bluuebunny/crossref_metadata_2025 huggingface dataset:
Outlier Detection Algorithms for Open Environments
Authors: Kou Aijun , Huang Xu , Sun Wenxue
Published: April 2023

The high dimensionality and massive amount of data in open environments make the existing low-dimensional outlier detection methods time-consuming. The support vector machine (SVM) is a commonly used outlier detection method. However, the SVM still faces the problem of difficulty in obtaining optimal parameters quickly and effectively, resulting in low detection efficiency, poor stability, and difficulty in applying to open environment datasets. In order to improve the efficiency and stability of outlier detection, this paper proposes an improved sparrow search algorithm and uses it to optimize SVM parameters. First, the traditional sparrow search algorithm is improved by using improved backtracking learning and variable logarithmic spirals. Then, the improved sparrow search method is used to optimize SVM parameters, and the optimized support vector machine is applied to the field of outlier detection. Simulation experimental results show that the proposed method is significantly better than the compared classification algorithms in multiple evaluation indicators, with better detection efficiency, stability, and generalization ability.
Performance of Concrete Developed by Enhanced Gradation of Natural Fine River Sands by Partial Replacement of Waste Quarry Dust
Authors: Akmal Usman , Fatima Sana , Khurram Nauman , Shaukat Khan Qasim , Ahmed Tauqir , Alabduljabbar Hisham , Ahmed Awad Youssef
Published: April 2023

As construction activity continues to increase on a daily basis, the demand for fine and coarse aggregates is also rising. However, relying on a few sources would quickly deplete the natural sources of aggregates. In Lahore, Punjab, Pakistan, costly coarse pit sand from northern areas is used for concrete, as the local river sands (Ravi and Chenab) are fine and do not meet ASTM specifications for fine aggregates. To alleviate the pressure on one source, it is necessary to improve the gradation of natural river sand by utilizing quarry dust obtained during the process of crushing rock into crushed stones. This study conducted detailed experimental work to enhance the gradation of natural river sand by adding normalized quarry dust. Concrete mixes with three strengths of 21 MPa, 28 MPa, and 35 MPa were prepared by partially replacing natural river sand with quarry sand. Workability and hardened concrete properties were evaluated for all mixes, and cost analysis was performed for 28 MPa concrete. The results were compared with control concrete made with coarse pit sand. When river sand was enhanced by combining 40% river sand and 60% normalized quarry dust, the resulting sand met ASTM requirements. Furthermore, when some fines were removed from river sand and replaced with 50% normalized quarry dust, the sand also met ASTM grading requirements. The compressive and flexural strengths of concrete made with enhanced sand gradation increased by 10–25% and 9–17%, respectively, for 28 MPa concrete compared to the control concrete. Cost analysis showed that 28 MPa concrete made with enhanced natural river sand gradation was 8.6% more economical than concrete made with coarse pit sand.
Expression of Th1/2/17 Cytokines in CML with or without Pulmonary Bacterial and Fungal Coinfection
Authors: Guan Xin , Zhang Chaoran , Hu Peng , Yang Zefeng , Zhang Jinping , Zou Yunlian , Wen Yan , Li Huiyuan , Yang Tonghua , Zhao Renbin , Li Zengzheng
Published: April 2023

