bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermohydraulic Characteristics of Printed Circuit Recuperators in a Supercritical CO2 Brayton Cycle with Nonuniform Minichannels
Authors: Khoshvaght-Aliabadi Morteza , Ghodrati Parvaneh , Kang Yong Tae
Published: February 2023

Supercritical carbon dioxide (SCO2) technologies have been under the spotlight of developed countries because they believe that such applied sciences can be ingenious solutions to resolve energy and environmental problems. The SCO2 power cycle is one of the most promising technologies in this field due to its high efficiency and low expenditure. However, optimal designs of heat exchange devices are a vital issue in the SCO2 power cycle because they account for almost 80% of the capital costs. In this study, the comparison of diverse combinations of convergent and divergent minichannels inside the low temperature recuperator (LTR) and high temperature recuperator (HTR) is suggested to recognize the strengths and weaknesses of nonuniform minichannels at high operating pressures and temperatures. Three-dimensional conjugate simulations are carried out, and existing data in the literature are used to validate the obtained results. The comparison reveals a slight deviation (less than 10%) in temperature and pressure profiles. After the evaluation of the studied cases in terms of thermal and hydraulic characteristics, different criteria are employed to explore optimal combinations of the hot side and cold side minichannels. Totally, the minichannel convergence enhances thermal performance of recuperators (up to 26%), and their divergence improves the hydraulic behavior. Nonetheless, diverging the minichannels imposes greater positive effects than converging them. The overall analysis specifies that the most efficient LTR and HTR would be attained by diverging the hot side minichannel, while the cold side minichannel is kept unchanged. This combination of minichannels allows reaching the highest SCO2 temperature at the outlet of LTR and HTR (456 K and 656 K) with the minimum pressure drops (around 0.02% of inlet pressures) and achieving the best performance indexes (approximately 2). Finally, the comparative study discloses that at low Reynolds numbers (less than 14000 for the hot side and 10000 for the cold side), the nonuniform patterns of minichannels perform better than the complicated structures, such as zigzag, wavy, and other optimized geometries. The average performance enhancements for the hot and cold sides are 36.3% and 37.4%, respectively.
Comparison of Efficacy and Safety of First-Line Chemoimmunotherapy in Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Network Meta-Analysis
Authors: Ma Xiaolu , Ding Yongfeng , Qian Jiong , Wan Mingyu , Chen Xiaoyu , Xu Nong
Published: February 2023

Background. Chemoimmunotherapy has become the first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). We aimed to compare the efficacy and toxicity of different chemoimmunotherapy combinations to determine the optimal treatment option. Methods. PubMed, Web of Science, Cochrane Library, Embase, and abstracts of recent relevant meetings were searched to identify phase III randomized controlled trials (RCTs) of first-line programmed cell death-1 (PD-1)/its receptor (PD-L1) inhibitors plus chemotherapy for ESCC up to July 2022. A network meta-analysis (NMA) following Bayesian approaches was conducted in R software. Result. Our study included six RCTs and 3,611 patients. According to the NMA, toripalimab plus chemotherapy ranked first to prolong overall survival (OS). Sintilimab plus chemotherapy and camrelizumab plus chemotherapy consistently yielded the greatest benefits regarding progression-free survival (PFS). The maximal complete response rate (CRR) and objective response rate (ORR) were achieved with nivolumab plus chemotherapy. Tislelizumab plus chemotherapy attained the highest likelihood of achieving a disease control rate (DCR). The addition of immunotherapy to chemotherapy was associated with improved survival and increased adverse events. Subgroup analysis revealed that patients with PD-L1 tumor positive score (TPS) ≥10% showed a better OS than those with lower values when undergoing first-line chemoimmunotherapy. Anti-PD-1 inhibitor with platinum plus paclitaxel (TP) regimen showed a superior PFS benefit over anti-PD-1 inhibitor with platinum plus fluorouracil (FP) regimen. Conclusion. The NMA analysis suggested that sintilimab plus chemotherapy was the preferred regimen for treatment-naive advanced ESCC patients with the best balance between efficacy and safety. Anti-PD-1 inhibitors with the TP regimen were associated with more favorable PFS than those with the FP regimen.
WHIM Syndrome: First Reported Case in a Patient of African Ancestry
Authors: Gandhi Jinal , Lee Michelle H. , Adams Lynsie , Allen Tara Shrout , Li Julie , Edwards Camille Vanessa
Published: February 2023

