bluuebunny/crossref_metadata_2025 huggingface dataset:
Oceans, Lakes, and Stromatolites on Mars
Authors: Joseph Rhawn G. , Planchon Olivier , Duxbury N. S. , Latif K. , Kidron G. J. , Consorti L. , Armstrong R. A. , Gibson C. , Schild R.
Published: October 2020

Billions of years ago, the Northern Hemisphere of Mars may have been covered by at least one ocean and thousands of lakes and rivers. These findings, based initially on telescopic observations and images by the Mariner and Viking missions, led investigators to hypothesize that stromatolite fashioning cyanobacteria may have proliferated in the surface waters, and life may have been successfully transferred between Earth and Mars via tons of debris ejected into the space following bolide impact. Studies conducted by NASA’s robotic rovers also indicate that Mars was wet and habitable and may have been inhabited in the ancient past. It has been hypothesized that Mars subsequently lost its magnetic field, oceans, and atmosphere when bolides negatively impacted its geodynamo and that the remnants of the Martian seas began to evaporate and became frozen beneath the surface. As reviewed here, twenty-five investigators have published evidence of Martian sedimentary structures that resemble microbial mats and stromatolites, which may have been constructed billions of years ago on ancient lake shores and in receding bodies of water, although if these formations are abiotic or biotic is unknown. These findings parallel the construction of the first stromatolites on Earth. The evidence reviewed here does not prove but supports the hypothesis that ancient Mars had oceans (as well as lakes) and was habitable and inhabited, and life may have been transferred between Earth and Mars billions of years ago due to powerful solar winds and life-bearing ejecta propelled into the space following the bolide impact.
Sequence Analysis and Structure Prediction of SARS‐CoV‐2 Accessory Proteins 9b and ORF14: Evolutionary Analysis Indicates Close Relatedness to Bat Coronavirus
Authors: Baruah Chittaranjan , Devi Papari , Sharma Dhirendra K.
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has a single‐stranded RNA genome that encodes 14 open reading frames (ORFs), eight of which encode accessory proteins that allow the virus to infect the host and promote virulence. The genome expresses around 29 structural and nonstructural protein products. The accessory proteins of SARS‐CoV‐2 are not essential for virus replication but do affect viral release, stability, and pathogenesis and finally contribute to virulence. This paper has attempted the structure prediction and functional analysis of two such accessory proteins, 9b and ORF14, in the absence of experimental structures. Sequence analysis, structure prediction, functional characterization, and evolutionary analysis based on the UniProtKB reviewed the amino acid sequences of SARS‐CoV‐2 9b (P0DTD2) and ORF14 (P0DTD3) proteins. Modeling has been presented with the introduction of hybrid comparative and ab initio modeling. QMEANDisCo 4.0.0 and ProQ3 for global and local (per residue) quality estimates verified the structures as high quality, which may be attributed to structure‐based drug design targets. Tunnel analysis revealed the presence of 1‐2 highly active tunneling sites, perhaps which will able to provide certain inputs for advanced structure‐based drug design or to formulate potential vaccines in the absence of a complete experimental structure. The evolutionary analysis of both proteins of human SARS‐CoV‐2 indicates close relatedness to the bat coronavirus. The whole‐genome phylogeny indicates that only the new bat coronavirus followed by pangolin coronaviruses has a close evolutionary relationship with the novel SARS‐CoV‐2.
Planning Research on Application of Nanomaterial Technology in Disaster Prevention and Reconstruction
Authors: Shao Jun , Yan Huihui , Xu Haosheng
Published: October 2020

