bluuebunny/crossref_metadata_2025 huggingface dataset:
The Antiobesity Effect of GLP-1 Receptor Agonists Alone or in Combination with Metformin in Overweight /Obese Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis
Authors: Lyu Xiaorui , Lyu Taibiao , Wang Xue , Zhu Huijuan , Pan Hui , Wang Linjie , Yang Hongbo , Gong Fengying
Published: February 2021

Objectives. Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and metformin (MET) have markedly antiobesity effects in overweight/obese polycystic ovary syndrome (PCOS) patients. However, there was no literature to compare the antiobesity effects of these two medicines. Therefore, a systematic review and meta-analysis were conducted in our present study to evaluate the antiobesity effects of GLP-1RAs either as monotherapy or combined with MET in comparison with MET alone in overweight/obese PCOS patients. Methods. All randomized controlled trials (RCTs) which reported the efficacy of GLP-1RAs and MET in overweight/obese PCOS patients in Medline (from Pubmed), Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus databases were independently searched by two reviewers. The random-effect model was used to pool data extracted from the included literature. The weighted mean difference (WMD) and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD42020173199). Results. A total of eight eligible RCTs were finally enrolled in our meta-analysis from the 587 retrieved literature. The results showed that GLP-1RAs alone or combined with MET was associated with a greater weight loss (N = 318, WMD = −2.61, 95% CI: −3.51 to −1.72,

P
≤
0.001

, I2 = 77.5%), more obvious reduction of waist circumference (N = 276, WMD = −3.46, 95% CI: −4.36 to −2.56,

P
≤
0.001

, I2 = 0.0%), and body mass index (BMI) (N = 318, WMD = −0.93, 95% CI: −1.60 to −0.26,

P
=
0.007

, I2 = 84.9%) in overweight/obese PCOS patients when compared with MET alone. Further sensitivity analysis demonstrated that the meta-analysis results of the efficacy differences in terms of body weight, waist circumference, and BMI were relatively stable and reliable. Conclusion. Our meta-analysis demonstrated that the antiobesity effect of GLP-1RAs alone or combined with MET  was superior to MET  alone in terms of weight loss, the reduction of waist circumference, and BMI. More large-scale, high-quality RCTs are needed to further confirm these results in PCOS patients.
Molecular Insights into the Potential of Extracellular Vesicles Released from Mesenchymal Stem Cells and Other Cells in the Therapy of Hematologic Malignancies
Authors: Alsagaby Suliman A.
Published: February 2021

Hematologic cancer encompasses the heterogeneous group of neoplasms that affect different stages of blood cell linages. Despite the significant improvements made in the new modalities of anticancer therapy, many forms of blood cancer remain untreatable, putting the afflicted patients at high risk of death. Therefore, there has been an urgent need for novel therapy to improve the clinical outcomes of patients with blood cancer. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been reported to possess an anticancer activity. This review discusses (i) the therapeutic potential of MSC-EVs against blood cancer, (ii) the possibility of using EVs from sources other than MSCs as a mean for blood cancer vaccination and drug delivery, and (iii) areas to be optimized for MSC-EV-based clinical application on blood malignancies.
Application of Random Dynamic Grouping Simulation Algorithm in PE Teaching Evaluation
Authors: Hao Haitao
Published: February 2021

The probability ranking conclusion is an extension of the absolute form evaluation conclusion. Firstly, the random simulation evaluation model is introduced; then, the general idea of converting the traditional evaluation method to the random simulation evaluation model is analyzed; on this basis, based on the rule of “further ensuring the stability of the ranking chain on the basis of increasing the possibility of the ranking chain,” two methods of solving the probability ranking conclusion are given. Based on the rule of “further guaranteeing the stability of the ranking chain on the basis of improving the likelihood of the ranking chain,” two methods are given to solve the likelihood conclusion. This paper argues that this absolute form of conclusion hinders the approximation of the theory to the essence of the actual problem and is an important reason for the problem of “non‐consistency of multi‐evaluation conclusions.” To address this problem, a stochastic simulation‐based comprehensive evaluation solution algorithm based on the idea of “Monte Carlo simulation” is proposed, and the corresponding ranking method is investigated, which is characterized by generating evaluation conclusions with probability (reliability) information, and thus has more advantages than the absolute conclusion form in terms of problem interpretability. The method is characterized by the generation of evaluation conclusions with probabilistic (reliability) information and thus has more advantages than the absolute conclusion form in terms of problem interpretation. Because of the independence of the stochastic simulation solution method, it is applied to the “bottom‐up” evaluation model as an example, and a novel autonomous evaluation method is constructed. Finally, the application of the stochastic simulation evaluation model is illustrated by an example and compared with the absolute form evaluation. The evaluation model is an extension of the traditional evaluation model, which can further broaden the practical application of comprehensive evaluation theory.
Senkyunolide I Protects against Sepsis‐Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture
Authors: Xie Jian , Zhao Zhen-zhen , Li Peng , Zhu Cheng-long , Guo Yu , Wang Jun , Deng Xiao-ming , Wang Jia-feng
Published: February 2021

