bluuebunny/crossref_metadata_2025 huggingface dataset:
Large Eddy Simulation of the Flow Past a Soccer Ball
Authors: Iftikhar Sarmad , Sherbaz Salma , Haider Sehole Hafiz Ali , Maqsood Adnan , Mustansar Zartasha
Published: January 2022

The football game is the most popular, played, and loved sport around the world. The advent of technological breakthroughs and the continuous increase in consumer demand have led to a revolution in football’s design and manufacturing process. In the past, studies in soccer ball aerodynamics mainly were limited to the investigation of lift and drag forces inside a wind tunnel apparatus. A few researchers have analyzed the flow around the different soccer balls using computational fluid dynamics simulations with the Reynolds-Averaged-Navier–Stokes equations model. This study primarily intends to simulate a modern soccer ball (Adidas Telstar 18) using the Large Eddy Simulations technique. The whole research is divided into two phases. In the first phase, the flow around a smooth sphere is simulated numerically to validate the meshing strategy, boundary conditions, and solution methodology. The same modeling approach is used in the later stage to simulate the flow around a soccer ball. The effect of panels and seam on the boundary layer flow separation and overall turbulent flow structure around the soccer ball are visualized. The results indicate that the large-eddy simulations help predict the flow intricacies by resolving small eddies near the panels.
The Study of the Transport Mechanism of Isorhynchophylline in Liver
Authors: He Zhixian , Wang Jinyue , Wang Xing , Dong Yv
Published: January 2022

To investigate the transport mechanism of isorhynchophylline (IRN) by using the specific inhibitors of organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) and attempt illustrate the metabolic mechanism of IRN in the liver. All animals were randomly divided into three groups: control group (only inject IRN), RIF group (inject IRN and rifampicin), and ADR group (inject IRN and adrenalone). The control group was injected with IRN via the caudal vein. The RIF group was injected with rifampicin (RIF) by gavage, and after 1 h, IRN was injected into the caudal vein. Similarly, the ADR group received adrenalone by the caudal vein, and after 0.5 h, IRN was injected into the caudal vein. Thereafter, blood samples were obtained by the heart punctures at 90 min, 180 min, and 300 min following drug administration. Rats were sacrificed at 300 min after drug administration; then, the liver tissue was harvested. The level of IRN was measured by using high-performance liquid chromatography (HPLC), and the Kp values were calculated. After RIF administration (OATPs inhibitors), the Kp value of IRN was slightly decreased when compared with that of the control group. Meanwhile, the Kp value of IRN was dramatically reduced compared to that of the control group following ADR administration (OCTs inhibitors). The results suggested that OCTs have mainly participated in the hepatic uptake process of IRN.
Deep Neural Embedding for Software Vulnerability Discovery: Comparison and Optimization
Authors: Yuan Xue , Lin Guanjun , Tai Yonghang , Zhang Jun
Published: January 2022

Due to multitudinous vulnerabilities in sophisticated software programs, the detection performance of existing approaches requires further improvement. Multiple vulnerability detection approaches have been proposed to aid code inspection. Among them, there is a line of approaches that apply deep learning (DL) techniques and achieve promising results. This paper attempts to utilize CodeBERT which is a deep contextualized model as an embedding solution to facilitate the detection of vulnerabilities in C open-source projects. The application of CodeBERT for code analysis allows the rich and latent patterns within software code to be revealed, having the potential to facilitate various downstream tasks such as the detection of software vulnerability. CodeBERT inherits the architecture of BERT, providing a stacked encoder of transformer in a bidirectional structure. This facilitates the learning of vulnerable code patterns which requires long-range dependency analysis. Additionally, the multihead attention mechanism of transformer enables multiple key variables of a data flow to be focused, which is crucial for analyzing and tracing potentially vulnerable data flaws, eventually, resulting in optimized detection performance. To evaluate the effectiveness of the proposed CodeBERT-based embedding solution, four mainstream-embedding methods are compared for generating software code embeddings, including Word2Vec, GloVe, and FastText. Experimental results show that CodeBERT-based embedding outperforms other embedding models on the downstream vulnerability detection tasks. To further boost performance, we proposed to include synthetic vulnerable functions and perform synthetic and real-world data fine tuning to facilitate the model learning of C-related vulnerable code patterns. Meanwhile, we explored the suitable configuration of CodeBERT. The evaluation results show that the model with new parameters outperform some state-of-the-art detection methods in our dataset.
ROS-Induced Oxidative Damage and Mitochondrial Dysfunction Mediated by Inhibition of SIRT3 in Cultured Cochlear Cells
Authors: Zhang Lingjun , Du Zhengde , He Lu , Liang Wenqi , Liu Ke , Gong Shusheng
Published: January 2022

