the important liquid product of coal tar is produced, but its quality and utilization rate are degraded by entrained dust. The movement of coal tar and dust in the furnace is a key factor in causing particles such as dust to mix with coal tar. Therefore, the Euler–Lagrangian method is used to simulate the two-phase motion process of gas, tar, and dust in a furnace. By considering the effects of tar particle size, dust particle size, gas velocity, tar density, and dust density, the motion process mechanism is revealed, enabling the dust content in coal tar to be reduced and the quality improved. The results indicate that tar particles with sizes less than 0.20 mm can be removed from the furnace by gas, and the smaller the particle size is, the shorter the time required for removal. Dust particles greater than 0.18 mm in size cannot be completely removed from the furnace. As the gas velocity increases, the time required for complete removal of the tar mist and dust gradually decreases. When the speed is 0.70 m/s, all tar mist is removed, although some particles remain. Tar mist with a density of more than 900 kg/m3can be extensively removed, but dust with a density of more than 1400 kg/m3is difficult to remove and remains in the furnace. Finally, particle size distribution experiments in the product were conducted to verify the accuracy of the numerical simulation.
Preparation and Characterization of Spherical Submicron CL-20 by Siphon Spray Refinement
Authors: Xing Jiangtao , Wang Weili , Xu Wenzheng , Yao Tianle , Dong Jun , Miao Run
Published: March 2020

In order to improve the safety of hexanitrohexaazaisowurtzitane (CL-20), submicron CL-20 particles were prepared by a siphon ultrasonic-assisted spray refining experimental device. The samples were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC), and the impact sensitivity of the samples was tested. The results show that the particle size of siphon-refined CL-20 is about 800 nm~1 μm, which is more smooth, mellow, and dense than that of CL-20 prepared by a traditional pressure-refined method. The peak diffraction angle of pressure- and siphon-refined CL-20 is basically the same as that of raw CL-20, and their crystal forms are ε type. The peak strength of pressure- and siphon-refined CL-20 decreased obviously. The apparent activation energy of pressure-refined CL-20 and siphon-refined CL-20 is 13.3 kJ/mol and 11.95 kJ/mol higher than that of raw CL-20, respectively. The thermal stability of CL-20 is improved. The activation enthalpy (ΔH#) is significantly higher than that of raw CL-20, and the characteristic drop is 70.4% and 82.7% higher than that of raw CL-20. The impact sensitivity of siphon-refined CL-20 is lower than that of pressure-refined CL-20, so the safety performance of an explosive is improved obviously.
Simultaneous Determination of Synthetic Food Dyes Using a Single Cartridge for Preconcentration and Separation Followed by Photometric Detection
Authors: Rukosueva Elizaveta A. , Aliyarova Gulselem R. , Tikhomirova Tatyana I. , Apyari Vladimir V. , Nesterenko Pavel N.
Published: March 2020

A novel preconcentration/separation method for simultaneous sorption-spectrophotometric determination of anionic food dyes Sunset Yellow and Tartrazine is proposed. The method is based on preconcentration of the dyes using solid phase extraction on a cartridge filled with silica chemically modified with C16 groups from aqueous solution at pH 1 followed by elution with water/acetonitrile mixture containing 2 mmol·L−1 KH2PO4 adjusted to pH 3 with a step gradient of acetonitrile content. This elution allows quantitative separation of the dyes which makes their individual spectrophotometric determination possible. The detection limits for Tartrazine and Sunset Yellow are 0.15 and 0.11 μg·mL−1 and the linearity range is 2–20 μg·mL−1. The method is applied for analysis of beverages. The recovery of dyes is higher than 97% at the relative standard deviation not exceeding 10%.
La mirada de género en la práctica de la gestión y las organizaciones
Authors: Marcela Mandiola Cotroneo
Published: March 2020