An earthquake causes a huge loss of life and property. After an earthquake, many buildings are seriously damaged or collapsed. On the one hand, it is necessary to make full use of nanomaterials technology to improve seismic strength during reconstruction; on the other hand, scientific planning is needed to reduce pollution, carbon emissions, and energy consumption. This paper mainly studies the application of nanomaterial technology in disaster prevention and reconstruction. Through a series of planning safeguard measures, the overall seismic performance of the city is improved in order to provide theoretical guidance and technical support for disaster prevention and reconstruction. This paper mainly introduces the stress analysis of frame joints after earthquake and the planning of urban disaster prevention and reconstruction. In addition to the different types of concrete materials (ordinary concrete, nano silica fiber concrete, PVA fiber concrete), the fixed amount of water, superplasticizer, reinforcement, sand, and gravel, the concrete strength grade is C30. Then, three kinds of concrete frame joints are tested under low cycle cyclic loading to compare the seismic performance of the three kinds of concrete. The experimental results show that the fuzzy evaluation of urban disaster prevention and reconstruction planning has been carried out for 6 communities in this city. Among them, 4 communities are qualified and 2 communities are unqualified. Therefore, it is necessary to focus on seismic reinforcement or carry out urban planning research again. Compared with ordinary concrete, the bearing capacity and ductility coefficient of nano silica fiber concrete and PVA fiber concrete are increased by 37.8% and 15.6%, respectively. It is proved that the seismic performance of nano silica fiber reinforced concrete is far better than that of ordinary concrete.
Coal Mine Gas Safety Evaluation Based on Adaptive Weighted Least Squares Support Vector Machine and Improved Dempster–Shafer Evidence Theory
Authors: Sun Zhenming , Li Dong
Published: October 2020

Gas safety evaluation has always been vital for coal mine safety management. To enhance the accuracy of coal mine gas safety evaluation results, a new gas safety evaluation model is proposed based on the adaptive weighted least squares support vector machine (AWLS-SVM) and improved Dempster–Shafer (D-S) evidence theory. The AWLS-SVM is used to calculate the sensor value at the evaluation time, and the D-S evidence theory is used to evaluate the safety status. First, the sensor data of gas concentration, wind speed, dust, and temperature were obtained from the coal mine safety monitoring system, and the prediction results of sensor data are obtained using the AWLS-SVM; hence, the prediction results would be the input of the evaluation model. Second, because the basic probability assignment (BPA) function is the basis of D-S evidence theory calculation, the BPA function of each sensor is determined using the posterior probability modeling method, and the similarity is introduced for optimization. Then, regarding the problem of fusion failure in D-S evidence theory when fusing high-conflict evidence, using the idea of assigning weights, the importance of each evidence is allocated to weaken the effect of conflicting evidence on the evaluation results. To prevent the loss of the effective information of the original evidence followed by modifying the evidence source, a conflict allocation coefficient is introduced based on fusion rules. Ultimately, taking Qing Gang Ping coal mine located in Shaanxi province as the study area, a gas safety evaluation example analysis is performed for the assessment model developed in this paper. The results indicate that the similarity measures can effectively eliminate high-conflict evidence sources. Moreover, the accuracy of D-S evidence theory based on enhanced fusion rules is improved compared to the D-S evidence theory in terms of the modified evidence sources and the original D-S evidence theory. Since more sensors are fused, the evaluation results have higher accuracy. Furthermore, the multisensor data evaluation results are enhanced compared to the single sensor evaluation outcomes.
The Efficacy of Washed Microbiota Transplantation on Helicobacter pylori Eradication: A Pilot Study
Authors: Ye Zhi-Ning , Xia Harry Hua-Xiang , Zhang Ran , Li Lan , Wu Li-Hao , Liu Xu-Juan , Xie Wen-Rui , He Xing-Xiang
Published: October 2020

Aim. The fecal microbiota transplantation by washed preparation was recently coined as washed microbiota transplantation (WMT). This pilot study is aimed at exploring the feasibility and efficacy of WMT on Helicobacter pylori eradication. Methods. Consecutive patients who had been treated with WMT for various indications and who were positive for H. pylori infection before WMT treatment but had never received eradication therapy for H. pylori infection were invited to take a follow-up 13C-urea breath test. The associations of demographic, clinical factors, and laboratory indicators for gastric function and intestinal barrier function with the therapeutic effect were determined. Results. A total of 32 eligible patients were included, and the overall H. pylori eradication rate was 40.6% (13/32). Patients with H. pylori eradication had a higher pepsinogen ratio (PGR) than those without (

13.00
±
6.97

vs.

