bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Sedation on Adenoma Detection Rate and Cecal Intubation Rate in Colonoscopy
Authors: Zhang Qiongmei , Dong Zhiyu , Jiang Yuanxi , Zhan Tingting , Wang Junwen , Xu Shuchang
Published: December 2020

Purpose. To explore the effect of sedation on the quality of colonoscopy. Methods. The data collected from the Digestive Endoscopy Center of Shanghai Tongji Hospital from March 2012 to June 2019 were retrospectively analyzed. The rate of sedation and quality metrics of colonoscopy such as adenoma detection rate (ADR) and cecal intubation rate (CIR) were calculated. The logistic regression model was used to explore the relationship between sedation and quality metrics of colonoscopy. The interaction effects between experience of endoscopists and sedation on quality of colonoscopy was also investigated in subgroups stratified by total number of colonoscopies during career using the logistic regression model. Results. A total of 63,417 colonoscopies including 11,417 colonoscopies without sedation and 52,000 colonoscopies with sedation were enrolled in our study. The proportion of colonoscopy with sedation was 82.0%. The ADR and CIR were all significantly higher in cases with sedation compared with cases without sedation (ADR, 22.5% vs. 17.0%,

p
<
0.001

; CIR, 94.7% vs. 91.2%,

p
<
0.001

). Multivariate analysis showed that the sedation was an independent factor associated with adenoma detection (

OR
=
1.448

, 95% CI: 1.372~1.529,

p
<
0.001

) and cecal intubation (

OR
=
1.560

, 95% CI: 1.446~1.683,

p
<
0.001

). A total of 14 endoscopists with complete colonoscopy data in our database and corresponding 20,949 colonoscopies data were enrolled for further analysis. The logistic regression model yielded a similar result that sedation was an independent factor on adenoma detection and cecal intubation when the factor, experience of endoscopists, was also entered into the model as a confounder (adenoma detection,

OR
=
1.408

, 95% CI: 1.333~1.487,

p
<
0.001

; cecal intubation,

OR
=
1.601

, 95% CI: 1.482-1.729,

p
<
0.001

). Conclusion. Colonoscopy with sedation has a positive effect on ADR and CIR in all endoscopists with different experience of colonoscopy, which makes the quality of colonoscopy better.
Complementary and Alternative Medicines for the Treatment of Hepatitis C: Perspectives of Users and CAM Practitioners
Authors: Ali Salamat , Ullah Shahan , Paudyal Vibhu , Ali Mashhood , Khalid Tipu Muhammad , Ur-Rehman Tofeeq
Published: December 2020

Background. Despite substantial progress in the treatment of hepatitis C through the use of direct‐acting antivirals which have been shown to cure the disease, complementary and alternative medicines (CAM) are popular among patients as a substitute or complement of allopathic medicines. This study aimed to explore the perspectives of patients and CAM practitioners on the use of CAM for the treatment of hepatitis C in Pakistan. Methods. A cross‐sectional design was adopted. Participants (CAM practitioners and patients) were recruited from the capital and two provinces: Khyber Pakhtunkhwa and Punjab of Pakistan. A survey using paper‐based questionnaires, each specific for patients and CAM practitioners, was conducted to gather information pertaining to demography, disease status, treatment history, and participants’ perspectives (about the disease, reasons to switch to CAM, and referring source). Results. A total of 417 respondents (n = 284 patients, n = 133 practitioners) were recruited. Of the total patients, 170 (59.9%) had started CAM during the previous three months. There were 168 (59.2%) of the total patients who had used allopathic treatments for hepatitis C prior to their use of CAM. The confidence in CAM (24.6%), high cost (19%), and unbearable side effects (52.1%) of allopathic medicines were the main reasons to switch to CAM treatment. Majority (49.3%) of the patients were referred to CAM on the recommendations of relatives or care givers (17.3%) whereas only 9.5% were referred by health care professionals. Out of 133 practitioners, 48 (36.1%) were practicing herbal medicines. From practitioners’ perspectives, club‐moss (Lycopodium clavatum) was the best treatment option for hepatitis C. The majority, 73 (54.9%), of the patients had chosen to use CAM because of the side effects of allopathic medicines. Patients who had previous “good experience” with CAM were the most common referral source (56.4%) for CAM use in hepatitis C. Conclusions. Patients’ beliefs in CAM, side effects of allopathic therapy, high cost of allopathic medicines, and referrals from previous CAM users are key factors in the switching of hepatitis C patients to CAM.
Efficacy and Safety of Tetrahydrocurcuminoids for the Treatment of Canker Sore and Gingivitis
Authors: Majeed Muhammed , Majeed Shaheen , Nagabhushanam Kalyanam
Published: December 2020

Background. Tetrahydrocurcuminoids (THCs) are among the major metabolites of curcuminoids with a higher bioavailability and physiological stability and exhibit a broad spectrum of therapeutic activities. The objective of this study was to evaluate the efficacy of THCs in patients suffering from canker sore and gingivitis designed as an exploratory clinical trial. Methods. This is an open label prospective pilot clinical trial carried out at two clinical centers: Noble Hospital, Pune, Maharashtra, and Sri Venkateshwara Hospital, Bangalore, Karnataka in India. Participants were assigned to 21 days of treatment with chewable oral THCs supplement. Patients were instructed to self‐administer one chewable tablet containing 100 mg of THCs twice daily for up to 21 days. This clinical trial was registered at a public Clinical Trial Registry in India (http://www.ctri.nic.in). Thirty‐one canker sore and twenty‐nine gingivitis patients participated in this study. Body mass index, throat numbness/relief, Visual Analog Scale (VAS) pain score, canker sore lesions, gingival appearance, inflammation and bleeding were assessed before and after treatment, at 14 and 21 days. Vital signs and laboratory parameters were assessed for safety. Results. THCs treatment significantly reduced the reddening at the site, difficulty in chewing, swallowing, and VAS pain score in the canker sore patients. Further, both single and multiple lesions were completely healed. In gingivitis patients, gingival appearance, bleeding, and inflammation were significantly reduced. No adverse effects were observed during the study. Conclusion. Overall, the findings of this study show that supplementation of THCs for 21 days reduced the pain and prevented the progression of the disease in patients suffering from canker sore and gingivitis without adverse side effects.
Bayesian Analysis of the Weibull Paired Comparison Model Using Numerical Approximation
Authors: Ullah Khalil , Aslam Muhammad
Published: December 2020