Sensorineural hearing loss (SNHL) is one of the most common causes of disability worldwide. Previous evidence suggests that reactive oxygen species (ROS) may play an important role in the occurrence and development of SNHL, while its mechanism remains unclear. We cultured dissected organs of Corti in medium containing different concentrations (0, 0.25, 0.5, 0.75, 1, and 1.25 mM) of hydrogen peroxide (H2O2) and established a four-concentration model of 0, 0.5, 0.75, and 1 mM to study different degrees of damage. We examined ROS-induced mitochondrial damage and the role of sirtuin 3 (SIRT3). Our results revealed that the number of ribbon synapses and hair cells appeared significantly concentration-dependent decrease with exposure to H2O2. Outer hair cells (OHCs) and inner hair cells (IHCs) began to be lost, and activation of apoptosis of hair cells (HCs) was observed at 0.75 mM and 1 mM H2O2, respectively. In contrast with the control group, the accumulation of ROS was significantly higher, and the mitochondrial membrane potential (MMP) was lower in the H2O2-treated groups. Furthermore, the expression of SIRT3, FOXO3A, and SOD2 proteins declined, except for an initial elevation of SIRT3 between 0 and 0.75 mM H2O2. Administration of the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine resulted in increased damage to the cochlea, including loss of ribbon synapses and hair cells, apoptosis of hair cells, more production of ROS, and reduced mitochondrial membrane potential. Thoroughly, our results highlight that ROS-induced mitochondrial oxidative damage drives hair cell degeneration and apoptosis. Furthermore, SIRT3 is crucial for preserving mitochondrial function and protecting the cochlea from oxidative damage and may represent a possible therapeutic target for SNHL.
Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals
Authors: Ahmad Saheem , Alouffi Sultan , Khan Saif , Khan Mahvish , Akasha Rihab , Ashraf Jalaluddin Mohammad , Farhan Mohd , Shahab Uzma , Khan Mohd Yasir
Published: January 2022

Hundreds of millions of people around the globe are afflicted by diabetes mellitus. The alteration in glucose fixation process might result into hyperglycaemia and could affect the circulating plasma proteins to undergo nonenzymatic glycation reaction. If it is unchecked, it may lead to diabetes with increase in advanced glycation end products (AGEs). Therefore, the present study was designed to inhibit the diabetes and glycation by using natural antioxidant “ellagic acid” (EA). In this study, we explored the antidiabetes and antiglycation potential of EA in both in vitro (EA at micromolar concentration) and in vivo systems. The EA concentrations of 10 and 20 mg kg-1B.W./day were administered orally for 25 days to alloxan‐induced diabetic rats, a week after confirmation of stable diabetes in animals. Intriguingly, EA supplementation in diabetic rats reversed the increase in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) level. EA also showed an inhibitory role against glycation intermediates including dicarbonyls, as well as AGEs, investigated in a glycation mixture with in vitro and in vivo animal plasma samples. Additionally, EA treatment resulted in inhibition of lipid peroxidation‐mediated malondialdehyde (MDA) and conjugated dienes (CD). Furthermore, EA exhibited an antioxidant property, increased the level of plasma glutathione (GSH), and also helped to decrease histological changes evaluated by histoimmunostaining of animal kidney tissues. The results from our investigation clearly indicates the antiglycative property of EA, suggesting EA as an adequate inhibitor of glycation and diabetes, which can be investigated further in preclinical settings for the treatment and management of diabetes‐associated complications.
Exosome-Mediated miR-4792 Transfer Promotes Bladder Cancer Cell Proliferation via Enhanced FOXC1/c-Myc Signaling and Warburg Effect
Authors: Wu Jian-Hong , Sun Ke-Ning , Chen Zhi-Hao , He Yi-Jun , Sheng Lu
Published: January 2022

Bladder cancer is the second-most common malignancy in the urogenital system and the most common in men. However, our understanding of the driving mechanisms of bladder cancer remains incomplete. The forkhead box (FOX) family of transcription factors is implicated in urogenital development and bladder malignancies. Many exosomal microRNAs have been identified as regulators and mediators of the expression of FOX, including the expression of FOXC1. miR-4792 has been known as a tumor miRNA suppressor. However, the function of miR-4792/FOXC1 signaling in bladder cancer development remains unknown. Here, we studied the role of miR-4792/FOXC1 signaling in bladder cancer by using multiple bladder cancer cell lines and bladder cancer mouse models through in vitro and in vivo approaches. We showed that FOXC1 is highly expressed in multiple bladder cancer cell lines and bladder tumor tissues. The knockdown of FOXC1 expression in bladder cancer cell lines decreases c-Myc expression levels, retards cell growth, and reduces aerobic glycolysis (also known as the Warburg effect) and lactic acid content. By contrast, the overexpression of FOXC1 elicits the opposite effects. FOXC1-downregulated bladder cancer cells form significantly smaller tumors in vivo. The inhibition of c-Myc reverses the effects of FOXC1 overexpression and leads to reduced cell proliferation, aerobic glycolysis, and lactic acid content. miR-4792 expression is downregulated in bladder tumor tissues. miR-4792 exposure to bladder cancer cells reduces the expression levels of FOXC1 and c-Myc, slows down cell growth, and decreases aerobic glycolysis and lactic acid content. However, the enhanced miR-4792 expression elicits opposite effects. These findings provided the first evidence that the exosome-mediated delivery of miR-4792 could play an important role in bladder cancer development through the downregulation of FOXC1 and c-Myc, which further inhibited aerobic glycolysis and lactic acid content.
Perceived Security Risk Based on Moderating Factors for Blockchain Technology Applications in Cloud Storage to Achieve Secure Healthcare Systems
Authors: Mustafa Malik , Alshare Marwan , Bhargava Deepshikha , Neware Rahul , Singh Balbir , Ngulube Peter
Published: January 2022