La relevancia del enfoque de género para el mundo del trabajo radica en las contribuciones que logra hacer en la discusión y reflexión de las más variadas prácticas de la gestión organizacional y del trabajo. Dichas contribuciones nos invitan a pensar en el género, no como algo que se es, si no como algo que se hace. Género, es entonces, un concepto que no solo significa una construcción social, una identidad binaria y sus imágenes, género es también una categoría analítica, en otras palabras, una forma de hablar de poder. Lo que este número especial nos invita a considerar es una perspectiva que implica un análisis de las prácticas organizacionales que mantienen la división del trabajo entre los sexos, en otras palabras, su uso en las organizaciones permite una sensibilidad respecto de las contradicciones y las ambigüedades presentes en las relaciones de género y de lo que se considera discriminación e igualdad de oportunidades en el trabajo.
NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors
Authors: Ford Kirsty , Hanley Christopher J. , Mellone Massimiliano , Szyndralewiez Cedric , Heitz Freddy , Wiesel Philippe , Wood Oliver , Machado Maria , Lopez Maria-Antoinette , Ganesan Anusha-Preethi , Wang Chuan , Chakravarthy Ankur , Fenton Tim R. , King Emma V. , Vijayanand Pandurangan , Ottensmeier Christian H. , Al-Shamkhani Aymen , Savelyeva Natalia , Thomas Gareth J.
Published: March 2020

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.

Significance:

NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.
Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers
Authors: Forrest Suzanne J. , Al-Ibraheemi Alyaa , Doan Duong , Ward Abigail , Clinton Catherine M. , Putra Juan , Pinches R. Seth , Kadoch Cigall , Chi Susan N. , DuBois Steven G. , Leavey Patrick J. , LeBoeuf Nicole R. , Mullen Elizabeth , Collins Natalie , Church Alanna J. , Janeway Katherine A.
Published: March 2020

Purpose:

Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.

Experimental Design:

We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing.

Results:

SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.

Conclusions:

A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.
A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features
Authors: Sarkozy Clémentine , Morschhauser Franck , Dubois Sydney , Molina Thierry , Michot Jean Marie , Cullières-Dartigues Peggy , Suttle Benjamin , Karlin Lionel , Le Gouill Steven , Picquenot Jean-Michel , Dubois Romain , Tilly Hervé , Herbaux Charles , Jardin Fabrice , Salles Gilles , Ribrag Vincent
Published: March 2020

Purpose:

The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma.

Patients and Methods:

The primary objective of this dose-escalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat.

Results:

A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and Cmax of tazemetostat were similar compared with the single-agent study (E7438-G000-101).

Conclusions:

The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.
RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia
Authors: Anande Govardhan , Deshpande Nandan P. , Mareschal Sylvain , Batcha Aarif M.N. , Hampton Henry R. , Herold Tobias , Lehmann Soren , Wilkins Marc R. , Wong Jason W.H. , Unnikrishnan Ashwin , Pimanda John E.
Published: March 2020

Purpose:

RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.

Experimental Design:

We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.

Results:

We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.

Conclusions:

Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.

See related commentary by Bowman, p. 3503
RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis
Authors: Wu Lei , Zhang Xiao , Zheng Lu , Zhao Huakan , Yan Guifang , Zhang Qi , Zhou Yu , Lei Juan , Zhang Jiangang , Wang Jingchun , Xin Rong , Jiang Lu , Peng Jin , Chen Qian , Lam Sin Man , Shui Guanghou , Miao Hongming , Li Yongsheng
Published: March 2020

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)–associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.
GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells
Authors: Koh Choong-Hyun , Kim Il-Kyu , Shin Kwang-Soo , Jeon Insu , Song Boyeong , Lee Jeong-Mi , Bae Eun-Ah , Seo Hyungseok , Kang Tae-Seung , Kim Byung-Seok , Chung Yeonseok , Kang Chang-Yuil
Published: March 2020

Although treatment with the glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21–producing follicular helper T (Tfh) cells play a crucial role in DTA-1–induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6fl/flCd4Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.
Ендодонто-ендоосальна імплантація у сучасній стоматології: можливості, проблеми та перспективи застосування методу (огляд літератури)
Authors: Brechlichuk P. P. , Maistruk P. O.
Published: March 2020