The method of paired comparisons (PC) is widely used to rank items using sensory evaluations. The PC models are developed to provide basis for such comparisons. In this study, the Weibull PC model is analyzed under the Bayesian paradigm using noninformative priors and different loss functions, namely, Squared Error Loss Function (SELF), Quadratic Loss Function (QLF), DeGroot Loss Function (DLF), and Precautionary Loss Function (PLF). Numerical approximation is used to illustrate the entire estimation procedure. A real dataset showing usage preferences for different cellphone brands, Huawei (HW), Samsung (SS), Oppo (OP), QMobile (QM), and Nokia (NK), is used. Quadrature method is used to evaluate the Bayes estimates, their posterior risks, preference probabilities, predictive probabilities, and posterior probabilities to establish and verify ranking order of the competing cellphone brands under study. The results show that the paired comparison model under the study using Bayesian approach involving various loss functions can offer mathematical approach to evaluate cellphone brand preferences. The ranking provided by the model is justifiable according to the usage preference for these cellphone brands. The ranking given by the model indicates that cellphone brand Samsung is preferred the most and QMobile is the least preferred. The plausibility of the model is also assessed using the Chi square test of goodness of fit.
Determinants of Preterm Birth among Mothers Who Gave Birth in Dilla University Referral Hospital, Southern Ethiopia: A Case‐Control Study
Authors: Wakeyo Dagmawit , Addisu Yohannes , Mareg Moges
Published: December 2020

Globally, every year, 1.1 million newborns die due to prematurity. In Ethiopia, 320,000 preterm births occur each year; out of these, 24,400 deaths were due to preterm complications. However, there is little evidence about preterm birth in the study area. Therefore, this study provides an important direction for health professionals, health programmers, and researchers. A facility‐based unmatched case‐control study design was employed among 244 women (61 cases and 183 controls) who gave birth in Dilla University Referral Hospital and were selected with purposive sampling. The bivariate and multivariable logistic regression model was used to select independent predictors of preterm birth. The multivariate analysis was used, and the results were interpreted using an adjusted odds ratio at 95% confidence interval and statistically significant level at a P value less than 0.05. A total of 240 mothers (60 cases and 180 controls) were included in the study with a 98.3% response rate. Factors like attending secondary educational and above [adjusted odd ratio (aOR) = 0.07 (0.08‐0.65)] and attending antenatal care [aOR = 0.41 (0.18‐0.93)] were protective whereas having urinary tract infection [aOR = 3.6 (1.1‐11)], having human immune virus diseases [aOR = 4.2 (0.9‐18)], having a history of abortion [aOR = 2.3 (1.1‐5)], having a history of preterm delivery [aOR = 5 (1.6‐15)], and having hypertensive disorders of pregnancy [aOR = 5 (1.9‐13)] were significantly associated risk factors for preterm birth. The main determinant factors for preterm birth are having antenatal care follow‐up, attending secondary education and above, hypertensive disorders of pregnancy, having HIV/AIDS, and history of abortion. This shows a need to strengthen female education; screen mothers for HIV/AIDS, urinary tract infection, and hypertension; and strengthen nutritional counseling, during ANC visits.
Multilane Spatiotemporal Trajectory Optimization Method (MSTTOM) for Connected Vehicles
Authors: Wang Pangwei , Wang Yunfeng , Deng Hui , Zhang Mingfang , Zhang Juan
Published: December 2020

It is agreed that connected vehicle technologies have broad implications to traffic management systems. In order to alleviate urban congestion and improve road capacity, this paper proposes a multilane spatiotemporal trajectory optimization method (MSTTOM) to reach full potential of connected vehicles by considering vehicular safety, traffic capacity, fuel efficiency, and driver comfort. In this MSTTOM, the dynamic characteristics of connected vehicles, the vehicular state vector, the optimized objective function, and the constraints are formulated. The method for solving the trajectory problem is optimized based on Pontryagin’s maximum principle and reinforcement learning (RL). A typical scenario of intersection with a one-way 4-lane section is measured, and the data within 24 hours are collected for tests. The results demonstrate that the proposed method can optimize the traffic flow by enhancing vehicle fuel efficiency by 32% and reducing pollutants emissions by 17% compared with the advanced glidepath prototype application (GPPA) scheme.
An Empirical Study on GAN-Based Traffic Congestion Attack Analysis: A Visualized Method
Authors: Li Yike , Xiang Yingxiao , Tong Endong , Niu Wenjia , Jia Bowei , Li Long , Liu Jiqiang , Han Zhen
Published: December 2020