Background. Tyrosine kinase inhibitors (TKIs) are the standard therapy for patients with chronic myeloid leukemia (CML). While their use greatly increases patient survival rates and can lead to normal life expectancy, bacterial infections in the lungs continue to play a significant role in determining patient outcomes. Methods. In this study, the medical records of 272 CML and 53 healthy adults were analyzed. Information on age, sex, body temperature, procalcitonin (PCT), C-reactive protein (CRP), and cytokine levels were collected from patients. Since the data belonged to a nonstate distribution, we used the Mann–Whitney U test to examine differences between groups. Cut-off values were analyzed by receiver operating characteristic (ROC) curves. Results. No significant differences in the Th1/2/17 levels were observed in relation to TKI treatment. Further analysis showed that the levels of the interleukins IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-22, IL-12p70, IL-17A, IL-17F, and IL-1β, interferon (IFN-γ), and tumor necrosis factors (TNF α and β) were higher in patients with pulmonary bacterial infections compared with uninfected patients. IL-6, IL-8, and IL-10 levels in CML patients with bacterial and fungal coinfection were higher than those in patients without infection. The areas under the ROC curves (AUCs) were found to be 0.73 for IL-5, 0.84 for IL-6, 0.82 for IL-8, 0,71 for IL-10, and 0.84 for TNF-α. AUC values were higher for patients with pulmonary bacterial infection, especially IL-6 (AUC = 0.84, cut-off = 13.78 pg/ml) and IL-8 (AUC = 0.82, cut-off = 14.35 pg/ml), which were significantly better than those for CRP (AUC = 0.80, cut-off = 6.18 mg/l), PCT (AUC = 0.71, cut-off = 0.25 ng/ml), and body temperature (AUC = 0.68, cut-off = 36.8°C). In addition, according to the cut-off values, we found that 83.33% of patients with pulmonary bacterial infections had IL-6 ≥ 13.78 pg/ml, while when IL-6, IL-8, and IL-10 levels simultaneously exceeded the cut-off values, the probability of pulmonary bacterial infection was 93.55%. Conclusions. TKI treatment did not appear to affect cytokine expression in CML patients. However, CML patients with pulmonary bacterial infection had significantly higher levels of Th1/2/17 cytokines. In particular, abnormally elevated IL-6, IL-8, and IL-10 levels were associated with a pulmonary bacterial infection in patients with CML.
Association between the Treatment Pattern of Drug-Induced Liver Injury and Clinical Outcomes: A Retrospective Study
Authors: Wang Xuanxuan , Huang Anqi , Gao Suyu , Hu Wen , Wu Jianyuan , Cheng Hong
Published: April 2023

What is Known and Objective? In China, patients with drug-induced liver injury (DILI) are commonly treated with one or more types of hepatoprotective drugs, despite a lack of evidence. We performed this study to investigate the association between the treatment pattern of DILI, including withdrawal of suspected drugs and use of hepatoprotective drugs, and recovery following DILI. Methods. A retrospective study was conducted at a tertiary hospital in Central China. Data of patients with a diagnosis of DILI hospitalized between January 2015 and December 2020 were collected through the Electronic Medical Records System. We excluded cases that did not meet the biochemical criteria of DILI and had a Roussel Uclaf Causality Assessment Method score of less than 3. Univariate and multivariate logistic regression models were used to analyze the association between treatment patterns and clinical outcomes. Results and Discussion. In total, 699 patients were included. Suspected drugs were discontinued in 619 patients (88.6%). 693 patients (99.1%) were treated with hepatoprotective drugs, among whom only 14.7% patients received monotherapy with hepatoprotective drugs. Recovery following DILI was seen in 593 cases (84.8%). By multivariate analysis, the number of hepatoprotective drugs combined did not show significance (

p
=
0.363

), while the withdrawal of suspected drugs was associated with recovery following DILI (

p
=
0.015

). What is New and Conclusion. The withdrawal of suspected drugs is associated with the recovery following DILI, and hepatoprotective drug combinations do not contribute to better outcomes than monotherapy. The findings indicate that DILI patients should stop suspected drugs as soon as possible and the combination therapy of hepatoprotective drugs is unnecessary.
Investigating the Cost-Effectiveness of Solar Electricity Compared to Grid Electricity in the Capitals of Middle Eastern Countries: A Residential Scale Case Study
Authors: Shahgholian Sepehr , Taheri Mahdi , Jahangiri Mehdi
Published: April 2023

Despite of being rich in fossil fuels, the Middle East is currently the main energy consumer and is projected to have the highest growth in energy demand in the world. Due to its great potential in the Middle East, solar energy can play an important role in the plans of energy decision-makers in the region. According to the studies done so far, no study has been done to show the potential benefit of using home-scale solar systems in the Middle East. Therefore, in this work for the first time, the potential of solar electricity production in the capitals of Middle Eastern countries has been studied using HOMER V2.81 software. The investigations are technical, economic, energy, and environmental, and the studied solar system is connected to the national electricity grid. The results showed that in Nicosia, due to the sale of electricity to the grid, the levelized cost of electricity (LCOE) is equal to -0.759 $, which is the lowest price for produced electricity and leads to a return on investment time of 5.69 years for this system. The solar fraction for the Nicosia station is 92%, which prevents the emission of more than 8 tons of CO2 pollutants during the year. The highest value of LCOE with the amount of $0.25 is related to Sana’a, whose investment return time, solar fraction, and annual CO2 emission prevention amount are 14.1 years, 53%, and 1162 kg, respectively. Ranking analysis was done on the results of 5 outputs of the HOMER software as well as 3 other influential parameters using 4 multicriteria decision-making (MCDM) methods. TOPSIS, GRA, WSM, and AHP methods were used, and the final ranking of each station was considered the average of the 4 methods. According to the results, Cyprus and Kuwait stations were the best and worst, respectively.
Inhibition of miR-146a Expression and Regulation of Endotoxin Tolerance by Rhesus Theta-Defensin-1
Authors: Tongaonkar Prasad , Trinh Katie K. , Ouellette André J. , Selsted Michael E.
Published: April 2023

