bluuebunny/crossref_metadata_2025 huggingface dataset:
Similar Repair Effects of Human Placenta, Bone Marrow Mesenchymal Stem Cells, and Their Exosomes for Damaged SVOG Ovarian Granulosa Cells
Authors: Chen Shuwen , Wang Yanbin , Liao Liming , Meng Li , Li Juanjuan , Shi Cheng , Han Hongjing , Zheng Xiaofeng , Shen Huan
Published: December 2020

Background. This study is aimed at investigating the repairing effect of mesenchymal stem cells and their exosomes from different sources on ovarian granulosa cells damaged by chemotherapy drugs—phosphoramide mustard (PM). Methods. In this study, we choose bone marrow mesenchymal stem cells (BMSCs) and human placental mesenchymal stem cells (HPMSCs) for research. Then, they were cocultured with human ovarian granulosa cells (SVOG) injured by phosphoramide mustard (PM), respectively. β-Galactosidase staining, flow cytometry, and Western blot were used to detect the changes in the senescence and apoptosis of SVOG cells before and after their coculture with the above two types of MSCs. Subsequently, exosomes from these two types of MSCs were extracted and added to the culture medium of SVOG cells after PM injury to test whether these two types of exosomes played a role similar to that of MSCs in repairing damaged SVOG cells. Results. PM treatment-induced apoptotic SVOG cells were significantly decreased after HPMSCs and BMSCs as compared with control group. After coculturing with these two types of MSCs, PM-treated SVOG cells showed significantly reduced senescence and apoptosis proportions as well as cleaved-Caspase 3 expression, and HPMSCs played a slightly stronger role than BMSCs in repairing SVOG cells in terms of the above three indicators. In addition, the ratios of senescent and apoptotic SVOG cells were also significantly reduced by the two types of exosomes, which played a role similar to that of MSCs in repairing cell damages. Conclusions. The results indicated that BMSCs, HPMSCs, and their exosomes all exerted a certain repair effect on SVOG cells damaged by PM, and consistent repair effect was observed between exosomes and MSCs. The repair effect of exosomes secreted from BMSCs and HPMSCs on the SVOG cells was studied for the first time, and the results fully demonstrated that exosomes are the key carriers for MSCs to play their role.
Application of the Lomb-Scargle Periodogram to InvestigateHeart Rate Variability during Haemodialysis
Authors: Stewart Jill , Stewart Paul , Walker Tom , Gullapudi Latha , Eldehni Mohamed T. , Selby Nicholas M. , Taal Maarten W.
Published: December 2020

Short-term cardiovascular compensatory responses to perturbations in the circulatory system caused by haemodialysis can be investigated by the spectral analysis of heart rate variability, thus providing an important variable for categorising individual patients’ response, leading to a more personalised treatment. This is typically accomplished by resampling the irregular heart rate to generate an equidistant time series prior to spectral analysis, but resampling can further distort the data series whose interpretation can already be compromised by the presence of artefacts. The Lomb–Scargle periodogram provides a more direct method of spectral analysis as this method is specifically designed for large, irregularly sampled, and noisy datasets such as those obtained in clinical settings. However, guidelines for preprocessing patient data have been established in combination with equidistant time-series methods and their validity when used in combination with the Lomb–Scargle approach is missing from literature. This paper examines the effect of common preprocessing methods on the Lomb–Scargle power spectral density estimate using both real and synthetic heart rate data and will show that many common techniques for identifying and editing suspect data points, particularly interpolation and replacement, will distort the resulting power spectrum potentially misleading clinical interpretations of the results. Other methods are proposed and evaluated for use with the Lomb–Scargle approach leading to the main finding that suspicious data points should be excluded rather than edited, and where required, denoising of the heart rate signal can be reliably accomplished by empirical mode decomposition. Some additional methods were found to be particularly helpful when used in conjunction with the Lomb–Scargle periodogram, such as the use of a false alarm probability metric to establish whether spectral estimates are valid and help automate the assessment of valid heart rate records, potentially leading to greater use of this powerful technique in a clinical setting.
Multisignal VGG19 Network with Transposed Convolution for Rotating Machinery Fault Diagnosis Based on Deep Transfer Learning
Authors: Zhou Jianye , Yang Xinyu , Zhang Lin , Shao Siyu , Bian Gangying
Published: December 2020

