bluuebunny/crossref_metadata_2025 huggingface dataset:
Exhaustive endurance exercise activates brain glycogen breakdown and lactate production more than insulin-induced hypoglycemia
Authors: Matsui Takashi
Published: February 2021

Brain glycogen localized in astrocytes produces lactate via cAMP signaling, which regulates memory functions and endurance capacity. Exhaustive endurance exercise with hypoglycemia decreases brain glycogen, although the mechanism underlying this phenomenon remains unclear. Since insulin-induced hypoglycemia decreases brain glycogen, this study tested the hypothesis that hypoglycemia mediates exercise-induced brain glycogen decrease. To test the hypothesis, the effects of insulin- and exhaustive exercise-induced hypoglycemia on brain glycogen levels were compared using the microwave irradiation method in adult Wistar rats. The insulin challenge and exhaustive exercise induced similar levels of severe hypoglycemia. Glycogen in the hypothalamus and cerebellum decreased similarly with the insulin challenge and exhaustive exercise; however, glycogen in the cortex, hippocampus, and brainstem of the exercise group were lower compared with the insulin group. Brain lactate and cAMP levels in the hypothalamus and cerebellum increased similarly with the insulin challenge and exhaustive exercise, but those in the cortex, hippocampus, and brainstem of the exercise group were higher compared with the insulin group. Blood glucose correlated positively with brain glycogen, but the slope of regression lines was greater in the exercise group compared with the insulin group in the cortex, hippocampus, and brainstem, but not the hypothalamus and cerebellum. These findings support the hypothesis that hypoglycemia mediates the exercise-induced reduction in brain glycogen, at least in the hypothalamus and cerebellum. However, glycogen reduction during exhaustive endurance exercise in the cortex, hippocampus, and brainstem is not due to hypoglycemia alone, implicating the role of exercise-specific neuronal activity in brain glycogen decrease.
Combined mental task and metaboreflex impair cerebral oxygenation in patients with type 2 diabetes mellitus
Authors: Pinna Virginia , Doneddu Azzurrra , Roberto Silvana , Magnani Sara , Ghiani Giovanna , Mulliri Gabriele , Sanna Irene , Serra Stefano , Hosseini Kakhak Seyed Alireza , Milia Raffaele , Fadda Daniela , Lecis Romina , Guicciardi Marco , Crisafulli Antonio
Published: February 2021

Cardiovascular regulation is altered by type 2 diabetes mellitus (DM2), producing an abnormal response to muscle metaboreflex. During physical exercise, cerebral blood flow is impaired in patients with DM2, and this phenomenon may reduce cerebral oxygenation (COX). We hypothesized that the simultaneous execution of a mental task (MT) and metaboreflex activation would reduce COX in patients with DM2. Thirteen individuals suffering from DM2 (6 women) and 13 normal age-matched controls (CTL, 6 women) participated in this study. They underwent five different tests, each lasting 12 min: postexercise muscle ischemia (PEMI) to activate the metaboreflex, control exercise recovery (CER), PEMI + MT, CER + MT, and MT alone. COX was evaluated using near-infrared spectroscopy with sensors applied to the forehead. Central hemodynamics was assessed using impedance cardiography. We found that when MT was superimposed on the PEMI-induced metaboreflex, patients with DM2 could not increase COX to the same extent reached by the CTL group (101.13% ± 1.08% vs. 104.23% ± 2.51%, P < 0.05). Moreover, patients with DM2 had higher mean blood pressure and systemic vascular resistance as well as lower stroke volume and cardiac output levels compared with the CTL group, throughout our experiments. It was concluded that patients with DM2 had reduced capacity to enhance COX when undertaking an MT during metaboreflex. Results also confirm that patients with DM2 had dysregulated hemodynamics during metaboreflex, with exaggerated blood pressure response and vasoconstriction. This may have implications for these patients’ lack of inclination to exercise.
Sugar-sweetened soft drink consumption acutely decreases spontaneous baroreflex sensitivity and heart rate variability
Authors: Chapman Christopher L. , Reed Emma L. , Worley Morgan L. , Pietrafesa Leonard D. , Kueck Paul J. , Bloomfield Adam C. , Schlader Zachary J. , Johnson Blair D.
Published: February 2021