Theta- (θ-) defensins are pleiotropic host defense peptides with antimicrobial- and immune-modulating activities. Immune stimulation of cells with lipopolysaccharide (LPS, endotoxin) activates proinflammatory gene expression and cytokine secretion, both of which are attenuated by rhesus theta-defensin-1 (RTD-1) inhibition of NF-κB and MAP kinase pathways. Endotoxin tolerance is a condition that ensues when cells have an extended primary exposure to low levels of LPS, resulting in resistance to a subsequent LPS challenge. Recognition of LPS by Toll-like receptor-4 (TLR4) activates NF-κB, elevating levels of microRNA-146a (miR-146a), which targets IRAK1 and TRAF6 transcripts to reduce their protein levels and inhibits TLR signaling on secondary LPS stimulation. Here, we report that RTD-1 suppressed the expression of miR-146a and stabilized the IRAK1 protein in immune-stimulated, monocytic THP-1 cells. Cells that had primary exposure to LPS became endotoxin-tolerant, as evident from their failure to secrete TNF-α upon secondary endotoxin challenge. However, cells incubated with RTD-1 during the primary LPS stimulation secreted TNF-α after secondary LPS stimulation in an RTD-1 dose-dependent manner. Consistent with this, compared to the control treatment, cells treated with RTD-1 during primary LPS stimulation had increased NF-κB activity after secondary LPS stimulation. These results show that RTD-1 suppresses endotoxin tolerance by inhibiting the NF-κB pathway and demonstrates a novel inflammatory role for RTD-1 that is mediated by the downregulation of miR-146a during the innate immune response.
Application of Augmented Reality Technology in the Teaching of Literacy at Low Learning Stage
Authors: Li Jing
Published: April 2023

In primary school Chinese education, literacy is a very important work. Literacy is an important part of primary school Chinese and also an important part of primary school Chinese. At present, literacy education is increasingly valued by teachers. However, there are still many problems to be solved in China’s literacy education. In traditional education and teaching, teachers should let students recite a large number of concepts, formulas, and rules in order to improve students’ learning effect. However, due to the lack of practical support, this has become a major obstacle in education and teaching. Therefore, the main purpose of this paper is to use augmented reality (AR) technology to explore the literacy teaching of junior students. From the result of the test of students’ literacy teaching, it can be seen that the number of people who scored 81–100 points in the experimental class and the control class before the experiment was 9 and 4, respectively. After the experiment, the number of people who scored 81–100 points in the experimental class and the control board was 15 and 7, respectively. Therefore, it is very necessary to use AR technology to carry out applied research on literacy teaching at the low learning stage.
Effects of Individual and Built Environmental Features on Commuting Mode Shifts before and after the COVID-19 Outbreak in Guangzhou, China
Authors: Gao Yuyue , Chen Jian , Ji Keke , Liu Keliang , Liu Haizhou , Wang Lankai
Published: April 2023

The novel coronavirus disease (COVID-19) pandemic has had a significant impact on transportation. Understanding how the epidemic in China has affected people’s travel mode choices can help city managers analyze the travel mode of different populations in the postepidemic phase. Based on a travel behavior questionnaire conducted in Guangzhou, China, during the COVID-19 epidemic and points-of-interest data, this study explored the impact of the built environment, travel characteristics, and socioeconomic factors on changes in commuters’ travel modes during the postepidemic phase. We found that gender, age, occupation, the decline in the rate of travel frequency, and built environment characteristics significantly influenced the change in travel mode. When respondents had to give up public transport, those in different professions had different options for alternative means of transportation. The density of residential facilities, bus stations, and government institutions had a more significant impact on the change in the travel mode of commuters. The research results provide a theoretical basis for policy and practice. After the outbreak of a major public health event, urban transport managers and policymakers should consider individual heterogeneity and environmental factors when formulating strategies to address public travel in unconventional situations.
The Damage Induced by Blasting Excavation and Seepage Characteristics of Deep Rock under High Seepage Pressure
Authors: Dong Qian , Liu Xin , Gong Hangli , Luo Yi , Li Xinping , Wang Liangjun
Published: April 2023