Відомим методом покращення біомеханічних параметрів стабілізації зубів  після проведення оперативного втручання резекції верхівки кореня є їх армування ендодонто-ендоосальними імплантатами. Недивлячись на позитивний клінічний досвід, метод не знайшов широкого розповсюдження в стоматологічній практиці через складність та недосконалість методики проведення самої операції ендодонто-ендоосальної імплантації, відсутність чітких показань до його застосування, короткого терміну функціонування конструкцій у ротовій порожнині, складнощі, пов’язані з остеоінтеграцією імплантатів, установлених через ендодонт. Мета дослідження – провести комплексний аналіз наявних віт­чизняних та зарубіжних даних, що стосуються можливостей, проблем реалізації та подальших перспектив застосування методу ендодонто-ендоосальної імплантації у сучасній стоматологічній практиці. Матеріали і методи. Систематизація наукових публікацій, що стосувалися мети дослідження, проводилась на основі результатів пошукових запитів у системі Google Академія за ключовими словами («ендодонто-ендоосальна імплантація», «ендодонтичні імплантати», «трансдентальна імплантація» та їх аналогів російською та англійською мовами). Результати досліджень та їх обговорення. В якості найважливіших для урахування у клінічній практиці аспектів процедури ендодонто-ендоосальної імплантації, за даними літературних джерел, необхідо виокремити наступні:  оцінку стану зуба, через який безпосередньо буде встановлений ЕЕІ; оцінку ступеня рухомості зуба; оцінку ступеня резорбції міжальвеолярних перегородок; оцінку кількості зубів, які мають нагальну необхідність у проведенні імплантації; оцінку величини кісткового післяопераційного дефекту та можливості його заміщення остеопластичним матеріалом. Висновки. За наявними даними клінічних та лабораторних досліджень використання методу ендодонто-ендоосальної імплантації можна розцінювати як альтернативний підхід щодо оптимізації біомеханічної стабільності та забезпечення сприятливого функціонального прогнозу зуба після проведення процедур із резекцією частини кореня в умовах наявного патологічного чи післяопераційного дефекту навколишньої кісткової тканини. В ході проведеного літературного огляду було ідентифіковано наявний дефіцит даних щодо можливостей застосування методу ендодонто-ендоосальної імплантації у клінічній стоматологічній практиці, відносний низький рівень доказовості представлених результатів попередніх досліджень та відсутність чітких протоколів щодо реалізації даного методу за різних вихідних клінічних умов.
Особливості зубощелепних деформацій у пацієнтів із вродженими незрощеннями верхньої губи та піднебіння
Authors: Oliinyk A. Yu. , Oliinyk H. V.
Published: March 2020

Вступ. В огляді описано літературні джерела, що стосуються динаміки формування деформацій зубних рядів верхньої щелепи у пацієнтів із різними формами вроджених незрощень верхньої губи і піднебіння (ВНВГП) після пластичних операцій.

Мета дослідження – вивчити особливості формування деформацій зубощелепної системи у пацієнтів із ВГВГП і динаміки їх розвитку.

Матеріали і методи. Опрацьовано джерела науково-медичної інформації, що стосувалися зубощелепних деформацій у пацієнтів, які в минулому перенесли операційні втручання з приводу ВНВГП, шляхом їх аналізу за 2003–2018 рр.

Результати досліджень та їх обговорення. У статті подано огляд літератури стосовно характерних морфофункціональних зубощелепних деформацій у пацієнтів із ВНВГП. Проаналізувавши результати досліджень їх особливостей, можна провести певну типізацію деформацій зубощелепного комплексу в дорослих осіб із ВНВГП після пластичних операцій з точки зору завдань і потреб протетичного лікування.