In healthy humans, fructose-sweetened water consumption increases blood pressure variability (BPV) and decreases spontaneous cardiovagal baroreflex sensitivity (cBRS) and heart rate variability (HRV). However, whether consuming commercially available soft drinks containing high levels of fructose elicits similar responses is unknown. We hypothesized that high-fructose corn syrup (HFCS)-sweetened soft drink consumption increases BPV and decreases cBRS and HRV to a greater extent compared with artificially sweetened (diet) and sucrose-sweetened (sucrose) soft drinks and water. Twelve subjects completed four randomized, double-blinded trials in which they drank 500 mL of water or commercially available soft drinks matched for taste and caffeine content. We continuously measured beat-to-beat blood pressure (photoplethysmography) and R-R interval (ECG) before and 30 min after drink consumption during supine rest for 5 min during spontaneous and paced breathing. BPV was evaluated using standard deviation (SD), average real variability (ARV), and successive variation (SV) methods for systolic and diastolic blood pressure. cBRS was assessed using the sequence method. HRV was evaluated using the root mean square of successive differences (RMSSD) in R-R interval. There were no differences between conditions in the magnitude of change from baseline in SD, ARV, and SV ( P ≥ 0.07). There were greater reductions in cBRS during spontaneous breathing in the HFCS (−3 ± 5 ms/mmHg) and sucrose (−3 ± 5 ms/mmHg) trials compared with the water trial (+1 ± 5 ms/mmHg, P < 0.03). During paced breathing, HFCS evoked greater reductions in RMSSD compared with water (−26 ± 34 vs. +2 ± 26 ms, P < 0.01). These findings suggest that sugar-sweetened soft drink consumption alters cBRS and HRV but not BPV.
Lack of evidence for impaired preload or Bezold-Jarisch activation during brief umbilical cord occlusions in fetal sheep
Authors: Lear Christopher A. , Bennet Laura , Lear Benjamin A. , Westgate Jenny A. , Gunn Alistair J.
Published: February 2021

Impaired cardiac preload secondary to umbilical cord occlusion (UCO) has been hypothesized to contribute to intrapartum decelerations, brief falls in fetal heart rate (FHR), through activation of the Bezold-Jarisch reflex. This cardioprotective reflex increases parasympathetic and inhibits sympathetic outflows triggering hypotension, bradycardia, and peripheral vasodilation, but its potential to contribute to intrapartum decelerations has never been systematically examined. In this study, we performed bilateral cervical vagotomy to remove the afferent arm and the efferent parasympathetic arm of the Bezold-Jarisch reflex. Twenty-two chronically instrumented fetal sheep at 0.85 of gestation received vagotomy ( n = 7) or sham vagotomy (control, n = 15), followed by three 1-min complete UCOs separated by 4-min reperfusion periods. UCOs in control fetuses were associated with a rapid fall in FHR and reduced femoral blood flow mediated by intense femoral vasoconstriction, leading to hypertension. Vagotomy abolished the rapid fall in FHR ( P < 0.001) and, despite reduced diastolic filling time, increased both carotid ( P < 0.001) and femoral ( P < 0.05) blood flow during UCOs, secondary to carotid vasodilation ( P < 0.01) and delayed femoral vasoconstriction ( P < 0.05). Finally, vagotomy was associated with an attenuated rise in cortical impedance during UCOs ( P < 0.05), consistent with improved cerebral substrate supply. In conclusion, increased carotid and femoral blood flows after vagotomy are consistent with increased left and right ventricular output, which is incompatible with the hypothesis that labor-like UCOs impair ventricular filling. Overall, the cardiovascular responses to vagotomy do not support the hypothesis that the Bezold-Jarisch reflex is activated by UCO. The Bezold-Jarisch reflex is therefore mechanistically unable to contribute to intrapartum decelerations.
Optimization of Ionic Soil Stabilizer Dilution and Understanding the Mechanism in Red Clay Treatment
Authors: Lu Xuesong , Luo Jin , Wan Meinan
Published: February 2021

Due to the insufficient understanding of the mechanism for soil strengthening by using Ionic Soil Stabilizer (ISS), the application of ISS in soil treatment is limited. In this paper, red clay samples were treated by using ISS and the effects were examined by the Atterberg test and uniaxial pressure test. In order to understand the mechanism, ISS dilution‐based seepage test and ξ‐potential test have been carried out. The results show that the ISS‐Water mixture of 1 : 200 was the most effective ratio to reduce the plasticity index. The measurements indicate the thickness of the pair‐electricity layer of adjacent clay layers and the repulsion force among soil particles is reduced, which in turn enhances the attraction force of the clay layers. This process strengthens the connection among the soil particles and thus increases the strength of the soil as detected by the experimental tests.
In Vivo Antitumor Effect against Murine Cells of CT26 Colon Cancer and EL4 Lymphoma by Autologous Whole Tumor Dead Cells
Authors: Barrera-Avalos Carlos , Díaz Ximena , Madrid Bastián , Michelson Sofía A. , Robles-Planells Claudia , Sánchez-Guerrero Giselle , Ahumada Viviana , Mella-Torres Andrea , Rojo Leonel E. , Imarai Mónica , Milla Luis A. , Leiva-Salcedo Elías , Murgas Paola , Fernández Ricardo , Escobar Alejandro , Acuña-Castillo Claudio
Published: February 2021