By taking the blasting excavation of a deeply buried karst tunnel in the North Tianshan Mountains in China as research objects, the damage induced by blasting excavation and seepage characteristics of deep rock under high seepage pressure was investigated. The COMSOL Multiphysics® software was adopted to establish a simulation model for the blasting excavation of a deeply buried tunnel. By embedding the stress-damage-seepage multifield coupled constitutive relationship, the mechanism of the influences of factors including blasting load, geostress, and hydraulic pressure of karst caves on the blasting excavation-induced damage to, and seepage characteristic of, the surrounding rocks of the tunnel. The results indicate that blasting excavation in the karst tunnel triggers the damage of surrounding rocks, which consists of blasting-induced damage and unloading damage. The time-history curve of the variable for surrounding rock damage rises and consequently tends to a constant value. With the increases in blasting load, geostress, and hydraulic pressure of karst caves, the degree of damage to surrounding rocks is intensified; an increase in geostress will weaken the effect of blasting-induced damage to rock while increasing rock damage arising from unloading. Meanwhile, the degree of damage to the surrounding rock can affect the seepage velocity of water in the surrounding rock to a certain extent. A strong damage and seepage coupled effect occur in the blasting excavation process of the karst tunnel. The such coupled effect is strengthened little by little with the increases in the degree of surrounding rock damage and hydraulic pressures. The results are expected to provide theoretical guidance for hazard prevention and control of blasting excavation in karst tunnels under high geostress conditions.
Network Structure of Comorbidity Patterns in U.S. Adults with Depression: A National Study Based on Data from the Behavioral Risk Factor Surveillance System
Authors: Ramos-Vera Cristian , Barrientos Antonio Serpa , Vallejos-Saldarriaga José , Calizaya-Milla Yaquelin E. , Saintila Jacksaint
Published: April 2023

Background. People with depression are at increased risk for comorbidities; however, the clustering of comorbidity patterns in these patients is still unclear. Objective. The aim of the study was to identify latent comorbidity patterns and explore the comorbidity network structure that included 12 chronic conditions in adults diagnosed with depressive disorder. Methods. A cross-sectional study was conducted based on secondary data from the 2017 behavioral risk factor surveillance system (BRFSS) covering all 50 American states. A sample of 89,209 U.S. participants, 29,079 men and 60,063 women aged 18 years or older, was considered using exploratory graphical analysis (EGA), a statistical graphical model that includes algorithms for grouping and factoring variables in a multivariate system of network relationships. Results. The EGA findings show that the network presents 3 latent comorbidity patterns, i.e., that comorbidities are grouped into 3 factors. The first group was composed of 7 comorbidities (obesity, cancer, high blood pressure, high blood cholesterol, arthritis, kidney disease, and diabetes). The second pattern of latent comorbidity included the diagnosis of asthma and respiratory diseases. The last factor grouped 3 conditions (heart attack, coronary heart disease, and stroke). Hypertension reported higher measures of network centrality. Conclusion. Associations between chronic conditions were reported; furthermore, they were grouped into 3 latent dimensions of comorbidity and reported network factor loadings. The implementation of care and treatment guidelines and protocols for patients with depressive symptomatology and multimorbidity is suggested.
Smile Attractiveness and Treatment Needs of Maxillary Midline Diastema with Various Widths: Perception among Laypersons, Dental Students, and Dentists in Malaysia
Authors: Sabri Nur Amirah Binti Mohamad , Ridzwan Sarah Batrisyia Binti , Soo Suet Yeo , Wong Lishen , Tew In Meei
Published: April 2023