8.31
±
3.733

;

P
=
0.02

). Female patients had a higher, albeit not statistically significant, eradication rate than male patients (53.85% vs. 31.58%;

P
=
0.208

). Compared with lower gastrointestinal tract delivery route, middle gastrointestinal tract delivery route seems to be a more suitable way for the treatment of H. pylori infection (58.33% vs 16.67%;

P
=
0.152

). There was no significant difference in other demographic and clinical factors between patients with and without H. pylori eradication. Conclusion. H. pylori infection is eradicated in a proportion of patients who have received WMT. An increased pre-WMT PGR appears to be associated with the therapeutic effect. Further studies are required to confirm the efficacy of WMT, especially in combination with currently recommended regimens in randomized controlled trials.
Effect of Roughness on Shear Characteristics of the Interface between Silty Clay and Concrete
Authors: Wang Yonghong , Liu Xueying , Zhang Mingyi , Bai Xiaoyu
Published: October 2020

In order to study the effect of roughness on the mechanical parameters of silty clay‐concrete interface, and to explore the applicability of silicon piezoresistive sensor to test the interface pressure, a large‐scale direct shear test system was used to carry out experimental research on the shear characteristics of silty clay‐concrete interface under different roughness conditions. Based on silicon piezoresistive sensor, the shear characteristics of silty clay‐concrete interface are analyzed. The results show that the silicon piezoresistive sensor has excellent performance in measuring the interface pressure and can accurately obtain the shear characteristics of the silty clay‐concrete interface. The roughness has a significant influence on the shear strength, shear stiffness, and other mechanical properties of the prefabricated pile‐soil interface. With the increase of roughness, interface shear strength, interface friction angle, shear stiffness coefficient, and interface residual shear stress all show an increasing trend, with the maximum increase of 37.0%. The interface adhesion decreased first and then increased with the increase of roughness, with an increase of 23.7%. The test results can provide reference for the engineering practice of jacked pile.
Elastic Wave Properties of an Adaptive Electromechanical Metamaterial Beam
Authors: Zhao Xi-Ning , Yang Xiao-Dong
Published: October 2020

An adaptive metamaterial beam with a couple of electromechanical resonators in each unit cell is proposed in this study to open Bragg bandgap or locally resonant bandgap for flexural wave attenuation in Euler–Bernoulli beams. The electromechanical resonator is composed of a piezoelectric layer with segmented electrodes and shunt circuits, which affect the dynamic equivalent stiffness. It is illustrated that there is only a Bragg bandgap when the circuits of the two adjacent resonators are approximate to a short circuit or open circuit, and the locally resonant bandgap will be generated in the pure inductance circuits when the resonant frequencies are different in general. The locally resonant bandgap can be broadened by adding more resonators into the unit cell with the resonant frequencies of the shunting circuits satisfying a proper ratio.
Learning a Second Language in Adulthood Changes Subcortical Neural Encoding
Authors: Liu Dongxin , Wang Shuo , Gao Qi , Dong Ruijuan , Fu Xinxing , Pugh Esther , Hu Jiong
Published: October 2020

Second language learning has been shown to impact and reshape the central nervous system, anatomically and functionally. Most of the studies on second language learning and neuroplasticity have been focused on cortical areas, whereas the subcortical neural encoding mechanism and its relationship with L2 learning have not been examined extensively. The purpose of this study was to utilize frequency-following response (FFR) to examine if and how learning a tonal language in adulthood changes the subcortical neural encoding in hearing adults. Three groups of subjects were recruited: native speakers of Mandarin Chinese (native speakers (NS)), learners of the language (L2 learners), and those with no experience (native speakers of foreign languages (NSFL)). It is hypothesized that differences would exist in FFRs obtained from the three language experience groups. Results revealed that FFRs obtained from L2 learners were found to be more robust than the NSFL group, yet not on a par with the NS group. Such results may suggest that in human adulthood, subcortical neural encoding ability may be trainable with the acquisition of a new language and that neuroplasticity at the brainstem level can indeed be influenced by L2 learning.
Seismic Behavior of Large‐Span Open‐Web Floors Consisting of I‐Shaped Steel Chords and Steel Tube Webs
Authors: Zhou Li , Huang Yong , Chen Bo , Hu Song , Zhang Chenyun
Published: October 2020