Active immunotherapy against cancer is based on immune system stimulation, triggering efficient and long‐lasting antigen‐specific immune responses. Immunization strategies using whole dead cells from tumor tissue, containing specific antigens inside, have become a promising approach, providing efficient lymphocyte activation through dendritic cells (DCs). In this work, we generate whole dead tumor cells from CT26, E.G7, and EL4 live tumor cells as antigen sources, which termed immunogenic cell bodies (ICBs), generated by a simple and cost‐efficient starvation‐protocol, in order to determine whether are capable of inducing a transversal anticancer response regardless of the tumor type, in a similar way to what we describe previously with B16 melanoma. We evaluated the anticancer effects of immunization with doses of ICBs in syngeneic murine tumor models. Our results showed that mice’s immunization with ICBs‐E.G7 and ICBs‐CT26 generate 18% and 25% of tumor‐free animals, respectively. On the other hand, all carrying tumor‐animals and immunized with ICBs, including ICBs‐EL4, showed a significant delay in their growth compared to not immunized animals. These effects relate to DCs maturation, cytokine production, increase in CD4+T‐bet+ and CD4+ROR‐γt+ population, and decrease of T regulatory lymphocytes in the spleen. Altogether, our data suggest that whole dead tumor cell‐based cancer immunotherapy generated by a simple starvation protocol is a promising way to develop complementary, innovative, and affordable antitumor therapies in a broad spectrum of tumors.
Influence of PPA on the Short‐Term Antiaging Performance of Asphalt
Authors: Gao Lining , Cai Nana , Fu Xiaohong , He Rui , Zhang Honggang , Zhou Jiayin , Kuang Dongliang , Liu Shaowen
Published: February 2021

It has been confirmed that polyphosphoric acid (PPA) can significantly improve the high‐temperature resistance, storage stability, and aging resistance of asphalt. The low price of PPA is conducive to the development of modified asphalt with high performance and excellent economy, suggesting its great application prospects. At present, there is little research on the role of PPA in delaying the aging process of PPA‐modified asphalt, and a consensus has not yet been reached. Therefore, PPA‐modified asphalt with different blending amounts (0 wt%, 0.4 wt%, 0.8 wt%, and 1.2 wt%) was prepared in this study. On the basis of variable performance, the role of PPA in the short‐term antiaging process of asphalt is analyzed through Fourier transform infrared spectroscopy (FTIR) analysis of PPA‐modified asphalt before and after aging, combined with the analysis of the change in components. The results showed that after PPA addition, the high‐temperature resistance and the thermal stability of asphalt were improved and the temperature sensitivity was weakened. Both curves of ductility and G∗ indicate the potential saturation effect of PPA addition; together with infrared spectroscopy, we proved that there are both chemical reactions and physical mixing in the PPA‐modified asphalt. The component fractions show that PPA will cause the asphalt to transform from sol to gel and the main function of PPA in retarding asphalt aging is the dispersion of the agglomerates of asphaltene micelles by PPA.
Effect of Methylene Blue on White Matter Injury after Ischemic Stroke
Authors: Cheng Quancheng , Chen Xuhao , Ma Jiayi , Jiang Xingyuan , Chen Jiahui , Zhang Mengqin , Wu Yejun , Zhang Weiguang , Chen Chunhua
Published: February 2021

Methylene blue, the FDA‐grandfathered drug was proved to be neuroprotective in ischemic stroke in rat. However, the mechanism of the protective effect was unknown. In this study, we used different animal models to investigate the effect of MB administration given within and beyond the therapeutic time window on behavioral deficits and infarct volume and related mechanism about the white matter protection. Middle cerebral artery occlusion and reperfusion (MCAO) and photothrombotic middle cerebral artery occlusion (PT‐MCAO) models were used. Behavioral deficits and infarct volume were measured by foot fault test, Garcia neurological score, and TTC staining. Black gold staining and western blot were used to evaluate the brain white matter injury. We found that intraperitoneal administration of MB immediately or 24 h after the MCAO or PT‐MCAO surgery reduced infarct volume, improved the neurological deficits, and reduced the white matter injury via myelin basic protein (BMP) protection. These findings suggested that MB relieved the white matter injury besides neuronal protection and has potential therapeutic effects on ischemic stroke.
Moxibustion Improves Chronic Heart Failure by Inhibiting Autophagy and Inflammation via Upregulation of mTOR Expression
Authors: Li Qingling , Wang Wei , Ma Qiang , Xia Ran , Gao Bing , Zhu Guoqi , Wang Jing
Published: February 2021