With the development of emerging intelligent traffic signal (I-SIG) system, congestion-involved security issues are drawing attentions of researchers and developers on the vulnerability introduced by connected vehicle technology, which empowers vehicles to communicate with the surrounding environment such as road-side infrastructure and traffic control units. A congestion attack to the controlled optimization of phases algorithm (COP) of I-SIG is recently revealed. Unfortunately, such analysis still lacks a timely visualized prediction on later congestion when launching an initial attack. In this paper, we argue that traffic image feature-based learning has available knowledge to reflect the relation between attack and caused congestion and propose a novel analysis framework based on cycle generative adversarial network (CycleGAN). Based on phase order, we first extract four-direction road images of one intersection and perform phase-based composition for generating new sample image of training. We then design a weighted L1 regularization loss that considers both last-vehicle attack and first-vehicle attack, to improve the training of CycleGAN with two generators and two discriminators. Experiments on simulated traffic flow data from VISSIM platform show the effectiveness of our approach.
Dynamic Scheduling Model of Bike-Sharing considering Invalid Demand
Authors: He Liu , Guo Tangyi , Tang Kun
Published: December 2020

System resources allocation optimization through dynamic scheduling is key to improving the service level of bike-sharing. This study innovatively introduces three types of invalid demand with negative effect including waiting, transfer, and abandoning, which consists of the total demand of bike-sharing system. Through exploring the dynamic relationship among users’ travel demands, the quantity and capacity of bikes at the rental points, the records of bicycles borrowed and returned, and the vehicle scheduling schemes, a demand forecasting model for bike-sharing is established. According to the predicted bikes and the maximum capacity limit at each rental point, an optimization model of scheduling scheme is proposed to reduce the invalid demand and the total scheduling time. A two-layer dynamic coupling model with iterative feedback is obtained by combining the demand prediction model and scheduling optimization model and is then solved by Nicked Pareto Genetic Algorithm (NPGA). The proposed model is applied to a case study and the optimal solution set and corresponding Pareto front are obtained. The invalid demand is greatly reduced from 1094 to 26 by an effective scheduling of 3 rounds and 96 minutes. Empirical results show that the proposed model is able to optimize the resource allocation of bike-sharing, significantly reduce the invalid demand caused by the absence of bikes at the rental point such as waiting in a place, walking to other rental points, and giving up for other travel modes, and effectively improve the system service level.
Detecting Overlapping Data in System Logs Based on Ensemble Learning Method
Authors: Liu Chunbo , Ren Yitong , Liang Mengmeng , Gu Zhaojun , Wang Jialiang , Pan Lanlan , Wang Zhi
Published: December 2020

Machine learning techniques are essential for system log anomaly detection. It is prone to the phenomenon of class overlap because of too many similar system log data. The occurrence of this phenomenon will have a serious impact on the anomaly detection of the system logs. To solve the problem of class overlap in system logs, this paper proposes an anomaly detection model for class overlap problem on system logs. We first calculate the relationship between the sample data and the membership of different classes, normal or anomaly, and use the fuzziness to separate the sample data of the overlapping parts of the classes from the data of the other parts. AdaBoost, an ensemble learning approach, is used to detect overlapping data. Compared with machine learning algorithms, ensemble learning can better classify the data of the overlapping parts, so as to achieve the purpose of detecting the anomalies of the system logs. We also discussed the possible impact of different voting methods on ensemble learning results. Experimental results show that our model can be effectively applied in a variety of basic algorithms, and the results of each measure have been improved.
A Novel Adaptive Directional Interpolation Algorithm for Digital Video Resolution Enhancement
Authors: Sun Dong , Xie Qingqing , Li Teng , Lu Yixiang , Zhu De , Gao Qingwei
Published: December 2020

In this paper, a novel digital video resolution enhancement algorithm based on adaptive directional interpolation is proposed, where the directionality of the edge structure and the nonlocal self-similarity prior within the current frame as well as its adjacent frames are both considered. First, we establish the regularization equation that conforms to the prior model of a video frame and then take the classic bicubic interpolation result as the initial estimation to iteratively solve the restoration equation, in which the edge structures and contours in low resolution (LR) input are reconstructed to estimate and refine the desired high resolution (HR) output. Experimental results show that the proposed algorithm can effectively enhance the clarity of a video frame, with satisfying subjective visual quality and PSNR value.
Mean Empirical Likelihood Inference for Response Mean with Data Missing at Random
Authors: He Hanji , Deng Guangming
Published: December 2020

We extend the mean empirical likelihood inference for response mean with data missing at random. The empirical likelihood ratio confidence regions are poor when the response is missing at random, especially when the covariate is high-dimensional and the sample size is small. Hence, we develop three bias-corrected mean empirical likelihood approaches to obtain efficient inference for response mean. As to three bias-corrected estimating equations, we get a new set by producing a pairwise-mean dataset. The method can increase the size of the sample for estimation and reduce the impact of the dimensional curse. Consistency and asymptotic normality of the maximum mean empirical likelihood estimators are established. The finite sample performance of the proposed estimators is presented through simulation, and an application to the Boston Housing dataset is shown.
Polysaccharides of Scrophularia ningpoensis Hemsl.: Extraction, Antioxidant, and Anti‐Inflammatory Evaluation
Authors: Wang Jian’an , Huang Lufen , Ren Qiang , Wang Yanjun , Zhou Lirun , Fu Yingjie , Sai Chunmei , Pella Shafii Shaibu , Guo Yingying , Gao Li-Na
Published: December 2020