To realize high-precision and high-efficiency machine fault diagnosis, a novel deep learning framework that combines transfer learning and transposed convolution is proposed. Compared with existing methods, this method has faster training speed, fewer training samples per time, and higher accuracy. First, the raw data collected by multiple sensors are combined into a graph and normalized to facilitate model training. Next, the transposed convolution is utilized to expand the image resolution, and then the images are treated as the input of the transfer learning model for training and fine-tuning. The proposed method adopts 512 time series to conduct experiments on two main mechanical datasets of bearings and gears in the variable-speed gearbox, which verifies the effectiveness and versatility of the method. We have obtained advanced results on both datasets of the gearbox dataset. The dataset shows that the test accuracy is 99.99%, achieving a significant improvement from 98.07% to 99.99%.
Study on the Effect of Huanglian Jiedu Decoction on the Composition of Gut Microflora in SD Rats Based on 16S rRNA Sequencing
Authors: Du Haiyang , Zhang Gengxin , Yang Guangyong , Tian Weiyi , Wang Wenjia , Wang Ping , He Guangzhi
Published: December 2020

Objective. To study the effects of Huanglian Jiedu Decoction (HJD) on gut microflora of SD rats. Method. After 3 days of adaptive feeding, 36 rats were randomly divided into 4 groups, namely, the normal control group (NC, 10 mL/kg, distilled water), high_HJD dose group (H_HJD, 6.25 g/kg, weight ratio between crude drug and rat), medium_HJD dose group (M_HJD, 3.125 g/kg), and low_HJD dose group (L_HJD, 1.56 g/kg), and each group consisted of 9 mice. The HJD groups were then treated with orally administered HJD for 21 days, while the NC group was treated with distilled water. After 7 days, 14 days, and 21 days of the experiment and after 12 hours of fasting and water deprivation, 3 SD rats in each group were randomly sacrificed by cervical dislocation and sterile operation to collect stool faces. Sample DNA was extracted by Fecal total DNA extraction kit, sequenced using Illumina MiSeq platform, and analyzed. Results. The abundance of Romboutsia, Turicibacter, Lactobacillus, and Gemella decreased, while that of Escherichia_Shigella, Coprobacillus, Blautia, Akkermansia, Klebsiella, Rhodococcus, Parabacteroides, Citrobacter, Enterococcus, Bacteroides, and Erysipelotrichaceae_incertae_sedis increased after using H_HJD. The abundance of Gemella, Turicibacter, Romboutsia, and Lactobacillus decreased, while that of Blautia, Akkermansia, Escherichia_Shigella, Thiobacillus, Rothia, Enterococcus, Lactobacillus, and Erysipelotrichaceae-incertae-sedis increased after using M_HJD. The abundance of Romboutsia, Turicibacter, Lactobacillus, and Gemella decreased, while that of Escherichia_Shigella, Bacteroides, Akkermansia, Enterococcus, Rhodococcus, Parabacteroides, Desulfovibrio, Blautia, Fusobacterium, Rothia, and Streptococcus increased after using L_HJD. Conclusion. HJD can regulate gut microbiota, and its effect varies with different dosage and duration of medication.
Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology‐Based Strategy
Authors: Han Zijian , Song Luping , Qi Kele , Ding Yang , Wei Mingjun , Jia Yongcun
Published: December 2020

Background. Yisui Qinghuang powder (YSQHP) is an effective traditional Chinese medicinal formulation used for the treatment of myelodysplastic syndromes (MDS). However, its pharmacological mechanism of action is unclear. Materials and Methods. In this study, the active compounds of YSQHP were screened using the traditional Chinese medicine systems pharmacology (TCMSP) and HerDing databases, and the putative target genes of YSQHP were predicted using the STITCH and DrugBank databases. Then, we further screened the correlative biotargets of YSQHP and MDS. Finally, the compound‐target‐disease (C‐T‐D) network was conducted using Cytoscape, while GO and KEGG analyses were conducted using R software. Furthermore, DDI‐CPI, a web molecular docking analysis tool, was used to verify potential targets and pathways. Finally, binding site analysis was performed to identify core targets using MOE software. Results. Our results identified 19 active compounds and 273 putative target genes of YSQHP. The findings of the C‐T‐D network revealed that Rb1, CASP3, BCL2, and MAPK3 showed the most number of interactions, whereas indirubin, tryptanthrin, G‐Rg1, G‐Rb1, and G‐Rh2 showed the most number of potential targets. The GO analysis showed that 17 proteins were related with STPK activity, PUP ligase binding, and kinase regulator activity. The KEGG analysis showed that PI3K/AKT, apoptosis, and the p53 pathways were the main pathways involved. DDI‐CPI identified the top 25 proteins related with PI3K/AKT, apoptosis, and the p53 pathways. CASP8, GSK3B, PRKCA, and VEGFR2 were identified as the correlative biotargets of DDI‐CPI and PPI, and their binding sites were found to be indirubin, G‐Rh2, and G‐Rf. Conclusion. Taken together, our results revealed that YSQHP likely exerts its antitumor effects by binding to CASP8, GSK3B, PRKCA, and VEGFR2 and by regulating the apoptosis, p53, and PI3K/AKT pathways.
Health Risk Assessment and Determination of Some Heavy Metals in Commonly Consumed Traditional Herbal Preparations in Northeast Ethiopia
Authors: Meseret Mihreteab , Ketema Gebremariam , Kassahun Haile
Published: December 2020