A composite large‐span open‐web floor (COF) system is introduced in this paper, which is composed of I‐shaped steel chords, steel tube webs, and concrete slabs. One COF specimen was fabricated and tested under cyclic loadings. The failure process and hysteretic curve of the specimen were discussed in detail. Moreover, a finite element (FE) model was developed and verified by experimental results. A parametric study was performed to examine the effects of the concrete strength, steel strength, section steel thickness, and structural height. The parametric study demonstrates that the effects of the steel strength, section steel thickness, and structural height on the load‐displacement hysteretic curve are proved to be significant. As for the bearing capacity and stiffness degradation of the COF system, the influence of the steel strength and section steel thickness is stronger than that of the concrete strength and structural height. Additionally, it is also found that the influence of the steel strength and section steel thickness on the energy dissipation is remarkable; the energy dissipation ability of the structure decreased with increasing the steel strength and increased with increasing the thickness of section steels.
Antimicrobial Resistance Patterns of Bacterial Isolates from Blood Culture among HIV/AIDS Patients at Felege Hiwot Referral Hospital, Northwest Ethiopia
Authors: Jemal Mohabaw , Deress Teshiwal , Belachew Teshome , Adem Yesuf
Published: October 2020

Background. The emergence and spread of antimicrobial resistance in bacteria is recognized as a global public health problem. Bloodstream infection with antimicrobial-resistant bacteria in HIV/AIDS patients makes the problem more challenging. So, regular and periodic diagnosis and use of the appropriate antimicrobial susceptibility pattern determination is the only option for decreasing the prevalence and development of drug-resistant bacteria. Methods. An institution-based cross-sectional study was conducted among 384 HIV/AIDS patients. Sociodemographic data of patients were recorded using structured questionnaires. Blood cultures were collected with BACTEC aerobic blood culture bottles. A pair of samples was collected from each patient aseptically and incubated at 37°. If samples are positive for bacterial agents, they were subcultured to solid media such as blood agar plate, chocolate agar plate, and MacConkey agar plates. Identification was performed using colony characteristics and standard biochemical techniques. The antimicrobial susceptibility test was determined by the Kirby–Bauer disc diffusion method. Data entry and analysis were performed while using SPSS version 20. Descriptive statistics were performed to calculate frequencies. Results. Altogether, 384 patients were included, and 123 blood cultures were positive, so that the yield was thus 32%. About 46 (37.4%) of Gram-negative and 77 (62.6%) of Gram-positive bacterial species were identified. Among Gram-negative bacterial isolates, K. pneumoniae was the leading pathogen, 19 (41.3%), whereas S. aureus, 38 (49.4%), was predominant among Gram-positive isolates. In his study, the majority of Gram-positive isolates showed high level of resistance to penicillin, 72 (95.5%), tetracycline, 55 (71.4%), and cotrimoxazole, 45 (58.4%). About 28 (73.6%) of S. aureus isolates were also methicillin-resistant. Gram-negative bacterial isolates also showed a high resistance to ampicillin (91.3%), tetracycline (91.3%), and gentamicin (47.8%). Overall, about 78% of multidrug resistance was observed. Conclusion. Several pathogens were resistant to greater than five antimicrobial agents, so that proper management of patients with bacteremia is needed, and a careful selection of effective antibiotics should be practiced.
Optimization and Design of a Railway Wheel Profile Based on Interval Uncertainty to Reduce Circular Wear
Authors: Lu Yongjie , Yang Yun , Wang Jianxi , Zhu Bowen
Published: October 2020

Wheel tread wear is a form of wheel damage that can seriously affect the performance of freight vehicles. A new numerical approach to optimizing wheel profiles can reduce circular wear on the LM wheel in the design cycle. This approach considers the influence of different line conditions and speed fluctuation on wheel wear, along with the performance of the wheel and the rail as the materials wear. In this approach, a nonlinear numerical optimization model for the wheel tread profile is built through a backpropagation (BP) neural network method. The multipoint Kik–Piotrowski (KP) contact mechanics model is applied to calculate the wheel/rail normal force, tangential creep force, the stick-slip area, and the size and shape of the contact patch. The optimal profile is obtained through the genetic algorithm (GA) method. In order to better reflect the random characteristics of wheel/rail matching and interval uncertainty, a random sampling technique is used to generate a random data sample at typical operating speeds.
Peritoneal Spread of Ovarian Cancer Harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling
Authors: Parashar Deepak , Nair Bindu , Geethadevi Anjali , George Jasmine , Nair Ajay , Tsaih Shirng-Wern , Kadamberi Ishaque P. , Gopinadhan Nair Gopa Kumar , Lu Yiling , Ramchandran Ramani , Uyar Denise S. , Rader Janet S. , Ram Prahlad T. , Mills Gordon B. , Pradeep Sunila , Chaluvally-Raghavan Pradeep
Published: October 2020

Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells.