Smile attractiveness and the need for treatment of maxillary midline diastema with various widths are perceived differently between dentally trained and nondentally trained individuals of different sociodemographic backgrounds. This study aims to evaluate how laypersons, dental students, and dentists in Malaysia differ in their perceptions on smile attractiveness and treatment needs of maxillary midline diastema. A smiling photograph with well-aligned maxillary central incisors with proportionate width-to-height ratio and healthy gingival tissues was selected and digitally manipulated to create maxillary midline diastema with 0.5, 2.0, and 4.0 mm widths. The smile attractiveness and the perceived need for treatment of varying widths of maxillary midline diastemas were rated by laypersons, dental students, and dentists using the Likert scale via a single set of self-administered questionnaires. The impact of sociodemographic variables on aesthetic perception of different gap widths was tested using univariate analysis followed by a multiple linear regression model. A total of 158 laypersons, 118 dental students, and 138 dentists participated in this study. Both laypersons and dentists showed significantly higher mean aesthetic scores for 0.5 mm maxillary midline diastema, lower mean aesthetic scores, and hence higher mean treatment needs scores for 4.0 mm maxillary midline diastema as compared with dental students (

p
<
0.05

). In general, female respondents perceived a gap width of up to 2.0 mm as aesthetically pleasing. Higher educational group and the Malay ethnicity had tolerance threshold of 0.5 mm gap width. The older group considered 4.0 mm gap width as aesthetically unpleasing. In conclusion, both laypersons and dentists accepted a 0.5 mm maxillary midline diastema as an attractive smile but considered 4.0 mm maxillary midline diastema as unpleasing smile which required treatment. Perceptions of laypersons and dentists were significantly different from dental students. Educational level, gender, ethnicity, and age were significantly associated with smile attractiveness of maxillary midline diastema at different investigated widths.
Metabolic Reprogramming Driven by IGF2BP3 Promotes Acquired Resistance to EGFR Inhibitors in Non–Small Cell Lung Cancer
Authors: Lin Ziyou , Li Jingwei , Zhang Jian , Feng Weineng , Lu Jiaye , Ma Xiaofan , Ding Wen , Ouyang Shumin , Lu Jinjian , Yue Peibin , Wan Guohui , Liu Peiqing , Zhang Xiaolei
Published: April 2023

Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) mediated by IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3–COX6B2 axis. IGF2BP3 was upregulated in patients with TKI-resistant non–small cell lung cancer, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3′-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3–COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3–COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.

Significance:

IGF2BP3 stabilizes COX6B2 to increase oxidative phosphorylation and to drive resistance to EGFR inhibitors in lung cancer, which provides a therapeutic strategy to overcome acquired resistance by targeting metabolic transitions.
Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
Authors: DeBlasi Janine M. , Falzone Aimee , Caldwell Samantha , Prieto-Farigua Nicolas , Prigge Justin R. , Schmidt Edward E. , Chio Iok In Christine , Karreth Florian A. , DeNicola Gina M.
Published: April 2023

Mutations in the KEAP1–NRF2 (Kelch-like ECH-associated protein 1–nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non–small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

Significance:

Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis.
Supplementary Table 5 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Table 5. The Cox proportional analyses of malnutrition scores with overall survival in patients with brain metastases in lung cancer and non-lung cancer patients.
Supplementary Figure 7 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Figure 7 Kaplan-Meier curves for overall survival in patients who received target therapy and immune checkpoint blockade.
Supplementary Figure 2 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Figure 2 The flow chart of patient selection.
Data from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

AbstractBackground:
Malnutrition is a severe but modifiable risk factor for cancers. However, the relationship between malnutrition and the survival of patients with brain metastases has not been fully revealed. We aimed to evaluate the prevalence of malnutrition and assess its prognostic value on patients with brain metastases
Methods:
We retrospectively recruited 2,633 patients with brain metastases between January 2014 and September 2020. Three malnutrition scores were used to evaluate patients’ malnutrition status at their first admission, including controlling nutritional status, the nutritional risk index, and the prognostic nutritional index. The association between malnutrition and overall survival (OS) was estimated.
Results:
The three malnutrition scores were associated with each other and with body mass index (BMI). Malnutrition assessed by any of the three scores was significantly associated with poor OS. All three malnutrition scores were better indicators than BMI, and adding malnutrition scores to the Graded Prognostic Assessment (GPA) scoring system could significantly improve the accuracy of prognosis prediction.
Conclusions:
Malnutrition monitoring using any of the three malnutrition scores on patients’ first admission could be a better survival indicator for patients with brain metastases compared with BMI alone.
Impact:
Malnutrition is a more significant indicator of survival stratification compared with BMI. Adding malnutrition to the GPA score system achieves better survival prediction.
Supplemental Table 1 from Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia
Authors: Fathi Amir T. , Kim Haesook T. , Soiffer Robert J. , Levis Mark J. , Li Shuli , Kim Annette S. , DeFilipp Zachariah , El-Jawahri Areej , McAfee Steve L. , Brunner Andrew M. , Amrein Philip C. , Mims Alice S. , Knight Laura W. , Kelley Devon , Bottoms AJ S. , Perry Lindsey H. , Wahl Jonathan L. , Brock Jennifer , Breton Elayne , Marchione Dylan M. , Ho Vincent T. , Chen Yi-Bin
Published: April 2023