Background. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, primary immunodeficiency syndrome characterized by warts, hypogammaglobulinemia, immunodeficiency, and characteristic bone marrow features of myelokathexis. The pathophysiology of WHIM syndrome is due to an autosomal dominant gain of function mutation in the CXCR4 chemokine receptor resulting in increased activity that impairs neutrophil migration from the bone marrow into the peripheral blood. This results in bone marrow distinctively crowded with mature neutrophils whose balance is shifted towards cellular senescence developing these characteristic, apoptotic nuclei termed myelokathexis. Despite the resultant severe neutropenia, the clinical syndrome is often mild and accompanied by a variety of associated abnormalities that we are just beginning to understand. Case Report. Diagnosis of WHIM syndrome is incredibly difficult due to phenotypic heterogeneity. To date, there are only about 105 documented cases in the scientific literature. Here, we describe the first case of WHIM syndrome documented in a patient of African ancestry. The patient in question was diagnosed at the age of 29 after a comprehensive work-up for incidental neutropenia discovered at a primary care appointment at our center in the United States. In hindsight, the patient had a history of recurrent infections, bronchiectasis, hearing loss, and VSD repair that could not be previously explained. Conclusions. Despite the challenge of timely diagnosis and the wide spectrum of clinical features that we are still discovering, WHIM syndrome tends to be a milder immunodeficiency that is highly manageable. As presented in this case, most patients respond well to G-CSF injections and newer treatments such as small-molecule CXCR4 antagonists.
In Silico Study of Coumarins: Wedelolactone as a Potential Inhibitor of the Spike Protein of the SARS-CoV-2 Variants
Authors: Katuwal Saurav , Upadhyaya Siddha Raj , Marahatha Rishab , Shrestha Asmita , Regmi Bishnu P. , Khadayat Karan , Basnet Saroj , Basnyat Ram Chandra , Parajuli Niranjan
Published: February 2023

Despite the rigorous global efforts to control SARS-CoV-2 transmission, it continues to pose a serious threat to humans with the frequent emergence of new variants. Thus, robust therapeutics to combat the virus are a desperate need. The SARS-CoV-2 spike (S) protein is an important target protein as it mediates the entry of the virus inside the host cells, which is initiated by the binding of the receptor-binding domain (RBD) to its cognate receptor, angiotensin-converting enzyme 2 (ACE-2). Herein, the inhibition potential of several naturally occurring coumarins was investigated against the spike proteins of SARS-CoV-2 variants using computational approaches. Molecular docking studies revealed 26 coumarins with better binding energies than the reference ligands, molnupiravir and ceftazidime, against the S-RBD of the omicron variant. The top 10 best-docked coumarins were further analyzed to understand their binding interactions against the spike proteins of other variants (wild-type, Alpha, Beta, Gamma, and Delta), and these studies also demonstrated decent binding energies. Physicochemical, QSAR, and pharmacokinetics analyses of the coumarins revealed wedelolactone as the best inhibitor of the spike protein with ideal Lipinski’s drug-likeness and optimal ADMET properties. Furthermore, coarse-grained molecular dynamics (MD) simulation studies of spike protein-wedelolactone complexes validated the stable binding of wedelolactone in the respective binding pockets. As an outcome, wedelolactone could be utilized to develop a potent drug candidate against COVID-19 by blocking the viral entry into the host cell.
Osteogenesis of Human iPSC-Derived MSCs by PLLA/SF Nanofiber Scaffolds Loaded with Extracellular Matrix
Authors: Zhang Junming , Che Lingbin , Wu Yunliang , Zhou Lei , Liu Li , Yue Yuanhang , Song Dianwen , Lou Xiangxin
Published: February 2023

Bone defects that arise from trauma, skeletal diseases, or tumor resections have become the commonest and most thorny problems in orthopedic clinics. Recently, biocomposite materials used as artificial bone repair materials have provided a promising approach for bone regeneration. In this study, poly (l-lactide acid) (PLLA) and silk fibroin (SF) were used to fabricate nanofiber scaffolds by electrospinning technology. In order to simulate a biomimetic osteoblast microenvironment, decellularized extracellular matrix from osteoblasts was loaded into the biocomposite scaffolds (O-ECM/PLLA/SF). It was found that the O-ECM/PLLA/SF scaffolds were nontoxic for L929 cells and had good cytocompatibility. Their effects on mesenchymal stem cells derived from human-induced pluripotent stem cell (iPSC-MSC) behavior were investigated. As a result, the scaffolds with the addition of O-ECM showed enhanced alizarin red S (ARS) activity. In addition, higher expression of osteogenic gene markers such as runt-related transcription factor 2 (Runx2), collagen type I (Col-1), and osteocalcin (OCN) as well as upregulated expression of osteogenic marker protein osteopontin (OPN) and Col-1 further substantiated the applicability of O-ECM/PLLA/SF scaffolds for osteogenesis. Furthermore, the in vivo study also indicated maximal new bone formation in the skull defect model of Sprague Dawley (SD) rats treated with the O-ECM/PLLA/SF carried by human iPSC-MSCs. Hence, this study suggests that O-ECM/PLLA/SF scaffolds have a potential application in bone tissue engineering.
Comparative Study on LC3-50 with OPC Concrete Using Raw Materials from Pakistan
Authors: Sheikh Muhammad Danyal , Jamil Tariq , Ayub Tehmina , Khan Asad-ur-Rehman , Bilal Syed Muhammad , Hu Chuanlin
Published: February 2023