Due to the high amount of electronic health records, hospitals have prioritized data protection. Because it uses parallel computing and is distributed, the security of the cloud cannot be guaranteed. Because of the large number of e-health records, hospitals have made data security a major concern. The cloud’s security cannot be guaranteed because it uses parallel processing and is distributed. The blockchain (BC) has been deployed in the cloud to preserve and secure medical data because it is particularly prone to security breaches and attacks such as forgery, manipulation, and privacy leaks. An overview of blockchain (BC) technology in cloud storage to improve healthcare system security can be obtained by reading this paper. First, we will look at the benefits and drawbacks of using a basic cloud storage system. After that, a brief overview of blockchain cloud storage technology will be offered. Many researches have focused on using blockchain technology in healthcare systems as a possible solution to the security concerns in healthcare, resulting in tighter and more advanced security requirements being provided. This survey could lead to a blockchain-based solution for the protection of cloud-outsourced healthcare data. Evaluation and comparison of the simulation tests of the offered blockchain technology-focused studies can demonstrate integrity verification with cloud storage and medical data, data interchange with reduced computational complexity, security, and privacy protection. Because of blockchain and IT, business warfare has emerged, and governments in the Middle East have embraced it. Thus, this research focused on the qualities that influence customers’ interest in and approval of blockchain technology in cloud storage for healthcare system security and the aspects that increase people’s knowledge of blockchain. One way to better understand how people feel about learning how to use blockchain technology in healthcare is through the United Theory of Acceptance and Use of Technology (UTAUT). A snowball sampling method was used to select respondents in an online poll to gather data about blockchain technology in Middle Eastern poor countries. A total of 443 randomly selected responses were tested using SPSS. Blockchain adoption has been shown to be influenced by anticipation, effort expectancy, social influence (SI), facilitation factors, personal innovativeness (PInn), and a perception of security risk (PSR). Blockchain adoption and acceptance were found to be influenced by anticipation, effort expectancy, social influence (SI), facilitating conditions, personal innovativeness (PInn), and perceived security risk (PSR) during the COVID-19 pandemic, as well as providing an overview of current trends in the field and issues pertaining to significance and compatibility.
Intelligent CO2 Monitoring for Diagnosis of Sleep Apnea Using Neural Cryptography Techniques
Authors: Hamza Manar Ahmed , Althobaiti Maha M. , Ali Ola Abdelgney Omer , Larabi-Marie-Sainte Souad , Eltahir Majdy M. , Hilal Anwer Mustafa , Al Duhayyim Mesfer , Yaseen Ishfaq
Published: January 2022

In biomass wastage, carbon is one of the adsorbent materials. Biomass wastage contains complex materials, and pressure, various temperatures, and presence of various chemical components which are subjected to the adsorption of carbon are a tedious task, and it is used in the sustainable waste management system. While screening the biomass wastage management system, prediction of activated carbon’s quality and understanding of the mechanism of adsorption of [Formula: see text] are a complicated task. Many research works have been developed; the main issues are inaccurate and inefficient prediction of carbon available in the various feedstock of biomass wastage. To overcome these issues, this paper proposed gene expression programming (GEP) with [Formula: see text]-nearest neighbour (GEP-KNN). The key advantage of the proposed work shows excellent performance in the prediction of adsorbing carbon and accuracy. The accuracy of the GEP-KNN algorithm with different [Formula: see text] values produced the highest accuracy at [Formula: see text] and [Formula: see text] of 95.12% and 95.67%; the lowest accuracy is [Formula: see text] of 65.34%.
The Value of CT Angiography Based on Intelligent Segmentation Algorithm for Survival of Hemodialysis Patients
Authors: Luo Wei , Zhang Ruidong , He Da , Sun Zhenyi , Zhou Yunlong , Cheng Li , Li Hongbo
Published: January 2022

This study was to explore the application value for central venous stenosis and occlusion in hemodialysis patients under the CT angiography based on intelligent segmentation algorithm, so that patients can survive better. Spiral CT was used to examine upper limb swelling in 62 uremic hemodialysis patients at a speed of 3.8 mL/s. Nonionic iodine contrast agent was injected around the contralateral limb. The total dosage of 90-102 mL, it was scanned by intelligent trigger technology. The trigger scanning threshold was set. The monitoring point was located in the superior vena cava. CT with convolutional neural network intelligent segmentation algorithm was used to process image data. Finally, the quality of life and related biochemical levels of patients before and after hemodialysis were detected. Under the CT angiography of intelligent segmentation algorithm, 77 stenoses were found in 62 uremic patients, including 48 stenoses of the brachial vein and 17 stenoses of the superior vena cava. The correlation coefficient between CT angiography and digital subtraction angiography (DSA) imaging results of intelligent segmentation algorithm was 0.411. Segmentation effect of the algorithm in this study: automatic segmentation accuracy was greater than 79%. After hemodialysis treatment, the scores of physical fitness, pain, social function, and energy status of patients were significantly increased compared with those before treatment, and the levels of albumin, serum phosphorus, and parathyroid hormone were significantly decreased (