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis‐associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7‐day survival rate and reduced the excessive release of cytokines including TNF‐α, IL‐6, and IL‐1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP‐induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p‐ERK, p‐JNK, p‐P38, and p‐P65, and the level of inflammatory cytokines, including TNF‐α, IL‐6, and IL‐1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c‐FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis‐associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.
Optimization Model of Process Parameters for Full-Plate Long-Roll Straightening considering Equipment Bounce
Authors: Zhu Xiaoyu , Han Peisheng , Liu Xiaoxiao , Wang XiaoGang
Published: February 2021

Roll straightening is an important process link in sheet production. Due to the step change of the straightening force during the straightening bite and the tail flick, the whole-plate length straightening and pressing process changes will affect the straightening effect. Based on the solution of the curvature integral straightening process, this paper introduces the stiffness coefficient of the straightening equipment. Through C language programming, the iterative solution has been realized, and the process parameters of the dynamic change of the straightening reduction have been obtained. The enumeration method was used to establish a calculation method to optimize the entire board-length straightening process. The laboratory comparison of the 11-roll straightening machine proves that the straightening process optimization model meets the application requirements.
Lumbar Intervertebral Disc Degeneration Does Not Affect Muscle Synergy for Rowing Activities
Authors: Sekine Chie , Matsunaga Naoto , Okubo Yu , Hangai Mika , Kaneoka Koji
Published: February 2021

Rowers with disc degeneration may have motor control dysfunction during rowing. This study is aimed at clarifying the trunk and lower extremity muscle synergy during rowing and at comparing the muscle synergy between elite rowers with and without lumbar intervertebral disc degeneration. Twelve elite collegiate rowers (with disc degeneration,

n
=
6

; without disc degeneration,

n
=
6

) were included in this study. Midline sagittal images obtained by lumbar T2-weighted magnetic resonance imaging were used to evaluate disc degeneration. Participants with one or more degenerated discs were classified into the disc degeneration group. A 2000 m race trial using a rowing ergometer was conducted. Surface electrodes were attached to the right rectus abdominis, external oblique, internal oblique, latissimus dorsi, multifidus, erector spinae, rectus femoris, and biceps femoris. The activity of the muscles was measured during one stroke immediately after 20% and 80% of the rowing trial. Nonnegative matrix factorization was used to extract the muscle synergies from the electromyographic data. To compare the muscle synergies, a scalar product (SP) evaluating synergy coincidence was calculated, and the muscle synergies were considered identical at

SP
>
75
%

. Both groups had only one module in the 20% and 80% time points of the trial. At the 20% time point of the 2000 m rowing trial, the SP of the module was 99.8%. At the 80% time point, the SP of the module was 99.9%. The SP results indicate that, at 20% and 80% time points, both groups had the same module. The module showed a high contribution in all muscles. The activation coefficients indicated that the module was always highly activated throughout the rowing stroke in both groups. The trunk and lower extremity muscles are mobilized through the rowing stroke and maintain coordination during rowing. There was no difference in the muscle synergy between the rowers with and without lumbar intervertebral disc degeneration.
Patterns of Fish Assemblage, Growth, and Diet Composition in a Tropical River between Two Cascading Hydropower Dams
Authors: Nyanti Lee , Soo Chen-Lin , Chundi Afina-Yian , Lambat Elsa-Cordelia-Durie , Tram Alvinna , Ling Teck-Yee , Sim Siong-Fong , Grinang Jongkar , Ganyai Tonny , Lee Karen-Suan-Ping
Published: February 2021