The cement industry is expanding rapidly around the globe, despite its significant contribution to global carbon dioxide emissions. Likewise, in Pakistan, the cement industry produces million tons of cement and has a history of contributing as high as 10% of the country’s carbon dioxide emissions annually. The most effective technique for reducing carbon dioxide emissions is to use supplementary cementitious materials (SCMs). Limestone Calcined Clay Cement (LC3-50) is a recently developed cement blend comprised of 50% clinker, 30% calcined clay, 15% raw limestone, and 5% gypsum by weight. The focus of this research is to assess the mechanical properties and durability performance of LC3-50 cement composition formulated using raw materials from Pakistan. The comprehensive case study would help advance the research and commercialization activities in the country. In this study, compressive strength, split tensile, flexural, and pull-out tests were performed for evaluating the mechanical properties. For the assessment of durability, water permeability, sorptivity, carbonation, and rapid chloride penetration test (RCPT) tests were performed as per the available standards. It is concluded that the use of LC3-50 instead of ordinary Portland cement (OPC) improved the strength and durability of the end concrete.
Study on Neuroprotective Mechanism of Houshiheisan in Ischemic Stroke Based on Transcriptomics and Experimental Verification
Authors: Cheng Hongfa , Zhang Yawen , Guo Xiaoyao , Wang Xuan , Wang Hanyu , Zhao Hui , Wang Lei , Zou Haiyan , Zhang Qiuxia
Published: February 2023

Houshiheisan (HSHS), a classic prescription in traditional Chinese medicine (TCM), has shown outstanding efficacy in treating stroke. This study investigated various therapeutic targets of HSHS for ischemic stroke using mRNA transcriptomics. Herein, rats were randomly separated into the sham, model, HSHS 5.25 g/kg (HSHS5.25), and HSHS 10.5 g/kg (HSHS10.5) groups. Rats suffering from stroke were induced by permanent middle cerebral artery occlusion (pMCAO). After seven days of HSHS treatment, behavioral tests were conducted, and histological damage was examined with hematoxylin‐eosin (HE). The mRNA expression profiles were identified using microarray analysis and quantitative real‐time PCR (qRT‐PCR) validated gene expression changes. An analysis of gene ontology and pathway enrichment was conducted to analyze potential mechanisms confirmed using immunofluorescence and western blotting. HSHS5.25 and HSHS10.5 improved neurological deficits and pathological injury in pMCAO rats. The intersections of 666 differentially expressed genes (DEGs) were chosen using transcriptomics analysis in the sham, model, and HSHS10.5 groups. The enrichment analysis suggested that the therapeutic targets of HSHS might regulate the apoptotic process and ERK1/2 signaling pathway, which was related to neuronal survival. Moreover, TUNEL and immunofluorescence analysis indicated that HSHS inhibited apoptosis and enhanced neuronal survival in the ischemic lesion. Western blot and immunofluorescence assay indicated that HSHS10.5 decreased Bax/Bcl‐2 ratio and suppressed caspase‐3 activation, while the phosphorylation of ERK1/2 and CREB was upregulated in a stroke rat model after HSHS treatment. Effective inhibition of neuronal apoptosis by activating the ERK1/2‐CREB signaling pathway may be a potential mechanism for HSHS in the treatment of ischemic stroke.
Evaluating Histological Subtypes Classification of Primary Lung Cancers on Unenhanced Computed Tomography Based on Random Forest Model
Authors: Huang Jianfeng , He Wei , Xu Haijia , Yang Shan , Dai Jiajun , Guo Weifeng , Zeng Mengsu
Published: February 2023

Lung cancer is the leading cause of cancer-related death in many countries, and an accurate histopathological diagnosis is of great importance in subsequent treatment. The aim of this study was to establish the random forest (RF) model based on radiomic features to automatically classify and predict lung adenocarcinoma (ADC), lung squamous cell carcinoma (SCC), and small cell lung cancer (SCLC) on unenhanced computed tomography (CT) images. Eight hundred and fifty-two patients (mean age: 61.4, range: 29–87, male/female: 536/316) with preoperative unenhanced CT and postoperative histopathologically confirmed primary lung cancers, including 525 patients with ADC, 161 patients with SCC, and 166 patients with SCLC, were included in this retrospective study. Radiomic features were extracted, selected, and then used to establish the RF classification model to analyse and classify primary lung cancers into three subtypes, including ADC, SCC, and SCLC according to histopathological results. The training (446 ADC, 137 SCC, and 141 SCLC) and testing cohorts (79 ADC, 24 SCC, and 25 SCLC) accounted for 85% and 15% of the whole datasets, respectively. The prediction performance of the RF classification model was evaluated by F1 scores and the receiver operating characteristic (ROC) curve. On the testing cohort, the areas under the ROC curve (AUC) of the RF model in classifying ADC, SCC, and SCLC were 0.74, 0.77, and 0.88, respectively. The F1 scores achieved 0.80, 0.40, and 0.73 in ADC, SCC, and SCLC, respectively, and the weighted average F1 score was 0.71. In addition, for the RF classification model, the precisions were 0.72, 0.64, and 0.70; the recalls were 0.86, 0.29, and 0.76; and the specificities were 0.55, 0.96, and 0.92 in ADC, SCC, and SCLC. The primary lung cancers were feasibly and effectively classified into ADC, SCC, and SCLC based on the combination of RF classification model and radiomic features, which has the potential for noninvasive predicting histological subtypes of primary lung cancers.
Prediction of Biogas Yield from Codigestion of Lignocellulosic Biomass Using Adaptive Neuro-Fuzzy Inference System (ANFIS) Model
Authors: Fajobi Moses Oluwatobi , Lasode Olumuyiwa Ajani , Adeleke Adekunle Akanni , Ikubanni Peter Pelumi , Balogun Ayokunle Olubusayo , Paramasivam Prabhu
Published: February 2023