Significance:

This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis.
RIG-I–Like Receptor LGP2 Is Required for Tumor Control by Radiotherapy
Authors: Zheng Wenxin , Ranoa Diana Rose E. , Huang Xiaona , Hou Yuzhu , Yang Kaiting , Poli Elizabeth C. , Beckett Michael A. , Fu Yang-Xin , Weichselbaum Ralph R.
Published: October 2020

Dendritic cells (DC) play an essential role in innate immunity and radiation-elicited immune responses. LGP2 is a RIG-I–like receptor involved in cytoplasmic RNA recognition and antiviral responses. Although LGP2 has also been linked to cell survival of both tumor cells and T cells, the role of LGP2 in mediating DC function and antitumor immunity elicited by radiotherapy remains unclear. Here, we report that tumor DCs are linked to the clinical outcome of patients with breast cancer who received radiotherapy, and the presence of DC correlates with gene expression of LGP2 in the tumor microenvironment. In preclinical models, host LGP2 was essential for optimal antitumor control by ionizing radiation (IR). The absence of LGP2 in DC dampened type I IFN production and the priming capacity of DC. In the absence of LGP2, MDA5-mediated activation of type I IFN signaling was abrogated. The MDA5/LGP2 agonist high molecular weight poly I:C improved the antitumor effect of IR. This study reveals a previously undefined role of LGP2 in host immunity and provides a new strategy to improve the efficacy of radiotherapy.

Significance:

These findings reveal an essential role of LGP2 in promoting antitumor immunity after radiotherapy and provide a new strategy to enhance radiotherapy.
Risk of Injuries around Diagnosis of Cervical Cancer and Its Precursor Lesions: A Nationwide Cohort Study in Sweden
Authors: Shen Qing , Lu Donghao , Andrae Bengt , Schelin Maria E.C. , Sjölander Arvid , Cao Yang , Sparén Pär , Fang Fang
Published: October 2020

Background:

Highly increased risk of injuries has been noted around the time of cancer diagnosis. Whether there is a similar increase in risk around the diagnosis of cervical cancer and its precursor lesions was unknown.

Methods:

We performed a cohort study including 3,016,307 Swedish women that participated in cervical screening during 2001 to 2012. We calculated the incidence rates (IR) of hospitalized iatrogenic or noniatrogenic injuries during the diagnostic workup, and the time interval from smear or punch biopsy until surgical treatment or 2 months after the last smear or biopsy, among women with invasive cervical cancer (ICC) or its precursor lesions. We calculated the IRs of injuries during the 2 months after a normal smear among the other women as reference. IR ratios (IRR) and 95% confidence intervals (CI) were calculated using Poisson regression.

Results:

Compared with other women, there was an increased rate of iatrogenic injuries during the diagnostic workup of women with ICC (IR, 0.58 per 1,000 person-months; IRR, 8.55; 95% CI, 3.69–19.80) as well as of women with cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ (IR, 0.09 per 1,000 person-months; IRR, 3.04; 95% CI, 1.73–5.34). We also found an increased rate of noniatrogenic injuries during the diagnostic workup of women with invasive cancer (IR, 0.65 per 1,000 person-months; IRR, 2.48; 95% CI, 1.30–4.47).

Conclusions:

Although rare, there was an increased risk of inpatient care for iatrogenic and noniatrogenic injuries during the diagnostic workup of women with ICC.