The roots of Scrophularia ningpoensis Hemsl. are a famous traditional Chinese medicinal herb and are also used as health food. However, information about polysaccharides from S. ningpoensis (SNPS) is very limited. We applied the ultrasonic‐assisted extraction (UAE) process to extract SNPS. The UAE conditions were optimized using single‐factor experiments and response surface analysis. Under the optimized conditions of ultrasonic power of 550 W, extraction time of 26 min, and extraction temperature at 50°C, the highest yield of 13.47% ± 1.63% was obtained, which was in accordance with the predicted value of 13.71%. In comparison with traditional hot water extraction, the optimized UAE method significantly increased the extraction yield with lower extraction temperature and shorter extraction time. Furthermore, the in vitro antioxidant evaluation showed that EC50 values of SNPS were 2.43 ± 0.21, 4.40 ± 0.35, and 0.56 ± 0.062 mg/mL for 2,2‐diphenyl‐1‐picrylhydrazyl radical (DPPH) radical, hydroxyl free radical, and 2,2’‐azinobis (3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) radical scavenging assay, respectively. The anti‐inflammatory potential of SNPS was detected in lipopolysaccharide (LPS) induced ICR mice. Real‐time reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay showed that SNPS significantly improved LPS‐stimulated inflammatory response by decreasing mRNA and protein expression of interleukin (IL)‐6 and tumour necrosis factor (TNF)‐α in a dose‐dependent manner. In conclusion, the extraction process of SNPS established in this study is reliable, and SNPS possesses potential antioxidant and anti‐inflammatory activities, which will provide a theoretical basis for guiding the clinical application of S. ningpoensis.
A Very Long-Acting PARP Inhibitor Suppresses Cancer Cell Growth in DNA Repair-Deficient Tumor Models
Authors: Fontaine Shaun D. , Ashley Gary W. , Houghton Peter J. , Kurmasheva Raushan T. , Diolaiti Morgan , Ashworth Alan , Peer Cody J. , Nguyen Ryan , Figg William D. , Beckford-Vera Denis R. , Santi Daniel V.
Published: December 2020

PARP inhibitors are approved for treatment of cancers with BRCA1 or BRCA2 defects. In this study, we prepared and characterized a very long-acting PARP inhibitor. Synthesis of a macromolecular prodrug of talazoparib (TLZ) was achieved by covalent conjugation to a PEG40kDa carrier via a β-eliminative releasable linker. A single injection of the PEG∼TLZ conjugate was as effective as ∼30 daily oral doses of TLZ in growth suppression of homologous recombination-defective tumors in mouse xenografts. These included the KT-10 Wilms' tumor with a PALB2 mutation, the BRCA1-deficient MX-1 triple-negative breast cancer, and the BRCA2-deficient DLD-1 colon cancer; the prodrug did not inhibit an isogenic DLD-1 tumor with wild-type BRCA2. Although the half-life of PEG∼TLZ and released TLZ in the mouse was only ∼1 day, the exposure of released TLZ from a single safe, effective dose of the prodrug exceeded that of oral TLZ given daily over one month. μPET/CT imaging showed high uptake and prolonged retention of an 89Zr-labeled surrogate of PEG∼TLZ in the MX-1 BRCA1-deficient tumor. These data suggest that the long-lasting antitumor effect of the prodrug is due to a combination of its long t1/2, the high exposure of TLZ released from the prodrug, increased tumor sensitivity upon continued exposure, and tumor accumulation. Using pharmacokinetic parameters of TLZ in humans, we designed a long-acting PEG∼TLZ for humans that may be superior in efficacy to daily oral TLZ and would be useful for treatment of PARP inhibitor-sensitive cancers in which oral medications are not tolerated.

Significance:

These findings demonstrate that a single injection of a long-acting prodrug of the PARP inhibitor talazoparib in murine xenografts provides tumor suppression equivalent to a month of daily dosing of talazoparib.
Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function
Authors: Kon Ning , Churchill Michael , Li Huan , Mukherjee Siddhartha , Manfredi James J. , Gu Wei
Published: December 2020

p53 is a short-lived protein with low basal levels under normal homeostasis conditions. However, upon DNA damage, levels of p53 dramatically increase for its activation. Although robust stabilization of p53 serves as a “trademark” for DNA damage responses, the requirement for such dramatic protein stabilization in tumor suppression has not been well addressed. Here we generated a mutant p53KQ mouse where all the C-terminal domain lysine residues were mutated to glutamines (K to Q mutations at K367, K369, K370, K378, K379, K383, and K384) to mimic constitutive acetylation of the p53 C-terminus. Because of p53 activation, p53KQ/KQ mice were perinatal lethal, yet this lethality was averted in p53KQ/− mice, which displayed normal postnatal development. Nevertheless, p53KQ/− mice died prematurely due to anemia and hematopoiesis failure. Further analyses indicated that expression of the acetylation-mimicking p53 mutant in vivo induces activation of p53 targets in various tissues without obviously increasing p53 levels. In the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model, expression of the acetylation-mimicking p53-mutant protein effectively suppressed K-Ras–induced PDAC development in the absence of robust p53 stabilization. Together, our results provide proof-of-principle evidence that p53-mediated transcriptional function and tumor suppression can be achieved independently of its robust stabilization and reveal an alternative approach to activate p53 function for therapeutic purposes.

Significance:

Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.
Glia-Selective Deletion of Complement C1q Prevents Radiation-Induced Cognitive Deficits and Neuroinflammation
Authors: Markarian Mineh , Krattli Robert P. , Baddour Jabra D. , Alikhani Leila , Giedzinski Erich , Usmani Manal T. , Agrawal Anshu , Baulch Janet E. , Tenner Andrea J. , Acharya Munjal M.
Published: December 2020