One of the major challenges confronting researchers is how to predict biogas yield because it is a herculean task since research in the field of modeling and optimization of biogas yield is still limited, especially with the adaptive neuro-fuzzy inference system (ANFIS). This study used ANFIS to model and predict biogas yield from anaerobic codigestion of cow dung, mango pulp, and Chromolaena odorata. Asides from the controls, 13 experiments using various agglomerates of the selected substrates were carried out. Cumulatively (for 40 days), the agglomerate that comprised 50% cow dung, 25% mango pulp, and 25% Chromolaena odorata produced the highest volume of biogas, 4750 m3/kg, while the one with 50% cow dung, 12.5% mango pulp, and 37.5% Chromolaena odorata produced the lowest volume of biogas, 630 m3/kg. The data articulated for modeling were those of the optimum biogas yield. Data implemented for modeling comprised two inputs (temperature in Kelvin and pressure in kN/m2) and one output (biogas yield). The Gaussian membership function (Gauss-mf) was implemented for the fuzzification of input variables, while the hybrid algorithm was selected for the learning and mapping of the input-output dataset. The developed ANFIS architecture was simulated at varied membership functions, MFs, and epoch numbers to determine the minimum root mean square error, RMSE, and maximum R-squared R2 values. The one that fulfilled the conditions was considered to be the optimized model. The minimum RMSE and maximum R2 values recorded for the developed model are 14.37 and 0.99784, respectively. The implication is that the model was able to efficiently predict not less than 99.78% of the experimental data. These results prove that the ANFIS model is a reliable tool for modeling data and predicting biogas yield in the biomass anaerobic digestion process. Therefore, the use of the developed ANFIS model is recommended for biogas producers and other allies for predicting biogas yield adequately.
An Improved Geometric Theoretical Model and Throughflow Prediction Method for a CO2 Scroll Compressor of Automotive Air Conditioning System
Authors: Song Panpan , Wu Ding , Lu Zhenbo , Zheng Siyu , Wei Mingshan , Zhuge Weilin , Zhang Yangjun
Published: February 2023

The scroll-type compressor is the core component of the refrigeration system using the natural refrigerant carbon dioxide. An accurate scroll geometric theoretical model is essential for evaluating and enhancing compressor performance. The present paper proposed and validated an improved geometric theoretical model of a scroll compressor. A vector triangle method-based general piecewise function describes precisely the volume variation of the working chambers, based on which the transient throughflow modeling and performance evaluation of a carbon dioxide scroll compressor were conducted. The mechanisms and influencing factors of the suction precompression and the asymmetry discharging were analyzed. The results indicate that the strength of the suction precompression is mainly influenced by the suction vacuum under different rotating speeds, partly associated with the tangential leakage under low rotating speeds. The increasing initial suction pressure contributes to the linear raising of the pressure difference between suction initial and ending pressures, decreasing the precompression extension slightly. The variation of the discharge throughflow areas of two symmetric discharge chambers dominates the pressure asymmetry, which is gradually eliminated by the overlapping throughflow area. Compared with the circular discharge structure, the waist-shape port reduces the pressure asymmetry degree and shortens its duration.
Rheological Properties and Microscopic Characterization of Delayed Decay-Modified Asphalt Based on UV Ageing
Authors: Gu Hening , Zhu Yongqiang , Zhu Yunchu , Chu Lijing , Peng Qinyuan , Chen Qian
Published: February 2023

For clarifying the applying feasibility of hindered amine light stabilizers in asphalt binder, two types of hindered amine light stabilizers were chosen as a UV ageing resistance modifier and the modified asphalt was prepared with a selected UV ageing resistance modifier. The ultraviolet aging testing method of asphalt materials was proposed for UV ageing behavior characterization. Under the condition of different frequencies, the impact of UV ageing resistance modifier on asphalt was investigated through using the frequency sweep test of DSR. Under the effect of ultraviolet aging, the variation of thermal properties of UV ageing resistance-modified asphalt was deeply analyzed by means of a temperature scanning test of DSR following the increase of temperature. The change law of the surface morphology of light stabilizer-modified asphalt was characterized by atomic force microscopy (AFM) dynamically with the UV aging time extension. The research results showed that the hindered amine light stabilizer could improve the high temperature performance of asphalt and achieve the UV aging behavior of asphalt materials effectively. Meanwhile, the corresponding reaction mechanism was explored at the microscopic level.
A Generalized Blockchain-Based Government Data Sharing Protocol
Authors: Liu Zilin , Yang Anjia , Zeng Huang , Jiang Changkun , Ma Li
Published: February 2023

In order to catch the express train of the digital age and seize the opportunities brought by the development of blockchain technology, many government departments have begun to build blockchain-based data sharing protocols. Most existing data sharing protocols are built on different blockchains with different specific features. The interaction between them is not trivial, leading to the phenomenon of “data islands.” Therefore, we consider building a data sharing protocol compatible with various blockchains. In this work, we propose a generalized blockchain-based data sharing protocol, which takes fairness, privacy, auditability, and generality into account simultaneously. With adaptor signature and zero-knowledge techniques, the proposed protocol ensures a secure and fair data sharing process and is compatible with various blockchains since it only requires the underlying blockchain to perform signature verification. Finally, we implement our construction on an Ethereum test network and conduct a series of experiments. The results demonstrate the practicality of our construction while remaining good functionalities.
Germline Cancer Gene Expression Quantitative Trait Loci Are Associated with Local and Global Tumor Mutations
Authors: Liu Yuxi , Gusev Alexander , Kraft Peter
Published: February 2023

Somatic mutations drive cancer development and are relevant to patient responses to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline–somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene (“local impact”) or a set of recurrently mutated cancer genes across the genome (“global impact”) through their regulatory effect on gene expression. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline–somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes.