Висновки. Деформації зубних рядів верхньої і нижньої щелеп та динаміка їх формування у хворих із ВНВГП повинні бути обов’язково враховані в процесі надання їм ортодонтичної допомоги, так і при виборі алгоритму застосування відповідної ортопедичної конструкції у наступному їх протезуванні.
РОЗРОБКА МЕТОДИКИ СПЕКТРОФОТОМЕТРИЧНОГО ВИЗНАЧЕННЯ РЕКОМБІНАНТНОГО РЕЦЕПТОРНОГО АНТАГОНІСТА ІНТЕРЛЕЙКІНУ-1 ЛЮДИНИ В НАПІВФАБРИКАТІ-РОЗЧИНІ
Authors: Miedviedieva K. P. , Burlaka B. S. , Buhaiova V. V. , Vasyuk S. O. , Belenichev I. F. , Suprun E. V.
Published: March 2020

Мета роботи. Розробка та валідація нової методики спектрофотометричного кількісного визначення рекомбінантного рецепторного антагоніста інтерлейкіну-1 людини (РРАІЛ-1) у напівфабрикаті-розчині.

Матеріали і методи. У дослідженні використано напівфабрикат-розчин (РРАІЛ-1 – 50 мг, динатрію едетат – 0,12 мг, натрію дигідрофосфат дигідрат – 7,8 мг, полісорбат-20 – 0,10 мг, вода для ін’єкцій до 1 мл), а як розчинник – воду очищену. Аналітичне обладнання: спектрофотометр Specord 200, ваги електронні АВТ-120-5DM.

Результати й обговорення. Розроблено нову, просту методику кількісного визначення РРАІЛ-1 у напівфабрикаті-розчині методом спектрофотометрії в УФ-області, яка базується на вимірюванні оптичної густини водного розчину сполуки при 280 нм. Методика була валідована за такими характеристиками як лінійність, прецизійність, правильність, специфічність та робасність. Лінійна залежність абсорбції від концентрації знаходиться в діапазоні 0,6–1,1 мг/мл. Аналіз прогнозованої повної невизначеності аналізу свідчить про можливість застосування розробленої методики в інших лабораторіях.

Висновки. Розроблено та валідовано методику визначення вмісту РРАІЛ-1 у напівфабрикаті-розчині згідно з вимогами ДФУ. Доведено, що за такими валідаційними характеристиками, як лінійність, специфічність, прецизійність, правильність та робасність методика є коректною.
RISK FACTORS FOR FEMALE INFERTILITY AT A TERTIARY HEALTH FACILITY IN AKURE, SOUTH-WEST NIGERIA
Authors: Irinyenikan T. A.
Published: March 2020

Background. The inability of couples to achieve pregnancy is a major cause of psycho-social problems in family relationship that could lead to marital disharmony.

Objective. The aim of this study was to find out the possible risk factors for female infertility.

Methods. A case-control design and a sample size of 400 (200 cases of infertility and 200 controls) were used in the study. Cases and controls were selected at random at the infertility and family planning clinic of the University of Medical Sciences Teaching Hospital Complex, Akure and were subjected to a predesigned interviewer administered questionnaire to collect the data. The cases were classified into primary and secondary infertility; binary and stepwise logistic regressions were used to generate the Odds ratio and 95% confidence interval of the possible risk factors and the level of significance was set at P<0.05.

Results. The mean age of the women with infertility was 28.5±5.43 years and the mean age of those in the control group was 29.1±5.62 years. Among the cases, 155 (77.5%) had secondary infertility, while 45 (22.5%) had primary infertility. Significant risk factors for female infertility included presence of fibroids, having had fibroid operation, multiple sexual partners, previous abortion, polycystic ovary syndrome (PCOS), sexually transmitted infection (STI) and post abortion sepsis.