P
<
0.05

). In summary, CT angiography with intelligent segmentation algorithm can obtain clear, intuitive, and complete vascular walking images, and better display subclavian vein, brachiocephalic vein, and superior vena cava. It can provide more valuable support for surgical intervention and has certain application value for better survival of hemodialysis patients.
Cinnamaldehyde Downregulation of Sept9 Inhibits Glioma Progression through Suppressing Hif-1α via the Pi3k/Akt Signaling Pathway
Authors: Wang Zhiwen , Wang Changfeng , Fu Jieping , Liu Ruen , Zhou Xinhui
Published: January 2022

Purpose. Cinnamaldehyde (CA) is the main ingredient in cinnamon, and it has been proven to have an inhibitory effect on many different tumor types. However, it lacks effect on glioma. This paper explores the effect CA has on glioma cells U87 and U251 at the cellular and molecular levels. Methods. The relationship between Hif-1α and Sept9 was found by CGGA. Cell Viability Assay (CCK8) was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. Annexin V-FITC/PI were used to detect the cell apoptosis. Western blotting was used to determine the specified protein level. Results. Cell proliferation assay results revealed CA to inhibit the proliferation of glioma cells in a dose-dependent manner. It promoted apoptosis for upregulating the expression of Bax and downregulating the expression of Bcl-2. Wound Healing Assay and transwell test found CA to have anti-invasion ability and that it upregulated the expression of E-cadherin and downregulated the expressions of MMP-2 and MMP-9. The molecular mechanism was studied from a tumor microenvironment (TME) perspective. Pi3k inhibitor (LY294002) was used for interfering with cells, and the results found CA to demonstrate a similar effect. Hif-1α and Sept9 expressions were inhibited, and Akt and p-Akt were also inhibited. By using CoCl2 to make hypoxia, CA was discovered to inhibit the high expression of Hif-1α and Sept9, demonstrating a correlation with the Pi3k/Akt pathway. It is suggested that the mechanism of Sept9 under hypoxia regulation can be realized through the Pi3k/Akt pathway. Conclusions. This study proves for the first time that CA is an effective drug for inhibiting the proliferation of glioma through Sept9 and reveals Sept9 to be related to the Pi3k/Akt pathway in terms of tumor microenvironment, providing a molecular basis for the further study of CA in glioma treatment.
Evaluating the Performance of Feature Selection Methods Using Huge Big Data: A Monte Carlo Simulation Approach
Authors: Khan Faridoon , Urooj Amena , Khan Saud Ahmed , Khosa Saima K. , Muhammadullah Sara , Almaspoor Zahra
Published: January 2022

In this article, we compare autometrics and machine learning techniques including Minimax Concave Penalty (MCP), Elastic Smoothly Clipped Absolute Deviation (E-SCAD), and Adaptive Elastic Net (AEnet). For simulation experiments, three kinds of scenarios are considered by allowing the multicollinearity, heteroscedasticity, and autocorrelation conditions with varying sample sizes and the varied number of covariates. We found that all methods show improved their performance for a large sample size. In the presence of low and moderate multicollinearity and low and moderate autocorrelation, the considered methods retain all relevant variables. However, for low and moderate multicollinearity, excluding AEnet, all methods keep many irrelevant predictors as well. In contrast, under low and moderate autocorrelation, along with AEnet, the Autometrics retain less irrelevant predictors. Considering the case of extreme multicollinearity, AEnet retains more than 93 percent correct variables with an outstanding gauge (zero percent). However, the potency of remaining techniques, specifically MCP and E-SCAD, tends towards unity with augmenting sample size but capturing massive irrelevant predictors. Similarly, in case of high autocorrelation, E-SCAD has shown good performance in the selection of relevant variables for a small sample, while in gauge, Autometrics and AEnet are performed better and often retained less than 5 percent irrelevant variables. In the presence of heteroscedasticity, all techniques often hold all relevant variables but also suffer from overspecification problems except AEnet and Autometrics which circumvent the irrelevant predictors and establish the true model precisely. For an empirical application, we take into account the workers’ remittance data for Pakistan along its twenty-seven determinants spanning from 1972 to 2020 for Pakistan. The AEnet selected thirteen relevant covariates of workers’ remittance while E-SCAD and MCP suffered from an overspecification problem. Hence, the policymakers and practitioners should focus on the relevant variables selected by AEnet to improve workers' remittance in the case of Pakistan. In this regard, the Pakistan government has devised policies that make it easy to transfer remittances legally and mitigate the cost of transferring remittances from abroad. The AEnet approach can help policymakers arrive at relevant variables in the presence of a huge set of covariates, which in turn produce accurate predictions.
Strengthening of Traditional Chinese Medicine in the Health System Reform: Effect on Health Outcomes and Financial Protection
Authors: He Ping , Zhu Dawei , Man Xiaowei , Bai Qian , Huang Lieyu , Shi Xuefeng , Meng Qingyue
Published: January 2022