Significance:

Analysis of associations between the germline genetic background and somatic mutations in patients with cancer suggests that germline variants can influence local and global tumor mutations by altering expression of cancer-related genes.

See related commentary by Kar, p. 1165.
HPV-based Cervical Cancer Screening on Self-samples in the Netherlands: Challenges to Reach Women and Test Performance Questions
Authors: Arbyn Marc , Costa Stefanie , Latsuzbaia Ardashel , Kellen Eliane , Girogi Rossi Paolo , Cocuzza Clementina E. , Basu Partha , Castle Philip E.
Published: February 2023

In 2017, cervical cancer screening in the Netherlands switched from cytology to human papillomavirus (HPV) testing using the validated PCR-based cobas 4800. Women could order and subsequently received a free self-sampling kit (Evalyn Brush) at their home address instead of clinician sampling. In the laboratory, the shipped brush was placed into 20 mL of PreservCyt fluid, before testing. In the first 2 years of the new program, only 7% of screening tests were performed on a self-sample. Those who chose self-sampling versus clinician sampling were more likely to have never been screened previously and differed also with respect to sociodemographic factors. Subsequent more active promotion and increasing the ease to obtain kits increased the proportion opting for self-sampling (16% in 2020). HPV positivity and detection rate of precancer (CIN3+) were lower in the self-sampling compared with the clinician-sampling group (adjusted ORs of 0.65 and 0.86, respectively). Although population differences may partially explain these results, self-samples may have been too dilute, thereby reducing the analytic and clinical sensitivity. The Dutch findings demonstrate the importance of optimizing outreach, specimen handling and testing protocols for self-samples to effectively screen the target population and reach in particular the women at highest risk for cervical cancer.

See related article by Aitken et al., p. 183
Racial Differences in Breast Cancer Therapeutic Toxicity: Implications for Practice
Authors: Rosenzweig Margaret Quinn , Mazanec Susan R.
Published: February 2023

Disparities in treatment intensity can contribute to racial disparities in overall breast cancer survival. A natural extension of measuring racial disparities in treatment intensity is consideration of the distribution of treatment toxicities, symptoms, and distress that lead to chemotherapy dose reductions, holds or early termination. There is growing evidence that therapeutic toxicity during early-stage breast cancer treatment may be greater among Black women than White. Important components of symptom management involve the communication of symptoms, the self-care abilities of the patient, the patient's perception of the clinical encounter, and the patient centeredness of the clinical encounter. Racial differences in the symptom reporting, the clinical “reception” and response to symptoms, the prescribed management, and the patient adherence to symptom management requires further investigation. Further research must also consider the structural inequities, as well as institutional and interpersonal racism that contribute to racial differences in cancer symptom burden leading to potential decreases in dose intensity of potentially life-saving early cancer treatment.

See related article by Hu et al., p. 167
Elucidating the Drivers for the Rising Incidence of Early-Onset Colorectal Cancer: How Ecologic Studies Could Help and What Is Next
Authors: Ni Peiyun , Lansdorp-Vogelaar Iris , Zauber Ann G. , Cao Yin
Published: February 2023

The incidence of colorectal cancer diagnosed before age 50, often referred to as early-onset colorectal cancer, has been increasing, whereas the overall colorectal cancer incidence has declined. Elucidating the drivers for the rising burden of early-onset colorectal cancer is a priority in cancer epidemiology and prevention. In this issue of Cancer Epidemiology, Biomarkers & Prevention, Chen and colleagues demonstrated that ecologic studies are a helpful method to reveal emerging risk factors at the population level and concluded that alcohol use might be a potential contributor to the rising incidence of early-onset colorectal cancer. Moving forward, because of the observed birth cohort effect in early-onset colorectal cancer, where younger generations have a steeper increase, hypothesis-driven investigations on emerging risk factors in recent generations, especially during early life, are warranted. Ultimately, the identified risk factors could be integrated with well-established microsimulation models of colorectal cancer, powerful tools that can simultaneously capture population-level secular changes in risk factors, relative risk estimates for each risk factor, and the natural history of colorectal cancer. This would allow us to quantitatively estimate the explained and unexplained portion of the rising incidence of early-onset colorectal cancer by calendar period and birth cohorts, and to help identify priorities in etiologic research, prevention, and early detection.

See related article by Chen et al., p. 217
Discovery of Targets for Immune–Metabolic Antitumor Drugs Identifies Estrogen-Related Receptor Alpha
Authors: Sahu Avinash , Wang Xiaoman , Munson Phillip , Klomp Jan P.G. , Wang Xiaoqing , Gu Shengqing Stan , Han Ya , Qian Gege , Nicol Phillip , Zeng Zexian , Wang Chenfei , Tokheim Collin , Zhang Wubing , Fu Jingxin , Wang Jin , Nair Nishanth Ulhas , Rens Joost A.P. , Bourajjaj Meriem , Jansen Bas , Leenders Inge , Lemmers Jaap , Musters Mark , van Zanten Sanne , van Zelst Laura , Worthington Jenny , Liu Jun S. , Juric Dejan , Meyer Clifford A. , Oubrie Arthur , Liu X. Shirley , Fisher David E. , Flaherty Keith T.
Published: February 2023

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell–specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune–metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti–PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.