Background. Most traditional medicines were prepared from plant origins. These plants could be contaminated by heavy metals, pesticides, and/or toxins. Therefore, the aim of the present study was to determine the level of heavy metals such as lead (Pb), cadmium (Cd), chromium (Cr), and copper (Cu) in frequently used traditional herbal preparations sold in Northeast Ethiopia and to estimate their health risks associated with their daily intake. Methods. A total of 6 traditional herbal preparations were randomly collected from local herbal shops of Dessie and Kombolcha town, Northeast Ethiopia. The samples were prepared for analysis by wet digestion method using nitric acid and hydrochloric acid treatment. The accuracy of the method was analyzed by the spike recovery test. Determination of Pb, Cd, Cr, and Cu by microwave plasma atomic emission spectroscopy was made in herbal preparations traditionally used in Dessie and Kombolcha town, Northeast Ethiopia. By calculating estimated daily intake (EDI), hazard quotients (HQ), and Hazard Index (HI) of metals, the health risk associated with the consumption of the analyzed herbal preparations was also evaluated. Results. The levels of heavy metals were in the range of 3.0–3.92 mg/kg for Pb, 5.35–10.7 mg/kg for Cr, and 0.815–12.3 mg/kg for Cu. However, cadmium was not detected in any of the traditional herbal preparations. This study revealed that the level of Pb and Cu in all analyzed samples was within the WHO maximum permissible limit of 10 mg/kg and 40 mg/kg, respectively. The level of Cr in all traditional herbal preparations was beyond the WHO maximum permissible limit (2 mg/kg). From the health point of view, the HQ value of Cr for KD-03 and KD-04 is greater than 1, suggesting potential health risk. Furthermore, the HI value had revealed that the consumption of KD-02, KD-03, and KD-04 samples had the potential of posing health risks to consumers over long-term consumption of herbal preparations. Conclusion. This study showed that most of the metal concentration levels in the herbal products were within the WHO maximum permissible limits. However, all samples had Cr levels above the WHO maximum permissible limit. Based on the results of this study, there would be a noncarcinogenic health risk to the consumer associated with the consumption of some herbal preparations marketed in Northeast Ethiopia.
Clinical Characteristics and Prognosis of Adult Orbital Cellulitis in a Tertiary General Hospital
Authors: Yao Bangtao , Ding Yuhua , Zhao Xiaogui , Wang Bei , Liu Gang , Wang Fei
Published: December 2020

Purpose. Adult orbital cellulitis (OC) occurs relatively rarely, and comprehensive studies that retrospectively evaluate OC are lacking. Here, we aimed to examine the clinical characteristics and prognosis of OC in a tertiary general hospital. Methods. Between October 2010 and May 2019, patients presenting with clinical symptoms of OC in a tertiary general hospital were analyzed in this retrospective study. Twenty-six cases were identified for a detailed review. In these cases, 16 males and 10 females were diagnosed with orbital cellulitis by clinical characteristics and multimodal examinations. We divided patients into three groups: (1) patients secondary to rhinosinusitis, (2) patients secondary to endogenous infection(s) without endophthalmitis, and (3) patients secondary to endophthalmitis. For each group, age, gender, eye type, combined systemic diseases, clinical presentation, leukocyte count, blood culture, diagnostic imaging, therapeutic methods, length of stay, time of postoperation, and patient prognosis were analyzed in detail. Results. There were no significant differences regarding age, gender, preoperative leukocyte count, exophthalmia, blood culture, treatment, or visual changes within the three groups (

P
<
0.05

). There were significant differences, however, in postoperative leukocyte count and ophthalmoplegia between the three groups (

P
<
0.05

). The preoperative and postoperative logarithms of the minimum resolution angle scored by the best-corrected visual acuity (LogMAR BCVA) of group 3 were statistically significant compared to group 1 and group 2 (

P
<
0.05

). Conclusion. We confirmed that the prognosis of OC patients combined with systemic diseases was poor. Patients with OC secondary to endophthalmitis infrequently experience ophthalmoplegia; however, these patients still have poor visual outcomes. Patients cultured positive for Klebsiella pneumoniae infection may not be associated with liver abscess. The level of leukocytes may indicate the condition of the disease.
Experimental Investigation into the Influences of Weathering on the Mechanical Properties of Sedimentary Rocks
Authors: Li Xiaoshuang , Li Yingchun , Wu Saisai
Published: December 2020