Conclusion. The study showed that secondary infertility is still the most prevalent and the risk factors were multi factorial. Efforts should be intensified to reduce infertility due to preventable causes.
PRIMARY LARYNGEAL ASPERGILLOSIS IN AN IMMUNOCOMPETENT PATIENT
Authors: Rajmohan K.S. , Khan I. D. , Kapoor U. , Hashmi S. A. , Gupta R. M. , Sen S. , Nair G. L. , Singh K. K. , Tandel K. , Malik M.
Published: March 2020

Background. Aspergillus is an inherently ubiquitous, weakly pathogenic fungus causing opportunistic infections. It is very rarely localized in the larynx, although laryngeal Aspergillosis may develop in the immunocompromised patients including those with leukaemia and severe aplastic anaemia.
Objective. The aim of the research was to explore the primary laryngeal Aspergillosis in an immunocompetent patient thru a case report.
Methods. A case report of primary laryngeal Aspergillosis in an immunocompetent patient is presented.
Results. A male patient of 40 years old, presenting with chronic worsening hoarseness, was found to have a smooth, white spheroid submucosal growth on left vocal cord with preserved bilateral cord movements on videostroboscopy. Histopathological examination of vocal cord growth revealed squamous epithelium containing septate hyphae with acute angle dichotomous branching pattern consistent with Aspergillus. Voice improved after a four-week course of oral itraconazole 200 mg/day. Post therapy follow up of 24 months was unremarkable.
Conclusions. Primary laryngeal Aspergillosis develops in the immunocompetent patients. Iatrogenic, vocal abuse, occupation and lifestyle factors may be contributory. Optimal diagnosis and management mandates a high index of suspicion.
ВПЛИВ РЕПЕРФУЗІЇ НИЖНІХ КІНЦІВОК НА ДИНАМІКУ ЗМІН ПОКАЗНИКІВ ЕНДОГЕННОЇ ІНТОКСИКАЦІЇ ЗА УМОВ ПОЄДНАНОЇ ТРАВМИ ОРГАНІВ ЧЕРЕВНОЇ ПОРОЖНИНИ ТА МАСИВНОЇ КРОВОВТРАТИ
Authors: Fedoseeva O. V.
Published: March 2020

Вступ. У статті наведено результати експериментального дослідження, під час якого вивчали вплив реперфузії нижніх кінцівок на розвиток ендогенної інтоксикації при закритій травмі органів черевної порожнини та масивній зовнішній крововтраті. Відомо, що ендогенна інтоксикація є складним багатокомпонентним процесом, зумовленим патологічною біологічною активністю ендогенних продуктів або дисфункцією систем природної детоксикації. Результати дослідження показали, що реперфузія нижніх кінцівок посилює розвиток ендогенної інтоксикації при поєднаній травмі в експерименті.

Мета дослідження – вивчити вплив реперфузії нижніх кінцівок на зміну окремих показників ендогенної інтоксикації на моделі поєднаної травми органів черевної порожнини на тлі масивної крововтрати.

Методи дослідження. Експеримент проведено на 80-ти нелінійних щурах-самцях масою 190–220 г. У дослідних групах було змодельовано реперфузію нижніх кінцівок у поєднанні із закритою травмою органів черевної порожнини на тлі масивної крововтрати та проаналізовано вміст маркерів ендогенної інтоксикації (молекул середньої маси фракцій, що визначались при довжині хвилі 254 і 280 нм) та еритроцитарний індекс інтоксикації. Достовірність відмінностей між контрольною та дослідною групами оцінювали з використанням непараметричного критерію Манна – Уїтні.

Результати й обговорення. Накладання кровоспинного джгута на дві нижні кінцівки викликало значне достовірне підвищення показника ендогенного індексу інтоксикації у всіх дослідних групах. Максимальне його збільшення відзначено у групі тварин, в яких накладання джгута поєднувалось із травмою органів черевної порожнини та масивною крововтратою. Це довело потенціюючу дію реперфузійного синдрому на розвиток системних змін при поєднаній травмі. Також доведено, що прояв ендогенної інтоксикації протягом перших 24 год після накладання кровоспинного джгута за своєю силою аналогічний до такого, що виникає внаслідок поєднаної травми органів черевної порожнини на тлі масивної зовнішньої крововтрати.

Висновок. Накладання кровоспинного джгута на дві нижні кінцівки протягом 2 год посилює розвиток ендогенної інтоксикації на моделі поєднаної травми органів черевної порожнини на тлі масивної крововтрати, що підтверджується достовірним зростанням показника ендогенного індексу інтоксикації та молекул середньої маси через 7 діб після реперфузії.