Representativeness of Study Participants
Supplemental Figure 1 from Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia
Authors: Fathi Amir T. , Kim Haesook T. , Soiffer Robert J. , Levis Mark J. , Li Shuli , Kim Annette S. , DeFilipp Zachariah , El-Jawahri Areej , McAfee Steve L. , Brunner Andrew M. , Amrein Philip C. , Mims Alice S. , Knight Laura W. , Kelley Devon , Bottoms AJ S. , Perry Lindsey H. , Wahl Jonathan L. , Brock Jennifer , Breton Elayne , Marchione Dylan M. , Ho Vincent T. , Chen Yi-Bin
Published: April 2023

Supplemental Figure 1: Overall and progression-free survival for patients, according to whether the transplant followed first line or second line treatment.
Supplementary Methods from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

Additional methodological details
Supplementary Figure S2 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

On-treatment ctDNA fraction, PSA and LDH changes and durability of treatment response
Supplementary Table S1 from Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Authors: Grant Michael J. , Aredo Jacqueline V. , Starrett Jacqueline H. , Stockhammer Paul , van Alderwerelt van Rosenburgh Iris K. , Wurtz Anna , Piper-Valillo Andrew J. , Piotrowska Zofia , Falcon Christina , Yu Helena A. , Aggarwal Charu , Scholes Dylan , Patil Tejas , Nguyen Christina , Phadke Manali , Li Fang-Yong , Neal Joel , Lemmon Mark A. , Walther Zenta , Politi Katerina , Goldberg Sarah B.
Published: April 2023

Supplementary Table S1. Descriptive analysis of patient characteristics and outcomes for those with tumors harboring uncommon exon 19 deletions treated with osimertinib. Each variant represented ≤2.5% of the study cohort. Patients with + for “Smoking History” are those with either a prior or current smoking history. PFS=Progression free survival; OS= Overall survival; à denotes patients who have not yet experienced an event for a time to event endpoint.
Supplementary Figure S2 from G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer
Authors: Ray Anita L. , Saunders Apryl S. , Nofchissey Robert A. , Reidy Megan A. , Kamal Maria , Lerner Megan R. , Fung Kar-Ming , Lang Mark L. , Hanson Joshua A. , Guo Shaoxuan , Urdaneta-Perez Maria G. , Lewis Samara E. , Cloyde Michael , Morris Katherine T.
Published: April 2023

Supplementary Figure S2
Supplementary Data 1 from A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma
Authors: Kelly Ciara M. , Qin Li-Xuan , Whiting Karissa A. , Richards Allison L. , Avutu Viswatej , Chan Jason E. , Chi Ping , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Adamson Travis , Singer Samuel , Bartlett Edmund K. , Crago Aimee M. , Yoon Sam S. , Hwang Sinchun , Erinjeri Joseph P. , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: April 2023

Representativeness of study participants.
Supplementary Table S1: Pooled analyses of oncology clinical trial data 2018-2021 from FDA Oncology Center of Excellence Crowdsourcing Initiative: Outreach to the Scientific Community to Identify Research Questions for Pooled Analyses of Oncology Clinical Trial Data
Authors: Schneider Julie A. , Eckstein Julia , Goldberg Kirsten B. , Ascione Mark C. , Bailey Thamar , Taylor Kimberly , Coffey Aisha M. , Satchi Darshini , Philips Howard , Sridhara Rajeshwari , Nair Abhilasha , Pazdur Richard , Theoret Marc R.
Published: April 2023

Pooled analyses of oncology clinical trial data 2018-2021
Supplemental Figure 6 from Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: April 2023

Supplemental Figure 6.Cell survival of GIST T1 cells treated with imatinib or avapritinib for 72h in complete media.Each data point represents an average of 10 wells.
Supplemental Figure 2 from Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: April 2023