How moxibustion improves chronic heart failure is extremely complex and still unclear. This study aimed to explore whether moxibustion inhibits autophagy and reduces inflammation by regulating mTOR expression to induce myocardial protective effects and alleviate symptoms associated with chronic heart failure. Echocardiography was used to detect cardiac function and cardiac structure of rats, including heart rate (HR), left atrium diameter (LA), left ventricular diameter (LV), left ventricular posterior wall (LVPW), interventricular septum (IVS), ejection fraction (EF), and fractional shortening (FS). BNP and NT-pro BNP levels were measured by enzyme-linked immunosorbent assay (ELISA). Autophagy-associated protein (ATG) genes and mTOR were detected by PCR. The expression of mTOR and phosphorylated-mTOR was detected through western blotting of proteins from myocardial tissue samples. The left ventricular inflammatory response was detected by immunohistochemistry and included ICAM-1, VCAM-1, MMP-2, and MMP-9 expression. The relationship between autophagy and inflammation was analyzed by correlation analysis. The results from echocardiography and ELISA showed that moxibustion could significantly improve heart function and structure. Western blot and PCR results showed that moxibustion treatment elevated mTOR expression. Further, moxibustion could inhibit autophagy and regulate the expression of key autophagy-related genes, including Vps34, ATG3, ATG5, ATG7, ATG12, and ATG13. By contrast, rapamycin could partially reduce the effects of moxibustion. Immunohistochemistry results indicated that moxibustion could reduce myocardial inflammation. Moreover, there was a positive correlation between autophagy and inflammation. Moxibustion can protect cardiac function in rats with heart failure, possibly inhibiting excessive autophagy of cardiomyocytes and reducing inflammatory reactions through the elevation of mTOR expression.
Adaptive Sliding Mode Control for a Class of Manipulator Systems with Output Constraint
Authors: Li Guangshi
Published: February 2021

In this paper, an adaptive sliding mode control method based on neural networks is presented for a class of manipulator systems. The main characteristic of the discussed system is that the output variable is required to keep within a constraint set. In order to ensure that the system output meets the time‐varying constraint condition, the asymmetric barrier Lyapunov function is selected in the design process. According to Lyapunov stability theory, the stability of the closed‐loop system is analyzed. It is demonstrated that all signals in the resulted system are bounded, the tracking error converges to a small compact set, and the system output limits in its constrained set. Finally, the simulation example is used to show the effectiveness of the presented control strategy.
Mesenchymal Stem Cells: A New Choice for Nonsurgical Treatment of OA? Results from a Bayesian Network Meta‐Analysis
Authors: Cao Ziqin , Li Yajia , Gao Fuqiang , Wu Ren , Dou Pengcheng , Wang Wanchun , Li Qiangxiang
Published: February 2021

Objective. Osteoarthritis (OA) is the most common degenerative joint disease, causing joint pain, stiffness, and even disability. Guidelines recommend intra‐articular injections as an alternative treatment to relieve OA symptoms for patients who demonstrate poor tolerability or compliance to oral administration of drugs. Mesenchymal stem cells (MSCs) are a potential treatment for of OA. We conducted this network meta‐analysis to comprehensively compare the efficacy and safety between hyaluronic acid (HA), corticosteroids (GCs), platelet‐rich plasma (PRP), and MSCs. Design. Systematic review and Bayesian network meta‐analysis. Data Sources. Relevant studies, published from January 2000 to January 2020, in the PubMed, Cochrane library, EMBASE, and CKNI databases. Methods. Bayesian network and conventional meta‐analyses were conducted. Pain relief, functional improvement, improvement in joint stiffness, and risk of adverse effects (AEs) were assessed. Results. Twenty‐five articles with 4642 patients were included. Overall, MSC therapy was the most effective treatment for pain relief (standardized mean difference compared with placebo = 3.61, 95% CI [1.87 to 5.35]). Both MSC and PRP therapies improved every symptom of OA effectively and have an advantage over HA and GCs which are recommended by guidelines. MSCs, PRP, HA, and GCs are tolerated well for patients in long‐term treatment of OA compared with placebo. Conclusions. The results show that MSCs relieve pain, stiffness, and dysfunction due to OA better than PRP, HA, and GCs and are not statistically correlated with greater safety concerns. More high‐quality trials are needed to reconfirm the findings of this study, however, standardization of preparation of MSCs and PRP should be investigated in the future.
The Revolution of Breast Milk: The Multiple Role of Human Milk Banking between Evidence and Experience—A Narrative Review
Authors: Quitadamo Pasqua Anna , Palumbo Giuseppina , Cianti Liliana , Lurdo Paola , Gentile Maria Assunta , Villani Antonio
Published: February 2021

The review recalls the importance of breast milk and deepens the theme of human milk banking, a virtuous reality that is expanding all over the world but is still little known. In the last 15 years, modern biological technologies have crystallized the concept of uniqueness and irreproducibility of human milk, by establishing three new principles: first: human milk: a “life-saving” drug; second: human milk: the best food for preterm infants; and third: human milk: the main component of premature infant care. Our experience teaches us that human milk banking plays many roles that need to be known and shared.
Spontaneous Evisceration of Incisional Hernia with Strangulation of Small Bowel: A Life Threatening Complication
Authors: Thalahitiyage Nanduni , Ravindrakumar Sanjeevan , Nandasena Janaka , Krishnakumar Arooran , KirushanthanVeerasingam  , Jayarajah Umesh , Rodrigo V. S. D.
Published: February 2021