The adverse neurocognitive sequelae following clinical radiotherapy (RT) for central nervous system (CNS) malignancies are often long-lasting without any clinical recourse. Despite recent progress, the cellular mechanisms mediating RT-induced cognitive deficits (RICD) are poorly understood. The complement system is an immediate sensor of a disturbed inflammatory environment and a potent mediator of gliosis with a range of nonimmune functions in the CNS, including synaptic pruning, which is detrimental if dysregulated. We hypothesize that complement-mediated changes in glial cell function significantly contribute to RICD. The underlying alterations in CNS complement cascade proteins (C1q, C3), TLR4, and colabeling with glia (IBA1, GFAP) were examined using gene expression, immunofluorescence, and in silico modeling approaches in the adult mouse brain following 9 Gy cranial RT. Three-dimensional volumetric quantification showed elevated molecular signatures of gliosis at short- and long-term post-RT times. We found significant elevations in complement C1q, C3, and TLR4 post-RT accompanied by increased colabeling of astrocytes and microglia. To address the mechanism of RT-induced complement cascade activation, neuroinflammation, and cognitive dysfunction, we used a genetic approach—conditional, microglia-selective C1q (Flox) knockdown mice—to determine whether a glia-specific, upstream complement cascade contributes to RICD. C1q-Flox mice exposed to cranial RT showed no cognitive deficits compared with irradiated WT mice. Further, irradiated C1q-Flox mice were protected from RT-induced microglial activation and synaptic loss, elevation of anaphylatoxin C5a receptor, astrocytic-C3, and microglial-TLR4 expression in the brain. Our findings demonstrate for the first time a microglia-specific mechanism of RICD involving an upstream complement cascade component, C1q.

Significance:

Clinically-relevant radiotherapy induces aberrant complement activation, leading to brain injury. Microglia-selective genetic deletion of CNS complement C1q ameliorates radiation-induced cognitive impairments, synaptic loss, and neuroinflammation, highlighting the potential for C1q as a novel therapeutic target.

See related commentary by Korimerla and Wahl, p. 1635
Dissecting the Functional Significance of DNA Polymerase Mutations in Cancer
Authors: Wisdom Amy J. , Kirsch David G.
Published: December 2020

DNA polymerase mutations can cause hypermutant cancers, but the mechanisms of tumorigenesis and the impact of various DNA polymerase mutations on treatment response is poorly understood. In this issue of Cancer Research, Galati and colleagues investigate the effects of cancer-associated DNA polymerase ε (Pole) mutations on tumorigenesis and response to immune checkpoint blockade. They describe novel genetically engineered mouse models harboring cancer-associated Pole mutations and examine the effects of these mutations on tumorigenesis, the tumor mutational landscape, and the tumor immune microenvironment. Integrating this information with an emerging understanding of how different tumor mutations influence the response to immunotherapy may aid in prediction, diagnosis, and treatment of Pole-mutant tumors.

See related article by Galati et al., p. 5606
Macrophages Come To The Rescue
Authors: Coppes Robert P.
Published: December 2020

The study by Zhao and colleagues, in this issue of Cancer Research, builds on previous work where they showed that transient activation of Hedgehog signaling within the murine submandibular gland rescued radiation-induced salivary gland dysfunction. The current study provides mechanistic insight into this phenomenon by showing that restoration of radiation-depleted resident macrophages through prorepair paracrine interactions with endothelial cells and epithelial progenitors rescued salivary function.

See related article by Zhao et al., p. 5531
Opportunities for Gene and Environment Research in Cancer: An Updated Review of NCI's Extramural Grant Portfolio
Authors: Ghazarian Armen A. , Simonds Naoko Ishibe , Lai Gabriel Y. , Mechanic Leah E.
Published: December 2020

Background:

The study of gene–environment (GxE) interactions is a research priority for the NCI. Previously, our group analyzed NCI's extramural grant portfolio from fiscal years (FY) 2007 to 2009 to determine the state of the science in GxE research. This study builds upon our previous effort and examines changes in the landscape of GxE cancer research funded by NCI.

Methods:

The NCI grant portfolio was examined from FY 2010 to 2018 using the iSearch application. A time–trend analysis was conducted to explore changes over the study interval.

Results:

A total of 107 grants met the search criteria and were abstracted. The most common cancer types studied were breast (19.6%) and colorectal (18.7%). Most grants focused on GxE using specific candidate genes (69.2%) compared with agnostic approaches using genome-wide (26.2%) or whole-exome/whole-genome next-generation sequencing (NGS) approaches (19.6%); some grants used more than one approach to assess genetic variation. More funded grants incorporated NGS technologies in FY 2016–2018 compared with prior FYs. Environmental exposures most commonly examined were energy balance (46.7%) and drugs/treatment (40.2%). Over the time interval, we observed a decrease in energy balance applications with a concurrent increase in drug/treatment applications.

Conclusions:

Research in GxE interactions has continued to concentrate on common cancers, while there have been some shifts in focus of genetic and environmental exposures. Opportunities exist to study less common cancers, apply new technologies, and increase racial/ethnic diversity.

Impact:

This analysis of NCI's extramural grant portfolio updates previous efforts and provides a review of NCI grant support for GxE research.
Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma
Authors: Roane Brandon M. , Meza-Perez Selene , Katre Ashwini A. , Goldsberry Whitney N. , Randall Troy D. , Norian Lyse A. , Birrer Michael J. , Arend Rebecca C.
Published: December 2020