The time-dependent behaviors of the sedimentary rocks which refer to the altering of the mechanical and deformable properties of rock elements in the long-term period are of increasing importance in the investigation of the failure mechanism of the rock strata in underground coal mines. In order to obtain the accurate and reliable mechanical parameters of the sedimentary rocks at different weathering grades, the extensive experimental programs including the Brazilian splitting test, uniaxial compression tests, and direct shear tests have been carried out on the specimens that exposed to the nature environments at different durations. The correlation between the weathering grades and mechanical parameters including uniaxial tensile strength, uniaxial compression strength, elastic modulus, Poisson’s ratio, cohesion, and friction coefficient was proposed. The obtained results suggested that uniaxial tensile strength, uniaxial compressive strength, elastic modulus, and cohesion dramatically decreased with increasing weathering time, characterized as the negative exponential relationship in general. The influences of various weathering grades on fracture behavior of the rock specimens were discussed. The cumulative damage of the rock by the weathering time decreased the friction coefficient of the specimens which led to the initiation and propagation of microcrack within the rock at lower stress conditions. The obtained results improved the understanding of the roles of weathering on the mechanical properties of sedimentary rocks, which is helpful in the design of the underground geotechnical structures.
Power Management Controller for Microgrid Integration of Hybrid PV/Fuel Cell System Based on Artificial Deep Neural Network
Authors: Nureddin Abdulbaset Abdulhamed Mohamed , Rahebi Javad , Ab-BelKhair Adel
Published: December 2020

Nowadays, the power demand is increasing day by day due to the growth of the population and industries. The conventional power plant alone is incompetent to meet the consumer demand due to environmental concerns. In this present situation, the essential thing is to be find an alternate way to meet the consumer demand. In present days most of the developed countries concentrate to develop alternative resources and invest huge money for its research and development activities. Most renewable energy sources are naturally friendly sources such as wind, solar, fuel cell, and hydro/water sources. The results of power generation using renewable energy sources only depend on the availability of the resources. The availability of renewable energy sources throughout the day is variable due to fluctuations in the natural resources. This research work discusses two major renewable energy power generating sources: photovoltaic (PV) cell and fuel cell. Both of them provide foundations for power generation, so they are very popular because of their impressive performance mechanisms. The mentioned renewable energy-based power generating systems are static devices, so the power losses are generally ignorable as compared to line losses in the main grid. The PV and fuel cell (FC) power systems need a controller for maximum power generation during fluctuations in the input resources. Based on the investigation report, an algorithm is proposed for an advanced maximum power point tracking (MPPT) controller. This paper proposes a deep neural network- (DNN-) based MPPT algorithm, which has been simulated using MATLAB both for PV and for FC. The main purpose behind this paper has been to develop the latest DNN controller for improving the output power quality that is generated using a hybrid PV and fuel cell system. After developing and simulating the proposed system, we performed the analysis in different possible operating conditions. Finally, we evaluated the simulation outcomes based on IEEE 1547 and 519 standards to prove the system’s effectiveness.
Real-World Safety and Efficacy of Nivolumab in Advanced Squamous and Nonsquamous Non-Small-Cell Lung Cancer: A Retrospective Cohort Study in Croatia, Hungary, and Malta
Authors: Vrdoljak Eduard , Jakopović Marko , Geczi Lajos , Bogos Krisztina , Bošković Lidija , Magri Claude , Bitar Lela , Bajić Žarko , Samaržija Miroslav
Published: December 2020

Background. There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) especially in South East Europe, a region with particularly high incidence and an unfavorable mortality-to-incidence ratio for lung cancer. Objectives. To evaluate the real-world safety and efficacy of nivolumab in patients with previously treated advanced squamous and nonsquamous NSCLC in South East Europe. Methods. This is a multicenter, retrospective cohort study on patients with stage IIIB or IV disease with at least one previous systemic treatment who received nivolumab through an expanded-access program between 2015 and 2017 in Croatia, Malta, and Hungary. The primary endpoint was the proportion of patients whose therapy was discontinued because of toxicity. Secondary endpoints were the incidence of adverse events (AEs), objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results. We analyzed data on 239 patients with a median (IQR) age of 62 (57–68), and 33% of them were women. Treatment was discontinued because of toxicity in 11.6% (95% CI 7.8% to 16.5%) of patients. The PFS was 6.4 (95% CI 5.2 to 8.6) months, and the median OS was 14.1 (10.6 to 18.0) months. Conclusions. The safety and efficacy of nivolumab in previously treated patients with advanced NSCLC in the real-world South East Europe clinical settings were consistent with the results of randomized clinical trials and comparable to the results from other countries.
Gut Microbiome Components Predict Response to Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Prospective, Longitudinal Study
Authors: Yi Yuxi , Shen Lijun , Shi Wei , Xia Fan , Zhang Hui , Wang Yan , Zhang Jing , Wang Yaqi , Sun Xiaoyang , Zhang Zhiyuan , Zou Wei , Yang Wang , Zhang Lingyi , Zhu Ji , Goel Ajay , Ma Yanlei , Zhang Zhen
Published: December 2020

Purpose:

The gut microbiome is involved in antitumor immunotherapy and chemotherapy responses; however, evidence-based research on the role of gut microbiome in predicting response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) remains scarce. This prospective, longitudinal study aimed to evaluate the feasibility of the gut microbiome in predicting nCRT responses.