Construction of cascade dams has been shown to have impacts on fish assemblages and biodiversity. Yet, there is no literature on fish assemblages in the Murum River that connects the cascading Bakun and Murum dams in Sarawak, Malaysia. Hence, study on this modified ecosystem is necessitated to better understand the effects of the cascade dam construction on fish fauna. For this, fish samples were caught at five stations located along the river during both dry and wet seasons. Environmental parameters were taken concurrently with fish sampling. Length-weight relationship, condition factors, and diet composition of selected fish species in the river were also determined. The present study demonstrated that there are indications of the impact of cascading dams on the formation of a complex ecosystem in the Murum River, that is, changing from the shallow downstream of the Murum Dam to the deep transitional and inundated zone of the Bakun reservoir. The transitional zone in the Murum River exhibited the lowest fish species diversity, richness, and evenness during the dry season due to low pH and DO coupled with high turbidity. The biological indices improved when the water quality improved during the wet season. On the contrary, the diversity and evenness indices at the inundated tributary station decreased remarkably during the wet season, likely due to the migration of fish during the onset of the rainy season. This study showed that Barbonymus schwanenfeldii has a wider feeding habit which contributes to its higher distribution and abundance in the Murum River. The growth patterns of B. schwanenfeldii, Cyclocheilichthys apogon, Hampala macrolepidota, Lobocheilos ovalis, and Osteochilus enneaporos were better during wet than dry season. Overall, the condition factor of all native fish species in the Murum River was in poor to fair condition, whereas the exotic species, Oreochromis mossambicus, exhibited excellent condition (K value > 2) for both seasons. The increase in the number of O. mossambicus coupled with its high condition factor indicates biological intrusion and a potential threat to the native fish species in the Murum River. Continuous monitoring is essential to detect in-time risk issues associated with environmental degradation and biological invasion in this regulated and inundated river ecosystem.
Performance of Cotton, Cotton-Polyester, and Polyester-Elastane Fabrics Impregnated with Ultrafine Polymeric Nanoparticles Loaded with Lavender Oil
Authors: Saade H. , de León-Gómez R. Díaz , Treviño M. E. , Rodríguez-Fernández O. S. , Soriano-Corral F. , Borjas J. J. , Castellanos F. , Enríquez-Medrano F. J. , Valdez J. A. , López R. G.
Published: February 2021

Lavender oil- (LO-) loaded ultrafine nanoparticles (NP) (

diameter
<
50
 
nm

) of a copolymer were used for impregnating fabrics of cotton, cotton polyester, and polyester-elastane. The copolymer was composed mainly of methyl methacrylate (MMA) units with a low proportion of methacrylic acid (MAA). Moreover, two kinds of NP were used: one containing uncrosslinked copolymer and another one composed of crosslinked material. All the fabrics impregnated with NP of uncrosslinked copolymer keep the aroma up to 25 washes. Under storage at ambient conditions, the fabrics impregnated with NP of either uncrosslinked or crosslinked copolymer emitted aroma for up to almost 60 days. The long duration of aroma emission from fabrics is attributed to ease of the small nanoparticles used in this study of penetrating and staying inside the pores of the fabric fibers.
Intelligent Perturb and Observe Based MPPT Approach Using Multilevel DC-DC Converter to Improve PV Production System
Authors: Ait Ayad Imane , Elwarraki Elmostafa , Baghdadi Mohamed
Published: February 2021

In this paper, an optimized maximum power point tracking (MPPT) control for a standalone photovoltaic (PV) system using a three-level boost (TLB) converter is introduced. The proposed MPPT method is based on an intelligent perturb and observe algorithm using the artificial neural network (ANN-P&O) to reduce the oscillations at the maximum power point (MPP). In advance, The ANN provides the values of the voltage and the current at the MPP for any solar irradiance and cell temperature. Based on the provided voltage and current, the P&O algorithm generates the optimal duty cycle of the TLB converter to perfectly track the MPP of the PV generator for different values of cell temperature and sunlight irradiance. Besides, a proportional-integral (PI) controller is added to ensure the TLB capacitor voltage balance. The established ANN-P&O approach is validated in Matlab/Simulink and compared to the conventional P&O algorithm under various scenarios: (i) irradiance variations, (ii) temperature variations, and (iii) load variations.
Representation of Differential Learning Method for Mitosis Detection
Authors: Ali Haider , Li Hansheng , Afele Retta Ephrem , Haq Imran Ul , Guo Zhenzhen , Han Xin , Cui Lei , Yang Lin , Feng Jun
Published: February 2021

The breast cancer microscopy images acquire information about the patient’s ailment, and the automated mitotic cell detection outcomes have generally been utilized to ease the massive amount of pathologist’s work and help the pathologists make clinical decisions quickly. Several previous methods were introduced to solve automated mitotic cell count problems. However, they failed to differentiate between mitotic and nonmitotic cells and come up with an imbalance problem, which affects the performance. This paper proposes a Representation Differential Learning Method (RDLM) for mitosis detection through deep learning to detect the accurate mitotic cell area on pathological images. Our proposed method has been divided into two parts: Global bank Feature Pyramid Network (GLB-FPN) and focal loss (FL). The GLB feature fusion method with FPN essentially makes the encoder-decoder pay attention, to further extract the region of interest (ROIs) for mitotic cells. On this basis, we extend the GLB-FPN with a focal loss to mitigate the data imbalance problem during the training stage. Extensive experiments have shown that RDLM significantly outperforms on visualization view and achieves the best performance in quantitative matrices than other proposed approaches on the MITOS-ATYPIA-14 contest dataset. Our framework reaches a 0.692 F1-score. Additionally, RDLM achieves 5% improvements than GLB with FPN in F1-score on the mitosis detection task.
Antioxidant and Anti‐Inflammatory Effects of Crocin Ameliorate Doxorubicin‐Induced Nephrotoxicity in Rats
Authors: Hussain Mona A. , Abogresha Noha M. , AbdelKader Ghada , Hassan Ranya , Abdelaziz Eman Z. , Greish Sahar M.
Published: February 2021