Impact:

Women experienced burden of medical complications and psychologic distress around diagnosis of a potential cervical cancer.
Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma
Authors: Bruzek Amy K. , Ravi Karthik , Muruganand Ashwath , Wadden Jack , Babila Clarissa May , Cantor Evan , Tunkle Leo , Wierzbicki Kyle , Stallard Stefanie , Dickson Robert P. , Wolfe Ian , Mody Rajen , Schwartz Jonathan , Franson Andrea , Robertson Patricia L. , Muraszko Karin M. , Maher Cormac O. , Garton Hugh J.L. , Qin Tingtin , Koschmann Carl
Published: October 2020

Purpose:

Pediatric high-grade glioma (pHGG) diagnosis portends poor prognosis and therapeutic monitoring remains difficult. Tumors release cell-free tumor DNA (cf-tDNA) into cerebrospinal fluid (CSF), allowing for potential detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of cf-tDNA with a handheld platform (Oxford Nanopore MinION) could quantify patient-specific CSF cf-tDNA variant allele fraction (VAF) with improved speed and limit of detection compared with established methods.

Experimental Design:

We performed ultra-short fragment (100–200 bp) PCR amplification of cf-tDNA for clinically actionable alterations in CSF and tumor samples from patients with pHGG (n = 12) alongside nontumor CSF (n = 6). PCR products underwent rapid amplicon-based sequencing by Oxford Nanopore Technology (Nanopore) with quantification of VAF. Additional comparison to next-generation sequencing (NGS) and droplet digital PCR (ddPCR) was performed.

Results:

Nanopore demonstrated 85% sensitivity and 100% specificity in CSF samples (n = 127 replicates) with 0.1 femtomole DNA limit of detection and 12-hour results, all of which compared favorably with NGS. Multiplexed analysis provided concurrent analysis of H3.3A (H3F3A) and H3C2 (HIST1H3B) mutations in a nonbiopsied patient and results were confirmed by ddPCR. Serial CSF cf-tDNA sequencing by Nanopore demonstrated correlation of radiological response on a clinical trial, with one patient showing dramatic multi-gene molecular response that predicted long-term clinical response.

Conclusions:

Nanopore sequencing of ultra-short pHGG CSF cf-tDNA fragments is feasible, efficient, and sensitive with low-input samples thus overcoming many of the barriers restricting wider use of CSF cf-tDNA diagnosis and monitoring in this patient population.
Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial
Authors: Xu Jianming , Shen Jie , Gu Shanzhi , Zhang Yun , Wu Lihua , Wu Jian , Shao Guoliang , Zhang Yanqiao , Xu Li , Yin Tao , Liu Jingfeng , Ren Zhenggang , Xiong Jianping , Mao Xianhai , Zhang Ling , Yang Jiayin , Li Lequn , Chen Xiaoming , Wang Zhiming , Gu Kangsheng , Chen Xi , Pan Zhanyu , Ma Kuansheng , Zhou Xinmin , Yu Zujiang , Li Enxiao , Yin Guowen , Zhang Xiao , Wang Shuni , Wang Quanren
Published: October 2020

Purpose:

We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).

Patients and Methods:

This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1.

Results:

Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.

Conclusions:

Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.

See related commentary by Pinato et al., p. 908
Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET
Authors: Simonetta Federico , Alam Israt S. , Lohmeyer Juliane K. , Sahaf Bita , Good Zinaida , Chen Weiyu , Xiao Zunyu , Hirai Toshihito , Scheller Lukas , Engels Pujan , Vermesh Ophir , Robinson Elise , Haywood Tom , Sathirachinda Ataya , Baker Jeanette , Malipatlolla Meena B. , Schultz Liora M. , Spiegel Jay Y. , Lee Jason T. , Miklos David B. , Mackall Crystal L. , Gambhir Sanjiv S. , Negrin Robert S.
Published: October 2020

Purpose:

Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Noninvasive molecular imaging of CAR T cells by PET is a promising approach with the ability to provide spatial, temporal, and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T-cell molecular imaging. In this study, we assessed the ability of antibody-based PET (immunoPET) to noninvasively visualize CAR T cells.

Experimental Design:

After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer, which we have previously reported.

Results:

Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow–containing skeletal sites of CAR T-cell–treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T-cell persistence and function.

Conclusions:

This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T-cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.