Background. The challenges of modern medicine in addressing chronic diseases necessitate a shift of attention towards traditional medicine (TM) and other supplementary care systems. China has prioritized the strengthening of traditional Chinese medicine (TCM) in the health system reform since 2009. This study sought to assess the effects of the reform on TCM and the resultant effect of a strengthened TCM on health outcomes and financial protection. Methods. Longitudinal data were obtained from the China Statistical Yearbook, China Health Statistical Yearbook, China Population Statistical Yearbook, and Statistical Extract of Traditional Chinese Medicine in 31 provinces of mainland China between 2002 and 2016. Dependent variables included health outcomes measured by age-standardized excess mortality and life expectancy at birth and financial protection measured by the proportion of health expenses in total consumption expenses. The independent variables consisted of the number and proportion of TCM physicians. The fixed effects (FEs) models were established to identify the effect of the independent variables on outcomes. Results. From 2009 to 2016, the number and proportion of TCM physicians increased from 22 to 36 physicians per 100,000 population and from <12% to >15%, respectively. The changes were more rapid and higher than that in the period before the reform. An increase of 1 TCM physician per 100,000 population was associated with a decrease of 1.944 excess deaths, a 5.84-day increase in male life expectancy, and a decrease of 0.051% of health expenses among both urban and rural residents. An increase in proportion of 1% of TCM physicians was associated with a decrease of 5.097 excess deaths, a 17.52-day increase of life expectancy (both genders), an increase of 21.535-day in life expectancy (males) per 100,000 population, and a decrease of 0.082% of health expenses among rural residents. Conclusion. During China’s health system reform, the increased physician number has strengthened TCM. Higher TCM physician supply was associated with improved health outcomes and financial protection, which implies that the reform may have important implications on health system performance in China.
In Vitro Regeneration of Korarima (Aframomum corrorima (Braun) P. C. M. Jansen): A Threatened Spice and Medicinal Herb from Ethiopia
Authors: Hailu Tilahun , Haileselassie Teklehaimanot , Feyissa Tileye
Published: January 2022

Developing an in vitro regeneration system is very important to increase production and productivity of plants as well as for the conservation of rare and threatened medicinal plants like korarima (Aframomum corrorima (Braun) P. C. M. Jansen). To date, no study dealing with in vitro indirect regeneration system of korarima has been reported. Thus, in this study, we developed an efficient and reproducible protocol for in vitro regeneration of korarima via callus. The procedure involved soaking seeds in 50% H2SO4 for 16 h that resulted in 92.5% germination on plant growth regulators (PGRs)-free half-strength Murashige and Skoog (MS) basal medium after a month. Shoot and rhizome induction rate of 93.75% was obtained on the MS medium containing 1.5 mg/l BAP in combination with 0.1 mg/l IBA after five weeks. Whitish yellow friable callus was obtained from rhizome culture taken from in vitro grown plantlets. The MS medium containing 2.0 mg/l 2, 4D in combination with 0.5 mg/l kinetin, resulted in 77.5% callus induction. The shoot regeneration rate of 45% was obtained from callus on the MS medium containing 2.0 mg/l TDZ in combination with 0.5 mg/l IBA. The mean shoot number of 10.83 per explant was obtained upon multiplication on the MS medium containing 1.5 mg/l BAP with a mean shoot height of 5.37 cm. The best rooting responses were obtained on half MS medium supplemented with 0.5 mg/l IAA resulting in a mean number of root of 18.59, mean root length of 9.71 cm, and mean shoot height of 7.32 cm. The plantlets showed 75% survival efficiency after acclimatization. The present regeneration protocol offers a conceivable system towards effective conservation and genetic improvement of the crop by increasing the efficiency of genetic transformation.
Few, but Efficient: The Role of Mast Cells in Breast Cancer and Other Solid Tumors
Authors: Majorini Maria Teresa , Colombo Mario Paolo , Lecis Daniele
Published: January 2022

Tumor outcome is determined not only by cancer cell–intrinsic features but also by the interaction between cancer cells and their microenvironment. There is great interest in tumor-infiltrating immune cells, yet mast cells have been less studied. Recent work has highlighted the impact of mast cells on the features and aggressiveness of cancer cells, but the eventual effect of mast cell infiltration is still controversial. Here, we review multifaceted findings regarding the role of mast cells in cancer, with a particular focus on breast cancer, which is further complicated because of its classification into subtypes characterized by different biological features, outcome, and therapeutic strategies.
Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment
Authors: Yaddanapudi Kavitha , Stamp Bryce F. , Subrahmanyam Priyanka B. , Smolenkov Andrei , Waigel Sabine J. , Gosain Rahul , Egger Michael E. , Martin Robert C.G. , Buscaglia Robert , Maecker Holden T. , McMasters Kelly M. , Chesney Jason A.
Published: January 2022

Purpose:

Improving our understanding of the immunologic response to cancer cells within the sentinel lymph nodes (SLN) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity.