Doxorubicin is a drug that belongs to the anthracycline antibiotics. Nephrotoxicity is one of the serious side effects of doxorubicin treatment. Crocin, which is one of the most bioactive components of saffron, has antioxidant, anti‐inflammatory, and antitumor effects. The current study was aimed at investigating the possible protective effects of crocin against doxorubicin‐induced nephrotoxicity to elucidate the underlying mechanism of this effect. The study included four groups, six rats in each group: normal control, crocin control, doxorubicin, and crocin/doxorubicin. Doxorubicin and crocin/doxorubicin groups received intraperitoneal injections of doxorubicin (3.5 mg/kg twice weekly for 3 weeks). Rats in the crocin control group and the crocin/doxorubicin group were treated with intraperitoneal injections of crocin (100 mg/kg body weight per day) for 3 weeks. Biomarkers of kidney function and oxidative stress as well as the abundance of mRNA for nuclear factor‐κβ and inducible nitric oxide synthase were evaluated. In addition, the abundance of cyclooxygenase 2 and tumor necrosis factor α immunoreactivity was evaluated. Crocin treatment had renoprotective effects manifested by significant improvement in kidney function as well as a reduction in the abundance of biomarkers of oxidative stress markers and inflammatory mediators. In conclusion, crocin has a protective effect against doxorubicin‐induced nephrotoxicity in rats by serving as an antioxidant and attenuating the expression of NF‐κB, iNOS, COX2, and TNFα.
Hypoxia-Induced Autophagy Enhances Cisplatin Resistance in Human Bladder Cancer Cells by Targeting Hypoxia-Inducible Factor-1α
Authors: Mao Xiawa , Nanzhang  , Xiao Jiaquao , Wu Huifeng , Ding Kefeng
Published: February 2021

Purpose. To investigate the effect of hypoxia on chemoresistance and the underlying mechanism in bladder cancer cells. Methods. BIU-87 bladder cancer cell line was treated with cisplatin under hypoxic and normoxic conditions and tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting. All the data were expressed as

mean
±
standard
 
error

from three independent experiments and analyzed by multiple

t

-tests. Results. Apoptosis of bladder cancer cells caused by cisplatin was attenuated in hypoxic conditions. Hypoxia enhanced autophagy caused by cisplatin. The autophagy inhibitor and HIF-1α inhibitor can reverse the chemoresistance in hypoxic condition. Apoptosis and autophagy of bladder cancer cells were downregulated by HIF-1α inhibitor YC-1. Hypoxia-induced autophagy enhanced chemoresistance to cisplatin via the HIF-1 signaling pathway. Conclusion. Resistance to cisplatin in BIU-87 bladder cancer cells under hypoxic conditions can be explained by activation of autophagy, which is regulated by HIF-1α-associated signaling pathways. The hypoxia–autophagy pathway may be a target for improving the efficacy of cisplatin chemotherapy in bladder cancer.
Bearing Fault Diagnosis Using Synthetic Quantitative Index-Based Adaptive Underdamped Stochastic Resonance
Authors: Li Baochen , Tong Rui , Kang Jianshe , Chi Kuo
Published: February 2021

Stochastic resonance is like a nonlinear filter to detect the weak bearing fault-induced impulses that submerged in strong noises. Signal-to-noise ratio (SNR) is often used as the index to evaluate the SR output, but the fault characteristic frequency (FCF) must be known in order to calculate SNR. A novel bearing fault diagnosis method called synthetic quantitative index-based adaptive underdamped stochastic resonance (SQI-AUSR) is proposed. The synthetic quantitative index (SQI) is composed of power spectrum kurtosis, kurtosis, margin index, and correlation coefficient. The SQI is independent of FCF, which avoids the limitation that the calculation of SNR must know the FCF. Numeric simulations and two case studies of bearing faults are carried out. The results show that (1) the SQI is more effective than other proposed indexes such as correlation coefficient and weight power spectrum kurtosis and (2) the proposed SQI-AUSR is effective for bearing fault diagnosis and is better than SNR-AOSR.
Human Intestinal Parasitic Infections: Prevalence and Associated Risk Factors among Elementary School Children in Merawi Town, Northwest Ethiopia
Authors: Damtie Destaw , Sitotaw Baye , Menkir Sissay , Kerisew Bizuayehu , Hussien Kedir
Published: February 2021