Spontaneous evisceration of abdominal viscera is a rare complication of incisional hernia which could pose a serious threat to life if intervention is delayed. We report a case of a 62-year-old female with a history of curative resection for stage 1 endometrial adenocarcinoma 3 years ago, presenting with spontaneous evisceration of incisional hernia with strangulation of small bowel. Immediate resuscitation followed by emergency surgery was mandatory. During surgery, priority should be given to release the strangulation as soon as possible and the type of repair would depend on the viability of the bowel and the anatomy of the incisional hernia.
Automatic Recommendation Algorithm for Video Background Music Based on Deep Learning
Authors: Kai Hong
Published: February 2021

As one of the traditional entertainment items, video background music has gradually changed from traditional consumption to network consumption, which naturally also has the problem of information overload. From the perspective of model design and auxiliary information, this paper proposes a tightly coupled fusion model based on deep learning and collaborative filtering to alleviate the problem of poor prediction accuracy due to sparse matrix in the scoring prediction problem. In the use of auxiliary information, this paper uses crawler technology to obtain auxiliary information on the user side and the video background music side and compensates for the model’s sensitivity to the sparsity of the score matrix from a data perspective. In terms of model design, this paper conducts auxiliary information mining based on the diversity and structural differences of auxiliary information, uses an improved stack autoencoder to learn user’s interests, and uses convolutional neural networks to mine hidden features of video background music. Based on the idea of probabilistic matrix decomposition, the tightly coupled fusion of multiple deep learning models and collaborative filtering is realized. By comprehensively considering user’s interest and video background music characteristics, the collaborative filtering process is supervised, and the optimized prediction result is finally obtained. The performance test and function test of the system were carried out, respectively, to verify the effectiveness of the hybrid recommendation algorithm and the effect of the system for recommendation. Through experimental analysis, it is proved that the algorithm designed in this paper can improve the recommendation quality and achieve the expected goal.
The Clinical Efficacy of Phytochemical Medicines Containing Tanshinol and Ligustrazine in the Treatment of Stable Angina: A Systematic Review and Meta-Analysis
Authors: Gao Li , Wu Tong , Wang Juan , Xiao Zhuoran , Jia Chunhua , Wang Wei
Published: February 2021

Background. Phytochemical medicines containing tanshinol and ligustrazine are commonly used in the treatment of stable angina in China, but their clinical effectiveness and risk have not been adequately assessed. In this paper, we conducted a systematic review and meta-analysis to evaluate the clinical efficacy. Methods. Relevant randomized controlled trials (RCTs) of phytochemical medicines containing tanshinol and ligustrazine in the treatment of stable angina were searched in electronic databases. The search date was up to March 31, 2020, and the languages of the RCTs were limited to English and Chinese. Results. A total of 28 studies, including 2518 patients, were included in the meta-analysis. It was shown that the adjunctive therapy of phytochemical medicines containing tanshinol and ligustrazine was better than the conventional therapies in the improvement of stable angina according to the clinical efficacy in symptoms (n = 2518, RR = 1.24, 95% CI: 1.20 to 1.29,

P
<
0.01

) and clinical efficacy in electrocardiography (n = 1766, RR = 1.29, 95% CI: 1.19 to 1.40,

P
<
0.01

). Conclusion. The meta-analysis supported the use of phytochemical medicines containing tanshinol and ligustrazine in the treatment of stable angina. However, quality of the evidence for this finding was low due to a high risk of bias in the included studies. Therefore, well-designed RCTs are still needed to further evaluate the efficacy.
Chromatin Regulation in Development: Current Understanding and Approaches
Authors: Zheng Zi Hao , Sam Tsz Wing , Zeng YingYing , Chu Justin Jang Hann , Loh Yuin-Han
Published: February 2021

The regulation of mammalian stem cell fate during differentiation is complex and can be delineated across many levels. At the chromatin level, the replacement of histone variants by chromatin-modifying proteins, enrichment of specific active and repressive histone modifications, long-range gene interactions, and topological changes all play crucial roles in the determination of cell fate. These processes control regulatory elements of critical transcriptional factors, thereby establishing the networks unique to different cell fates and initiate waves of distinctive transcription events. Due to the technical challenges posed by previous methods, it was difficult to decipher the mechanism of cell fate determination at early embryogenesis through chromatin regulation. Recently, single-cell approaches have revolutionised the field of developmental biology, allowing unprecedented insights into chromatin structure and interactions in early lineage segregation events during differentiation. Here, we review the recent technological advancements and how they have furthered our understanding of chromatin regulation during early differentiation events.
Strength Recovery Model of Clay during Thixotropy
Authors: Tang Bin , Zhou Biaohe , Xie Liang , Yin Jianfeng , Zhao Shengnan , Wang Zhibing
Published: February 2021