Experimental Design:

We collected 167 fecal samples from 84 patients with LARC before and after nCRT and 31 specimens from healthy individuals for 16S rRNA sequencing. Patients were divided into responders and nonresponders according to pathologic response to nCRT. After identifying microbial biomarkers related to nCRT responses, we constructed a random forest classifier for nCRT response prediction of a training cohort of baseline samples from 37 patients and validated the classifier in another cohort of 47 patients.

Results:

We observed significant microbiome alterations represented by a decrease in LARC-related pathogens and an increase in Lactobacillus and Streptococcus during nCRT. Furthermore, a prominent microbiota difference between responders and nonresponders was noticed in the baseline samples. Microbes related with butyrate production, including Roseburia, Dorea, and Anaerostipes, were overrepresented in responders, whereas Coriobacteriaceae and Fusobacterium were overrepresented in nonresponders. Ten biomarkers were selected for the response-prediction classifier, including Dorea, Anaerostipes, and Streptococcus, which yielded an area under the curve value of 93.57% [95% confidence interval (CI), 85.76%–100%] in the training cohort and 73.53% (95% CI, 58.96%–88.11%) in the validation cohort.

Conclusions:

The gut microbiome offers novel potential biomarkers for predicting nCRT responses, which has important manifestations in the clinical management of these patients.
Identification of Genes Required for Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells In Vitro
Authors: Kohrt Sarah E. , Awadallah Wisam N. , Phillips Robert A. , Case Thomas C. , Jin Renjie , Nanda Jagpreet S. , Yu Xiuping , Clark Peter E. , Yi Yajun , Matusik Robert J. , Anderson Philip D. , Grabowska Magdalena M.
Published: December 2020

Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes (TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11, and ACAT1) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (ACAT1, MAP3K11, and PSMD12) as supporters of enzalutamide resistance in vitro. Although ACAT1 expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of ACAT1 was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. MAP3K11 expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of MAP3K11 reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro.
Preclinical Characterization of Linrodostat Mesylate, a Novel, Potent, and Selective Oral Indoleamine 2,3-Dioxygenase 1 Inhibitor
Authors: Balog Aaron , Lin Tai-an , Maley Derrick , Gullo-Brown Johnni , Kandoussi Enzo Hamza , Zeng Jianing , Hunt John T.
Published: December 2020

Tumors can exploit the indoleamine 2,3-dioxygenase 1 (IDO1) pathway to create an immunosuppressive microenvironment. Activated IDO1 metabolizes tryptophan into immunosuppressive kynurenine, leading to suppressed effector T-cell (Teff) proliferation, allowing for tumor escape from host immune surveillance. IDO1 inhibition counteracts this immunosuppressive tumor microenvironment and may improve cancer outcomes, particularly when combined with other immunotherapies. Linrodostat mesylate (linrodostat) is a potent, selective oral IDO1 inhibitor that occupies the heme cofactor–binding site to prevent further IDO1 activation and is currently in multiple clinical trials for treatment of patients with advanced cancers. Here, we assess the in vitro potency, in vivo pharmacodynamic (PD) activity, and preclinical pharmacokinetics (PKs) of linrodostat. Linrodostat exhibited potent cellular activity, suppressing kynurenine production in HEK293 cells overexpressing human IDO1 and HeLa cells stimulated with IFNγ, with no activity against tryptophan 2,3-dioxygenase or murine indoleamine 2,3-dioxygenase 2 detected. Linrodostat restored T-cell proliferation in a mixed-lymphocyte reaction of T cells and allogeneic IDO1-expressing dendritic cells. In vivo, linrodostat reduced kynurenine levels in human tumor xenograft models, exhibiting significant PD activity. Linrodostat demonstrated a PK/PD relationship in the xenograft model, preclinical species, and samples from patients with advanced cancers, with high oral bioavailability in preclinical species and low to moderate systemic clearance. Our data demonstrate that linrodostat potently and specifically inhibits IDO1 to block an immunosuppressive mechanism that could be responsible for tumor escape from host immune surveillance with favorable PK/PD characteristics that support clinical development.
Predicting Tumor Killing and T-Cell Activation by T-Cell Bispecific Antibodies as a Function of Target Expression: CombiningIn VitroExperiments with Systems Modeling
Authors: Van De Vyver Arthur J. , Weinzierl Tina , Eigenmann Miro J. , Frances Nicolas , Herter Sylvia , Buser Regula B. , Somandin Jitka , Diggelmann Sarah , Limani Florian , Lehr Thorsten , Bacac Marina , Walz Antje-Christine
Published: December 2020