Experimental Design:

We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T-cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of patients with melanoma.

Results:

We found increased effector-memory αβ T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non–melanoma-bearing SLNs, consistent with possible activation of an antitumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells, which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared with non–melanoma-bearing SLNs include (i) reduced CD8+CD69+ T cell/T regulatory cell ratio, (ii) high PD-1 expression on CD4+ and CD8+ T cells, and (iii) high CTLA-4 expression on γδ T cells.

Conclusions:

Our data suggest that these immunologic changes compromise antimelanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti–PD-1 antibodies prior to SLN resection in patients with stage III melanoma.

See related commentary by Lund, p. 1996
Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors
Authors: Palmer Adam C. , Izar Benjamin , Hwangbo Haeun , Sorger Peter K.
Published: January 2022

Purpose:

Combinations of immune-checkpoint inhibitors (ICI) with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are under way to test new combinations. However, the mechanisms that account for the superiority of approved ICI combinations relative to their constituent monotherapies remain unknown.

Experimental Design:

We analyzed 13 phase III clinical trials testing combinations of ICIs with each other or other drugs in patients with advanced melanoma and lung, breast, gastric, kidney, and head and neck cancers. The clinical activity of the individual constituent therapies, measured in the same or a closely matched trial cohort, was used to compute progression-free survival (PFS) curves expected under a model of independent drug action. To identify additive or synergistic efficacy, PFS expected under this null model was compared with observed PFS by Cox regression.

Results:

PFS elicited by approved combination therapies with ICIs could be accurately predicted from monotherapy data using the independent drug action model (Pearson r = 0.98, P < 5 × 10−9, N = 4,173 patients, 8 types of cancer). We found no evidence of drug additivity or synergy except in one trial in which such interactions might have extended median PFS by 9 days.

Conclusions:

Combining ICIs with other cancer therapies affords predictable and clinically meaningful benefit by providing patients with multiple chances of response to a single agent. Conversely, there exists no evidence in phase III trials that other therapies interact with and enhance the activity of ICIs. These findings can inform the design and testing of new ICI combination therapies while emphasizing the importance of developing better predictors (biomarkers) of ICI response.
The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer
Authors: Ma Cynthia X. , Luo Jingqin , Freedman Rachel A. , Pluard Timothy J. , Nangia Julie R. , Lu Janice , Valdez-Albini Frances , Cobleigh Melody , Jones Jason M. , Lin Nancy U. , Winer Eric P. , Marcom P. Kelly , Thomas Shana , Anderson Jill , Haas Brittney , Bucheit Leslie , Bryce Richard , Lalani Alshad S. , Carey Lisa A. , Goetz Matthew P. , Gao Feng , Kimmick Gretchen , Pegram Mark D. , Ellis Matthew J. , Bose Ron
Published: January 2022

Purpose:

HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor–positive (ER+) breast cancer.

Patients and Methods:

In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER−)/HER2mut MBC received neratinib monotherapy in an exploratory ER− cohort (n = 5).

Results:

The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%–62%), 30% (7%–65%), and 25% (1%–81%) in the fulvestrant-treated, fulvestrant-naïve, and ER− cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression.

Conclusions:

Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.
First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy
Authors: Diamond Jennifer R. , Boni Valentina , Lim Emerson , Nowakowski Grzegorz , Cordoba Raul , Morillo Daniel , Valencia Ray , Genvresse Isabelle , Merz Claudia , Boix Oliver , Frigault Melanie M. , Greer Joy M. , Hamdy Ahmed M. , Huang Xin , Izumi Raquel , Wong Harvey , Moreno Victor
Published: January 2022

Purpose:

To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor.

Patients and Methods:

Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined.

Results:

Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment).

Conclusions:

VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
SynPathy: Predicting Drug Synergy through Drug-Associated Pathways Using Deep Learning
Authors: Tang Yi-Ching , Gottlieb Assaf
Published: January 2022

Drug combination therapy has become a promising therapeutic strategy for cancer treatment. While high-throughput drug combination screening is effective for identifying synergistic drug combinations, measuring all possible combinations is impractical due to the vast space of therapeutic agents and cell lines. In this study, we propose a biologically-motivated deep learning approach to identify pathway-level features from drug and cell lines' molecular data for predicting drug synergy and quantifying the interactions in synergistic drug pairs. This method obtained an MSE of 70.6 ± 6.4, significantly surpassing previous approaches while providing potential candidate pathways to explain the prediction. We further demonstrate that drug combinations tend to be more synergistic when their top contributing pathways are closer to each other on a protein interaction network, suggesting a potential strategy for combination therapy with topologically interacting pathways. Our computational approach can thus be utilized both for prescreening of potential drug combinations and for designing new combinations based on proximity of pathways associated with drug targets and cell lines.