See related commentary by Volpe et al., p. 911
Reprogramming of Nucleotide Metabolism Mediates Synergy between Epigenetic Therapy and MAP Kinase Inhibition
Authors: Shorstova Tatiana , Su Jie , Zhao Tiejun , Dahabieh Michael , Leibovitch Matthew , De Sa Tavares Russo Mariana , Avizonis Daina , Rajkumar Shivshankari , Watson Ian R. , del Rincón Sonia V. , Miller Wilson H. , Foulkes William D. , Witcher Michael
Published: October 2020

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo. Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass spectrometry, coupled with knockdown of newly found targets such as thymidylate synthase, revealed that the repression of a panel of proteins involved in nucleotide synthesis underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell-cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian cancer subtypes.
Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers
Authors: Rashmi Ramachandran , Jayachandran Kay , Zhang Jin , Menon Vishnu , Muhammad Naoshad , Zahner Michael , Ruiz Fiona , Zhang Sisi , Cho Kevin , Wang Yuting , Huang Xiaojing , Huang Yi , McCormick Michael L. , Rogers Buck E. , Spitz Douglas R. , Patti Gary J. , Schwarz Julie K.
Published: October 2020

The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN−/− cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer
Authors: Dees Sundee , Ganesan Rajkumar , Singh Sanjaya , Grewal Iqbal S.
Published: October 2020

Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype that lacks estrogen receptor, progesterone receptor, and HER2 expression, does not respond to traditional endocrine and anti–HER2-targeted therapies. Current treatment options for patients with TNBC include a combination of surgery, radiotherapy, and/or systemic chemotherapy. FDA-approved therapies that target DNA damage repair mechanisms in TNBC, such as PARP inhibitors, only provide marginal clinical benefit. The immunogenic nature of TNBC has prompted researchers to harness the body's natural immune system to treat this aggressive breast cancer. Clinical precedent has been recently established with the FDA approval of two TNBC immunotherapies, including an antibody–drug conjugate and an anti-programmed death-ligand 1 monoclonal antibody. Chimeric antigen receptor (CAR)-T cell therapy, a type of adoptive cell therapy that combines the antigen specificity of an antibody with the effector functions of a T cell, has emerged as a promising immunotherapeutic strategy to improve the survival rates of patients with TNBC. Unlike the remarkable clinical success of CAR-T cell therapies in hematologic cancers with Kymriah and Yescarta, the development of CAR-T cell therapies for solid tumors has been much slower and is associated with unique challenges, including a hostile tumor microenvironment. The aim of the present review is to discuss novel approaches and inherent challenges pertaining to CAR-T cell therapy for the treatment of TNBC.
The Landscape of Glycogen Synthase Kinase-3 Beta Genomic Alterations in Cancer
Authors: Borden Brittany A. , Baca Yasmine , Xiu Joanne , Tavora Fabio , Winer Ira , Weinberg Benjamin A. , Vanderwalde Ari M. , Darabi Sourat , Korn W. Michael , Mazar Andrew P. , Giles Francis J. , Crawford Lorin , Safran Howard , El-Deiry Wafik S. , Carneiro Benedito A.
Published: October 2020

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3β, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3β alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between GSK-3β–mutated and wild-type tumors. GSK-3β was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3β–mutated tumors were observed for B cells (P = 0.018), monocytes (P = 0.002), dendritic cells (P = 0.005), neutrophils (P = 0.0003), and endothelial cells (P = 0.014). GSK-3β mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3β–mutated tumors compared with wild type in colorectal cancer (P = 0.03), endometrial cancer (P = 0.05), melanoma (P = 0.02), ovarian carcinoma (P = 0.0001), and uterine sarcoma (P = 0.002). Overall, GSK-3β molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3β mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3β mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.
Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft
Authors: Morton J. Jason , Alzofon Nathaniel , Keysar Stephen B. , Chimed Tugs-Saikhan , Reisinger Julie , Perrenoud Loni , Le Phuong N. , Nieto Cera , Gomez Karina , Miller Bettina , Yeager Randi , Gao Dexiang , Tan Aik-Choon , Somerset Hilary , Medina Theresa , Wang Xiao-Jing , Wang Jing H. , Robinson William , Roop Dennis R. , Gonzalez Rene , Jimeno Antonio
Published: October 2020

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines.