Targeted T-cell redirection is a promising field in cancer immunotherapy. T-cell bispecific antibodies (TCB) are novel antibody constructs capable of binding simultaneously to T cells and tumor cells, allowing cross-linking and the formation of immunologic synapses. This in turn results in T-cell activation, expansion, and tumor killing. TCB activity depends on system-related properties such as tumor target antigen expression as well as antibody properties such as binding affinities to target and T cells. Here, we developed a systems model integrating in vitro data to elucidate further the mechanism of action and to quantify the cytotoxic effects as the relationship between targeted antigen expression and corresponding TCB activity. In the proposed model, we capture relevant processes, linking immune synapse formation to T-cell activation, expansion, and tumor killing for TCBs in vitro to differentiate the effect between tumor cells expressing high or low levels of the tumor antigen. We used cibisatamab, a TCB binding to carcinoembryonic antigen (CEA), to target different tumor cell lines with high and low CEA expression in vitro. We developed a model to capture and predict our observations, as a learn-and-confirm cycle. Although full tumor killing and substantial T-cell activation was observed in high expressing tumor cells, the model correctly predicted partial tumor killing and minimal T-cell activation in low expressing tumor cells when exposed to cibisatamab. Furthermore, the model successfully predicted cytotoxicity across a wide range of tumor cell lines, spanning from very low to high CEA expression.
ABBV-085, Antibody–Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric Preclinical Testing Consortium
Authors: Hingorani Pooja , Roth Michael E. , Wang Yifei , Zhang Wendong , Gill Jonathan B. , Harrison Douglas J. , Teicher Beverly , Erickson Stephen , Gatto Gregory , Smith Malcolm A. , Kolb Edward A. , Gorlick Richard
Published: December 2020

Membrane protein leucine–rich repeat containing 15 (LRRC15) is known to be expressed in several solid tumors including osteosarcoma. ABBV-085, an antibody–drug conjugate against LRRC15, conjugated to monomethyl auristatin E (MMAE), was studied in osteosarcoma patient-derived xenografts (PDXs) by the Pediatric Preclinical Testing Consortium (PPTC). LRRC15 expression data were obtained from PPTC RNA-sequencing data for the PDX models. The TARGET database was mined for LRRC15 expression in human osteosarcoma. Protein expression was confirmed via IHC in three PDX models. Seven osteosarcoma PDX models (OS1, OS9, OS33, OS34, OS42, OS55, and OS60) with varying LRRC15 gene expression were studied. ABBV-085 was administered at 3 mg/kg (OS33), 6 mg/kg (all seven PDXs), and 12 mg/kg (OS60) weekly for 4 consecutive weeks via intraperitoneal injection. Control cohorts included vehicle and an isotype MMAE-linked antibody. Tumor volumes and responses were reported using PPTC statistical analysis. OS1, OS33, OS42, OS55, and OS60 had high LRRC15 expression while OS9 and OS34 had low LRRC15 expression. ABBV-085 inhibited tumor growth in six of seven PDX models as compared with vehicle control and significantly improved event-free survival in five of seven models as compared with isotype controls. Two models showed maintained complete responses while all others showed progressive disease. Response correlated with LRRC15 expression. ABBV-085’s antitumor activity against osteosarcoma PDX suggests LRRC15 may be a rational target for pursuing clinical trials in patients with this disease.
Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide
Authors: Huang Luping , Wang Denian , Feng Zhongxue , Zhao Huan , Xiao Fei , Wei Yong'gang , Zhang Heng , Li Hongyu , Kong Lingmiao , Li Min , Liu Fei , Zhang Haili , Zhang Wei
Published: December 2020

Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.
G9a Promotes Invasion and Metastasis of Non–Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway
Authors: Sun Ting , Zhang Keqiang , Pangeni Rajendra P. , Wu Jun , Li Wendong , Du Yong , Guo Yuming , Chaurasiya Shyambabu , Arvanitis Leonidas , Raz Dan J.
Published: December 2020

Potential roles of euchromatic histone methyltransferase 2 (EHMT2 or G9a) in invasion and metastasis are not well understood in non–small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while knockdown of G9a drastically suppressed in vivo growth and metastasis of A549 and H1299 NSCLC cells. Knockdown or inhibition of G9a significantly decreased the expression of focal adhesion kinase (FAK) protein and activation of FAK pathway. In addition, defactinib, a potent FAK inhibitor, partially abolished the G9a-enhanced invasion in these NSCLC cells. Furthermore, targeting G9a was found to suppress NF-κB transcriptional activity in NSCLC cells through stabilizing NF-κB inhibitor alpha (IκBα), while an NF-κB inhibitor Parthenilide partially abolished the G9a-enhanced FAK activation, which suggests that G9a-enhanced invasion and activation of FAK is mediated by elevated NF-κB activity. Notably, a strong positive correlation between the IHC staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408).