Thixotropy is a hot topic in the field of rheology of dispersed systems. Many researchers have proposed different models and hypotheses to explain the thixotropy of clay. In this paper, the strength recovery model of Zhanjiang Formation clay in the process of thixotropy is studied. Firstly, through unconfined compressive strength test, the influence of soil sensitivity, moisture content, and density on the strength growth of remolded soil was studied. The results show great influence of sensitivity, moisture content, and density on the thixotropic strength of the Zhanjiang Formation clay: the higher the sensitivity and the density, the stronger the thixotropy of soil; the higher the moisture content, the weaker the thixotropy of soil. Based on the test results, a strength recovery model of Zhanjiang Formation clay in the process of thixotropy was established. The model was verified by the validation test data and the data obtained from the existing literature. The results suggest that the model prediction is in good agreement with the verification test data and data from existing literature, which proves the confidence of the model in predicting the degree of strength recovery in the process of thixotropy of Zhanjiang Formation clay. The model provides basis for stability calculation of surrounding soil after construction disturbance of underground structures in this stratum.
Effects of Novel Anti-VEGF Agents with Intravitreal Conbercept in Diabetic Retinopathy: A Systematic Review and Meta-Analysis
Authors: Wang Hui , Zhou Jing , Sun Caoyu , Dong Xu
Published: February 2021

To evaluate the efficacy and safety of intravitreal conbercept (IVC) for diabetic retinopathy (DR) compared with intravitreal triamcinolone acetonide (IVTA). PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched from their earliest records to January 2020. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of conbercept in DR patients compared with ITVA. Outcomes included the mean changes from the baseline in best corrected visual acuity (BCVA) score, central macular thickness (CMT), quality of life (QoL) over time, and the incidence of adverse events (AEs). A total of 19 RCTs involving 1,811 eyes were included in this meta-analysis. IVC might improve BCVA (WMD = 0.10, 95% CI (0.07, 0.12),

P
<
0.001

) and reduce CMT (WMD = −102.5, 95% CI (−148.48, −56.53),

P
<
0.001

) compared to IVTA. The incidence of AEs in patients receiving IVC was significantly lower than those receiving IVTA (RR = 0.29, 95% CI (0.21, 0.40),

P
<
0.001

). Patients with IVC treatments acquired better self-care, mobility, social, and mental scores compared with IVTA (

P
<
0.001

). Current evidence shows that IVC has better effects and safety than IVTA in treating DR, and it can significantly enhance the QoL of patients with DR.
Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer
Authors: De Angelis Carmine , Fu Xiaoyong , Cataldo Maria Letizia , Nardone Agostina , Pereira Resel , Veeraraghavan Jamunarani , Nanda Sarmistha , Qin Lanfang , Sethunath Vidyalakshmi , Wang Tao , Hilsenbeck Susan G. , Benelli Matteo , Migliaccio Ilenia , Guarducci Cristina , Malorni Luca , Litchfield Lacey M. , Liu Jiangang , Donaldson Joshua , Selenica Pier , Brown David N. , Weigelt Britta , Reis-Filho Jorge S. , Park Ben H. , Hurvitz Sara A. , Slamon Dennis J. , Rimawi Mothaffar F. , Jansen Valerie M. , Jeselsohn Rinath , Osborne C. Kent , Schiff Rachel
Published: February 2021

Purpose:

Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor–positive (ER+)/HER2− breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.

Experimental Design:

Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation–resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.

Results:

Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an “IFN-related palbociclib-resistance Signature” (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2− tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.

Conclusions:

Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.
Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth
Authors: Cheng Jonathan D. , Valianou Matthildi , Canutescu Adrian A. , Jaffe Eileen K. , Lee Hyung-Ok , Wang Hao , Lai Jack H. , Bachovchin William W. , Weiner Louis M.
Published: February 2021

Tumor-associated fibroblasts are functionally and phenotypically distinct from normal fibroblasts that are not in the tumor microenvironment. Fibroblast activation protein is a 95 kDa cell surface glycoprotein expressed by tumor stromal fibroblasts, and has been shown to have dipeptidyl peptidase and collagenase activity. Site-directed mutagenesis at the catalytic site of fibroblast activation protein, Ser624 → Ala624, resulted in an ∼100,000-fold loss of fibroblast activation protein dipeptidyl peptidase (DPP) activity. HEK293 cells transfected with wild-type fibroblast activation protein, enzymatic mutant (S624A) fibroblast activation protein, or vector alone, were inoculated subcutaneously into immunodeficient mouse to assess the contribution of fibroblast activation protein enzymatic activity to tumor growth. Overexpression of wild-type fibroblast activation protein showed growth potentiation and enhanced tumorigenicity compared with both fibroblast activation protein S624A and vector-transfected HEK293 xenografts. HEK293 cells transfected with fibroblast activation protein S624A showed tumor growth rates and tumorigenicity potential similar only to vector-transfected HEK293. In vivo assessment of fibroblast activation protein DPP activity of these tumors showed enhanced enzymatic activity of wild-type fibroblast activation protein, with only baseline levels of fibroblast activation protein DPP activity in either fibroblast activation protein S624A or vector-only xenografts. These results indicate that the enzymatic activity of fibroblast activation protein is necessary for fibroblast activation protein–driven tumor growth in the HEK293 xenograft model system. This establishes the proof-of-principle that the enzymatic activity of fibroblast activation protein plays an important role in the promotion of tumor growth, and provides an attractive target for therapeutics designed to alter fibroblast activation protein–induced tumor growth by targeting its enzymatic activity.
Abstract IA03: Engineering artificial antigen presenting cells, aAPC, for cancer immunotherapy: From bench to bedside
Authors: Schneck Jonathan P.
Published: February 2021