The immunosuppressive effects of TGFβ promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53−/− tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFβ ligands was used to neutralize TGFβ. Ascites and omentum were collected and changes in T-cell response were measured using flow. Treatment with anti-TGFβ therapy every other day following injection of tumor cells resulted in decreased ascites volume (4.1 mL vs. 0.7 mL; P < 0.001) and improved the CD8:Treg ratio (0.37 vs. 2.5; P = 0.02) compared with untreated mice. A single dose of therapy prior to tumor challenge resulted in a similar reduction of ascites volume (2.7 vs. 0.67 mL; P = 0.002) and increased CD8:Tregs ratio (0.36 vs. 1.49; P = 0.007), while also significantly reducing omental weight (114.9 mg vs. 93.4 mg; P = 0.017). Beginning treatment before inoculation with tumor cells and continuing for 6 weeks, we observe similar changes and prolonged overall survival (median 70 days vs. 57.5 days). TGFβ neutralization results in favorable changes to the T-cell response within the tumor microenvironment, leading to decreased tumor progression in ovarian cancer. The utilization of anti-TGFβ therapy may be an option for management in patients with ovarian cancer to improve clinical outcomes and warrants further investigation.
Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes
Authors: Alhalabi Omar , Hahn Andrew W. , Msaouel Pavlos , Andreev-Drakhlin Alexander Y. , Meric-Bernstam Funda , Naing Aung , Piha-Paul Sarina , Filip Janku , Pant Shubham , Yap Timothy A. , Hong David S. , Fu Siqing , Karp Daniel , Campbell Erick , Le Hung , Campbell Matthew T. , Shah Amishi Y. , Tannir Nizar M. , Siefker-Radtke Arlene O. , Gao Jianjun , Roszik Jason , Subbiah Vivek
Published: December 2020

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration.

Implications:

Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor.

Visual Overview:

http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.
Relevance of the Bruton Tyrosine Kinase as a Target for COVID-19 Therapy
Authors: Rada Miran , Qusairy Zahraa , Massip-Salcedo Marta , Macip Salvador
Published: December 2020

The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton tyrosine kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared with those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (acalabrutinib and ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in severe acute respiratory syndrome coronavirus 2 infections and the suitability of its inhibitors as drugs to treat COVID-19. The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.
СИРОВАТКОВИЙ ВМІСТ 25-(OH) ВІТАМІНУ D НЕ ВПЛИВАЄ НА ЕФЕКТИВНІСТЬ БЕЗІНТЕРФЕРОНОВИХ РЕЖИМІВ ЛІКУВАННЯ ХВОРИХ НА HCV-ІНФЕКЦІЮ
Authors: Zhyvytsia D. H. , Tsariova O. V.
Published: December 2020

Поширеність HCV-інфекції відрізняється залежно від країни і є однією з найвищих в Україні. Вітамін D є жиророзчинним секостероїдом з різноманітними системними ефектами. Крім контролю гомеостазу кальцію, вітамін D має значний вплив на реакції вродженого і набутого імунітету, а також пригнічує реплікацію вірусу гепатиту С (HCV).

Мета роботи – дослідження впливу сироваткової концентрації 25-(OH) вітаміну D на ефективність лікування пацієнтів з HCV-інфекцією препаратами прямої противірусної дії.

Пацієнти і методи. У дослідження були включені 73 хворих на HCV-інфекцію старше 18 років. Чоловіків було 38 (52,1 %), жінок – 35 (47,9 %). У 55 (75,3 %) осіб був встановлений генотип 1b HCV, у 18 (24,7 %) – генотип 3а HCV. За шкалою METAVIR, мінімальний ступінь фіброзу (F0-1) було визначено у 7 (9,6 %) пацієнтів, середній ступінь фіброзу (F2) – у 17 (23,3 %), тяжкий фіброз (F3) – у 21 (28,7 %) і цироз печінки (F4) – у 28 (38,4 %) осіб. Залежно від генотипу HCV і ступеня фіброзу печінки в лікуванні 43 (58,9 %) пацієнтів застосовували комбінацію омбітасвіру/паритопревіру/ритонавіру і дасабувіру впродовж 12 тиж, а у 30 (41,1 %) – комбінацію софосбувіру і рибавірину впродовж 12 чи 24 тиж.

Результати. Серед 73 пацієнтів, які були включені в дослідження, медіана концентрації 25-(ОН) D становила 27,07 нг/мл (від 12,1 до 45,9 нг/мл). Нормальний вміст 25-(OH) вітаміну D зафіксований у 30 (41,1 %) осіб, недостатність виявили у 28 (38,4 %) пацієнтів, а дефіцит – у 15 (20,5 %) осіб. Показник СВВ12 не залежав (P>0,05) від сироваткової концентрації 25-(OH) вітаміну D і у пацієнтів з нормальним вмістом вітаміну D склав 100,0 % (95 % ДІ: 88,4-100,0 %), при недостатності – 96,4 % (95 %ДІ: 81,7-99,9 %), а при дефіциті – 93,3 % (95 %ДІ: 68,1-99,8 %). Також показник СВВ12 не залежав (P>0,05) від віку пацієнтів, генотипу HCV, вірусного навантаження HCV, попереднього лікування, наявності цирозу печінки і схеми лікування. Середній вміст 25-(ОН) вітаміну D у пацієнтів зі слабким фіброзом (F1) становив 37,8 (35,8-43,5) нг/мл. У пацієнтів з цирозом печінки (F4) концентрація 25-(ОН) вітаміну D дорівнювала 19,3 (18,1-25,84) нг/мл і була у 1,96-1,67 разу менше (P<0,05) порівняно з особами зі слабким фіброзом печінки (F1-F2) і у 1,38 разу менше (P<0,05), ніж при тяжкому фіброзі (F3). При цьому середній вміст 25-(ОН) вітаміну D у хворих зі стадією фіброзу F2-F3 був значущо меншим (P<0,05), ніж в осіб з портальним фіброзом (F1) – 32,3 (29,8-35,5) нг/мл і 26,8 (25,55-37,1) нг/мл порівняно з 37,8 (35,8-43,5) нг/мл, відповідно.