Background. Intestinal parasitic infection is still common in Ethiopia. Periodic evaluation of the current status of human intestinal parasitic infections (HIPIs) is a prerequisite to controlling these health threats. This study is aimed at assessing the prevalence and determinant factors of HIPIs among elementary school-age children in Merawi town. Methods. A school-based cross-sectional study design was used among 403 children. The direct wet mount method was used to diagnose the stool samples. The sociodemographic and behavioral characteristics of the respondents were collected using structured questionnaires. The data were analyzed using the chi-square test and logistic regression. Results. Out of the 403 students, the overall prevalence of HIPIs was 173 (42.9%). The magnitudes of single and double infections were 39.7% and 3.2%, respectively. Seventy-two (17.9%) were positive for Entamoeba histolytica, 63 (15.4%) for Giardia lamblia, 28 (9.6%) for Ascaris lumbricoides, 22 (6.9%) for hookworm, and 1 (0.2%) for Schistosoma mansoni. The prevalence of intestinal parasites was high in the age group of 6–11 years compared to other age groups. The following were the risk factors associated with HIPIs: groups aging 6 to 11 (AOR=9.581; 95% CI: 0.531-17.498;P=0.008), aging 12 to 18 (AOR=3.047; 95% CI: 0.055-1.828;P=0.008), not washing of hands after defecation (AOR=3.683; 95% CI; 1.577-8.598;P=0.003), not regularly washing of hands after defecation (AOR=2.417; 95% CI; 1.224-4.774;P=0.003), dirty fingernails (AOR=2.639; 95% CI: 1.388-5.020;P=0.003), not wearing shoes (AOR=2.779; 95% CI: 1.267-6.096;P=0.011), rural residence (AOR=6.6; 95% CI; 0.06-0.351;P<0.0001), and a family size greater than or equal to five (AOR=2.160; 95% CI: 1.179-3.956;P=0.013). Conclusion. The prevalence of HIPIs among elementary school children in Merawi town was very high. Thus, there is a need for intensive health education for behavioral changes related to personal hygiene and mass treatment for effective control of HIPIs in the study area.
Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Branching
Authors: Yu Rosemary , Longo Joseph , van Leeuwen Jenna E. , Zhang Cunjie , Branchard Emily , Elbaz Mohamad , Cescon David W. , Drake Richard R. , Dennis James W. , Penn Linda Z.
Published: February 2021

Aberrant N-glycan Golgi remodeling and metabolism are associated with epithelial–mesenchymal transition (EMT) and metastasis in patients with breast cancer. Despite this association, the N-glycosylation pathway has not been successfully targeted in cancer. Here, we show that inhibition of the mevalonate pathway with fluvastatin, a clinically approved drug, reduces both N-glycosylation and N-glycan-branching, essential components of the EMT program and tumor metastasis. This indicates novel cross-talk between N-glycosylation at the endoplasmic reticulum (ER) and N-glycan remodeling at the Golgi. Consistent with this cooperative model between the two spatially separated levels of protein N-glycosylation, fluvastatin-induced tumor cell death was enhanced by loss of Golgi-associated N-acetylglucosaminyltransferases MGAT1 or MGAT5. In a mouse model of postsurgical metastatic breast cancer, adjuvant fluvastatin treatment reduced metastatic burden and improved overall survival. Collectively, these data support the immediate repurposing of fluvastatin as an adjuvant therapeutic to combat metastatic recurrence in breast cancer by targeting protein N-glycosylation at both the ER and Golgi.

Significance:

These findings show that metastatic breast cancer cells depend on the fluvastatin-sensitive mevalonate pathway to support protein N-glycosylation, warranting immediate clinical testing of fluvastatin as an adjuvant therapy for breast cancer.
Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells
Authors: Assi Mohamad , Achouri Younes , Loriot Axelle , Dauguet Nicolas , Dahou Hajar , Baldan Jonathan , Libert Maxime , Fain Jean S. , Guerra Carmen , Bouwens Luc , Barbacid Mariano , Lemaigre Frédéric P. , Jacquemin Patrick
Published: February 2021

Pancreatic acinar cells are a cell type of origin for pancreatic cancer that become progressively less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth. This sensitivity is increased when Kras mutations are combined with pancreatitis. Molecular mechanisms underlying these observations are still largely unknown. To identify these mechanisms, we generated the first CRISPR-edited mouse models that enable detection of wild-type and mutant KRAS proteins in vivo. Analysis of these mouse models revealed that more than 75% of adult acinar cells are devoid of detectable KRAS protein. In the 25% of acinar cells expressing KRAS protein, transcriptomic analysis highlighted a slight upregulation of the RAS and MAPK pathways. However, at the protein level, only marginal pancreatic expression of essential KRAS effectors, including C-RAF, was observed. The expression of KRAS and its effectors gradually decreased after birth. The low sensitivity of adult acinar cells to Kras mutations resulted from low expression of KRAS and its effectors and the subsequent lack of activation of RAS/MAPK pathways. Pancreatitis triggered expression of KRAS and its effectors as well as subsequent activation of downstream signaling; this induction required the activity of EGFR. Finally, expression of C-RAF in adult pancreas was required for pancreatic tumorigenesis. In conclusion, our study reveals that control of the expression of KRAS and its effectors regulates the sensitivity of acinar cells to transformation by oncogenic Kras mutations.