Adoptive Cellular Therapies, ACT, are promising immunotherapeutic approaches for treatment of cancer that, clinically, have had significant successes and yet many challenges remain that prevent ACT approaches from becoming front line therapy. In this presentation we will discuss the challenges associated with current approaches and show how artificial Antigen Presenting Cells, aAPC-based approaches help overcome those challenges. Thus, aAPC based approaches represent an off-shelf, scalable approach to production of clinical scale and grade T cells for the adoptive immunotherapy of cancer.

Citation Format: Jonathan P. Schneck. Engineering artificial antigen presenting cells, aAPC, for cancer immunotherapy: From bench to bedside [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr IA03.
Abstract PO019: CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer
Authors: de Lara Paulino Tallón , Cuadrado Héctor Castañón , Vermeer Marijne , Núñez Nicolás , Silina Karina , Sobottka Bettina , Urdínez Joaquín , Cecconi Virginia , Attar Farkhondeh Movahedian , Hiltbrunner Stefanie , Glarner Isabelle , Moch Holger , Tugues Sònia , Becher Burkhard , van den Broek Maries
Published: February 2021

Some breast tumors metastasize aggressively whereas others remain in a state of metastatic dormancy for months or even years. The mechanism governing such metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping, we identified a discrete population of CD39+PD-1+CD8+ T cells present both in primary tumors and in dormant metastasis, which was hardly found in aggressively metastasizing tumors. Of note, the adoptive transfer of purified CD39+PD-1+CD8+ T cells prevented metastatic outgrowth. Stimulation of CD39+PD-1+CD8+ T cells with PD-1 blockade reduced the number of disseminated dormant cells. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not of total CD8+ T cells correlated with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Furthermore, density of CD39+PD-1+CD8+ T cells may serve as a novel biomarker and may serve as a potential immunotherapy target. Here, we discovered that a primary breast tumor primes a systemic, CD39+PD-1+CD8+ T cell response that is essential for metastatic dormancy in the lungs.

Citation Format: Paulino Tallón de Lara, Héctor Castañón Cuadrado, Marijne Vermeer, Nicolás Núñez, Karina Silina, Bettina Sobottka, Joaquín Urdínez, Virginia Cecconi, Farkhondeh Movahedian Attar, Stefanie Hiltbrunner, Isabelle Glarner, Holger Moch, Sònia Tugues, Burkhard Becher, Maries van den Broek. CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO019.
Abstract PO039: Cancer cells educate natural killer cells to a metastasis-promoting cell state
Authors: Chan Isaac S. , Knútsdóttir Hildur , Ramakrishnan Gayathri , Padmanaban Veena , Warrier Manisha , Ramirez Juan Carlos , Dunworth Matthew , Zhang Hao , Jaffee Elizabeth M. , Bader Joel S. , Ewald Andrew J.
Published: February 2021

Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14+ breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor–ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence.

Citation Format: Isaac S. Chan, Hildur Knútsdóttir, Gayathri Ramakrishnan, Veena Padmanaban, Manisha Warrier, Juan Carlos Ramirez, Matthew Dunworth, Hao Zhang, Elizabeth M. Jaffee, Joel S. Bader, Andrew J. Ewald. Cancer cells educate natural killer cells to a metastasis-promoting cell state [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO039.
Abstract PO043: Layer-by-layer nanoparticles for non-toxic delivery of interleukin 12 to disseminated syngeneic ovarian tumors
Authors: Smith Sean G. , Barberio Antonio E. , Pires Ivan S. , Melo Mariane , Irvine Darrell J. , Hammond Paula T.
Published: February 2021