Висновки. Сироватковий вміст 25-(ОН) вітаміну D не впливає на ефективність лікування пацієнтів з HCV-інфекцією препаратами прямої противірусної дії. У хворих на HCV-інфекцію і цироз печінки концентрація 25-(ОН) вітаміну D в 1,96-1,67 разу менше (P<0,05), порівняно з особами зі слабким фіброзом печінки (F1-F2) і в 1,38 разу менше (P<0,05), ніж при тяжкому фіброзі (F3).
РЕАБІЛІТАЦІЯ ПОРОДІЛЬ, ЯКІ ПЕРЕНЕСЛИ ПРЕЕКЛАМПСІЮ
Authors: Malanchyn I. M. , Martyniuk V. M. , Lymar L. Ye.
Published: December 2020

Резюме. Доведено роль гіпертензивних розладів та прееклампсії під час вагітності в розвитку кардіоваскулярних та цереброваскулярних захворювань у подальшому житті пацієнток. У літературі широко висвітлені питання діагностики, лікування, профілактики прееклампсії, але небагато є інформації щодо реабілітації пацієнток у післяпологовому періоді.

Мета дослідження – розробити комплекс реабілітаційних заходів з урахуванням індивідуальних особливостей для жінок, які перенесли прееклампсію.

Матеріали і методи. Під спостереженням перебували 127 породіль. Контрольну групу склали 40 жінок із фізіологічними пологами. В першій групі – 45 пацієнток, які перенесли прееклампсію середнього ступеня та отримували розроблену комплексну реабілітацію, в другій групі – 42 породіллі. Усім жінкам проводили загальноклінічні методи обстеження при госпіталізації, у динаміці лікування, перед випискою, через 1; 3; 6 місяців, а також через рік після пологів. Для пацієнток основної групи було розроблено комплексну реабілітаційну програму із залученням дієтолога, психолога, реабілітолога та фізіотерапевта.

Результати. Перебіг післяпологового періоду в породіль контрольної групи закінчився фізіологічно. У 71 % пацієнток основної групи нормалізація АТ починається з 5 доби післяпологового періоду, і лише в половини (52,4 %) із групи порівняння. Добовий діурез приходить у норму протягом двох тижнів у жінок першої групи, а у 78,6 % пацієнток другої групи лише на 30 добу спостереження. Зниження протеїнурії діагностували з 3-ї доби після пологів у всіх пацієнток основної групи та з 5–7 доби – у жінок групи порівняння. Концентрація загального білка у жінок першої групи повністю нормалізувалася на 15 добу післяпологового періоду, а у породіль другої групи – до 30 доби. Нормалізація кількості тромбоцитів у всіх жінок основної групи настала через місяць після пологів, у осіб групи порівняння – лише через півроку.

Висновки. Жінкам, які перенесли прееклампсію, у післяпологовому періоді доцільно розробляти індивідуальну реабілітаційну комплексну програму із залученням акушера-гінеколога, дієтолога, психолога, реабілітолога та фізіотерапевта, а також рекомендувати санаторно-курортне лікування після року спостереження.
ЗМІНИ МАКРО- І МІКРОЕЛЕМЕНТНОГО СКЛАДУ ПЕЧІНКИ ЩУРІВ У ДИНАМІЦІ РОЗВИТКУ СИНДРОМУ ТРИВАЛОГО СТИСНЕННЯ
Authors: Pylypchuk T. P.
Published: December 2020

Резюме. Враховуючи високу летальність при тяжких формах синдрому тривалого стиснення (СТС), вагоме місце займає вивчення механізмів, що перебігають у динаміці даного патологічного синдрому

Мета дослідження – вивчити в динаміці показники макро- і мікроелементного складу печінки щурів на моделі ендотоксикозу, що формується за умов синдрому тривалого стиснення.

Матеріали і методи. Досліди проведені на 40 безпо­родних статевозрілих білих щурах-самцях. Експериментальною моделлю слугував патологічний процес, що розвивався у тварин унаслідок стиснення м'яких тканин лівої тазової кінцівки протягом 4-х год у спе­ціальному пристрої. Площа стискаючої поверхні становила 4 см2, а сила компресії – 4,25 кг/см2. При цьому цілість великих судин і кісткових структур нижньої кінцівки зберігалась. Таким чином, у тварин моделювався синдром тривалого стиснення середнього ступеня. У печінці дослідних тварин визначали рівень макро- та мікроелементів методом атомно-абсорбційної спектрофотометрії на спектрофотометрі С-115 ПК.

Результати. Так, вміст кальцію у печінці підвищувався на 3 добу експерименту на 18,2 % та залишався вірогідно високим до 14 доби. Разом з тим, рівень магнію зменшувався вже на 1 добу на 19,2 %, коливаючись у цих межах до 7 доби, а потім знову знижувався на 106,7 % стосовно контрольної групи. Вміст цинку в печінці поступово зростав з 1 доби (на 12,8 %) до 14 доби (на 34,0 %) спостереження відносно контролю. Таку ж тенденцію відмічено щодо вмісту купруму, проте його рівень вірогідно підвищувався на 3 добу експерименту.