Supplemental Figure 2. GIST PDGFRA D842V PDXs are not sensitive to imatinib.
Fig S8 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Longitudinal changes in cfTL were re-analyzed for each patient, considering all plasma variants independent of origin. Survival analyses revealed that CH-unfiltered ctDNA responses were not associated with either (A) overall survival-OS or (B) progression-free survival-PFS. Comparison between CH-unfiltered ctDNA responses and radiographic assessments (PR/CR vs SD/PD/MR) in these patients revealed that CH-unfiltered responses we not predictive of (C) OS at 12 and (D) 36 months, and PFS at (E) 3 and (F) 12 months, compared to best overall radiographic responses.
Fig S6 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

(A) Comparison between ctDNA molecular responses and clinical benefit determined through radiographic imaging for patients treated with immunotherapy-containing regimens revealed concordance between each assessment (p = 0.019, Fisher’s exact test). For these comparisons, durable clinical benefit (DCB) was defined as a lack of progression or death within 6 months of treatment initiation; non-durable benefit (NDB) was defined as progression or death within 6 months of treatment initiation. Comparison between ctDNA molecular responses and radiographic assessments (PR/CR vs SD/PD/MR) for the determination of (B) overall survival (OS) at 64 months (maximum OS observed in patients with date of death recorded) and progression-free survival (PFS) at (C) 6 months, (D) 9 months and (E) 14 months (maximum PFS observed in patients with clinically documented progression following systemic treatment), is shown for all 33 patients included in the study cohort.
Supplementary Table S1 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

IC50 values of PI3K isoform inhibitors used. Duvelisib5, IPI-3063 (PI3K-d inhibitor)5, IPI-549 (PI3K-g inhibitor used in vitro)50, IPI-5243 (PI3K-g inhibitor used in vivo).
Supplementary Figure S5 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

Distinct actions of PI3K-δ and PI3K-γ on mouse cytokines in PDX model of U-CLL and M-CLL patients.
Supplementary Tables S5-S11 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

Supplementary MethodsTable S5. Clinical characteristics of the Sjöström and Servant cohortsTable S6. Comparison of included versus excluded patientsTable S7. 10-year follow-up for local recurrence (IBTR). Flexible parametric survival analysis with Royston-Parmar (RP) regression models used in Figures 2 and 3Table S8. 10-year follow-up for local recurrence (IBTR). Flexible parametric survival analysis with Royston-Parmar (RP) regression models with adjustment for other covariatesTable S9. Absolute number of events within different tertiles of Immunescore and Proliferative Index and depending on RT treatmentTable S10. Unadjusted and adjusted analysis of the interaction between the Integrated model and RT in the SweBCG91RT cohortTable S11. Distribution of subtypes in the tertiles of the Integrated score among high-risk patients
Supplementary Figure S5 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

Ki67 was evaluated by a board-certified pathologist on TMAs.  
Supplementary Figure S4 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

The interaction between the Integrated model and RT was significant in an unadjusted analysis (p=0.004) and an analysis adjusted for histological grade, age, ER status, and tumor size (p=0.008). The figure shows the predicted 10-year cumulative incidence of IBTR with 95% confidence intervals based on Integrated model score stratified by RT, based on Royston-Parmar models with estimates from Table S10. The stpm2 macro for Stata was used for the calculations. The dotted vertical lines represent percentiles of the Integrated score.
Supplementary Figure S3 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

The tumor-intrinsic model, Proliferative Index, could predict the prognostic effect from the immunological model, Immunescore. With high Proliferative Index values, Immunescore was strongly prognostic. However, with low Proliferative Index values, trends toward the opposite were observed.
Supplementary Figure S1 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

Gene sets from the molecular signatures database were used to create a model measuring immunological activity and immunomodulatory tumor-intrinsic factors. These were merged to create a model considering the interaction between the antitumoral immune response and tumor-intrinsic immunomodulatory factors.
Study protocol S1 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

Protocol for original SweBCG91RT trial
Data from A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma
Authors: Kelly Ciara M. , Qin Li-Xuan , Whiting Karissa A. , Richards Allison L. , Avutu Viswatej , Chan Jason E. , Chi Ping , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Adamson Travis , Singer Samuel , Bartlett Edmund K. , Crago Aimee M. , Yoon Sam S. , Hwang Sinchun , Erinjeri Joseph P. , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: April 2023

AbstractPurpose:
Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.
Patients and Methods:
This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.
Results:
Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.
Conclusions:
Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.
Data from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

AbstractPurpose:
Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.
Experimental Design:
Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.
Results:
We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells.
Conclusions:
Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.