Ovarian cancer presents a notable challenge for cancer immunotherapy with less than a 10% objective response rate to checkpoint inhibitors (CPI). One strategy to augment the impact of checkpoint therapy is to initiate the infiltration of leukocytes into the tumor prior to CPI using pro-inflammatory cytokines. One particularly potent and promising cytokine is interleukin-12 (IL-12) – the hallmark Th-1 cytokine known to drive an influx of antigen presenting cells, expansion of cytotoxic T-cells, and NK-cell activation in a variety of solid tumors. Unfortunately, IL-12 has been hampered clinically by toxicity issues when administered systemically – a necessity for disseminated tumors such as advanced ovarian cancer. We have previously shown that nanoparticles engineered for cytokine delivery target human ovarian tumors in mouse models and that delivery of IL-12 using those particles enables the non-toxic delivery of IL-12 when given intratumorally to syngeneic tumors. In this study we demonstrate that these particles given systemically continue to limit IL-12 toxicity, accumulate within syngeneic, orthotopic models of ovarian tumors, induce tumor regressions, and reshape the immune microenvironment within those tumors. IL-12 was loaded onto the surface of negatively charged liposomes using the Ni-His interaction. The layer-by-layer process was then used to add layers of poly-L-arginine and poly-L-glutamine producing a final diameter of 120 nm and zeta potential of -60 mV. These layered nanoparticles (LNPs) preferentially accumulated in intraperitoneal HM-1 ovarian tumor nodules when given intravenously and intraperitoneally with a 30% increase in concentration over unlayered nanoparticles (ULNPs) as measured via fluorescence. IL-12 accumulation measured using ELISA was shown to correlate with NP accumulation for LNPs but not ULNPs. LNPs were non-toxic (via weight loss) at doses deemed toxic with ULNPs or free IL-12. Intraperitoneal treatment with LNPs extended survival and caused tumor regression in 30% of mice at a dose deemed toxic for free IL-12 or ULNPs (10 µg IL-12 given once daily for 5 days). Flow cytometry revealed a marked increase in memory T-cells and a decrease in granulocytes. The LNPs also induced substantial upregulation of exhaustion markers in the infiltrating T-cells – especially the TIM3+TIGIT+PD1+ highly exhausted phenotype suggesting potential for future combination therapies.

Citation Format: Sean G. Smith, Antonio E. Barberio, Ivan S. Pires, Mariane Melo, Darrell J. Irvine, Paula T. Hammond. Layer-by-layer nanoparticles for non-toxic delivery of interleukin 12 to disseminated syngeneic ovarian tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO043.
Abstract PO091: Armed Myxoma virus demonstrates efficacy in syngeneic tumor models alone and in combination with immune checkpoint inhibitors
Authors: Franco Lina S. , Torres-Dominguez Lino E. , Mamola Joseph , de Matos Ana L. , Abrantes Mario , Walker Benjamin S. , Tacner Zachary , Kien Cassandra , Elliott Natalie M. , McFadden Grant , Sharp Leslie L.
Published: February 2021

Oncolytic Viruses (OV) selectively replicate in and lyse tumor cells and provide stimulation to the immune system. This represents a promising therapeutic option for cancer patients that do not respond well to treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Poxviridae family of double stranded DNA viruses. The natural host of MYXV is a subset of lagomorphs, but MYXV can infect cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenes making it an excellent oncolytic virus for introduction of immunomodulatory proteins. The current work describes the oncolytic activity, transgene production capability, in vivo activity and immunomodulatory mechanism of actions following intratumoral and intravenous administration of armed myxoma viruses in murine cancer models. Additional combination therapy with clinically relevant immune checkpoint inhibitors is demonstrated.

Citation Format: Lina S. Franco, Lino E. Torres-Dominguez, Joseph Mamola, Ana L. de Matos, Mario Abrantes, Benjamin S. Walker, Zachary Tacner, Cassandra Kien, Natalie M. Elliott, Grant McFadden, Leslie L. Sharp. Armed Myxoma virus demonstrates efficacy in syngeneic tumor models alone and in combination with immune checkpoint inhibitors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO091.
Abstract PR001: Cancer stem cells as origin of tumor associated immune cells
Authors: Hassan Ghmkin , Afify Said M. , Seno Akimasa , Seno Masaharu
Published: February 2021

Development of cancer stem cell (CSC) models from induced pluripotent stem cells (iPSCs) for different types of cancers will help to investigate the tumorigenesis and tumor microenvironment heterogeneity. In this context, our lab have developed a novel method to generate CSCs from iPSCs under cancer microenvironment using conditioned medium from different cancer cell lines. On the other hand, the ability of CSCs to exhibit different hematopoietic cells is still unclear. In our previous study, BT549 cell line conditioned media was used to obtain CSCs. CSCs (miPSCs-BT) converted from mouse iPSCs were tumorigenic and expressed stemmens and cancer stem cell markers. CSCs converted from miPSCs and injected into mice were used. CSCs isolated from malignant tumor were cultured in absence of Leukemia Inhibitory Factor(LIF) where undifferentiated cells were selected using puromycin. Non-adherent cells (NACs) arising from adherent CSCs collected and their viability, the morphology and the expression of hematopoietic cell markers were investigated. NACs were also injected into the tail vein of busulfan conditioned Balb/c nude mice. CSCs were also induced to differentiate into macrophages while using IL3 and SCF. The round nucleated NACs were viable, positive for hematopoietic lineage markers and had CD34 positive subpopulation as well as the ability of homing to the bone marrow. Moreover, after 4 weeks of injection, Wright-Giemsa staining showed that the number of white blood cells was higher in injected mice with NACs comparing to the control. CSCs also showed the ability to differentiate toward macrophages. In conclusion, CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs.

This abstract is also being presented as PO057.

Citation Format: Ghmkin Hassan, Said M. Afify, Akimasa Seno, Masaharu Seno. Cancer stem cells as origin of tumor associated immune cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PR001.