Implications:

Our computational framework may be translated in the future to clinical scenarios where synergistic drugs are tailored to the patient and additionally, drug development could benefit from designing drugs that target topologically close pathways.
Osilodrostat for Cushing Disease and Its Role in Pediatrics
Authors: Groselj Urh , Sikonja Jaka , Battelino Tadej
Published: January 2022

Background: Cushing disease (CD) is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of CD can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of CD are early or delayed puberty and hyperandrogenism in girls. Summary: We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for CD, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population. Key Messages: Osilodrostat is the first adrenal steroidogenesis inhibitor to be European Medicines Agency- and United States Food and Drug Administration-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary-free cortisol and a good safety profile. Osilodrostat’s pharmacological properties and safety are currently being evaluated in a small Phase II trial (NCT03708900) – the first trial in the pediatric population (<18 years) with an estimated completion date in the year 2023.
Can the Stone Scoring Systems Be Used to Predict Infective Complications of Retrograde Intrarenal Surgery?
Authors: Senel Samet , Ozden Cuneyt , Aslan Yilmaz , Kizilkan Yalcin , Gokkaya Cevdet Serkan , Aktas Binhan Kagan
Published: January 2022

Objective: We aimed to evaluate whether the retrograde intrarenal surgery (RIRS) scoring systems (Resorlu-Unsal Stone Score [RUSS], modified Seoul National University Renal Stone Complexity Score [modified S-ReCS], and R.I.R.S. score) can predict the infective complications after RIRS. Subject and Methods: A total of 581 patients who underwent RIRS for kidney stones were included in the study. All patients were evaluated for demographic data, medical history, radiological imaging methods before surgery, duration of surgery, and hospitalization time after surgery. Stone laterality, stone burden, stone size, stone density, the number of stones, stone localization, the presence of congenital kidney anomaly, and solitary kidney were evaluated preoperatively by computed tomography. The RUSS and modified S-ReCS and R.I.R.S. score of all patients were determined. Results: Infective complications were detected in 47 (8.1%) patients who underwent RIRS. Fever developed in 27 subjects (4.6%), urinary infection in 15 (2.5%), sepsis in 2 (0.3%), and septic shock in 3 (0.5%) patients. In multivariate logistic regression analysis, age (OR = 1.8; 95% CI = 1–3.4; p = 0.049), surgical duration of >60 min (OR = 1.9; 95% CI = 1.1–3.5; p = 0.027), and high R.I.R.S score (OR = 8.9; 95% CI = 1.9–42.4; p = 0.006) were shown to be independent risk factors for the infective complications after RIRS. A receiver operating characteristic curve analysis showed that the R.I.R.S. score can be used as a marker to predict infective complications (AUC = 0.619, CI = 0.55–0.69; p = 0.007). Conclusion: We suggest that the R.I.R.S. score can be used to predict infective complications in RIRS.
The Influence of Competence, Training and Employee Placement in Em-ployee Performance in Technical Executive Unit of Regional Finance Agen-cy, Bangka Belitung Islands Province, Bangka Regency
Authors: Mufti Muhammad Yusuf Khalied , Reniati Reniati , Hamsani Hamsani
Published: January 2022

The research was motived by the existing condition showing that employees have not been able to work optimally in a government agency. This study aimed to analyze and examine the influence of competence, training, and employee placement on employee performance in the Technical Executive Unit of Regional Financial Agency of Bangka Belitung Islands Province, Bangka Regency. This study is descriptive research. The method used was the quantitative research method because the data obtained was in the form of numbers derived from questionnaires. The number of samples was 44 respondents generated by the saturated sample method. The analysis model utilized multiple linear regression, with the t-test, f-test, and coefficient of determination. Based on multiple linear regression analysis found Y = 8,669 + 0,283 X1 + 0,447 X2 + 0,256 X3. Based on the results of research on competence, training and employee placement partially have a positive and significant effect on the performance of the employee of the Regional Finance Office of Bangka Regency, Bangka Belitung. Based on the results of the simultaneous test, it is known that competence, training and employee placement together have a significant effect onthe performance of the employees, while the results of the analysis of the coefficient of determination (R2) show the determination of R2 in this study is 76% and there are still 24% of other variables outside the study that can still be developed for further research.
Keterkaitan Antar Industri dan Antar Wilayah bagi Perekonomian Sulawe-si Barat: Studi Dampak Gempa
Authors: Wulandari Mirta Dwi , Ulfah Nasiyatul
Published: January 2022