Implications:

The findings of this study strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.
Longitudinal Analysis of Fetal Ventricular Rate for Risk Stratification in Immune Congenital Heart Block
Authors: Shokrzadeh Ayla , Maltret Alice , Morel Nathalie , Costedoat-Chalumeau Nathalie , Driessen Marine , Raisky Olivier , Ville Yves , Bonnet Damien , Stirnemann Julien
Published: December 2020

Objectives: To assess the perinatal risks of immune complete congenital heart block (iCCHB) based on the longitudinal analysis of fetal heart rate. Methods: Retrospective analysis of a cohort of grade III congenital heart block diagnosed in utero, in the absence of associated cardiac defect, with positive maternal serum antibodies. Longitudinal measurements of the fetal heart rate were used to estimate the average slope of ventricular rate as a function of gestational age. We then defined the following prognostic stratification based on longitudinal follow-up observations: the high-rate (HR) group included cases for which all prenatal ventricular rate measurements were above the age-specific mean of our population of iCCHB and the low-rate (LR) group included those with at least one observation below the mean during follow-up. The 2 groups were compared to analyze the potential relationship between prenatal ventricular rate and adverse neonatal outcome defined by in utero or perinatal death, neonatal heart rate <50 bpm, or hemodynamic failure requiring emergency pacing. Results: Forty-four cases were studied. Overall, the average heart rate significantly decreased during gestation from 65 bpm at 20 weeks to 55 bpm at 38 weeks. The HR and LR groups included 18 (41%) and 26 (59%) cases, respectively. Adverse perinatal outcome occurred in 1/18 (6%) and 22/26 (85%) cases in the HR and LR groups, respectively (p < 0.001). In the HR group, 33% of cases remained nonpaced at >6 months. The positive predictive values and negative predictive values for adverse perinatal outcome in the LR group were 85% (22/26) and 94% (17/18), respectively (100 and 80% <30 weeks and 88 and 78% at ≥30 weeks). Conclusions: The prognostic classification we developed based on longitudinal heart rate assessment may be used in the late 2nd or early 3rd trimester to identify iCCHB cases at high risk of adverse perinatal outcome. This prognostic stratification should help refine counseling and perinatal management earlier in pregnancy instead of waiting for late gestation or predelivery assessment.
Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS
Authors: Belbasis Lazaros , Bellou Vanesa , Tzoulaki Ioanna , Evangelou Evangelos
Published: December 2020

Background: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce. Methods: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS. Results: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90–0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24–1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79–0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach. Conclusions: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.
MMP9 rs17576 Is Simultaneously Correlated with Symptomatic Intracranial Atherosclerotic Stenosis and White Matter Hyperintensities in Chinese Population
Authors: Feng Xianjing , Yu Fang , Zhou Xiaoqing , Liu Zeyu , Liao Di , Huang Qin , Li Xi , Jin Xin , Xia Jian
Published: December 2020

Purpose: The aim of this study was screening for single nucleotide polymorphisms (SNPs) associated with white matter hyperintensities (WMHs) in symptomatic intracranial atherosclerotic stenosis (sICAS) patients and exploring a possible connection in the genetic background between macrovascular disease and small vessel disease. Methods: There were 400 sICAS patients enrolled in the study. Fazekas scores were applied to WMH classification. Healthy controls were referred to 1,000 Genome Project and GeneSky company who provided 1,007 Chinese healthy controls. Fast target sequencing technology was used to select the SNPs of 102 genes related to the pathogenesis of sICAS in the sICAS patients. Results: The allele frequencies of 88 SNPs were significantly different between the sICAS group and the healthy controls (p < 0.05). The allele frequencies of 53 SNPs were significantly different between the sICAS patients with and without WMHs (p < 0.05). Further analysis found that matrix metalloproteinase 9 (MMP9) rs17576 was simultaneously related to sICAS and WMHs. The frequency of the rs17576 A allele was significantly lower in sICAS patients when compared to the normal controls (p = 0.03, OR [95% CI] = 0.75 [0.625–0.91]). Also, the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.009), dominant (p = 0.014), and recessive (p= 0.023) models. The frequency of the rs17576 A allele was significantly higher in sICAS with WMH patients, compared to those without WMHs (p = 0.022, OR [95% CI] = 1.54 [1.06–2.22]); the frequency of the rs17576 genotypes was significantly different under codominant (p = 0.019) and recessive (p = 0.032) models. Logistic regression analysis showed that age, hypertension, and MMP9 rs17576 AA genotype were independent risk factors for sICAS with WMHs. Conclusion: MMP9 rs17576 may be simultaneously associated with the risk of sICAS and WMHs.
Investigation of Allergic Sensitization Pattern in 4,203 Children in Northern China
Authors: Wang Wei , Zhang Xian-hui , Zhu Lei , Liu Yu-xiang
Published: December 2020