Significance:

BipotentR presents resources for evaluating patient response and identifying targets for drugs that can kill tumors through multiple mechanisms concurrently. Inhibition of the topmost candidate target killed tumors by suppressing energy metabolism and effects on two immune mechanisms.

This article is highlighted in the In This Issue feature, p. 517
Black in Cancer: Two Years of Empowering the Next Generation
Authors: Bourne Christopher M. , Henderson Henry J. , White Elshaddai , Morris Julia , Bah Mamadou A. , Harewood Rhea , Pierre Stephanie , Martins Tanimola , Ntereke Tumisang , White Briana , Bonner Sigourney
Published: February 2023

In the 2 years since the inception of Black in Cancer, we have modeled an action-oriented commitment to improving Black representation across all levels of the cancer spectrum. We reflect on our successes and consider new ways to innovate and inspire the cancer community.
MAPK/AP-1 Signaling Pathway Is Involved in the Protection Mechanism of Bone Marrow Mesenchymal Stem Cells-Derived Exosomes against Ultraviolet-Induced Photoaging in Human Dermal Fibroblasts
Authors: Yan Tingting , Huang Lining , Yan Yunling , Zhong Yiping , Xie Heng , Wang Xiaohua
Published: February 2023

Introduction: The role of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exo) in skin photoaging was explored in human dermal fibroblasts (HDFs). The underlying mechanism was further explored. Methods: HDFs were exposed to UVB irradiation to establish the cell photodamage models. The cell viability and levels of oxidative stress-related factors were tested. ELISA was done to detect TNF-α, IL-6, and IL-1β concentrations. Western blot was applied for protein examination. Results: UVB treatment led to the inhibition of cell viability. But after BMSCs-exo addition, the inhibitory effect was returned in a dose manner. UVB exposure contributed to the increase of reactive oxygen species and LDH and the downregulation of superoxide dismutase. In addition, excessive secretion of TNF-α, IL-6, and IL-1β was also detected in cells exposed to UVB. However, BMSCs-exo addition eliminated the effects of UVB on oxidative stress and inflammation in HDFs. BMSCs-exo inhibited matrix metalloproteinases MMP-1 and MMP-3 expression but promoted collagen I expression. UVB radiation activated the MAPK/AP-1 signaling, manifested as the increase of p-p38, c-Jun, and c-Fos protein levels, which were reversed by BMSCs-exo. As a p38 agonist, anisomycin counteracted the effect of BMSCs-exo on HDF’s viability, oxidative stress, and inflammation. Conclusion: BMSCs-exo protected HDFs against UVB-induced inhibition of cell viability and the activation of cell oxidative stress and inflammation, which might be related to the inhibition of the MAPK/AP-1 signaling pathway.
Voice Improvement after Voice Therapy in Female Patients with Unilateral Vocal Fold Paralysis after Thyroid Surgery
Authors: Veselinović Mila , Škrbić Renata , Mumović Gordana , Dragičević Danijela , Despić Dajana , Milankov Vesela
Published: February 2023

Introduction: Dysphonic voice is present in patients with unilateral vocal fold paralysis (UVFP). The aim of this study was to present outcomes following rehabilitation of patients with UVFP, performed according to a voice therapy protocol. Methods: This prospective study comprised 27 women with UVFP who underwent pre- and post-voice therapy assessment. The mean age of patients was 53.19 ± 10.06 years. The protocol included the following: (1) multidimensional assessment of voice quality before treatment; (2) digital laryngeal manipulation voice therapy; (3) voice therapy evaluation which implied repeated multidimensional assessment of voice. Results: The results showed improvement in voice quality following voice therapy with regard to the parameters of the objective voice analysis (maximum fundamental frequency of voice, minimum intensity of voice, jitter, shimmer, harmonics-to-noise ratio, and signal-to-noise ratio, p ˂ 0.05), maximum phonation time, subjective analysis of voice, as well as self-assessment of voice quality on all the subscales and overall score (p ˂ 0.001). Conclusion: Implementing a protocol provides clear guidelines at each stage of the treatment. Voice therapy performed using digital laryngeal manipulation improves the majority of the acoustic and perceptual characteristics of the voice.
As estatais endógenas: reflexões doutrinárias sobre a natureza jurídica de uma velha (des)conhecida
Authors: Ribeiro Marcus Vinicius de Barros Magalhães
Published: February 2023

O presente artigo busca, por meio de pesquisa teórico-bibliográfica, investigar como a dogmática pátria vem tratando o fenômeno das Empresas Estatais que prestam suporte à própria Administração Pública, também denominadas de Empresas Estatais Endógenas. Após constatar que a natureza e o regime jurídico de tais Estatais, a despeito de suas relevantes peculiaridades, são artificialmente enquadrados, por parte significativa da doutrina administrativista, dentro da moldura dicotômica "prestação de serviço público/atividade econômica stricto sensu", este trabalho passa a propor um outro olhar, mais consentâneo com as múltiplas demandas e complexas atividades exercidas pela Administração Pública contemporânea.
O papel das agências reguladoras na tutela dos direitos do consumidor
Authors: Maradei Júnior João Carlos
Published: February 2023