Significance:

This study generates new mouse models to study regulation of KRAS during pancreatic tumorigenesis and highlights a novel mechanism through which pancreatitis sensitizes acinar cells to Kras mutations.
HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness
Authors: Bi Lei , Ren Yidan , Feng Maoxiao , Meng Peng , Wang Qin , Chen Weiping , Jiao Qinlian , Wang Yuli , Du Lutao , Zhou Fuqiong , Jiang Yucui , Chen Feiyan , Wang Chuanxin , Tang Bo , Wang Yunshan
Published: February 2021

Hepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC.

Significance:

This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.
Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment
Authors: Nguyen Tan-Trieu , Ramsay LeeAnn , Ahanfeshar-Adams Mozhdeh , Lajoie Mathieu , Schadendorf Dirk , Alain Tommy , Watson Ian R.
Published: February 2021

Purpose:

Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.

Experimental Design:

Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNA interference (RNAi) and pharmacologic inhibition and in Jak2 knockout (KO) B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas.

Results:

The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), respectively, compared with the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility.

Conclusions:

We provide mechanistic support for the use of OVs as a precision medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor–OV combination therapy for treatment-naïve melanomas without IFN signaling defects.

See related commentary by Kaufman, p. 3278
A Clinically Applicable 24-Protein Model for Classifying Risk Subgroups in Pancreatic Ductal Adenocarcinomas using Multiple Reaction Monitoring-Mass Spectrometry
Authors: Son Minsoo , Kim Hongbeom , Han Dohyun , Kim Yoseop , Huh Iksoo , Han Youngmin , Hong Seung-Mo , Kwon Wooil , Kim Haeryoung , Jang Jin-Young , Kim Youngsoo
Published: February 2021

Purpose:

Pancreatic ductal adenocarcinoma (PDAC) subtypes have been identified using various methodologies. However, it is a challenge to develop classification system applicable to routine clinical evaluation. We aimed to identify risk subgroups based on molecular features and develop a classification model that was more suited for clinical applications.

Experimental Design:

We collected whole dissected specimens from 225 patients who underwent surgery at Seoul National University Hospital [Seoul, Republic of Korea (South)], between October 2009 and February 2018. Target proteins with potential relevance to tumor progression or prognosis were quantified with robust quality controls. We used hierarchical clustering analysis to identify risk subgroups. A random forest classification model was developed to predict the identified risk subgroups, and the model was validated using transcriptomic datasets from external cohorts (N = 700), with survival analysis.

Results:

We identified 24 protein features that could classify the four risk subgroups associated with patient outcomes: stable, exocrine-like; activated, and extracellular matrix (ECM) remodeling. The “stable” risk subgroup was characterized by proteins that were associated with differentiation and tumor suppressors. “Exocrine-like” tumors highly expressed pancreatic enzymes. Two high-risk subgroups, “activated” and “ECM remodeling,” were enriched in terms such as cell cycle, angiogenesis, immunocompetence, tumor invasion metastasis, and metabolic reprogramming. The classification model that included these features made prognoses with relative accuracy and precision in multiple cohorts.

Conclusions:

We proposed PDAC risk subgroups and developed a classification model that may potentially be useful for routine clinical implementations, at the individual level. This clinical system may improve the accuracy of risk prediction and treatment guidelines.

See related commentary by Thakur and Singh, p. 3272
A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors
Authors: Shaikh Fyza Y. , White James R. , Gills Joell J. , Hakozaki Taiki , Richard Corentin , Routy Bertrand , Okuma Yusuke , Usyk Mykhaylo , Pandey Abhishek , Weber Jeffrey S. , Ahn Jiyoung , Lipson Evan J. , Naidoo Jarushka , Pardoll Drew M. , Sears Cynthia L.
Published: February 2021

Purpose:

While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.

Experimental Design:

We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach.

Results:

Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105).

Conclusions:

Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.
AraC-FdUMP[10] Is a Next-Generation Fluoropyrimidine with Potent Antitumor Activity in PDAC and Synergy with PARG Inhibition
Authors: Haber Alex O. , Jain Aditi , Mani Chinnadurai , Nevler Avinoam , Agostini Lebaron C. , Golan Talia , Palle Komaraiah , Yeo Charles J. , Gmeiner William H. , Brody Jonathan R.
Published: February 2021

AraC-FdUMP[10] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC50s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CF10 closer to a clinical trial for the treatment of PDAC.