Perekonomian Sulawesi Barat saling terkait antar industri dan antar wilayah. Kejadian gempa di Sulawesi Barat mungkin berdampak pada perekonomian wilayah sendiri dan wilayah lain. Penelitian ini bertujuan untuk mempelajari keterkaitan antar industri dan antar wilayah bagi perekonomian Sulawesi Barat, khususnya dengan adanya gempa bumi. Metode yang digunakan adalah analisis model IRIO. Hasil analisis IRIO menunjukkan bahwa lapangan Usaha Pertanian, Kehutanan, dan Perikanan yang memiliki share terbesar terhadap perekonomian Sulawesi Barat merupakan industri yang potensial untuk dikembangkan. Lapangan Usaha Pengadaan Air dan Gas; dan Industri Pengolahan merupakan industri unggulan di Sulawesi Barat. Adanya gempa bumi menyebabkan output dan NTB yang tercipta secara nasional turun sebesar 1.378,30 miliar rupiah dan 809,79 miliar rupiah. Dampak gempa juga dirasakan oleh provinsi lain. Provinsi yang merasakan dampak terbesar terhadap penurunan output dan NTB adalah DKI Jakarta, Sulawesi Selatan, Sulawesi Tengah, Jawa Tengah, dan Banten. Industri unggulan perlu dioptimalisasi kinerja guna mempercepat pemulihan ekonomi Sulawesi Barat.
Identifikasi Industri Unggulan untuk Akselerasi Pemulihan Ekonomi di Sulawesi Selatan dan Dampaknya pada Wilayah Lain di Indonesia
Authors: Lestari Wahyu Puji , Ruslam
Published: January 2022

Perencanaan pembangunan berdasarkan aspek kewilayahan membutuhkan tools untuk menentukan kebijakan kewilayahan. Data Inter Regional Input-Output (IRIO) dapat dimanfaatkan untuk mendukung kebijakan perekonomian suatu wilayah. Tabel IRIO mampu memberikan informasi mengenai struktur ketergantungan sektoral (sectoral interdependency) maupun ketergantungan antarwilayah (regional interdependency). Studi ini dilakukan untuk menganalisis keterkaitan antar industri di Sulawesi Selatan dan  menganalisis perekonomian Sulawesi Selatan dan hubungannya dengan wilayah lainnya menggunakan  tabel Inter Regional Input-Output (IRIO) 2016 yang telah diterbitkan oleh Badan Pusat Statistik pada tahun 2021 untuk mengidentifikasi industri unggulan dan dampaknya pada wilayah lainnya.Hasil analisis menunjukkan bahwa ada dua industri unggulan di Provinsi Sulawesi Selatan, yaitu Pengadaan Listrik dan Gas dan Industri Pengolahan. Selanjutnya, analisis antar wilayah menunjukkan bahwa shock permintaan akhir di Provinsi Sulawesi Selatan berdampak besar terhadap perekonomian provinsi-provinsi di Pulau Jawa, khususnya DKI Jakarta. Di sisi lain, perekonomian Sulawesi Selatan sangat dipengaruhi oleh shock permintaan akhir di Provinsi Sulawesi Barat. Sulawesi Selatan merupakan salah satu provinsi unggulan. Peluang untuk melakukan akselerasi pemulihan ekonomi dapat dilakukan pada industri unggulan seperti Industri Pengolahan.
Cost-Effectiveness of Coronary Artery Bypass Surgery Versus Medicine in Ischemic Cardiomyopathy: The STICH Randomized Clinical Trial
Authors: Chew Derek S. , Cowper Patricia A. , Al-Khalidi Hussein , Anstrom Kevin J. , Daniels Melanie R. , Davidson-Ray Linda , Li Yanhong , Michler Robert E. , Panza Julio A. , Piña Ileana L. , Rouleau Jean L. , Velazquez Eric J. , Mark Daniel B. ,   on behalf of the STICH Investigators
Published: January 2022

Background:

The STICH Randomized Clinical Trial (Surgical Treatment for Ischemic Heart Failure) demonstrated that coronary artery bypass grafting (CABG) reduced all-cause mortality rates out to 10 years compared with medical therapy alone (MED) in patients with ischemic cardiomyopathy and reduced left ventricular function (ejection fraction ≤35%). We examined the economic implications of these results.

Methods:

We used a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG and MED using patient-level resource use and clinical data collected in the STICH trial. Patient-level costs were calculated by applying externally derived US cost weights to resource use counts during trial follow-up. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective.

Results:

For the CABG arm, we estimated 6.53 quality-adjusted life-years (95% CI, 5.70–7.53) and a lifetime cost of $140 059 (95% CI, $106 401 to $180 992). For the MED arm, the corresponding estimates were 5.52 (95% CI, 5.06–6.09) quality-adjusted life-years and $74 894 lifetime cost (95% CI, $58 372 to $93 541). The incremental cost-effectiveness ratio for CABG compared with MED was $63 989 per quality-adjusted life-year gained. At a societal willingness-to-pay threshold of $100 000 per quality-adjusted life-year gained, CABG was found to be economically favorable compared with MED in 87% of microsimulations.

Conclusions:

In the STICH trial, in patients with ischemic cardiomyopathy and reduced left ventricular function, CABG was economically attractive relative to MED at current benchmarks for value in the United States.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00023595.