Na década de 1990, o Estado brasileiro transferiu atividades econômicas, até então sob a égide do setor público, para a iniciativa privada. Nesse contexto, surgem as agências reguladoras no Brasil. Nesse artigo, iniciamos com um breve histórico sobre a criação das agências reguladoras, com destaque para o modelo americano.  Seguimos com abordagem acerca dos motivos que levaram a sua estruturação no Brasil para, então, analisar nuances da Lei Geral das Agências Reguladoras em âmbito federal, sempre sob a perspectiva da tutela dos direitos consumeristas. Trazemos exemplos, como do setor de energia elétrica, para demonstrar que, mesmo em período pandêmico, a “manutenção do equilíbrio” das relações de consumo, quando o assunto é tarifário, pende para um único lado. Abordamos sobre o recente regramento do setor de saneamento, refletindo sobre a necessidade de expansão dos serviços, porém, sem que isso onere mais o consumidor. Enfim, procuramos analisar criteriosamente se a atividade regulatória do Estado tem espelhado os anseios da coletividade ou tem privilegiado setores econômicos e políticos. Ponderamos, por fim, ser fundamental a harmonização dos interesses e a observância dos ditames constitucionais acerca dos direitos dos consumidores para que o modelo regulatório brasileiro atenda os fins para os quais se destina.
Novas perspectivas do processo decisório das agências reguladoras
Authors: Borges Marcelo Monteiro Bonelli , França Vladimir da Rocha , Silveira Neto Otacilio dos Santos
Published: February 2023

O presente artigo estuda o processo decisório das agências reguladoras e as novas perspectivas derivadas das últimas alterações legislativas. Através do método teórico-descritivo, apresentam-se as relações estabelecidas entre Direito, Economia e Regulação para se compreender as razões que levaram à institucionalização das Agências Reguladoras. Apresentadas as principais características dessas instituições, realiza-se o estudo do processo administrativo, definido como instituto jurídico que disciplina e estabelece o sequenciar de fatos e atos administrativos antecedentes à tomada de decisões pela Administração Pública. Assentadas as premissas, é explorado o processo decisório das Agências Reguladoras e os novos parâmetros legais que trouxeram contornos realista, consequencialista e eficientista ao atuar dessas Autarquias especializadas.
Modalidade de licitação Convite: do desuso à extinção pela Lei nº 14.133/2021
Authors: Nascimento Renato Humberto Marcelino , Cichovski Patrícia Kristiana Blagitz
Published: February 2023

O artigo intenciona lançar um olhar crítico sobre a Modalidade de Licitação Pública Convite, realizada no Estado do Pará, em relação à obediência aos princípios administrativos licitatórios, destacando seu desuso e sua extinção pela Nova Lei de Licitação. Trataremos da dessuetude do Convite, apontando as mitigações dos princípios em licitação, bem como seus prejuízos. Para o percurso metodológico utilizamos a pesquisa bibliográfica, em uma abordagem qualitativa, com análise documental das Leis 8.666/1993, 10.520/2002 e 14.133/2021, partindo da compreensão comparativa de dados primários extraídos do Portal Compras Pará, site oficial do governo do Estado do Pará. O problema consiste em apontar os possíveis vícios normativos e administrativos em relação aos princípios norteadores da Administração Pública, na modalidade de licitação Convite, que a levou ao desuso e à posterior extinção.
Os serviços sociais autônomos no Brasil como modelo jurídico-administrativo único
Authors: Almeida Edvaldo Nilo de
Published: February 2023

Este artigo tem por objetivo estudar a concretização dos direitos fundamentais pelos serviços sociais autônomos no Brasil como modelo jurídico-brasileiro exclusivo, sem paralelo em outros países, passando por sua criação por meio de lei, personalidade jurídica de direito privado, fontes de custeio e finalidade social. O artigo utilizou-se do método hipotético-dedutivo, com base em procedimentos bibliográficos e documentais, por meio de doutrina, jurisprudência, legislação e notícias sobre o tema pesquisado.  As conclusões estabelecem que os serviços sociais autônomos desempenham atividades vinculadas à assistência social ou ao ensino profissional de certos grupos sociais ou categorias profissionais, com recursos derivados de contribuições e dotações orçamentárias, e que, além dessas fundamentais atividades vinculadas a grupos sindicais, os serviços sociais autônomos vêm crescendo com contribuições relevantes em serviços voltados para toda a coletividade na área dos direitos fundamentais sociais.
Responsabilidade extracontratual do Estado por atos jurisdicionais: uma análise dos julgados do tribunal de justiça de Minas Gerais
Authors: Castro Carolainy Aparecida Souza , Lelis Davi Augusto Santana de
Published: February 2023