Implications:

CF10 is a promising polymeric fluoropyrimidine with dual mechanisms of action (i.e., TS and Top1 inhibition) for the treatment of PDAC and synergizes with targeting of DNA repair.
Sudden Bilateral Deafness in a Patient with Transient Ischemic Attack: A Case Report
Authors: Pihl Caroline Ellinore , Back Christina Fredsby , Iversen Helle Klingenberg , Amin Faisal Mohammad
Published: February 2021

Sudden-onset bilateral cortical deafness is a very rare symptom of stroke, but must be recognized as stroke, as it is a treatable condition, and the treatment is highly time dependent. We report a 53-year-old man with an acute onset of complete bilateral hearing loss that gradually improved spontaneously over 4 h. The hearing loss was explained by an infarction visualized on magnetic resonance imaging, which showed a subacute temporoparietal ischemic lesion in the left cerebral hemisphere involving the insular cortex and an older infarction in the right temporoparietal region. The location of these kinds of lesions may typically not cause motor deficits, but sensory and cognitive (e.g., aphasia) symptoms, which can be challenging to recognize in a suddenly deaf patient. Taking the possible differential diagnoses into account, immediate stroke workup should always be prioritized in patients with sudden bilateral deafness, as acute revascularizing treatment is possible.
Practical Application of Patient-Reported Health Status Measures for Transcatheter Valve Therapies
Authors: Hejjaji Vittal , Cohen David J. , Carroll John D. , Li Zhuokai , Manandhar Pratik , Vemulapalli Sreekanth , Nelson Adam J. , Malik Ali O. , Mack Michael J. , Spertus John A. , Arnold Suzanne V.
Published: February 2021

Background:

Health status assessment is essential for documenting the benefit of transcatheter aortic valve replacement (TAVR) or transcatheter mitral valve repair on patients’ symptoms, function, and quality of life. Health status can also be a powerful marker for subsequent clinical outcomes, but its prognostic importance around the time of both TAVR and transcatheter mitral valve repair has not been fully defined.

Methods:

Among 73 699 patients who underwent transfemoral TAVR or transcatheter mitral valve repair between 2011 and 2018 (mean age, 81.9±7.0 years, 53% men, 92% TAVR), we constructed sequential models examining the association of health status (as assessed with the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score; KCCQ-OS) at baseline, 30 days, change from baseline to 30 days, and combinations of these assessments with death and heart failure (HF) hospitalization from 30 days to 1 year.

Results:

Although higher baseline KCCQ-OS and 30-day KCCQ-OS scores were each associated with lower risk of death and HF hospitalization (in individual models and in a model including both measures), the 30-day KCCQ-OS was most predictive (death: hazard ratio, 0.89 per 5-point increase [95% CI, 0.89–0.90]; HF hospitalization: hazard ratio, 0.91 [95% CI, 0.90–0.91]). The 30-day KCCQ-OS also was most predictive when included in a separate model with change in KCCQ from baseline to 30 days. Similar findings were noted for the outcomes of death and of HF hospitalization, unadjusted and adjusted for patient factors. All interaction terms between procedure type and KCCQ were not significant, suggesting that health status provided similar prognostic information in both procedures.

Conclusions:

The patient’s assessment of their health status immediately before and 30 days after TAVR and transcatheter mitral valve repair is associated with subsequent risk of death and HF hospitalization, with the 30-day assessment being most strongly associated with outcomes. Our findings support the routine use of KCCQ data as a prognostic tool.
Does Intravenous Thrombolysis Within 4.5 to 9 Hours Increase Clot Migration Leading to Endovascular Inaccessibility?
Authors: Lim Jeremy C. , Churilov Leonid , Bivard Andrew , Ma Henry , Dowling Richard J. , Campbell Bruce C.V. , Parsons Mark W. , Davis Stephen M. , Donnan Geoffrey A. , Mitchell Peter J. , Yan Bernard
Published: February 2021

Background and Purpose:

Distal clot migration is a recognized event following intravenous thrombolysis (IVT) in the setting of acute ischemic stroke. Of note, clots that were initially retrievable by endovascular thrombectomy may migrate to a distal nonretrievable location and compromise clinical outcome. We investigated the incidence of clot migration leading to clot inaccessibility following IVT in the time window of 4.5 to 9 hours.

Methods:

We performed a retrospective analysis of the EXTEND trial (Extending the Time for Thrombolysis in Emergency Neurological Deficits) data. Baseline and 12- to 24-hour follow-up clot location was determined on computed tomography angiogram or magnetic resonance angiogram. The incidence of clot migration leading to a change from retrievable to nonretrievable location was identified and compared between the two treatment groups (IVT versus placebo).

Results:

Two hundred twenty patients were assessed. Clot migration from a retrievable to nonretrievable location occurred in 37 patients: 21 patients (19.3%) in the placebo group and 16 patients (14.4%) in the IVT group. No significant difference was identified in the incidence of clot migration leading to inaccessibility between groups (
P
=0.336).