Objective: The objective of this study is to investigate the allergen sensitization pattern among 4,203 children in the Shanxi region of China and to provide guidance for diagnosis and prevention of allergic diseases. Methods: A retrospective analysis was conducted on the allergen-specific immunoglobulin E (sIgE) results of 4,203 children aged 0–12 years from January to December in 2019. SIgE antibodies to 19 allergens in the serum sample were detected by enzyme ALLERGO-SORBENT testing. Results: In total, 49.70% (2,089/4,203) of children with allergic diseases were positive for sIgE, and the top 5 allergens were egg white 18.63% (783/4,203), artemisia 14.47% (608/4,203), milk 13.04% (548/4,203), ragweed 8.66% (364/4,203), and poplar/willow/elm 8.52% (358/4,203). Significant differences in the positive rate of food allergens and aeroallergens in different ages were found (p < 0.05). 50.98% (1,065/2,089) patients were sensitive to 2 or more allergens. The high sensitization rate in the >3-year group was significantly higher than the ≤3-year group (p < 0.05). Conclusion: Egg white and artemisia are the most common allergens in children in northern China. This study provides allergic sensitization pattern of children and clinical epidemiological data in the region.
Excellent Response of Dermatophytoma and Nail Splitting to Nail Plate Debridement Plus Topical Ciclopirox Olamine 1% Solution
Authors: Abdo Hamed Mohamed
Published: December 2020

Onychomycosis often presents as thickened, discolored nails. Usually, one or both great toenails are affected. Eventually, the nail plate becomes friable and may split and break up, often due to trauma or invasion of the plate by dermatophytes that have keratolytic properties. Dermatophytoma is a unique feature of onychomycosis that occurred by abundant fungal filaments and spores forming a fungal ball under the nail plate. It is often refractory to traditional therapy. Based on the clinical and mycological examination, a case of onychomycosis in a 45-year-old woman presented as dermatophytoma with longitudinal nail splitting caused by Trichophyton rubrum is presented. The case was successfully treated with nail plate debridement plus topical ciclopirox olamine 1% solution. Nail debridement was performed using a 15-scalpel blade to remove the affected nail portion with the underlying subungual debris to enhance the effect of topical ciclopirox 1% solution which was then applied 3 times daily to the debrided area. Follow-up visits with nail photography were planned every 2 weeks after the procedure to check treatment progress. A complete clinical resolution was achieved after 5 months. This treatment option can be advocated for similar nail conditions avoiding unnecessary and expensive lines of treatment.
Usefulness of an Intrapartum Ultrasound Simulator (IUSim™) for Midwife Training: Results from an RCT
Authors: di Pasquo Elvira , Ramirez Zegarra Ruben , Kiener Ariane J.O. , Gobbi Laura , Dall’Asta Andrea , Fieschi Laura , Cugini Lodovica , Copelli Monica , Frusca Tiziana , Ghi Tullio
Published: December 2020

Introduction: We conducted a randomized study to determine whether a training session on a dedicated simulator (IUSim™) would facilitate the midwives in learning the technique of transperineal intrapartum ultrasound. Methods: Following a 30-min multimedia presentation including images and videos on how to obtain and measure the angle of progression (AoP) and the head-perineum distance (HPD), 6 midwives with no prior experience in intrapartum ultrasound were randomly split into 2 groups: 3 of them were assigned to the “training group” and 3 to the “control group.” The midwives belonging to the former group were taught to measure the 2 sonographic parameters during a 3-h practical session conducted on IUSim™ under the supervision of an expert obstetrician. In the following 3 months, all the 6 midwives were asked to independently perform transperineal ultrasound during their clinical practice and to measure on the acquired images either the AoP or the HPD. The sonographic images were examined in blind by the teaching obstetrician who assigned a 0–3 score to the image quality (IQS) and to the measurement quality (MQS). Results: A total of 48 ultrasound images (24 patients) from 5 midwives were acquired and included in the study analysis. A midwife of the “training group” declined participation after the practical session. Independently from the randomization group, the image quality score (IQS + MQS) was significantly higher for the HPD compared with the AoP (2.5 ± 0.66 vs. 1.79 ± 1.14; p = 0.01). In the training group, the MQS of either AoP (2.66 ± 0.5 vs.1.46 ± 1.45. p = 0.038) and the HPD (2.9 ± 0.33 vs. 1.87 ± 0.83 p = 0.002) was significantly higher in comparison with the control group, while the IQS of both measurements was comparable between the 2 groups (1.91 ± 1.24 vs. 2.25 ± 0.865; p = 0.28). Conclusion: The use of a dedicated simulator may facilitate the midwives in learning how to measure the AoP and the HPD on transperineal ultrasound images.