O trabalho apresentado estuda a responsabilidade extracontratual do Estado brasileiro –art. 37, §6º, da Constituição Federal de 1988 – aplicada aos atos jurisdicionais, de modo a se perquirir se o dispositivo constitucional incide ou não sobre esta espécie de ato. Foram propostas duas hipóteses de pesquisa, uma delas entendendo pela aplicação do art. 37, §6º, da Constituição de 1988 aos atos jurisdicionais e, a outra, contrária à primeira hipótese. Partimos da compreensão do que é a responsabilidade extracontratual do Estado, passando pela análise da figura dos magistrados no ordenamento jurídico do Brasil, pelas teorias que se relacionam à matéria e, ao final, analisamos julgados proferidos pelo Tribunal de Justiça do Estado de Minas Gerais, possibilitando a apreensão das consequências práticas do assunto em enfoque. Por meio do estudo da legislação e da teoria específica, do estabelecimento de relações entre temáticas jurídicas ligadas ao trabalho e do estudo da aplicação da responsabilidade extracontratual estatal na prática jurídica, foi possível concluir que o art. 37, §6º, do texto constitucional alcança os atos jurisdicionais, assim como traçar caminhos de pesquisa adicionais a serem trilhados em busca da consolidação do tema no ambiente jurídico brasileiro.
Lei, argumento e arte n’O Uraguai
Authors: Chauvin Jean Pierre
Published: February 2023

Neste artigo, propõe-se ler o poema O Uraguai, levando em conta pressupostos teológico-políticos e convenções poético-retóricas, sob o influxo da Lei da Boa Razão, promulgada pelo rei D. José I em 1769 – mesmo ano em que a epopeia de Basílio da Gama foi editada em Lisboa. A abordagem discute as categorias de autoria e literatura; problematiza os conceitos de verdade e originalidade e discute as concepções de nativismo e nacionalismo no universo setecentista luso-brasileiro.
O parecer da Real Mesa Censória: Certidão de nascimento de O Uraguai
Authors: Chaves Vania Pinheiro
Published: February 2023

Este artigo tem por objetivo transcrever e analisar o Parecer da Real Mesa Censória que, em 1769, permitiu a publicação de O Uraguai. Nele procura-se demonstrar que tal licença se deveu sobretudo às mudanças nas práticas da censura ocorridas no período pombalino. Assinala-se ainda que o perfil de João Pereira Ramos de Azevedo Coutinho, deputado que redigiu o relatório da censura, e os argumentos de que se serviu têm particular importância na liberação do poema épico basiliano.
O veneno da serpente e a beleza no rosto da morta: O suicídio de Lindoia em O Uraguai
Authors: Pinezi Gabriel Victor Rocha , André Willian
Published: February 2023

Apresentamos, neste artigo, algumas reflexões sobre um recorte bastante específico da narrativa lírica construída em O Uraguay (1769), de José Basílio da Gama: o suicídio de Lindóia, que toma corpo ao final do Canto IV do poema. Sem pretender desmerecer a riqueza contextual histórica e a fortuna crítica notável já produzida acerca da obra maior de Basílio da Gama, nossos esforços analíticos são concentrados, aqui, sobre alguns dos diversos aspectos que envolvem a morte voluntária de Lindóia, procurando estabelecer um diálogo com outras obras literárias e outras formas de manifestação artística, além do diálogo com estudos teóricos sobre o suicídio.
A muda linguagem das coisas
Authors: Finazzi-Agrò Ettore
Published: February 2023

O ensaio tenta, através da análise da obra de Clarice Lispector, responder à pergunta se é possível chegar até ao extremo do não-dito atravessando uma selva espessa de palavras, contrariando, assim, o movimento teogônico que acompanha a passagem do silêncio à voz (a phoné) e dela à palavra (o logos). A literatura produzida pela escritora brasileira nos coloca, de fato, diante de uma linguagem que perde, aos poucos, o seu sentido, reencontrando-o apenas num silêncio que nos diz aquele interdito que a palavra não consegue pronunciar, aquela essência que se esconde e, ao mesmo tempo, se revela nas entrelinhas ou no fundamento inacessível de todo discurso.
Para falar em verso convém saber falar: Basílio da Gama e "A declamação trágica"
Authors: Topa Francisco
Published: February 2023

O artigo é dedicado ao estudo do poema de José Basílio da Gama "A declamação trágica". Publicado em 1772, o texto é uma tradução livre ou adaptação de uma das partes da obra La Déclamation théâtrale, de Claude-Joseph Dorat. Depois de uma breve contextualização a propósito das ligações de Basílio ao teatro e de uma rápida apresentação de Dorat, procede-se a uma análise da tradução/adaptação. Destaca-se também a utilização do alexandrino, numa altura em que se faziam as primeiras experiências com este verso na língua portuguesa. O artigo termina com a edição crítica anotada do poema.
O Uraguai como fonte: A constituição do mito de Sepé Tiaraju
Authors: Póvoas Mauro Nicola , Moreira Maria Eunice
Published: February 2023

O artigo tem por objetivo o exame da trajetória literária do índio guarani Sepé Tiaraju, que morreu em 1756, em decorrência da Guerra Guaranítica, ocorrida na região das Missões, no Rio Grande do Sul, no âmbito do Tratado de Madri, um acordo entre as coroas portuguesa e espanhola visando à troca de terras na região meridional da América do Sul. Personagem de O Uraguai, poema épico de Basílio da Gama, Sepé, ao longo do século XX, torna-se protagonista de poemas e romances da literatura sul-rio-grandense, da autoria de João Simões Lopes Neto, Manoelito de Ornellas, Erico Verissimo, Fernandes Barbosa e Alcy Cheuiche, os quais serão aqui analisados.