Conclusions:

Our results did not show increased clot migration leading to clot inaccessibility in patients treated with IVT.
Body Mass Index and Arterial Stiffness Are Associated With Greater Beat-to-Beat Blood Pressure Variability After Transient Ischemic Attack or Minor Stroke
Authors: Webb Alastair J.S. , Lawson Amy , Mazzucco Sara , Li Linxin , Rothwell Peter M. ,   for the Oxford Vascular Study Phenotyped Cohort
Published: February 2021

Background and Purpose:

Blood pressure variability (BPV) from beat to beat is associated with an increased risk of cardiovascular events and enables rapid assessment of BPV, but the underlying causes of elevated BPV are unclear.

Methods:

In consecutive patients within 4 to 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), continuous noninvasive blood pressure was measured beat to beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). After automated and manual data cleaning, associations between BPV (residual coefficient of variation), demographic factors, and arterial stiffness were determined for both systolic and diastolic blood pressure, by ANOVA and linear models. Relationships between demographic factors and arterial stiffness were determined by interaction terms and mediation.

Results:

Among 1013 patients, 54 (5.3%) were in AF, and 51 (5%) had low-quality recordings. In a general linear model including the remaining 908 participants, systolic BPV (SBPV) was most strongly associated with age (
P
=0.00003), body mass index (BMI;
P
=0.003), and arterial stiffness (
P
=0.008), with weaker independent associations with current smoking (
P
=0.01) and a low diastolic blood pressure (
P
=0.046). However, while there was a linear increase in SBPV with BMI in men, in women, SBPV was lowest for a BMI in the normal range but was greater below 20 or above 30 (ANOVA,
P
=0.012; BMI-sex interaction,
P
=0.03). Although BMI and pulse wave velocity were partially independent, increased pulse wave velocity mediated ≈32% of the relationship between increased BMI and SBPV (
P
<0.001).

Conclusions:

Vascular aging, manifest as arterial stiffness, was a strong determinant of increased SBPV and partially mediated the effect of increased BMI. However, although high BMI was independently associated with SBPV in both sexes, a low BMI was associated with increased SBPV only in women. SBPV may partially mediate the relationship between BMI and cardiovascular events, while obesity may provide a modifiable target to reduce SBPV and cardiovascular events.
Two-State Kinetic Model of Rates of Stroke Recurrence in the POINT Study Population
Authors: Brorson James R. , Bulwa Zachary B.
Published: February 2021

Background and Purpose:

Following an acute ischemic stroke or transient ischemic attack, 2 rates of stroke recurrence are suggested by data from trials of acute secondary prevention treatments: a transient rapid rate followed by a persisting slower rate of stroke.

Methods:

A kinetic model was constructed based on underlying vulnerable and stabilized states of patients following acute ischemic events related by fixed transition rates. Its predictions were fitted by nonlinear regression to the observed timing of outcome events in patients in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke).

Results:

The modeled survivor function produced a close fit to the observed data. The model's predicted kinetic rates suggest that, among subjects in the control group, the event rate was 100-fold higher in the vulnerable state than in the stabilized state. Active treatment halved this rapid rate and had little effect on event rates in the stabilized state. If at least one-tenth of the study population began in the vulnerable state, the rate of transition from the vulnerable to the stabilized state was still faster, with a half-life of only 1 to 2 days.

Conclusions:

Examination of kinetics of stroke occurrence, and of the rates associated with modeled state transitions, may provide insights into the underlying pathophysiological events that are targets for acute secondary prevention of stroke.
Efficient Content-Based Sparse Attention with Routing Transformers
Authors: Roy Aurko , Saffar Mohammad , Vaswani Ashish , Grangier David
Published: February 2021

Self-attention has recently been adopted for a wide range of sequence modeling problems. Despite its effectiveness, self-attention suffers from quadratic computation and memory requirements with respect to sequence length. Successful approaches to reduce this complexity focused on attending to local sliding windows or a small set of locations independent of content. Our work proposes to learn dynamic sparse attention patterns that avoid allocating computation and memory to attend to content unrelated to the query of interest. This work builds upon two lines of research: It combines the modeling flexibility of prior work on content-based sparse attention with the efficiency gains from approaches based on local, temporal sparse attention. Our model, the Routing Transformer, endows self-attention with a sparse routing module based on online k-means while reducing the overall complexity of attention to O( n1.5d) from O( n2d) for sequence length n and hidden dimension d. We show that our model outperforms comparable sparse attention models on language modeling on Wikitext-103 (15.8 vs 18.3 perplexity), as well as on image generation on ImageNet-64 (3.43 vs 3.44 bits/dim) while using fewer self-attention layers. Additionally, we set a new state-of-the-art on the newly released PG-19 data-set, obtaining a test perplexity of 33.2 with a 22 layer Routing Transformer model trained on sequences of length 8192. We open-source the code for Routing Transformer in Tensorflow.1