Висновки. В умовах гіпоксії та оксидативного стресу, що розвиваються в тканинах організму щурів з експериментальним синдромом тривалого стиснення, відмічається дисбаланс макро- та мікроелементів, який характеризується підвищенням вмісту кальцію, цинку і купруму та зниження вмісту магнію в печінці тварин.
ОЦЕНКА БИОХИМИЧЕСКИХ ПОКАЗАТЕЛЕЙ КРОВИ И ПОЧЕЧНОЙ ДИСФУНКЦИИ У БОЛЬНЫХ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ
Authors: Rakhimova M. E. , Turakulov R. I. , Kadirova F. Sh. , Mirbayzaev A. A. , Korakhonov R. K. , Xudayberdieva J. D.
Published: December 2020

Вступление. Почечная дисфункция – основная причина распространения значимых сопутствующих состояний, ассоциированных с неблагоприятным клиническим прогнозом. Необходимо отметить, что хроническая сердечная недостаточность резко ухудшает качество жизни пациентов, а также увеличивает риск летальности. Уровень летальности в течение года составляет 15–50 %. Основным фактором ухудшения почечной функции является понижение сердечного выброса и венозного застоя. В связи с понижением сердечного выброса уменьшается почечная перфузия и, таким образом, скорость клубочковой фильтрации. Венозный застой относится к причинам повышения давления в выносящих артериолах и капиллярах клубочков. Цель исследования – изучить показатели дисфункции почек у больных с хронической сердечной недостаточностью. Методы исследования. Обследовано 96 больных с постинфарктным кардиосклерозом, осложненным хронической сердечной недостаточностью, в возрасте 40–60 лет. Их разделили на 2 группы по функциональному классу хронической сердечной недостаточности согласно классификации Нью-Йоркской ассоциации сердца (NYHA). У всех пациентов определяли уровень креатинина, по формуле MDRD (ModIfIcatIon of Diet In Renal Disease Study) вычисляли скорость клубочковой фильтрации. Спектрофотометричеким методом в моче определяли ферменты: аланинаминотрансферазу, аспартатаминотрансферазу, щелочную фосфатазу, холинэстеразу. Результаты и обсуждение. У 33,3 % больных со II функциональным классом хронической сердечной недостаточности и у 66,7 % пациентов с III функциональным классом хронической сердечной недостаточности скорость клубочковой фильтрации была <60 мл/мин/1,73 м2. Во время изучения показателей ферментурии у больных с хронической сердечной недостаточностью в зависимости от функционального состояния почек выявлено, что у пациентов со скоростью клубочковой фильтрации <60 мл/мин/1,73 м2, среди которых больные с III функциональным классом хронической сердечной недостаточности составляли 66,7 %, отмечали достоверно высокие показатели ферментурии. При этом уровень аланинаминотрансферазы был на 39 % (p<0,01), щелочной фосфатазы – на 35 % (p<0,001) выше по сравнению с показателями больных без нарушения функции почек. Выводы. У пациентов с хронической сердечной недостаточностью по мере прогрессирования заболевания отмечают субклиническое нарушение функции почек, характеризующееся уменьшением скорости клубочковой фильтрации, повышением уровня остаточного азота и ферментурии. Определение уровня ферментов в моче больных с хронической сердечной недостаточностью можно рассматривать как диагностический подход к ранней диагностике дисфункции почек.
ОСОБЛИВОСТІ ВУГЛЕВОДНОГО ТА ЛІПІДНОГО ОБМІНУ В ЖІНОК ПРЕМЕНОПАУЗАЛЬНОГО ВІКУ З ГІПОТИРЕОЗОМ АВТОІМУННОГО ГЕНЕЗУ
Authors: Chukur O. O.
Published: December 2020

Вступ. Дисфункцію щитоподібної залози вважають поширеним ендокринним захворюванням, у структурі якого переважає гіпотиреоз. У більшості випадків гіпотиреоз є наслідком автоімунного тиреоїдиту, що найчастіше трапляється в жінок. Зростання рівня тиреотропного гормону корелює з параметрами метаболічного синдрому, що збільшує серцево-судинні події та загальну смертність.

Мета дослідження – вивчити особливості кореляційних взаємозв’язків тиреотропного гормону, тиреоїдних гормонів та антитіл до тиреопероксидази з вуглеводно-ліпідними показниками в жінок пременопаузального віку, хворих на гіпотиреоз автоімунного генезу.

Методи дослідження. Обстежено 146 жінок пременопаузального віку з гіпотиреозом автоімунного генезу. Всім пацієнткам проводили антропометричні, загальноклінічні, біохімічні обстеження, включаючи визначення вуглеводного та ліпідного обміну, оцінювали функціональний стан їх щитоподібної залози, визначаючи рівні тиреотропного гормону, вільного тироксину, вільного трийодтироніну та антитіл до тиреопероксидази. Результати досліджень аналізували методом варіаційної статистики за допомогою програми STATISTICA 12 (“Statsoft”, США).

Результати й обговорення. Рівні тиреотропного гормону та антитіл до тиреопероксидази характеризувалися прямим кореляційним взаємозв’язком середньої сили із загальним холестерином, тригліцеридами, ліпопротеїнами низької щільності, коефіцієнтом атерогенності, а рівні вільного тироксину і вільного трийодтироніну – зворотним зв’язком. Встановлено достовірно позитивні кореляції середньої сили індексу маси тіла й індексу інсулінорезистентності HOMA-IR з тиреотропним гормоном, антитілами до тиреопероксидази та негативні кореляції середньої сили з вільним тироксином і вільним трийодтироніном. Виявлено позитивний кореляційний взаємозв’язок індексу маси тіла та індексу інсулінорезистентності НОМА-IR з рівнями загального холестерину, холестерину ліпопротеїнів низької щільності, тригліцеридів, коефіцієнтом атерогенності й негативний кореляційний взаємозв’язок з холестерином ліпопротеїнів високої щільності.

Висновок. Дослідження кореляційних взаємозв’язків вуглеводного та ліпідного обміну в жінок пременопаузального віку, хворих на гіпотиреоз автоімунного генезу, є актуальним і перспективним напрямком для вивчення механізмів розвитку метаболічного синдрому та його корекції. Замісна гормональна терапія левотироксином натрію в жінок з гіпотиреозом автоімунного генезу є недостатньою для досягнення цільових рівнів основних показників метаболічного обміну.