Implications:

Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.
Pediatric Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations
Authors: Maconochie Ian K. , Aickin Richard , Hazinski Mary Fran , Atkins Dianne L. , Bingham Robert , Couto Thomaz Bittencourt , Guerguerian Anne-Marie , Nadkarni Vinay M. , Ng Kee-Chong , Nuthall Gabrielle A. , Ong Gene Y.K. , Reis Amelia G. , Schexnayder Stephen M. , Scholefield Barnaby R. , Tijssen Janice A. , Nolan Jerry P. , Morley Peter T. , Van de Voorde Patrick , Zaritsky Arno L. , de Caen Allan R. , Moylan Alex , Topjian Alexis , Nation Kevin , Ohshimo Shinchiro , Bronicki Ronald A. , Kadlec Kelly D. , Knight Lynda J. , McCormick Taylor N. , Morgan Ryan W. , Roberts Joan S. , Tabbutt Sarah , Thiagarajan Ravi , Walsh Brian , Raymond Tia , Chan Melissa , Duff Jonathan P. , Joyner Benny L. , Lasa Javier J. , Levy Arielle , Roberts Kathryn E. , Sutton Robert M. , de Lucas Nieves , Hoffmann Florian , Turner Nigel , Biarent Dominique , Lauritsen Torsten , Brissaud Olivier , Johannesdottir Groa , Djakow Jana , Mejias Abel Martinez , Meckler Garth , Buchanan Matt , Morrison Laurie J.
Published: October 2020

This
2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations
(CoSTR) for pediatric life support is based on the most extensive evidence evaluation ever performed by the Pediatric Life Support Task Force. Three types of evidence evaluation were used in this review: systematic reviews, scoping reviews, and evidence updates. Per agreement with the evidence evaluation recommendations of the International Liaison Committee on Resuscitation, only systematic reviews could result in a new or revised treatment recommendation.

Systematic reviews performed for this 2020 CoSTR for pediatric life support included the topics of sequencing of airway-breaths-compressions versus compressions-airway-breaths in the delivery of pediatric basic life support, the initial timing and dose intervals for epinephrine administration during resuscitation, and the targets for oxygen and carbon dioxide levels in pediatric patients after return of spontaneous circulation. The most controversial topics included the initial timing and dose intervals of epinephrine administration (new treatment recommendations were made) and the administration of fluid for infants and children with septic shock (this latter topic was evaluated by evidence update). All evidence reviews identified the paucity of pediatric data and the need for more research involving resuscitation of infants and children.
Part 7: Systems of Care: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
Authors: Berg Katherine M. , Cheng Adam , Panchal Ashish R. , Topjian Alexis A. , Aziz Khalid , Bhanji Farhan , Bigham Blair L. , Hirsch Karen G. , Hoover Amber V. , Kurz Michael C. , Levy Arielle , Lin Yiqun , Magid David J. , Mahgoub Melissa , Peberdy Mary Ann , Rodriguez Amber J. , Sasson Comilla , Lavonas Eric J. ,   On behalf of the Adult Basic and Advanced Life Support, Pediatric Basic and Advanced Life Support, Neonatal Life Support, and Resuscitation Education Science Writing Groups
Published: October 2020

Survival after cardiac arrest requires an integrated system of people, training, equipment, and organizations working together to achieve a common goal. Part 7 of the
2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care
focuses on systems of care, with an emphasis on elements that are relevant to a broad range of resuscitation situations. Previous systems of care guidelines have identified a Chain of Survival, beginning with prevention and early identification of cardiac arrest and proceeding through resuscitation to post–cardiac arrest care. This concept is reinforced by the addition of recovery as an important stage in cardiac arrest survival. Debriefing and other quality improvement strategies were previously mentioned and are now emphasized. Specific to out-of-hospital cardiac arrest, this Part contains recommendations about community initiatives to promote cardiac arrest recognition, cardiopulmonary resuscitation, public access defibrillation, mobile phone technologies to summon first responders, and an enhanced role for emergency telecommunicators. Germane to in-hospital cardiac arrest are recommendations about the recognition and stabilization of hospital patients at risk for developing cardiac arrest. This Part also includes recommendations about clinical debriefing, transport to specialized cardiac arrest centers, organ donation, and performance measurement across the continuum of resuscitation situations.